Transdermal therapeutic system for transdermal administration of guanfacine and monocarboxylic acid thereof

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 methods of manufacture, treatment and use thereof. [Background technology]

[0002] The active agent guanfacine (also known as N-(aminoiminomethyl)-2,6-dichloro-benzeneacetamide, C9H9Cl2N3O, CAS Registry Number 29110-47-2) is a sympatholytic drug 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 commercially available in the form of immediate or controlled release tablets, for example containing 1 mg to 4 mg of guanfacine, which are suitable for once-daily administration.

[0004] However, oral administration of active agents has disadvantages, for example in terms of patient compliance. Moreover, once a sustained release tablet has been taken orally, it is not possible to terminate treatment quickly, for example in light of signs of overdosing or intolerance.

[0005] Thus, there is a need for a transdermal therapeutic system for the transdermal administration of guanfacine, in particular a TTS that is suitable for multi-day treatment with a single application, thereby improving patient compliance. Summary of the Invention

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

[0007] It is a further object of the present invention 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, more preferably about 84 hours. In particular, it is an object of the present invention to provide a therapeutically effective amount over a full period, where the TTS is applied to the skin to allow 24-hour treatment by replacing the TTS after a certain application time, e.g., at least 24 hours, preferably at least 72 hours, more preferably about 84 hours.

[0008] It is a further object of the present invention to provide a TTS for transdermal administration of guanfacine, which reduces the fluctuations in guanfacine plasma concentrations, especially at steady state, when compared to oral administration.

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

[0010] Another object of the present invention is to provide a TTS for transdermal administration of guanfacine that meets the need for convenient application in terms of size and thickness and / or is easy and cost-effective to manufacture.

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

[0012] The present invention achieves these and other objects and, according to one aspect, relates to a transdermal therapeutic system for the transdermal administration of guanfacine, comprising a guanfacine-containing layer structure, wherein said guanfacine-containing layer structure comprises: A) a backing layer; B) a guanfacine-containing layer comprising guanfacine and a monocarboxylic acid; Includes.

[0013] It has been found that the TTS comprising guanfacine and a monocarboxylic acid according to the present invention provides advantageous properties in terms of the utilization of the active ingredient and the constant and continuous delivery of guanfacine.In particular, the TTS according to the present invention provides a suitable permeation rate and a suitable permeation amount of guanfacine over a period of at least 24 hours, preferably at least 72 hours, more preferably about 84 hours.According to a particular embodiment, the present invention also relates to a transdermal therapeutic system for transdermal administration of guanfacine as described above, wherein the guanfacine-containing layer comprises: i) guanfacine and a monocarboxylic acid; ii) at least one polymer; and A guanfacine-containing matrix layer comprising:

[0014] In a particular preferred embodiment, the present invention relates to a transdermal therapeutic system as described above, wherein the guanfacine and the 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 a transdermal therapeutic system as described above, wherein the guanfacine and the monocarboxylic acid in the guanfacine-containing layer are present in the form of a premix, said premix being obtainable by dry grinding or slurrying methods.

[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 polymers, or Acrylic polymers containing -OH groups It is.

[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 dispersing agents, permeation enhancers and solubilizers.

[0018] According to one particular embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight, based on the total weight of the guanfacine-containing layer; ii) a mixture of an acrylic polymer and at least one silicone-based polymer, the acrylic polymer being present in an amount of 20-55% by weight and the at least one silicone-based polymer being 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, iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; Includes.

[0019] According to another particular aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine comprising a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case 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, iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; Includes.

[0020] According to a further particular aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine comprising a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-based polymers, the first silicone-based polymer being present in an amount of 20-55% by weight and the second silicone-based polymer being 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) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer. Includes.

[0021] According to another particular aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine comprising a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) an acrylic polymer in an amount of 65 to 95% 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, iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; Includes.

[0022] According to a further particular aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine comprising a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) an acrylic polymer containing -OH groups in an amount of 65 to 95% 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, iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; Includes.

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

[0024] According to certain embodiments, the present invention further relates to a method for treating a human patient, preferably a human patient aged 6-17 years, by applying a transdermal therapeutic system according to the present invention to the patient's skin. In particular, the present invention relates to a method for treating hypertension or Attention Deficit Hyperactivity Disorder (ADHD) in a human patient, preferably a human patient aged 6-17 years, by applying a transdermal therapeutic system according to the present invention to the patient's skin. In the context of these methods, it is preferred that the TTS according to the present invention is applied to the patient's skin for at least 24 hours, more preferably for at least 72 hours, and most preferably for about 84 hours.

[0025] According to another embodiment, the present invention provides 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 C of less than 3.5 max C 84 and / or has a C ratio of less than 3.0 max C 72 and / or has a C ratio of less than 2.0 max C 24The present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine as defined above, having a ratio of:

[0026] According to a further aspect, the present invention relates to a method for producing an active agent-containing layer for use in a transdermal therapeutic system, said method comprising the steps of: 1) At least one ingredient (i) a pharma- ceutical active agent; and (ii) at least one monocarboxylic acid; to obtain a premix; 2) (i) the premix of step 1); (ii) at least one polymer; to obtain a coating composition; 3) coating the coating composition onto a backing layer or release liner to obtain a coated coating composition; 4) drying the coated coating composition to form the active agent-containing layer; Includes.

[0027] According to yet another aspect, the present invention relates to a transdermal therapeutic system obtainable by the method according to the invention.

[0028] definition Within the meaning of the present invention, the term "transdermal therapeutic system" (TTS) refers to a system that administers an active agent (e.g., guanfacine) to the systemic circulation via transdermal delivery and refers to an individual dosage unit that is applied to the skin of a patient after removing a release liner that may be present, the entire dosage unit including a therapeutically effective amount of an active agent in an active agent-containing layer structure and an adhesive overlay that may be added on top of the active agent-containing layer structure. The active agent-containing layer structure may be disposed on a release liner (a removable protective layer), and thus the TTS may further include a release liner. Within the meaning of the present invention, the term "TTS" refers in particular to a system that provides transdermal delivery, excluding, for example, active agent delivery via iontophoresis or microporation. A transdermal therapeutic system may also be called a transdermal drug delivery system (TDDS) or a transdermal delivery system (TDS).

[0029] Within the meaning of the present invention, the term "active agent-containing layer structure" or "guanfacine-containing layer structure" refers to a layer structure comprising a backing layer and an active agent-containing layer. The active agent-containing layer structure comprises a therapeutically effective amount of an active agent. Preferably, the active agent-containing layer structure is an active agent-containing self-adhesive layer structure. Preferably, the active agent is guanfacine.

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

[0031] Within the meaning of the present invention, terms such as "active substance" and "active agent", as well as the term "guanfacine" refer to the respective active agent in any pharma- ceutically acceptable chemical and morphological form and physical state. Preferably, the active agent in the present invention is present in the form of a "co-salt" (i.e., the active agent (preferably guanfacine) is present in a premixture with at least one monocarboxylic acid), allowing, for example, proton transfer or hydrogen bond formation, preferably forming at least a partially monocarboxylic acid salt of guanfacine. In other words, the active agent (preferably guanfacine) may be present in at least a partially protonated form. Further forms include, but are not limited to, the active agent in protonated or partially protonated form, deprotonated or partially deprotonated form, salt or co-crystal. Further pharma-ceutically acceptable chemical and morphological forms and physical states include the active agent in the form of particles (which may be micronized crystalline and / or amorphous), as well as solvates, hydrates, clathrates, complexes, and the like, and any mixture of the aforementioned forms. When the active agent is contained in a medium such as a solvent, it may be dissolved or dispersed, or may be partially dissolved and partially dispersed. However, it should be understood that the present invention, in relation to the active agent (preferably guanfacine) and the monocarboxylic acid, encompasses any form obtained in the guanfacine-containing layer based on a premixture of guanfacine and monocarboxylic acid, and this form includes, for example, the option that guanfacine and monocarboxylic acid coexist without chemical interaction (i.e. proton transfer or hydrogen bond formation) and the option of co-salt formation as described above. Preferably, guanfacine free base and monocarboxylic acid may form a co-salt or any other type of acid addition salt together, so that the guanfacine-containing layer preferably at least partially comprises a co-salt or any other type of acid addition salt of guanfacine free base and monocarboxylic acid.In other words, the guanfacine-containing layer preferably comprises guanfacine in at least a partially protonated form and the monocarboxylic acid in at least a partially deprotonated form.

[0032] If it is mentioned that an active agent is used in a particular form in the preparation of the TTS, this does not exclude interactions between this form of the active agent and other components of the active agent-containing layer structure (which may still be present in the final TTS), such as, for example, when the active agent 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 active agent 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 part of it may be present in the final TTS as a free base. Unless otherwise indicated, in particular the amount of active agent in the layer structure relates to the amount of active agent included in the TTS during the preparation of the TTS, calculated on the basis of the active agent itself or on a premixture of the active agent with the monocarboxylic acid, but not on the basis of any other form.

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

[0034] Within the meaning of the present invention, the term "particle" refers to solid particulate materials, including individual particles, whose dimensions are negligible compared to the material. In particular, particles are solids, including plastic / deformable solids, including amorphous and crystalline materials.

[0035] Within the meaning of the present invention, the term "dispersing" refers to a process or combination of processes in which the starting material (e.g., guanfacine) is not completely dissolved. Dispersion in the meaning of the present invention includes 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 TTS for active agent delivery: matrix-type TTS and reservoir-type TTS. The release of the active agent in matrix-type TTS is mainly controlled by the matrix containing the active agent itself. In contrast, reservoir-type TTS typically requires a rate-controlling membrane to control the release of the active agent. In principle, matrix-type TTS may also contain a rate-controlling membrane. However, matrix-type TTS has the advantage over reservoir-type TTS in that a rate-determining membrane is usually not required and dose dumping due to membrane rupture cannot occur. In summary, matrix-type transdermal therapeutic systems (TTS) are less complicated to manufacture and easier and more convenient to use by patients.

[0037] Within the meaning of the present invention, a "matrix-type TTS" refers to a system or structure in which the active agent is homogeneously dissolved and / or dispersed in a polymeric carrier, i.e., a matrix, forming a matrix layer together with the active agent and optionally remaining ingredients. In such a system, the matrix layer controls the release of the active agent from the TTS. Preferably, the matrix layer has sufficient cohesion to be self-supporting so that sealing between other layers is not required. Thus, the active agent-containing layer may in one embodiment of the present invention be an active agent-containing matrix layer in which the active agent is homogeneously distributed in the polymeric matrix. In certain embodiments, the active agent-containing matrix layer may comprise two active agent-containing matrix layers that may be laminated together. A matrix-type TTS may in particular be in the form of a "drug-in-adhesive" type TTS, which refers to a system in which the active agent is homogeneously dissolved and / or dispersed in a pressure-sensitive adhesive matrix. In this context, the active agent-containing matrix layer may also be referred to as an active agent-containing pressure-sensitive adhesive layer or an active agent-containing pressure-sensitive adhesive matrix layer. A TTS that comprises an active agent dissolved and / or dispersed in a polymeric gel, e.g., a hydrogel, is also considered to be of matrix type according to the present invention. It should be understood that a TTS that includes an active agent-containing matrix layer may also additionally include a skin-contacting layer.

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

[0039] Within the meaning of the present invention, the term "active agent-containing layer" refers to a layer that contains an active agent and provides a release region. The term encompasses active agent-containing matrix layers and active agent-containing reservoir layers. When the active agent-containing layer is an active agent-containing matrix layer, said layer is present in a matrix-type TTS. When the polymer is a pressure-sensitive adhesive, the matrix layer may also represent the adhesive layer of the TTS, such that there is no additional skin contact layer. Alternatively, the 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 free of active agents. However, due to a concentration gradient, the active agent will migrate from the matrix layer to the additional skin contact layer over time until an equilibrium state is reached. The additional skin contact layer may be present on the active agent-containing matrix layer or may be separated from the active agent-containing matrix layer by a membrane, preferably a rate-controlling membrane. Preferably, the active agent-containing matrix layer has sufficient adhesive properties so that there is no additional skin contact layer. When the active agent-containing layer is an active agent-containing reservoir layer, said layer is present in a reservoir-type TTS, and the layer contains the active agent in a liquid reservoir. In addition, a skin contact layer may be present to provide adhesive properties. The additional skin contact layer is usually manufactured to be free of active agents. If the skin contact layer does not contain active agents, the active agent will migrate from the reservoir layer to the skin contact layer over time due to a concentration gradient until an equilibrium state is reached. In addition, an adhesive overlay may be provided.

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

[0041] Within the meaning of the present invention, the term "pressure-sensitive adhesive" (also abbreviated as "PSA") refers to a material that should adhere in particular with finger pressure, be permanently tacky, exert a strong holding force and be removable from a smooth surface without leaving a residue. When in contact with the skin, the pressure-sensitive adhesive layer is "self-adhesive", in other words it provides adhesion to the skin such that no further assistance is usually required for fixing to the skin. The "self-adhesive" layer structure according to the present invention comprises a pressure-sensitive adhesive layer for skin contact which may be provided in the form of a pressure-sensitive matrix layer or in the form of an additional layer, i.e. a pressure-sensitive adhesive skin contact layer. An adhesive overlay 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 meaning of the present invention, the term "silicone acrylic hybrid polymer" refers to a polymerization product that includes repeating units of silicone subspecies and acrylate subspecies. Thus, the silicone acrylic hybrid polymer includes a silicone phase and an acrylic phase. Preferably, the silicone acrylic hybrid polymer includes a silicone phase and an acrylate phase, in other words, a silicone subspecies and an acrylate subspecies, in a specific weight ratio, for example, 60:40 to 40:60. The term "silicone acrylic hybrid" is intended to mean more than a simple blend of a silicone-based subspecies and an acrylate-based subspecies. Instead, the term refers to a polymerized hybrid species that includes a silicone-based subspecies and an acrylate-based subspecies polymerized together. In the context of the hybrid polymer used in the present invention, the terms acrylate and acrylic are generally used interchangeably, so that the silicone acrylic hybrid polymer can also be called a "silicone acrylate hybrid polymer."

[0043] Within the meaning 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 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. Depending on the solvent in which the silicone acrylic hybrid PSA is supplied, it has been found that the arrangement of the silicone and acrylic phases is different, providing a continuous external phase of silicone or acrylic and a corresponding discontinuous internal phase. When the silicone acrylic hybrid PSA is supplied in n-heptane, the composition contains a continuous silicone external 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 external phase and a discontinuous silicone internal phase.

[0044] Within the meaning of the present invention, the term "non-hybrid polymer" is used synonymously with a polymer that does not contain hybrid species. Preferably, the non-hybrid polymer is a pressure-sensitive adhesive (e.g., silicone or acrylate-based pressure-sensitive adhesive). A preferred non-hybrid polymer according to the present invention is a "silicone-based polymer", as used herein, which is a polymer obtained by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin. Another preferred non-hybrid polymer is an acrylate-based polymer, i.e., an acrylic polymer, as used herein, which 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-octyl acrylamide, and vinyl acetate.

[0045] As used herein, an active agent-containing matrix layer is a layer that contains an active agent dissolved or dispersed in at least one polymer, or dissolved in a solvent to form an active agent-solvent mixture dispersed in the form of deposits (particularly droplets) in at least one polymer.Preferably, the at least one polymer is a polymer-based pressure-sensitive adhesive (e.g., acrylic polymer).Within the meaning 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 on a film and evaporating the solvent.

[0046] Within the meaning of the present invention, the term "skin contact layer" refers to the layer included in the active agent-containing layer structure that is in direct contact with the patient's skin during administration. If the TTS includes a skin contact layer, the other layers of the active agent-containing layer structure are not in contact with the skin and do not necessarily have self-adhesive properties. As outlined above, the additional skin contact layer attached to the active agent-containing layer may absorb part of the active agent over time. The size of the additional skin contact layer and the active agent-containing layer are usually coextensive and correspond to the release area. However, the area of ​​the skin contact layer may be larger than the area of ​​the active agent-containing layer. In such a case, the release area still refers to the area of ​​the active agent-containing layer.

[0047] Within the meaning of the present invention, the term "areal weight" means g / m 2 The area weight refers to the dry weight of a particular layer, e.g., the matrix layer, as provided in Table 1. Due to manufacturing variations, area weight values ​​require a tolerance of ±10%, preferably ±7.5%.

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

[0049] Within the meaning of the present invention, the term "polymer" refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, including homopolymers consisting of one type of monomer and copolymers consisting of two or more types of monomers. Polymers can be of any structure, such as linear polymers, star polymers, comb polymers, brush polymers, and in the case of copolymers, of any monomer sequence, for example 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 of, for example, more than 2000 Daltons, preferably more than 5000 Daltons, and more preferably more than 10,000 Daltons. Correspondingly, compounds with a molecular weight of less than 2000 Daltons, preferably less than 5000 Daltons, or more preferably less than 10,000 Daltons are usually referred to as oligomers.

[0050] Within the meaning of the present invention, the term "crosslinker" refers to a substance capable of crosslinking functional groups contained within a polymer.

[0051] Within the meaning of the present invention, the term "adhesive overlay" refers to a self-adhesive layer structure that does not contain an active agent, has a larger area than the active agent-containing structure, and provides an additional area for adhesion to the skin, but does not provide an area for release of the active agent, thereby improving the overall adhesive properties of the TTS. The adhesive overlay comprises a backing layer, which may provide occlusive or non-occlusive properties, and an adhesive layer. Preferably, the backing layer of the adhesive overlay provides non-occlusive properties.

[0052] Within the meaning of the present invention, the term "backing layer" refers to a layer that supports an active agent-containing layer or forms the backing of an adhesive overlay. At least one backing layer in a TTS, and usually the backing layer of an active agent-containing layer, is substantially impermeable to the active agent contained therein during storage and administration, thus preventing activity loss or cross-contamination in accordance with regulatory requirements. Preferably, the backing layer is also occlusive, meaning that 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 may be characterized by certain parameters measured in an in vitro skin permeation test.

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

[0055] Furthermore, in vitro permeation studies may be carried out in Franz diffusion cells using human or animal skin, preferably using skinned Gottinger minipigs with a thickness of about 800 μm and an intact epidermis, and using a 0.9% sodium chloride solution (32° C. with 0.1% azide saline).

[0056] Unless otherwise indicated, in vitro permeation tests are carried out using harvested Gottinger miniature pig skin with a thickness of about 800 μm and intact epidermis, using 0.9% sodium chloride solution (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 an HPLC method 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 active substance permeated relates to the amount permeated between the last two sample taking times and not to the total amount permeated up to that point.

[0057] Thus, within the meaning of the present invention, the parameter "permeation amount" is defined as μg / cm 2 and relates to the amount of active substance permeated during a sample section at a particular time elapsed. For example, in an in vitro permeation test as described above, where the amount of active substance permeated into the receptor medium is 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 for the sample section from 8 hours to 16 hours, corresponding to the measurement result at 16 hours, where the receptor medium has been completely replaced at 8 hours.

[0058] The permeation amount can also be given as a "cumulative permeation amount" which corresponds to the cumulative amount of active agent permeated at a particular time point. For example, in an in vitro permeation test as described above, where the amount of active agent permeated into the receptor medium is measured at, for example, 0, 4, 8, 16 and 24 hours, the "cumulative permeation amount" of active agent 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 meaning of the present invention, the parameter "skin permeability" for a particular sample interval at a particular time is expressed as μg / (cm 2 *h) in μg / cm in the in vitro permeation test as described above 2For example, in the case of a skin permeation rate in an in vitro permeation test as 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 "skin permeation rate" at 16 hours is calculated as the permeation amount in the sample section from 8 hours to 16 hours divided by 8 hours.

[0060] The "cumulative skin permeation rate" can be calculated from each cumulative permeation amount by dividing the cumulative permeation amount by the elapsed time. For example, in an in vitro permeation test as described above, in which 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 permeation rate" at 16 hours is calculated as the cumulative permeation amount at 16 hours (see above) divided by 16 hours.

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

number

number

number

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

[0063] Within the meaning of the present invention, the parameter "average release rate" refers to the average release rate in μg / h (μg / hour) or mg / day at which an active agent is released through the skin in humans into the systemic circulation over an administration period (e.g., 1-7 days) and is based on the AUC obtained over said administration period during clinical studies.

[0064] Within the meaning of the present invention, the term "extended period" relates 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 from about 24 hours to about 168 hours or from 1 to 7 days, or from about 24 hours to about 84 hours or from 1 to 3.5 days.

[0065] In the case of continuous drug treatment, the frequency of drug administration is preferably kept high enough to maintain therapeutically effective plasma concentration. In other words, the interval between two dosage forms administrations, also called the dosing interval, needs to be adjusted accordingly. Within the meaning of the present invention, the term "dosing interval" refers to the period between two successive TTS administrations, i.e., the interval between two successive time points when the TTS is applied to the patient's skin. Once applied, the TTS is usually maintained on the patient's skin throughout the dosing interval, and is only removed at the end of the dosing interval, at which point a 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 a new TTS is applied. Thus, a 24-hour or 1-day dosing interval allows for a daily TTS replacement pattern in around-the-clock treatment.

[0066] Within the meaning of the present invention, the term "room temperature" refers to the unaltered temperature found in the laboratory where the experiments are performed, which is usually within the range of 15-35°C, preferably about 18-25°C.

[0067] Within the meaning of the present invention, the term "patient" refers to a subject who exhibits clinical signs of one or more particular symptoms indicating the need for treatment, who is being treated preventatively or prophylactically against a condition, or who has been diagnosed with a condition to be treated.

[0068] Within the meaning of the present invention, the term "pharmacokinetic parameters" refers to the plasma curves, e.g., C, obtained in clinical studies, by single, multiple or steady-state administration of an active agent-containing TTS, e.g., a guanfacine-containing TTS, to healthy human subjects. max , C t , and AUC t1-t2 The pharmacokinetic parameters of individual subjects are expressed as arithmetic and geometric means, e.g., mean C max , average AUC t , and the average AUC INF , as well as additional statistics such as the respective standard deviations and standard errors, minimum, maximum, and mean values ​​(medians) if the list of values ​​is ranked. Unless otherwise indicated, in the context of the present invention, pharmacokinetic parameters, e.g., C max , C t and AUC t1-t2 refers to the geometric mean value. It cannot be excluded that the absolute mean value obtained for a certain TTS in clinical studies differs to some extent from study to study. To allow the comparison of absolute mean values ​​between studies, a reference formulation, for example, any product based on the present invention in the future, can be used as an internal standard. Using the comparison of the AUC per release area of ​​each reference product in the previous study and the later study, a correction factor can be obtained to take into account the differences between studies.

[0069] Clinical studies according to the present invention refer to studies conducted in full compliance with the International Conference for Harmonization of Clinical Trials (ICH) and all applicable regional Good Clinical Practices (GCP) and regulations.

[0070] Within the meaning of the present invention, the term "healthy human subject" refers to a male or female subject having a body weight ranging from 55 kg to 100 kg and a body mass index (BMI) ranging from 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 inclusion and exclusion criteria based on and following the ICH recommendations.

[0071] Within the meaning of the present invention, the term "subject population" refers to at least 5, preferably at least 10, individual healthy human subjects.

[0072] Within the meaning of the present invention, the term "geometric mean" refers to the mean of log-transformed data that has been transformed back to the original scale.

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

[0074] Within the meaning of the present invention, the parameter "AUC" corresponds to the area under the plasma concentration-time curve. The AUC value is proportional to the total amount of active agent absorbed into the blood circulation and is therefore a measure of bioavailability.

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

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

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

[0078] Within the meaning of the present invention, max The parameter is given in hours, C max It relates to the time at which a value is reached. In other words, t max is the time point of maximum observed plasma concentration.

[0079] Within the meaning of the present invention, the term "mean plasma concentration" is given in (ng / ml) and is the average of the individual plasma concentrations of an active agent, for example guanfacine, at each time point.

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

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

[0082] Within the meaning of the present invention, the term "dissolving" refers to a process that obtains a solution that is transparent to the naked eye and does not contain any particles.

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

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

[0085] Within the meaning of the present invention, the term "equimolar" refers to the amount of two or more components present. Preferably, "equimolar" means that the components are present in a 1:1 ratio.

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

[0087] Within the meaning of the present invention, a premix obtained by the "dry grinding method" refers to guanfacine and monocarboxylic acid obtained by a process comprising milling a mixture of guanfacine base, monocarboxylic acid and methanol with zirconium oxide milling beads (e.g., bead size 3 mm for a Retsch Mixer Mill MM 500) at 35 Hz for about 10 minutes. [Brief description of the drawings]

[0088] [Figure 1.1] 1 shows the cumulative permeation of guanfacine through TTS prepared according to Comparative Examples 1A and 1B. [Figure 1.2] 1 shows the cumulative permeation of guanfacine through the TTS prepared according to Comparative Example 1D. [Figure 1.3] 1 shows the cumulative permeation amount of guanfacine through the TTS prepared according to Examples 1A to 1E and Comparative Example 1C. [Diagram 2] 1 shows the cumulative permeation amount of guanfacine for the TTS prepared according to Examples 2A to C and Comparative Examples 2A and 2B. [Diagram 3] 1 shows the cumulative permeation amount of guanfacine through the TTS prepared according to Examples 3A to 3E and Comparative Example 3. [Figure 4.1] 1 shows the cumulative permeation amount of guanfacine through the TTS prepared according to Examples 4A to 4C and Comparative Example 4. [Figure 4.2]1 shows the cumulative permeation of guanfacine through the TTS prepared according to Example 4D. [Figure 5.1] 1 shows the cumulative permeation amount of guanfacine through the TTS prepared according to Examples 5A to E. [Figure 5.2] 1 shows the cumulative permeation of guanfacine through the TTS prepared according to Example 5F. [Figure 6] 1 shows the cumulative permeation amount of guanfacine through the TTS prepared according to Example 6 and Comparative Example 6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0089] TTS structure The present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising a) a backing layer and b) a guanfacine-containing layer comprising guanfacine and a monocarboxylic acid. This guanfacine-containing layer structure is preferably a guanfacine-containing self-adhesive layer structure, preferably not comprising an additional skin contact layer. Preferably, the guanfacine-containing layer is a guanfacine-containing matrix layer comprising guanfacine and a 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 a monocarboxylic acid. Preferably, guanfacine, in particular guanfacine free base and monocarboxylic acid, are premixed before addition to the guanfacine-containing layer.

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

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

[0092] Thus, according to one embodiment, 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; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine and a monocarboxylic acid; ii) at least one polymer; and Includes.

[0093] The guanfacine-containing layer structure is preferably a guanfacine-containing self-adhesive layer structure. In this connection, it is also preferred that the guanfacine-containing layer structure does not include an additional skin contact layer. Instead, the guanfacine-containing layer (preferably the guanfacine-containing matrix layer) is preferably self-adhesive. Thus, in a preferred embodiment, the guanfacine-containing layer structure is preferably a guanfacine-containing self-adhesive layer structure and does not include an additional skin contact layer. Alternatively or additionally, it is preferred 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 complicated layer structure is obtained. This is advantageous, for example, in terms of production costs.

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

[0097] In a more preferred embodiment of the present invention, the guanfacine and the monocarboxylic acid in the guanfacine-containing layer are present in the form of a premixture, said premixture being obtainable by dry milling or slurrying.

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

[0099] It should be understood that the TTS, preferably the guanfacine-containing layer, more preferably the guanfacine-containing matrix layer, comprises at least two polymers, the at least two polymers being selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers, and mixtures thereof. It should be understood that the TTS, preferably the guanfacine-containing layer, more preferably the guanfacine-containing matrix layer, comprises a polymer, the 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. The first polymer may provide an advantage, for example, in terms of high flux, while the second polymer may be used to reduce and / or optimize the flux, for example, to obtain a continuous and constant flux. Furthermore, the tackiness of the TTS may 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. Thus, in a preferred embodiment of the present invention, the guanfacine-containing layer structure contains a therapeutically effective amount of guanfacine. The guanfacine in the guanfacine-containing layer structure according to the present invention is present together with a monocarboxylic acid, preferably in the form of a co-salt, as described above or in more detail below. In a more preferred embodiment of the present invention, the guanfacine and the monocarboxylic acid are preferably dispersed in the guanfacine-containing layer. A preferred embodiment of the guanfacine and the monocarboxylic acid in the TTS according to the present invention is further provided below. Furthermore, it should be understood that the presence of guanfacine together with the monocarboxylic acid enhances 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 comprise at least one additive selected from the group consisting of dispersing agents, permeation enhancers and / or solubilizers, which are described in more detail below.

[0102] It should further be understood that the additive is 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 ​​the TTS is 1 to 100 cm 2 , preferably 2.5 to 50 cm 2 It is preferable that the range is 100%.

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

[0105] According to certain embodiments of the present invention, the TTS may further comprise an adhesive overlay, which is particularly larger in area than the guanfacine-containing layer structure and is bonded thereto to improve the adhesive properties of the entire transdermal therapeutic system. The adhesive overlay comprises a backing layer and an adhesive layer. The adhesive overlay provides additional area for adhesion to the skin, but does not add to the release area of ​​guanfacine. The adhesive overlay comprises 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 the same or different from any polymer or polymer mixture included in the guanfacine-containing layer structure.

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

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

[0108] In one embodiment of the present invention, 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 comprises: i) guanfacine and a monocarboxylic acid; ii) at least one polymer; and It should be understood that the at least one polymer contained in the guanfacine-containing layer is the at least one polymer contained in the TTS according to the present invention.

[0110] In a preferred embodiment, the guanfacine-containing layer comprises: i) guanfacine and a monocarboxylic acid; ii) at least one polymer; and It should be understood that the at least one polymer contained in the guanfacine-containing layer is the 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, and 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 at least one polymer is a pressure-sensitive adhesive.Thus, 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 preferred that the guanfacine and the monocarboxylic acid are present in the form of a co-salt. It should be further understood that the guanfacine and the monocarboxylic acid are premixed before addition to the guanfacine-containing layer so that a co-salt is formed.

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

[0114] Thus, the guanfacine-containing layer can be obtained by dispersing a guanfacine monocarboxylic acid premix, and preferably, the guanfacine and the monocarboxylic acid are present in the premix in the form of a co-salt. It should be understood that the guanfacine-monocarboxylic acid premix is ​​obtained by mixing the guanfacine free base with a monocarboxylic acid as described above. Preferably, the guanfacine in the present invention is present in the form of a "co-salt" (i.e., the guanfacine is present in the premix together with at least one monocarboxylic acid) to allow proton transfer, preferably at least partially forming a guanfacine salt of the monocarboxylic acid. In other words, the active agent (preferably, guanfacine) can be present in an at least partially protonated form. However, it should be understood that the present invention, in relation to the active agent (preferably, guanfacine) and the monocarboxylic acid, encompasses any form obtained in the guanfacine-containing layer based on a premix of guanfacine and a monocarboxylic acid, and this form includes, for example, the option in which the guanfacine and the monocarboxylic acid coexist without chemical interaction (i.e., proton transfer), and the option of co-salt formation as described above. Preferably, the guanfacine free base and the monocarboxylic acid may form a co-salt or any other kind of acid addition salt together, so that the guanfacine-containing layer preferably at least partially comprises a co-salt or any other kind of acid addition salt of the guanfacine free base and the monocarboxylic acid. In other words, the guanfacine-containing layer preferably comprises guanfacine in at least partially protonated form and the monocarboxylic acid in at least partially deprotonated form.

[0115] Thus, 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. Thus, 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 embodiment, it is surprising that the combination of guanfacine and a monocarboxylic acid, particularly the monocarboxylic acid sorbic acid, enhances the flux and permeation of the transdermal therapeutic system. In particular, it is surprising that the inventors of the present invention have found that the TTS comprising the combination of guanfacine base and sorbic acid in the guanfacine-containing layer exhibits improved cumulative permeation over 88 hours compared to the TTS comprising only guanfacine in the form of free base in the guanfacine-containing layer.

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

[0117] In another embodiment, the loading of guanfacine in the guanfacine-containing layer structure is 0.4 to 2 mg / cm 2 In another embodiment, the loading of guanfacine in the guanfacine-containing layer structure is in the range of 0.4 to 0.85 mg / cm. 2 Furthermore, the emission area of ​​the TTS is in the range of 1 to 100 cm 2 , preferably 2.5 to 50 cm 2 It should be understood that this refers to the loading of guanfacine and not the loading of the guanfacine-monocarboxylic acid premix.

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

[0119] In one embodiment of the present invention, the guanfacine-containing layer comprises 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 contained together with guanfacine in the guanfacine-containing layer is sorbic acid.

[0120] Guanfacine-containing layer structure, preferably guanfacine-containing layer, comprises at least one polymer.As explained above, at least one polymer is selected from the group consisting of acrylic polymer, silicone-based polymer, silicone-acrylic hybrid polymer and their mixture.It should be understood that preferably, TTS, preferably guanfacine-containing layer, more preferably guanfacine-containing matrix layer comprises polymer, and this polymer is selected from the mixture of acrylic polymer and at least one silicone-based polymer, the mixture of two silicone-acrylic hybrid polymers, the mixture of two silicone-based polymers, acrylic polymer, and the mixture of acrylic polymer containing -OH group.

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

[0122] In one preferred embodiment of the present invention, the guanfacine-containing layer comprises a mixture of an acrylic polymer and at least one silicone-based polymer, where 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 active agent-containing layer. When more than one silicone-based polymer is present, for example two silicone-based polymers, it should be understood that 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 the silicone-based polymer are provided below.

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

[0124] The silicone acrylic hybrid polymer as defined above comprises a silicone phase and an acrylate phase, preferably in a weight ratio of 60:40 to 40:60, most preferably in a weight ratio of 50:50. The silicone acrylic hybrid polymer typically comprises the reaction product of (a) a silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups, (b) an ethylenically unsaturated monomer, and (c) an initiator. Further details regarding components (a), (b) and (c) are further provided below. It should be understood that component (a) forms mainly the silicone phase, and component (b) forms mainly the acrylate phase of the silicone acrylic hybrid polymer. The acrylate phase influences the tack and viscosity of the silicone acrylic hybrid polymer. Thus, it is preferred that the ethylenically unsaturated monomer forming the acrylate phase is 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 tack, but the viscosity is lower in that case. A 50:50 ratio is preferred in view of the higher viscosity, but reduced tack.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 comprises at least one silicone acrylic hybrid polymer in an amount of 20-99% by weight, preferably 30-97% by weight, most preferably 35-94% by weight, based on the total weight of the guanfacine-containing layer. In a preferred embodiment, the guanfacine-containing layer comprises at least one silicone acrylic hybrid polymer in an amount of 74-94% by weight, preferably 74-89% 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 given above may refer to one silicone acrylic hybrid polymer, but may also refer to a combination of silicone acrylic hybrid polymers. Thus, the given amount refers to the total amount of silicone acrylic hybrid polymer.

[0126] In a preferred embodiment of the invention, the guanfacine-containing layer comprises only one silicone acrylic hybrid polymer in an amount of 60-97% by weight, preferably 70-94% 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, the total amount of the at least two silicone acrylic hybrid polymers being 35-94% by weight, preferably 74-94% by weight, based on the total weight of the guanfacine-containing layer. Preferably, the guanfacine-containing layer comprises the first silicone acrylic hybrid polymer in an amount of 60-90% by weight, and the second silicone acrylic hybrid polymer in an amount of 1-20% by weight, based on the total weight of the guanfacine-containing layer. In a particularly preferred embodiment, the guanfacine-containing layer comprises the first silicone acrylic hybrid polymer in an amount of 70-85% by weight, preferably 70-78% by weight, and the second silicone acrylic hybrid polymer in an amount of 1-8% by weight, preferably 3-5% by weight, based on the total weight of the guanfacine-containing layer.

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

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

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

[0131] In a preferred embodiment, the guanfacine-containing layer comprises at least one additive selected from the group consisting of a dispersing agent, a permeation enhancer, and a solubilizing agent. In one preferred embodiment, the at least one additive is a dispersing agent. In another preferred embodiment, the at least one additive is a permeation enhancer. In yet another preferred embodiment, the at least one additive is a solubilizing agent. In certain preferred embodiments, combinations of the aforementioned additives are also preferred. The aforementioned additives are particularly advantageous for providing guanfacine in a uniformly dispersed and releasable form. It should be understood that the dispersing agent may also act as a permeation enhancer, and vice versa. Similarly, the solubilizing agent may also additionally act as a dispersing agent or permeation enhancer. Furthermore, the solubilizing agent may stabilize the guanfacine dispersion in the TTS to avoid crystallization. Moreover, the solubilizing agent may help optimize the cohesiveness of the TTS. In certain preferred embodiments, the guanfacine-containing layer comprises at least one dispersing agent and at least one permeation enhancer, and optionally also at least one solubilizing agent.

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

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

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

[0135] In one embodiment, the TTS according to the present invention, in particular the guanfacine-containing layer, more particularly the guanfacine-containing matrix layer, comprises at least two additives selected from the group consisting of a dispersing agent, a permeation enhancer and a solubilizer.

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

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

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

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

[0140] Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, comprises a dispersing agent present in an amount of 1-10 wt. %, based on the total weight of the guanfacine-containing layer, and a permeation enhancer present in an amount of 1-10 wt. %, based on the total weight of the guanfacine-containing layer. Preferably, the dispersing agent is present in an amount of 1-6 wt. %, and the permeation enhancer is present in an amount of 2-9 wt. %. More preferably, the dispersing agent is present in an amount of 2-6 wt. %, and the permeation enhancer is present in an amount of 2-6 wt. %. Even more preferably, the dispersing agent is present in an amount of 3-5 wt. %, and the permeation enhancer is present in an amount of 3-5 wt. %, based on the total weight of the guanfacine-containing layer.

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

[0142] In a preferred embodiment, the dispersant is selected from the group consisting of esters of fatty acids and polyols, fatty alcohols, polyethylene glycols having a number average molecular weight of 300 to 400, and polyethylene glycol alkyl ethers, and the dispersant is preferably a polyethylene glycol C8-C10 having 2 to 10 EO units, preferably 2 to 6 EO units. 20 A particularly preferred dispersant is polyoxyethylene (4) lauryl ether (C 12 H 25 (OCH2CH2)4OH). This dispersant is available, for example, from Merck under the trade name Brij L4®.

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

[0144] In a preferred embodiment, the solubilizer is selected from the group consisting of copolymers derived from esters of acrylic and methacrylic acid, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers and polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymers, preferably polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymers. A particularly preferred solubilizer is polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer. Suitable polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymers are available, for example, from BASF under the trade name Soluplus® and preferably have 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 90000 to 140000 g / mol. [ka]

[0145] In a particular preferred embodiment, the guanfacine-containing layer comprises at least one dispersant in an amount of 2-6% by weight, at least one permeation enhancer in an amount of 2-9% by weight, and at least one solubilizer in an amount of 0.5-5% by weight, in each case based on the total weight of the guanfacine-containing layer. Preferably, the guanfacine-containing layer comprises at least one dispersant in an amount of 2-6% by weight, at least one permeation enhancer in an amount of 2-6% by weight, and at least one solubilizer in an amount of 0.5-5% by weight, in each case based on the total weight of the guanfacine-containing layer. More preferably, the guanfacine-containing layer comprises at least one dispersant in an amount of 3-5% by weight, at least one permeation enhancer in an amount of 3-5% by weight, and at least one solubilizer in an amount of 0.5-5% by weight, in each case based on the total weight of the guanfacine-containing layer. In relation to the above preferred weight % amounts, the above preferred dispersants, permeation enhancers and solubilizers are preferred.

[0146] Thus, in a particularly preferred embodiment, the guanfacine-containing layer is made of polyethylene glycols C8-C10 having 2 to 10 EO units, in each case based on the total weight of the guanfacine-containing layer. 20 % by weight, polyoxyethylene (4) lauryl ether, preferably in an amount of 2-6% by weight, oleyl alcohol in an amount of 2-9% by weight, and optionally, preferably, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specifically mentioned above in an amount of 0.5-5% by weight. In a more particularly preferred embodiment, the guanfacine-containing layer comprises polyethylene glycol C8-C10 having 2-10 EO units, in each case based on the total weight of the guanfacine-containing layer. 20% by weight, polyoxyethylene (4) lauryl ether, preferably in an amount of 2-6% by weight, oleyl alcohol in an amount of 2-6% by weight, and optionally, preferably, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specified above in an amount of 0.5-5% by weight. Most preferably, the guanfacine-containing layer comprises polyethylene glycol C8-C10 having 2-10 EO units, in each case based on the total weight of the guanfacine-containing layer. 20 -alkyl ether, polyoxyethylene (4) lauryl ether preferably in an amount of 3 to 5% by weight, oleyl alcohol in an amount of 3 to 5% by weight, and optionally, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, preferably as specified above, in an amount of 0.5 to 5% by weight.

[0147] Thus, in another particularly preferred embodiment, the guanfacine-containing layer is made of polyethylene glycol C8-C10 having 2 to 10 EO units, in each case based on the total weight of the guanfacine-containing layer. 20 % by weight, polyoxyethylene (4) lauryl ether, preferably in an amount of 2-6% by weight, lauroglycol in an amount of 2-9% by weight, and optionally, preferably, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specifically mentioned above in an amount of 0.5-5% by weight. In another more particularly preferred embodiment, the guanfacine-containing layer comprises polyethylene glycol C8-C10 having 2-10 EO units, in each case based on the total weight of the guanfacine-containing layer. 20% by weight, polyoxyethylene (4) lauryl ether, preferably in an amount of 2-6% by weight, lauroglycol in an amount of 2-6% by weight, and optionally, preferably, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specified above in an amount of 0.5-5% by weight. Most preferably, the guanfacine-containing layer comprises polyethylene glycol C8-C10 having 2-10 EO units, in each case based on the total weight of the guanfacine-containing layer. 20 -alkyl ether, polyoxyethylene (4) lauryl ether preferably in an amount of 3 to 5% by weight, lauroglycol in an amount of 3 to 5% by weight, and optionally, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, preferably as specified above, in an amount of 0.5 to 5% by weight.

[0148] Thus, in another particularly preferred embodiment, the guanfacine-containing layer is made of polyethylene glycol C8-C10 having 2 to 10 EO units, in each case based on the total weight of the guanfacine-containing layer. 20 % by weight, polyoxyethylene(4) lauryl ether, preferably in an amount of 2-6% by weight, oleoyl macrogol-6 glyceride (labrafil MS 1944) in an amount of 2-9% by weight, and optionally, preferably, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specifically mentioned above in an amount of 0.5-5% by weight. In another more particularly preferred embodiment, the guanfacine-containing layer comprises polyethylene glycol C8-C10 with 2-10 EO units, in each case based on the total weight of the guanfacine-containing layer. 20% by weight, polyoxyethylene(4) lauryl ether, preferably in an amount of 2-6% by weight, oleoyl macrogol-6 glyceride (labrafil MS 1944) in an amount of 2-6% by weight, and optionally, preferably, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specified above in an amount of 0.5-5% by weight. Most preferably, the guanfacine-containing layer comprises polyethylene glycol C8-C10 with 2-10 EO units, in each case based on the total weight of the guanfacine-containing layer. 20 -alkyl ether, preferably in an amount of 3-5% by weight, polyoxyethylene (4) lauryl ether, oleoyl macrogol-6 glyceride (labrafil MS 1944) in an amount of 3-5% by weight, and optionally, preferably in an amount of 0.5-5% by weight of a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specified above.

[0149] In one embodiment of the present invention, the area weight of the guanfacine-containing layer is 40 to 250 g / m 2 , preferably 50 to 180 g / m 2 , more preferably 70 to 180 g / m 2 , for example, 75 to 150 g / m 2 or 100~150g / m 2 In certain preferred embodiments, the area weight is in the range of 80 to 120 g / m 2 , preferably 90 to 100 g / m 2 The range is.

[0150] In view of the above, 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 comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of an acrylic polymer and at least one silicone-based polymer, the acrylic polymer being present in an amount of 20-55% by weight and the at least one silicone-based polymer being present in an amount of 20-55% by weight, based on the total weight of the guanfacine-containing layer; iii) at least one dispersing agent in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) at least one permeation enhancer in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; 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 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 to a transdermal therapeutic system for transdermal administration of guanfacine, which in one embodiment comprises a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine and sorbic acid in a total amount of 6 to 9% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of an acrylic polymer and at least one silicone-based polymer, the acrylic polymer being present in an amount of 20-55% by weight and the at least one silicone-based polymer being present in an amount of 20-55% by weight, based on the total weight of the guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer; iv) oleoyl macrogol-6 glyceride in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; 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 due to at least one polymer that is a mixture of an acrylic polymer and at least one silicone-based polymer.

[0151] 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 guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case based on the total weight of the guanfacine-containing layer; iii) at least one dispersing agent in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) at least one permeation enhancer in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer; 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 due to at least one polymer that is a mixture of two silicone-acrylic hybrid polymers.

[0152] 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 guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-based polymers, the first silicone-based polymer being present in an amount of 20-55% by weight and the second silicone-based polymer being present in an amount of 20-55% by weight, based on the total weight of the guanfacine-containing layer; iii) at least one dispersing agent in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) at least one permeation enhancer in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer; 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 due to at least one polymer that is a mixture of two silicone-based polymers.

[0153] 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 guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) an acrylic polymer in an amount of 65 to 95% by weight, based on the total weight of the guanfacine-containing layer; iii) at least one dispersing agent in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) at least one permeation enhancer in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer; 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 due to at least one polymer that is an acrylic polymer.

[0154] 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 guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) an acrylic polymer containing -OH groups in an amount of 65 to 95% by weight, based on the total weight of the guanfacine-containing layer; iii) at least one dispersing agent in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) at least one permeation enhancer in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer; 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 due to at least one polymer that is an acrylic polymer containing -OH groups.

[0155] In a more preferred 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) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of an acrylic polymer and at least one silicone-based polymer, the acrylic polymer being present in an amount of 20-55% by weight and the at least one silicone-based polymer being 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, iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; 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 due to at least one polymer that is a mixture of an acrylic polymer and at least one silicone-based polymer.

[0156] In another more preferred embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising, in one embodiment, a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case 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, iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; 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 due to at least one polymer that is a mixture of two silicone-acrylic hybrid polymers.

[0157] In another more preferred embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising, in one embodiment, a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-based polymers, the first silicone-based polymer being present in an amount of 20-55% by weight and the second silicone-based polymer being 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, iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; 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 due to at least one polymer that is a mixture of two silicone-based polymers. In an even more preferred embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising, in one embodiment, a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine and sorbic acid in a total amount of 6 to 9% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-based polymers, the first silicone-based polymer being present in an amount of 20-55% by weight and the second silicone-based polymer being present in an amount of 20-55% by weight, based on the total weight of the guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer; iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; 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 due to at least one polymer that is a mixture of two silicone-based polymers.

[0158] In another more preferred embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising, in one embodiment, a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) an acrylic polymer in an amount of 65 to 95% 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, iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; 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 due to at least one polymer that is an acrylic polymer. In an even 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, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine and sorbic acid in a total amount of 6 to 9% by weight based on the total weight of the guanfacine-containing layer; ii) an acrylic polymer in an amount of 65 to 95% by weight, based on the total weight of the guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer; iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; 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 due to at least one polymer that is an acrylic polymer.

[0159] In another more preferred embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising, in one embodiment, a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) an acrylic polymer containing -OH groups in an amount of 65 to 95% by weight, based on the 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, iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; In connection with this embodiment, it is further preferred that the guanfacine-containing layer structure does not comprise 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 -OH groups. In an even more preferred embodiment, the present invention relates in one embodiment to a transdermal therapeutic system for the transdermal administration of guanfacine, comprising a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine and sorbic acid in a total amount of 6 to 9% by weight based on the total weight of the guanfacine-containing layer; ii) an acrylic polymer containing -OH groups in an amount of 65 to 95% by weight, based on the total weight of the guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer; iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; 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 due to at least one polymer that is an acrylic polymer containing -OH groups.

[0160] In a particularly preferred embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising, in one embodiment, a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises 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 to a transdermal therapeutic system for transdermal administration of guanfacine, comprising, in one embodiment, a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine and sorbic acid, ii) a mixture of two silicone-acrylic hybrid polymers; iii) polyoxyethylene (4) lauryl ether; and iv) oleyl alcohol; Includes.

[0162] In another particularly preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine, comprising, in one embodiment, a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine and sorbic acid, ii) a mixture of two silicone-acrylic hybrid polymers; iii) polyoxyethylene (4) lauryl ether; and iv) lauroglycol, Includes.

[0163] In another particularly preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine, comprising, in one embodiment, a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises 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; and Includes.

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

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

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

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

[0168] In another even more particularly preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine, comprising, in one embodiment, a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case based on the total weight of the guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer; iv) lauroglycol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; Includes.

[0169] In another even more particularly preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine, comprising, in one embodiment, a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine and sorbic acid in a total amount of 6 to 9% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case based on the total weight of the guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer; iv) lauroglycol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; Includes.

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

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

[0172] In the above preferred and more preferred embodiments, the area weight of the guanfacine-containing layer is 50 to 180 g / m 2 , preferably 75 to 150 g / m 2 , more preferably 80 to 120 g / m 2 It is more preferable that the range is .

[0173] Guanfacine The TTS according to the present invention comprises a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising A) a backing layer and B) a guanfacine-containing layer comprising guanfacine and a monocarboxylic acid. The guanfacine-containing layer is preferably a guanfacine-containing matrix layer, as 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 premixture with monocarboxylic acid.In one embodiment of the present invention, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, comprises guanfacine and monocarboxylic acid, or the salt formed from guanfacine and monocarboxylic acid.Preferably, guanfacine and monocarboxylic acid are present in the form of co-salt.Furthermore, it should be understood that guanfacine and monocarboxylic acid are premixed before adding to the guanfacine-containing layer, so that co-salt is formed.

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

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

[0177] In a more preferred embodiment of the present invention, the guanfacine and the monocarboxylic acid in the guanfacine-containing layer are present in the form of a premixture, said premixture being obtainable by dry milling or slurrying.

[0178] In one preferred embodiment of the present invention, the guanfacine and the monocarboxylic acid are present in equimolar amounts in the guanfacine-containing layer. In this regard, it should be understood that the guanfacine free base added to the premix and the monocarboxylic acid added to the premix 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 contained together with guanfacine in the guanfacine-containing layer is sorbic acid.

[0180] In relation to the above embodiment, it is surprising that the combination of guanfacine and monocarboxylic acid, especially monocarboxylic acid sorbic acid, enhances the flux and permeation of transdermal therapeutic system.In particular, the inventors of the present invention surprisingly find that the TTS that comprises the combination of guanfacine base and sorbic acid in the guanfacine-containing layer shows improved cumulative permeation over 88 hours compared with the TTS that comprises only guanfacine in the form of free base in the guanfacine-containing layer.

[0181] In one 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, the guanfacine-containing layer can be obtained by dispersing the guanfacine-monocarboxylic acid premix.When the guanfacine-containing layer is a guanfacine-containing matrix layer, said layer can be obtained by dispersing the guanfacine-monocarboxylic acid premix 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 dispersing agent and at least one permeation enhancer.

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

[0185] polymer Silicone Acrylic Hybrid Polymer The TTS according to the present invention comprises at least one polymer, the at least one polymer being selected from the group consisting of acrylic polymers, silicone-based polymers, silicone-acrylic hybrid polymers and mixtures thereof. Further details regarding the mixture of polymers 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 that comprises a silicone-based subspecies and an acrylate-based subspecies 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 usually 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 modified 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 silicone to acrylate of 50:50 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 in ethyl acetate by DuPont™.

[0189] Preferred silicone acrylic hybrid pressure sensitive adhesives according to the present invention are characterized by a solution viscosity at 25° C. and about 50% solids content in ethyl acetate, preferably greater than about 400 cP, or from about 500 cP to about 3,500 cP, especially 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 equipped with spindle #5 at 50 RPM.

[0190] These silicone acrylic hybrid pressure sensitive adhesives may also be characterized by a complex viscosity at 30° C. at 0.1 rad / s, preferably less than about 1.0e9 poise, or from about 1.0e5 poise to about 9.0e8 poise, or 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, as measured using a Rheometrics ARES rheometer with an 8 mm plate and a zero-defined gap.

[0191] To prepare samples for measuring rheological behavior using the Rheometrics ARES rheometer, 2-3 grams of adhesive solution can be poured onto a SCOTCH-PAK1022 fluoropolymer release liner and allowed to sit for 60 minutes under ambient conditions. To achieve an essentially solvent-free film of adhesive, they can be left in an oven at 110°C + / - 10°C for 60 minutes. After removal from the oven, they are allowed to equilibrate to room temperature. The film can be removed from the release liner and folded back to form a square. To remove air bubbles, the film can be compressed using a Carver press. The sample can then be mounted 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 from 0.01 to 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 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, 7-6102 silicone acrylic hybrid PSA with a silicone / acrylate ratio of 50 / 50 is characterized by a solution viscosity of 2,500 cP at 25° C. and about 50% solids content in ethyl acetate, and a complex viscosity of 1.0e7 poise at 0.1 rad / s and 30° C. 7-6302 silicone acrylic hybrid PSA with a silicone / acrylate ratio of 50 / 50 is characterized by a solution viscosity of 1,500 cP at 25° C. and about 50% solids content in ethyl acetate, and a complex viscosity of 4.0e6 poise at 0.1 rad / s and 30° C.

[0193] Depending on the solvent in which the silicone acrylic hybrid pressure sensitive adhesive is provided, the arrangement of the silicone and acrylic phases will be different, providing a continuous silicone or acrylic external phase and a corresponding discontinuous internal phase. When the silicone acrylic hybrid pressure sensitive adhesive is provided in n-heptane, the composition will contain a continuous silicone external phase and a discontinuous acrylic internal phase. When the silicone acrylic hybrid pressure sensitive adhesive is provided in ethyl acetate, the composition will contain a continuous acrylic external phase and a discontinuous silicone internal phase. After evaporating the solvent in which the silicone acrylic hybrid pressure sensitive adhesive is provided, the phase arrangement of the resulting pressure sensitive adhesive film or layer will correspond to the phase arrangement of the solvent-containing adhesive coating composition. For example, in the absence of a 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 a silicone acrylic hybrid pressure sensitive adhesive in n-heptane will provide a continuous silicone external phase and a discontinuous acrylic internal phase, and a pressure sensitive adhesive layer prepared from a silicone acrylic hybrid pressure sensitive adhesive in ethyl acetate will provide a continuous acrylic external phase and a discontinuous silicone internal phase. The phase arrangement of the composition can be determined, for example, in a peel force test using a pressure-sensitive adhesive film or layer prepared from a silicone-acrylic hybrid PSA composition attached to a siliconized release liner. A pressure-sensitive adhesive film contains a continuous silicone external phase if the siliconized release liner cannot or hardly can be removed from the pressure-sensitive adhesive film (laminated to a backing film) due to blocking of the two silicone surfaces. Blocking results from the adhesion of two silicone layers that contain similar surface energies. The silicone adhesive shows good spreading on the siliconized liner and can therefore generate good adhesion to the liner. If the siliconized release liner can be easily removed, the pressure-sensitive adhesive film contains a continuous acrylic external phase. The acrylic adhesive does not have good spreading due to the difference in surface energy, and therefore has low or little adhesion to the siliconized liner.Preferably, in accordance with the present invention, the silicone acrylic hybrid pressure sensitive adhesive is provided in ethyl acetate, the composition containing a continuous acrylic exterior phase and a discontinuous silicone interior 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 the silicon-containing pressure-sensitive adhesive composition that contains acrylate or methacrylate functional groups.It should be understood that the silicon-containing pressure-sensitive adhesive composition that contains acrylate or methacrylate functional groups can contain only acrylate functional groups, only methacrylate functional groups, or both acrylate functional groups and methacrylate functional groups.

[0195] According to certain embodiments of the present invention, the silicone acrylic hybrid pressure sensitive adhesive comprises the reaction product of (a) a silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups, (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 the reaction product of (a) a silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups, (b) a (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 acrylate or methacrylate functionality, (b) an ethylenically unsaturated monomer, and (c) an initiator may contain a continuous silicone exterior phase and a discontinuous acrylic interior phase, or the reaction product of (a), (b), and (c) may contain a continuous acrylic exterior phase and a discontinuous silicone interior phase.

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

[0198] The ethylenically unsaturated monomer (b) is typically present in the silicone acrylic hybrid pressure sensitive adhesive in an amount of from 5 to 95 parts by weight, more typically from 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 from 0.005 to 3 parts by weight, more typically from 0.01 to 2 parts by weight, based on 100 parts by weight of the hybrid pressure sensitive adhesive.

[0200] According to certain embodiments of the present invention, the silicone-containing pressure-sensitive adhesive composition (a) containing acrylate or methacrylate functionality comprises the condensation reaction product of (a1) a silicone resin, (a2) a silicone polymer, and (a3) ​​a silicon-containing sealant that provides said acrylate or methacrylate functionality.

[0201] According to certain embodiments of the present invention, the silicon-containing pressure-sensitive adhesive composition (a) containing acrylate or methacrylate functional groups is (a1) a silicone resin; (a2) a silicone polymer; (a3) a silicon-containing sealant providing said acrylate or methacrylate functionality; and and the silicon-containing sealant comprises a condensation reaction product of the general formula XYR' b SiZ 3-b {In the formula, X is a monovalent radical of the general formula AE-, where E is -O- or -NH-; A is an acrylic or 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 a halogen; b is 0 or 1} having the silicone resin and the silicone polymer are reacted to form a pressure sensitive adhesive, and the silicon-containing sealant is introduced before, during, or after reacting the silicone resin and the silicone polymer; The silicon-containing sealant reacts with the pressure sensitive adhesive after the silicone resin and silicone polymer have condensed to form the pressure sensitive adhesive, or Silicon-containing sealants react in situ with silicone resins and silicone polymers.

[0202] According to a particular embodiment of the present invention, the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality comprises a condensation reaction product of a pressure-sensitive adhesive and a silicon-containing sealant that provides said acrylate or methacrylate functionality. That is, the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality is essentially a pressure-sensitive adhesive that is sealed or endblocked with a silicon-containing sealant that provides said acrylate or methacrylate functionality, and the pressure-sensitive adhesive comprises a condensation reaction product of a silicone resin and a silicone polymer. Preferably, the silicone resin is reacted in an amount of 30 to 80 parts by weight to form the pressure-sensitive adhesive, and the silicone polymer is reacted in an amount of 20 to 70 parts by weight to form the pressure-sensitive adhesive. All of these parts by weight are based on 100 parts by weight of pressure-sensitive adhesive. Although not required, the pressure-sensitive adhesive may include a catalytic amount of a condensation catalyst. A variety of silicone resins and silicone polymers are suitable for forming the pressure-sensitive adhesive.

[0203] According to certain embodiments of the present invention, the silicone acrylic hybrid pressure sensitive adhesive comprises: (a) a silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group, said silicon-containing pressure-sensitive adhesive composition comprising: (a1) a silicone resin; (a2) a silicone polymer; (a3) a silicon-containing sealant providing said acrylate or methacrylate functionality; and and the silicon-containing sealant comprises a condensation reaction product of the general formula XYR' b SiZ 3-b {In the formula, X is a monovalent radical of the general formula AE-, where E is -O- or -NH-; A is an acrylic or 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 a halogen; b is 0 or 1} having the silicone resin and the silicone polymer are reacted to form a pressure sensitive adhesive, and the silicon-containing sealant is introduced before, during, or after reacting the silicone resin and the silicone polymer; The silicon-containing sealant reacts with the pressure sensitive adhesive after the silicone resin and silicone polymer have condensed to form the pressure sensitive adhesive, or The silicon-containing sealant comprises a silicon-containing pressure sensitive adhesive composition comprising an acrylate or methacrylate functional group that reacts in situ with the silicone resin and the silicone polymer; (b) an ethylenically unsaturated monomer; (c) an initiator; and It is the reaction product of

[0204] The silicone acrylic hybrid composition used in the present invention comprises: (i) providing a silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups, said silicon-containing pressure sensitive adhesive composition comprising: A silicone resin, A silicone polymer; a silicon-containing sealant providing said acrylate or methacrylate functionality; and the silicon-containing sealant comprises a condensation reaction product of the general formula XYR' b SiZ3-b {In the formula, X is a monovalent radical of the general formula AE-, where E is -O- or -NH-; A is an acrylic or 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 a halogen; b is 0 or 1} having the silicone resin and the silicone polymer are reacted to form a pressure sensitive adhesive, and the silicon-containing sealant is introduced before, during, or after reacting the silicone resin and the silicone polymer; The silicon-containing sealant reacts with the pressure sensitive adhesive after the silicone resin and silicone polymer have condensed to form the pressure sensitive adhesive, or Silicon-containing sealants react in situ with silicone resins and silicone polymers; A process of providing (ii) optionally polymerizing the ethylenically unsaturated monomer and the silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functionality of step (i) in the presence of an initiator at a temperature of from 50° C. to 100° C., or from 65° C. to 90° C. to form a silicone acrylic hybrid composition; It can be described as being prepared by a process comprising:

[0205] During polymerization of the silicon-containing pressure-sensitive adhesive composition containing 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 illustrative example of one such mechanism is the rate-controlled addition of one or more ethylenically unsaturated monomers to the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups. In certain applications, it may be desirable to have the silicone-based subspecies, or the total silicone content, exceed the acrylate-based subspecies, or the total acrylic content. In other applications, it may be desirable for the reverse to be true. Independent of the end use, it is generally preferred, as already mentioned above, that the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups is 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 certain embodiments of the present invention, the silicone acrylic hybrid composition used in the present invention comprises: (i) providing a silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups, said silicon-containing pressure sensitive adhesive composition comprising: A silicone resin, A silicone polymer; a silicon-containing sealant providing said acrylate or methacrylate functionality; and the silicon-containing sealant comprises a condensation reaction product of the general formula XYR' b SiZ 3-b {In the formula, X is a monovalent radical of the general formula AE-, where E is -O- or -NH-; A is an acrylic or 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 a halogen, and b is 0 or 1. having the silicone resin and the silicone polymer are reacted to form a pressure sensitive adhesive, and the silicon-containing sealant is introduced before, during, or after reacting the silicone resin and the silicone polymer; The silicon-containing sealant reacts with the pressure sensitive adhesive after the silicone resin and silicone polymer have condensed to form the pressure sensitive adhesive, or Silicon-containing sealants react in situ with silicone resins and silicone polymers; A process of providing (ii) polymerizing the silicon-containing pressure sensitive adhesive composition comprising ethylenically unsaturated monomers and acrylate or methacrylate functional groups of step (i) in a first solvent in the presence of an initiator at a temperature between 50° C. and 100° C. to form a silicone acrylic hybrid composition; (iii) removing the first solvent; (iv) adding a second solvent to form a silicone acrylic hybrid composition, the phase distribution of the silicone acrylic hybrid composition being selectively controlled by the selection of the second solvent; It can be described as being prepared by a process comprising:

[0207] The silicone acrylic hybrid PSA compositions used in the present invention also include (i) providing a silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups, said silicon-containing pressure sensitive adhesive composition comprising: A silicone resin, A silicone polymer; a silicon-containing sealant providing said acrylate or methacrylate functionality; and the silicon-containing sealant comprises a condensation reaction product of the general formula XYR' b SiZ 3-b {In the formula, X is a monovalent radical of the general formula AE-, where E is -O- or -NH-; A is an acrylic or 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 a halogen; b is 0 or 1} having the silicone resin and the silicone polymer are reacted to form a pressure sensitive adhesive, and the silicon-containing sealant is introduced before, during, or after reacting the silicone resin and the silicone polymer; The silicon-containing sealant reacts with the pressure sensitive adhesive after the silicone resin and silicone polymer have condensed to form the pressure sensitive adhesive, or providing a silicon-containing sealant that reacts in situ with the silicone resin and the silicone polymer; (ii) polymerizing the silicon-containing pressure sensitive adhesive composition comprising ethylenically unsaturated monomers and acrylate or methacrylate functional groups of step (i) in a first solvent in the presence of an initiator at a temperature between 50° C. and 100° C. to form a silicone acrylic hybrid composition; (iii) adding a processing solvent, the processing solvent having a higher boiling point than the first solvent; (iv) applying heat at a temperature between 70° C. and 150° C. so as to selectively remove most of the first solvent; (v) removing the processing solvent; (vi) adding a second solvent to form a silicone acrylic hybrid composition, the phase distribution of the silicone acrylic hybrid composition being selectively controlled by the selection of the second solvent; It can be described as being prepared by a process comprising:

[0208] The silicone resin according to the previous paragraph has the formula R X 3SiO 1 / 2 and triorganosiloxy units of the formula SiO4 / 2 In one embodiment, the copolymer may contain tetrafunctional siloxy units of from about 0.1 to about 0.9, preferably about 0.6 to about 0.9, of triorganosiloxy units to each tetrafunctional siloxy unit. X independently represent a monovalent hydrocarbon group having 1 to 6 carbon atoms, a vinyl, a hydroxyl, or a phenyl group.

[0209] The silicone polymer according to the preceding paragraph may comprise at least one polydiorganosiloxane, preferably end-capped (end-blocked) with a functional group selected from the group consisting of hydroxyl, alkoxy, hydride, vinyl 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 methyl groups. 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 with a functional group selected from the group consisting of hydroxyl, alkoxy, hydride, vinyl 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 methyl groups. 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. X ASiO 1 / 2 AR terminated in units X and the polydiorganosiloxane has a viscosity of about 100 centipoise to about 30,000,000 centipoise at 25° C., and each A group is independently selected from the group consisting of R X or a halohydrocarbon group having 1 to 6 carbon atoms, each T group being independently selected from R X , OH, H or OR Y and each R Y is independently an alkyl group having 1 to 4 carbon atoms.

[0210] As an example, using the preferred silicone resin and the preferred silicone polymer morphology, one type of pressure sensitive adhesive is made as follows. (i) each SiO 2 present that contains a silicon-bonded hydroxyl group; 4 / 2 R with a molar ratio of 0.6 to 0.9 for units X 3SiO1 / 2 R in units X 3SiO 1 / 2 Units and SiO 4 / 2 (ii) 30 to 80 parts by weight (inclusive) of at least one resin copolymer consisting essentially of units; and X ASiO 1 / 2 AR terminated in units X about 20 to about 70 parts by weight of at least one polydiorganosiloxane 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 of 1 to 6 (inclusive) carbon atoms, and each A group is R X or a halohydrocarbon group having 1 to 6 (inclusive) carbon atoms, each T group being independently selected from R X , OH, H or OR Y and each R is independently selected from the group consisting of Y are independently an alkyl group of 1 to 4 (inclusive) carbon atoms; (iii) at least one silicon-containing sealing agent, also referred to throughout as an endblocking agent and described below, in a sufficient amount to provide a silanol content or concentration in the range of 5,000 to 15,000, more typically 8,000 to 13,000 ppm; (iv) if none 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 sealing agent(s) has reacted with the silicon-bonded hydroxyl and T groups of (i) and (ii). Additional organosilicon endblockers may be used in conjunction with the silicon-containing capping agent(s) (iii) of the present invention.

[0211] The silicon-containing sealant according to the previous paragraph may be selected from the group of acrylate-functional silanes, acrylate-functional silazanes, acrylate-functional disilazanes, acrylate-functional disiloxanes, methacrylate-functional silanes, methacrylate-functional silazanes, methacrylate-functional disilazanes, methacrylate-functional disiloxanes, and combinations thereof, and may be represented by the general formula XYR′ b SiZ 3-b where X is a monovalent radical of the general formula AE, where E is -O- or -NH-, and A is an acrylic or methacrylic group, Y is a divalent alkylene radical having 1 to 6 carbon atoms, R' is a methyl or phenyl group, Z is a monovalent hydrolyzable organic group or a halogen, and b is 0, 1, or 2. Preferably, the monovalent hydrolyzable organic group has the general formula R"0, where R" is an alkylene group. Most preferably, this particular endblocking 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)trimethoxysilane. silane, (methacryloxymethyl)dimethylethoxysilane, (methacryloxymethyl)methyldiethoxysilane, methacryloxymethyltriethoxysilane, methacryloxypropyltriisopropoxysilane, 3-methacryloxypropyldimethylsilazane, 3-acryloxy-propyldimethylchlorosilane, 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 can be a compound selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates, cycloaliphatic methacrylates, and combinations thereof.It should be understood that each of the compounds, i.e., aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates, and cycloaliphatic methacrylates, contains an alkyl group.The alkyl group of these compounds can contain up to 20 carbon atoms. The aliphatic acrylate that may be selected as one of the ethylenically unsaturated monomers is 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. The aliphatic methacrylate that may be selected as one of the ethylenically unsaturated monomers is 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. The alicyclic acrylate that may be selected as one of the ethylenically unsaturated monomers is cyclohexyl acrylate, and the alicyclic methacrylate that may be selected as one of the ethylenically unsaturated monomers is cyclohexyl methacrylate.

[0213] It should be understood that the ethylenically unsaturated monomer used to prepare the silicone acrylic hybrid pressure sensitive adhesive can be a plurality of ethylenically unsaturated monomers.That is, a combination of ethylenically unsaturated monomers can be polymerized, more specifically copolymerized, together with the silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups and 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 monomer, more preferably in the ratio of 50% 2-ethylhexyl acrylate and 50% methyl acrylate, or in the ratio of 60% 2-ethylhexyl acrylate and 40% methyl acrylate.

[0214] The initiator according to the previous paragraph may be any material suitable for initiating the polymerization of the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups and ethylenically unsaturated monomers 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 suitable silicone resins, silicone polymers, silicon-containing sealants, ethylenically unsaturated monomers, and initiators that can be used in accordance with the preceding paragraphs are detailed in WO2007 / 145996, EP2599847A1, and WO2016 / 130408.

[0216] According to certain embodiments of the present invention, the silicone acrylic hybrid polymer comprises the reaction product of a silicone polymer, a silicone resin and an acrylic polymer, where the acrylic polymer is covalently self-crosslinked and covalently bonded to the silicone polymer and / or the silicone resin.

[0217] According to certain other embodiments of the present invention, a silicone acrylic hybrid polymer comprises the reaction product of a silicone polymer, a silicone resin, and an acrylic polymer, wherein the silicone resin has triorganosiloxy units RSiO. 1 / 2 (R is an organic group), and tetrafunctional siloxy units SiO 4 / 2 Each SiO 4 / 2 RSiO of 0.1 to 0.9 1 / 2 The molar ratio of each component is expressed as:

[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 contains end-capped alkoxysilyl functional groups. The alkoxysilyl functional groups 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 that include polysiloxane-containing monomers, preferably mixtures that include polydimethylsiloxane mono(meth)acrylate.

[0220] The silyl-functional monomer is typically used in an amount of from 0.2 to 20 percent by weight of the acrylic polymer, and more preferably, the amount of silyl-functional monomer ranges from about 1.5 to about 5 percent by weight of the acrylic polymer.

[0221] The polysiloxane-containing monomer is typically used in an amount of from 1.5 to 50 percent by weight of the acrylic polymer, and more preferably, the amount of polysiloxane-containing monomer ranges from 5 to 15 percent by weight of the acrylic polymer.

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

[0223] The acrylic polymer includes an alkyl (meth)acrylate monomer. 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, isomers thereof, and combinations thereof. Butyl acrylate, 2-ethylhexyl acrylate, and isooctyl acrylate are particularly preferred. The acrylic polymer component can further include (meth)acrylate monomers having high Tg, 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] The acrylic polymer component may include nitrogen-containing polar monomers. Examples include N-vinylpyrrolidone, N-vinylcaprolactam, N-tertiary octylacrylamide, dimethylacrylamide, diacetone acrylamide, N-tertiary butylacrylamide, N-isopropylacrylamide, cyanoethyl acrylate, N-vinylacetamide, and N-vinylformamide.

[0226] The acrylic polymer component may include 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 include a carboxylic acid-containing monomer. Useful carboxylic acids preferably contain from about 3 to about 6 carbon atoms and include, among others, acrylic acid, methacrylic acid, itaconic acid, β-carboxyethyl acrylate, and the like. Acrylic acid is particularly preferred.

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

[0229] One acrylic polymer component that can be used in the practice of the present invention is an acrylic polymer that contains from about 90 to about 99.5 weight percent butyl acrylate and from about 0.5 to about 10 weight percent dimethoxymethylsilyl methacrylate.

[0230] According to certain embodiments 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 resultant product, and b) reacting the resultant product of a) with an acrylic polymer containing reactive functional groups, wherein these components are reacted in an organic solvent.

[0231] According to certain embodiments 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 resultant product, and b) reacting the resultant product of a) with a silicone polymer, where these components are reacted in an organic solvent.

[0232] According to certain embodiments 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 resultant product, and b) reacting the resultant product of a) with a silicone resin, wherein these components are reacted in an organic solvent.

[0233] Further suitable acrylic polymers, silicone resins and silicone polymers that can be used to chemically react together to provide a silicone acrylic hybrid polymer according to the previous paragraph are detailed in WO2010 / 124187.

[0234] Acrylic Polymers (Non-Hybrid) As indicated above, the TTS according to the present invention comprises 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 comprises an acrylic polymer in the guanfacine-containing layer.

[0235] As used herein, the terms acrylic polymer and acrylate polymer are used interchangeably. Preferably, the acrylic polymer is an acrylate-based pressure sensitive adhesive. The acrylate-based pressure sensitive adhesive may also be referred to as 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, preferably having a solids content of between 30% and 60%.

[0237] The acrylate-based pressure sensitive adhesives may or may not contain functional groups such as hydroxy groups, carboxylic acid groups, neutralized carboxylic acid groups, and mixtures thereof. Thus, the term "functional groups" refers specifically to hydroxy and carboxylic acid groups, as well as 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 (copolymers based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate, and glycidyl-methacrylate provided as a solution in ethyl acetate without a crosslinker), Duro-Tak™ 387-2516 or Duro-Tak™ 87-2516 (copolymers based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate provided as solutions in ethyl acetate, ethanol, n-heptane and methanol with a titanium crosslinker), Duro-Tak® 387-2051 or Duro-Tak® 87-2051 (copolymers based on acrylic acid, butyl acrylate, 2-ethylhexyl acrylate and vinyl acetate provided as a solution in ethyl acetate or heptane without a crosslinker), Duro-Tak® 387-2353 or Duro-Tak® 87-2353 (copolymers based on acrylic acid, 2-ethylhexyl acrylate, glycidyl methacrylate and methyl acrylate provided as a solution in ethyl acetate and hexane), Duro-Tak™ 87-4098™ (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 (copolymers based on acrylic acid, butyl acrylate, 2-ethylhexyl acrylate and vinyl acetate provided as a solution in ethyl acetate or heptane with a crosslinker).

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

[0241] Additional polymers may also be added to improve cohesion and / or adhesion.

[0242] Silicone-Based Polymers (Non-Hybrid) As indicated above, the TTS according to the present invention comprises 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 comprises at least one silicone-based polymer in the guanfacine-containing layer, preferably in 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 based on polysiloxane.Therefore, they can also be called polysiloxane-based polymers.Preferably, silicone-based polymers are silicone-based pressure-sensitive adhesives, i.e., polysiloxane-based pressure-sensitive adhesives.

[0244] Silicone-based polymers are preferably non-curable polymers and are therefore typically supplied and used in solvents such as n-heptane and ethyl acetate, with the solids content usually ranging from 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 provide suitable adhesion and fast bonding to various skin types, including wet skin, suitable adhesive and cohesive properties, long-lasting adhesion to skin, high flexibility, permeability to moisture, and compatibility with many actives 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 condensation reaction of silanol endblocked polydimethylsiloxane with silica resin (also called silicate resin) prepares a polysiloxane-based pressure-sensitive adhesive in which residual silanol functional groups are additionally capped with trimethylsiloxy groups for amine stability. The silanol endblocked polydimethylsiloxane content contributes to the viscous component of the viscoelastic behavior and influences the wetting and spreading properties of the adhesive. The resin acts as a tackifier and reinforcing agent and is responsible for the elastic component. The right balance between the silanol endblocked polydimethylsiloxane and the resin provides the right adhesion properties.

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

[0248] As indicated above, the adhesion of the silicone-based polymer may be modified by the resin-to-polymer ratio, i.e., the ratio of silanol endblocked polydimethylsiloxane to silicate resin, preferably in the range of 70:30 to 50:50, preferably 65:35 to 55:45. The adhesion increases with increasing amount of polydimethylsiloxane relative to resin. High adhesion silicone-based polymers preferably have a resin-to-polymer ratio of 55:45, medium adhesion silicone-based polymers preferably have a resin-to-polymer ratio of 60:40, and low adhesion silicone-based polymers preferably have a resin-to-polymer ratio of 65:35. High adhesion silicone-based polymers have a viscosity of about 5×10 at 0.01 rad / s and 30° C. 6 Preferably, the medium viscosity silicone-based polymer has a complex viscosity of about 5×10 at 0.01 rad / s and 30° C. 7 Preferably, the low tack silicone-based polymer has a complex viscosity of about 5×10 at 0.01 rad / s and 30° C. 8 The high adhesion amine compatible silicone based polymer has a complex viscosity of about 5×10 at 0.01 rad / s and 30° C. 6 Preferably, the medium tack amine compatible silicone based polymer has a complex viscosity of about 5×10 at 0.01 rad / s and 30° C. 8 Preferably, the low tack amine compatible silicone based polymer has a complex viscosity of about 5×10 at 0.01 rad / s and 30° C. 9 It is preferred that the complex viscosity be in 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 the amine-compatible (end-capped) BIO-PSA series (7-4100, 7-4200 and 7-4300 series) manufactured by DuPont™, which are 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 about 60% solids content in heptane, and a viscosity of 1×10 at 0.01 rad / s at 30° C. 8 It is characterized by a complex viscosity in poise. BIO-PSA 7-4301 has a solution viscosity of 500 mPa s at 25 °C and a solids content of about 60% in heptane, and a complex viscosity of 5 × 10 at 0.01 rad / s at 30 °C. 6 BIO-PSA 7-4202 has a solution viscosity of 800 mPa s at 25 °C and approximately 60% solids content in ethyl acetate, and a complex viscosity of 1 × 10 at 0.01 rad / s at 30 °C. 8 It is characterized by a complex viscosity in poise. BIO-PSA 7-4302 has a solution viscosity of 1200 mPa s at 25 °C and a solids content of about 60% in ethyl acetate, and a complex viscosity of 5 × 10 at 0.01 rad / s at 30 °C. 6 It has a complex viscosity in poise.

[0250] The polysiloxane-based pressure-sensitive adhesive is 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 usually 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, polysiloxane-based pressure sensitive adhesives available from DuPont™ may be obtained according to the following scheme: [ka] Such polysiloxane-based pressure-sensitive adhesives are available, for example, from DuPont under the trade names BIO-PSA 7-4401, BIO-PSA-7-4501 or BIO-PSA 7-4601 provided in n-heptane solvent (designated with the designation "01"), or BIO-PSA 7-4402, BIO-PSA 7-4502 and BIO 7-4602 provided in ethyl acetate solvent (designated with the designation "02"). Typical solids content in the solvent ranges from 60 to 75%. The designation "44" indicates a resin to polymer ratio of 65:35, resulting in low tack, the designation "45" indicates a resin to polymer ratio of 60:40, resulting in medium tack, and the designation "46" indicates a resin to polymer ratio of 55:45, resulting in high tack.

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

[0253] Preferred polysiloxane-based pressure sensitive adhesives according to the invention are characterized by a solution viscosity at 25° C. and 60% solids content in n-heptane, preferably greater than about 150 mPa·s, or from about 200 mPa·s to about 700 mPa·s, as measured using a Brookfield RVT viscometer at 50 rpm with spindle number 5. They also have a viscosity of about 1×10 at 0.01 rad / s at 30° C. 9 Less than poise, or about 1x10 5 ~ approx. 9x10 8 It may also be characterized by its complex viscosity in poise.

[0254] Polymer Mixture The TTS according to the 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 invention, the guanfacine-containing layer comprises at least one polymer, the at least one polymer being 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 polymers, or Acrylic polymers containing -OH groups It is.

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

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

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

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

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

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

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

[0265] Further Additives The TTS according to the present invention, particularly the layer containing guanfacine, may further comprise at least one additive or excipient.The particularly preferred additives according to the present invention include dispersing agents, permeation enhancers and solubilizers.Details on this point are provided above.However, the TTS according to the present invention, particularly the layer containing guanfacine, may further comprise additives or excipients.

[0266] In general, the additives or excipients are preferably selected from the group consisting of dispersants, solubilizers, permeation enhancers, film formers, emollients / plasticizers, tackifiers, skin care substances, pH adjusters, preservatives, stabilizers, and fillers. Such additives may be present in the guanfacine-containing layer in an amount of 0.001-15% by weight, for example 0.5-10% by weight or 1-10% by weight, or 0.01-6% by weight, based on the total weight of the guanfacine-containing layer, the amount of % by weight referring to a single additive.

[0267] It should be noted that in pharmaceutical formulations, formulation ingredients are classified according to their physicochemical and physiological properties and according to their functions. This means in particular that substances or compounds classified in one category of formulation ingredients are not excluded from classification in another category. For example, a certain polymer can be not only a film former but also a tackifier. Some substances can be, for example, a typical softener and at the same time act as a permeation enhancer. A person skilled in the art can determine, based on general knowledge, to which category(s) of formulation ingredients a certain substance or compound belongs. Below, details of excipients and additives are provided, but these should not be understood as being exclusive. Other substances not explicitly listed herein may be used according to the present invention as well, and substances and / or compounds explicitly listed as one category of formulation ingredients are not excluded from use as another formulation ingredient in the sense of the present invention.

[0268] In one embodiment, the guanfacine-containing layer comprises a dispersing agent as defined above, preferably a dispersing agent selected from the group consisting of esters of fatty acids and polyols, fatty alcohols, polyethylene glycols having a number average molecular weight of 300-400, and polyethylene glycol alkyl ethers. As explained above, the dispersing agent is preferably a polyethylene glycol C8-C10 alkyl ether having 2-10 EO units. 20 -alkyl ethers, in particular polyoxyethylene (4) lauryl ether. Alternatively or additionally, silicone polyethers may be used as dispersants. The dispersants help to disperse guanfacine evenly within the guanfacine-containing layer, in particular within the guanfacine-containing matrix layer, thereby improving the release characteristics of the TTS.

[0269] In one embodiment, the guanfacine-containing layer comprises a solubilizer. The solubilizer preferably improves the dispersibility of guanfacine in the guanfacine-containing layer and stabilizes the guanfacine-containing layer. In addition, the solubilizer may have a positive effect on the cohesion. Preferred solubilizers include, for example, glycerol esters, polyglycerol esters, propylene glycol esters, and polyoxyethylene esters of medium and / or long chain fatty acids, such as glyceryl monolinoleate, medium chain glycerides and medium chain triglycerides, non-ionic solubilizers made by reacting castor oil with ethylene oxide, and any mixtures thereof that may further contain fatty acids or fatty alcohols; cellulose and methylcellulose, and derivatives thereof, such as hydroxypropylcellulose and hypromellose acetate succinate; various cyclodextrins and their derivatives; non-ionic triblock copolymers with a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, known as poloxamers; water-soluble derivatives of vitamin E; pharmaceuticals such as glyceryl monolinoleate, medium chain glycerides and medium chain triglycerides; These include pharmaceutical grade or agglomerated spherical isomalt; polyester glycol, polyvinyl acetate, and polyvinyl caprolactam based 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, refined grades of polyethylene glycol 400, refined grades of polyoxyethylene sorbitan monooleate (such as Polysorbate 80), or refined grades of 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 may also act as solubilizers, and further, the film formers described below may simultaneously act as solubilizers and vice versa.

[0271] In one embodiment, the guanfacine-containing layer comprises a permeation enhancer. Options in this regard are provided above. Permeation enhancers are substances that affect the barrier properties of the stratum corneum in the sense of increasing the permeability of active agents. 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 dimethyldecylphosphoxide, methyl cetyl sulfoxide, dimethylaurylamine, dodecylpyrrolidone, isosorbitol, dimethylacetonide, dimethyl sulfoxide, decylmethyl sulfoxide, and dimethylformamide; salicylic acid; amino acids; benzyl nicotinate; and high molecular weight aliphatic surfactants such as lauryl sulfate. Other agents include oleic and linoleic acid, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, and isopropyl palmitate. If the guanfacine-containing layer includes a permeation enhancer, the permeation enhancer is preferably selected from the group consisting of diethylene glycol monoethyl ether (transcutol), oleic acid, levulinic acid, caprylic / capric triglyceride, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, triacetin, dimethylpropylene urea, oleyl alcohol, oleoyl macrogol-6 glycerides (labrafil MS 1944), and lauroglycol, preferably oleyl alcohol, lauroglycol, or oleoyl macrogol-6 glycerides (labrafil MS 1944).

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

[0273] If the layer containing guanfacine needs to have self-adhesive properties and one or more polymers are selected that do not / do not provide sufficient self-adhesive properties, tackifier is added.Preferred tackifiers include Miglyol, a liquid wax ester based on long-chain unsaturated even-numbered fatty acid and long-chain unsaturated even-numbered fatty alcohol of plant origin, and polyethylene glycol.In particular, tackifier may be selected from polyvinylpyrrolidone (which can maintain the adhesive properties of the matrix layer due to its ability to absorb water, and therefore can be considered as a tackifier in the broad sense), triglyceride, polyethylene glycol, dipropylene glycol, resin, resin ester, terpene and their derivatives, ethylene vinyl acetate adhesive, 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, dimethylpolysiloxanes, and polybutenes, and preferably polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone.

[0274] The term "soluble polyvinylpyrrolidone" refers to polyvinylpyrrolidone (also known as povidone) that is more than 10% soluble in at least ethanol, and preferably also 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. Commercially available examples of polyvinylpyrrolidone include Kollidon® 12PF, Kollidon® 17PF, Kollidon® 25, Kollidon® 30 and Kollidon® 90F, or Povidone K90F, supplied by BASF. Different grades of Kollidon® are defined in terms of K values, which reflect the average molecular weight of the polyvinylpyrrolidone grade. Kollidon® 12PF is characterized by a K-value range of 10.2-13.8, which corresponds to a nominal K-value of 12. Kollidon® 17PF is characterized by a K-value range of 15.3-18.4, which corresponds to a nominal K-value of 17. Kollidon® 25 is characterized by a K-value range of 22.5-27.0, which corresponds to a nominal K-value of 25, and Kollidon® 30 is characterized by a K-value range of 27.0-32.4, which corresponds to a nominal K-value of 30. Kollidon® 90F is characterized by a K-value range of 81.0-97.2, which corresponds to a nominal K-value of 90. Preferred Kollidon® grades are Kollidon® 12PF, Kollidon® 30, and Kollidon® 90F. Within the meaning of the present invention, the term "K value" refers to the 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 softener / plasticizer. Exemplary softeners / plasticizers include linear or branched, saturated or unsaturated alcohols having 6 to 20 carbon atoms, triglycerides, and polyethylene glycols.

[0276] In one embodiment, the guanfacine-containing layer further comprises a stabilizer, which includes tocopherol and its ester derivatives, ascorbic acid and its ester derivatives. Additional 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 adjusting agent. Suitable pH adjusting agents include amine derivatives, inorganic alkali derivatives, and weak acids and bases, including polymers with basic or acidic functional groups.

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

[0279] In one embodiment, the guanfacine-containing layer further comprises a skin care substance. Such substances may be used to avoid or reduce skin irritation detectable by skin response scores. Suitable skin care substances include sterol compounds such as cholesterol, dexpanthenol, alpha-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 conjunction with the polymer to affect certain physical parameters, such as cohesiveness and bond strength, in a desired manner.

[0281] Emission Characteristics The TTS according to the present invention is designed to administer guanfacine transdermally to the systemic circulation for a predetermined extended period of time, preferably at least 24 hours, more preferably at least 72 hours, especially about 84 hours.

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

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

[0284] In one embodiment, the TTS according to the present invention has an AUC of 10 to 600 ng*h / ml, preferably 20 to 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 values ​​preferably refer to the AUC values ​​obtained at steady state.

[0285] In one embodiment, the TTS according to the present invention has a C of less than 3.5. max Against C 84 In another embodiment, the TTS according to the present invention has a C ratio of less than 3.0. max Against C 72 In another embodiment, the TTS according to the present invention has a C ratio of less than 2.0. max Against C 24 These ratios are indicative of a flat plasma curve, which is advantageous in terms of the ongoing treatment of the patient.

[0286] In one embodiment, the TTS according to the present invention provides the following skin permeation rate of guanfacine as measured in Franz diffusion cells using excised human skin: 0.01μg / (cm in the first 24 hours 2 *h)~8μg / (cm 2 *h), From 24 hours to 88 hours, 0.05 μg / (cm 2 *h)~10μg / (cm 2 *h). In another embodiment, the TTS according to the present invention provides the following skin permeation rate of guanfacine as measured in Franz diffusion cells using excised human skin: 0.01μg / (cm in the first 24 hours 2 *h)~8μg / (cm 2 *h), From 24 hours to 88 hours, 0.05 μg / (cm 2 *h)~8μg / (cm 2 *h).

[0287] In one embodiment, the TTS according to the present invention has a TTS concentration of 0.01 μg / (cm) in the first 24 hours as measured in Franz diffusion cells using harvested Gottinger minipig skin. 2 *h)~8μg / (cm 2 *h), and 0.05 μg / (cm) from 24 hours to 88 hours 2 *h)~10μg / (cm 2 *h) The following skin permeation rates of guanfacine are provided.

[0288] In another embodiment, the TTS according to the present invention has a concentration of 0.01 mg / cm over an 88 hour period as measured in a Franz diffusion cell using harvested Gottinger minipig skin. 2 ~0.7mg / cm 2 , preferably 0.05 mg / cm 2 ~0.6mg / cm 2 , more preferably 0.10 mg / cm 2 ~0.5mg / cm 2 The cumulative permeation amount of guanfacine is provided.

[0289] In view of the above, the present invention also relates in one aspect to a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the transdermal therapeutic system providing, upon transdermal delivery, one or more pharmacokinetic parameter(s) 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 below 2.0 max Against C 24 ratio, C below 3.0 max Against C 72 Ratio, and C below 3.5 max Against 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, upon transdermal delivery, one or more pharmacokinetic parameter(s) 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 below 1.5 max Against C 24 ratio, C below 2.5 max Against C 72 Ratio, and C below 3.0 max Against 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, the transdermal therapeutic system providing an AUC of 70 to 1400 (ng / ml)h by transdermal delivery. 0-84 to provide.

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

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

[0294] In one embodiment, the present invention relates to a method for treating a human patient, preferably a human patient aged between 6 and 17 years, by applying a transdermal therapeutic system as 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 a human patient, preferably a human patient aged between 6 and 17 years, by applying a transdermal therapeutic system according to the present invention to the patient's skin.

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

[0296] In view of the above, the present invention relates in one aspect to a transdermal therapeutic system comprising guanfacine and a monocarboxylic acid for use in a method for treating a human patient, preferably a human patient aged 6-17 years, by transdermal administration of guanfacine, the transdermal therapeutic system being applied to the patient's skin for at least 24 hours, preferably at least 72 hours, more preferably about 84 hours. In a preferred embodiment, the transdermal therapeutic system is for use in a method for treating hypertension or attention deficit hyperactivity disorder (ADHD) and / or for use as an adjunct therapy to stimulant medication in a human patient. In a more preferred embodiment, the transdermal therapeutic system is a transdermal therapeutic system according to the invention, in particular a transdermal therapeutic system providing 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 below 2.0 max Against C 24 ratio, C below 3.0 max Against C 72 Ratio, and C below 3.5 max Against C 84 ratio. More preferably, it is 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 below 1.5 max Against C 24 ratio, C below 2.5 max Against C 72 Ratio, and C below 3.0 max Against C 84 ratio.

[0297] In connection with the above uses and methods of treatment, the TTS according to the invention is preferably applied to at least one body surface of the subject selected from the outer upper arm, the upper chest, the upper back, or the side of the chest at defined dosing intervals.

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

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

[0300] According to the invention, a method for producing an active agent-containing layer for use in a transdermal therapeutic system according to the invention comprises the steps of: 1) At least one ingredient (i) a pharma- ceutical active agent; and (ii) at least one monocarboxylic acid; to obtain a premix; 2) (i) the premix of step 1); (ii) at least one polymer; to obtain a coating composition; 3) coating the coating composition onto a backing layer or release liner to obtain a coated coating composition; 4) drying the coated coating composition to form the active agent-containing layer; Includes.

[0301] In one embodiment of the present invention, the premix according to step 1) of the process is obtained by combining (i) and (ii) by dry grinding and / or slurrying.

[0302] In one embodiment of the invention, the slurry process of the above method comprises: weighing out equimolar amounts of a pharma- ceutical active agent (i) and a monocarboxylic acid (ii); adding a solvent selected from the group consisting of dichloromethane, methanol and ethyl acetate; stirring the resulting mixture with a magnetic stirrer for at least 24 hours, preferably 24 to 36 hours; Includes.

[0303] Thus, the slurry process of step 1) of the process comprises 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 pharma- ceutical active agent and monocarboxylic acid in the slurry method of step 1), the solvent is removed from the above obtained mixture under reduced pressure and the residue is dried under vacuum for at least 24 hours.

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

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

[0307] Preferably, a solvent is added in step 2) of the method and / or a solvent is present because the polymer or polymers are provided in the form of a solution. The solvent is preferably selected from alcoholic solvents, in particular methanol, ethanol, isopropanol, and mixtures thereof, and non-alcoholic solvents, in particular 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 polymer as defined above, in particular a mixture of polymers as defined above, is provided as a solution, the solvent being ethyl acetate or n-heptane, preferably ethyl acetate.

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

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

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

[0312] In step 4) of the above production 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 method of manufacture defined in the above embodiment, the pharma- ceutical active agent (i) in the active agent-containing layer is guanfacine.

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

[0315] In relation to the above embodiment of the method of manufacture, it should be understood that the at least one polymer, the further additives, and the active agent-containing layer, preferably the guanfacine-containing layer, are as defined above with respect to the TTS. EXAMPLES

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

[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 1D are summarized in Tables 1.1 and 1.2 below. The % solids values ​​refer to the amount in % by weight (Amt).

[0318] [Table 1]

[0319] [Table 2]

[0320] Preparation of the Coating Composition The drug substance (sorbic acid, if present) and any accelerators 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 reverse order. The mixture was homogenized with a dissolver stirrer at 2000 rpm for 10 minutes.

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

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

[0323] Coating of the coating composition Considering the desired coating dry weight, according to the solids content of the mixture, the resulting guanfacine-containing coating composition is coated onto a polyethylene terephthalate film (Scotchpak 9755, which can serve as a release liner) using, for example, an Erichsen film applicator and dried for about 10 minutes at about 50° C. Depending on the target area weight, the corresponding film applicator gap will be between 325-350 μm.

[0324] By selecting the coating thickness, the areal weight of the guanfacine-containing layer upon removal of the solution was about 95 (Comparative Example 1A) g / m 2 , 96 (Comparative Example 1B) g / m 2 , 95 (Comparative Example 1C) g / m 2 , and 89 (Comparative Example 1D) g / m 2The dried film was then 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) Individual systems (TTS) were then punched out from the guanfacine-containing self-adhesive layer structure obtained as described above. The TTS were then sealed in pouches of the primary packaging material.

[0326] Measurement of skin permeability The permeation amount of the TTS prepared according to Comparative Examples 1A-D was measured according to the OECD guidelines (adopted on April 13, 2004) carried out using 7.0 mL Franz diffusion cells. Split-thickness Gottinger mini pig skin (female) was used. A dermatome was used to prepare skin with intact epidermis for all TTS at a thickness of 800 μm. 2 Die cuts with a release area of ​​were punched out of the TTS. The amount of guanfacine permeation in the receptor medium (0.9% sodium chloride solution containing 0.1% sodium azide as antimicrobial agent) in Franz diffusion cells at a temperature of 32±1°C was measured, and the corresponding cumulative amount of permeation was calculated.

[0327] The results are shown in Tables 1.3 and 1.4, and 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 below in Tables 1.4, 1.5 and 1.6. The % solids values ​​refer to the amount in % by weight (Amt).

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

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

[0333] [Table 7]

[0334] Preparation of the Coating Composition A premix of guanfacine base, sorbic acid and methanol was prepared. The premix was prepared according to the dry milling method by milling a mixture of guanfacine base, sorbic acid and methanol as a catalyst with zirconium oxide milling beads (bead size 3 mm, in a Retsch mixer mill MM500) at 35 Hz for about 10 minutes. Guanfacine base and sorbic acid were present in a 1:1 ratio. To prepare the coating composition, the premix and the accelerator used were dispersed in ethyl acetate solvent and 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 with a dissolver stirrer at 2000 rpm for 10 minutes.

[0335] Coating of the coating composition Considering the desired coating dry weight, according to the solids content of the mixture, the resulting guanfacine-containing coating composition is coated onto a polyethylene terephthalate film (Scotchpak 9755, which can serve as a release liner) using, for example, an Erichsen film applicator and dried for about 10 minutes at about 50° C. Depending on the target area weight, the corresponding film applicator gap will be between 300-400 μm.

[0336] By selecting the coating thickness, the areal weight of the guanfacine-containing layer upon removal of the solution is about 100 (Example 1A) g / m 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 The dried film was then 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-1D.

[0338] Measurement of skin permeability The permeation amount of the TTS prepared according to Examples 1A-E was measured according to the OECD guidelines (adopted on April 13, 2004) carried out using 7.0 mL Franz diffusion cells. Split-thickness Gottinger mini pig skin (female) was used. A dermatome was used to prepare skin with intact epidermis for all TTS at a thickness of 800 μm. 2 Die cuts with a release area of ​​were punched out of the TTS. The amount of guanfacine permeation in the receptor medium (0.9% sodium chloride solution containing 0.1% sodium azide as antimicrobial agent) in Franz diffusion cells at a temperature of 32±1°C was measured, and the corresponding cumulative amount of permeation 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 and 2B Coating Composition The formulations of the guanfacine-containing coating compositions of 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 values ​​refer to the amount in % by weight (Amt).

[0343] [Table 10]

[0344] [Table 11]

[0345] [Table 12]

[0346] Preparation of the Coating Composition The guanfacine / sorbic acid premix was prepared according to the slurry method, i.e., according to the following outline procedure. Guanfacine free base and sorbic acid were weighed in equimolar amounts. A solvent, e.g., 1 mL of DCM, was added and the mixture was stirred at room temperature with a magnetic stir bar for at least 1 day. 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 the case of Comparative Example 2, no premix was prepared, but guanfacine was used in the form of the free base.

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

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

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

[0350] The coating thickness was selected to give a guanfacine-containing layer with an areal weight of about 137 (Example 2A) g / m2 upon solution removal. 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 / m 2 The dried film was then 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-1D.

[0352] Measurement of skin permeability The permeation amount of the TTS prepared according to Examples 2A-C and Comparative Examples 2A and 2B was measured according to the OECD guidelines (adopted on April 13, 2004) carried out using 7.0 mL Franz diffusion cells. Split-thickness Gottinger mini pig skin (female) was used. A dermatome was used to prepare skin with intact epidermis for all TTS at a thickness of 800 μm. 2 Die cuts with a release area of ​​were punched out of the TTS. The amount of guanfacine permeation in the receptor medium (0.9% sodium chloride solution containing 0.1% sodium azide as antimicrobial agent) in Franz diffusion cells at a temperature of 32±1°C was measured, and the corresponding cumulative amount of permeation 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, and Comparative Example 3 are summarized in Tables 3.1, 3.2, 3.3 and 3.4 below. The % solids values ​​refer to the amount in % by weight (Amt).

[0357] [Table 15]

[0358] [Table 16]

[0359] [Table 17]

[0360] [Table 18]

[0361] Preparation of the Coating Composition The guanfacine / sorbic acid premix was prepared according to the slurry method, i.e., according to the following outline procedure. Guanfacine free base and sorbic acid were weighed in equimolar amounts. A solvent, e.g., 1 mL of DCM, was added and the mixture was stirred at room temperature with a magnetic stir bar for at least 1 day. 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 the case of Comparative Example 3, no premix was prepared, but guanfacine was used in the form of the free base.

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

[0363] Coating of the coating composition Considering the desired coating dry weight, according to the solids content of the mixture, the resulting guanfacine-containing coating composition is coated onto a polyethylene terephthalate film (Scotchpak 9755, which can serve as a release liner) using, for example, an Erichsen film applicator and dried for about 10 minutes at about 50° C. Depending on the target area weight, the corresponding film applicator gap will be between 300-400 μm.

[0364] The coating thickness was selected to give an areal weight of the guanfacine-containing layer upon solution removal of about 114 (Example 3A) g / m 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 The dried film was then laminated with a backing layer (MN19SIL or PET 15 μm) to provide a guanfacine-containing self-adhesive layer structure.

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

[0366] Measurement of skin permeability The permeation amount of the TTS prepared according to Examples 3A-E and Comparative Example 3 was measured according to the OECD guidelines (adopted on April 13, 2004) carried out using 7.0 mL Franz diffusion cells. Split-thickness Gottinger miniature pig skin (female) was used. A dermatome was used to prepare skin with intact epidermis for all TTS at a thickness of 800 μm. 2 Die cuts with a release area of ​​were punched out of the TTS. The amount of guanfacine permeation in the receptor medium (0.9% sodium chloride solution containing 0.1% sodium azide as antimicrobial agent) in Franz diffusion cells at a temperature of 32±1°C was measured, and the corresponding cumulative amount of permeation 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 values ​​refer to the amount in % by weight (Amt).

[0371] [Table 21]

[0372] [Table 22]

[0373] [Table 23]

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

[0375] To prepare the coating compositions, the guanfacine / sorbic acid premix or guanfacine free base, the accelerator used, and the adhesive were dispersed in ethyl acetate solvent and the mixture was homogenized with a dissolver stirrer at 2000 rpm for about 10 minutes. The adhesives SilAc6102 and SilAc6302, when used together, were mixed together and stirred at 2000 rpm for about 10 minutes until homogenized before mixing with the guanfacine / sorbic acid premix.

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

[0377] Coating of the coating composition Considering the desired coating dry weight, according to the solids content of the mixture, the resulting guanfacine-containing coating composition is coated onto a polyethylene terephthalate film (Scotchpak 9755, which can serve as a release liner) using, for example, an Erichsen film applicator and dried for about 10 minutes at about 50° C. Depending on the target area weight, the corresponding film applicator gap will be between 325-350 μm.

[0378] By selecting the coating thickness, the areal weight of the guanfacine-containing layer upon solution removal was approximately 103 (Example 4A) g / m 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 The dried film was then 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-1D.

[0380] Measurement of skin permeability The permeation amount of the TTS prepared according to Examples 4A-D and Comparative Example 4 was measured according to the OECD guidelines (adopted on April 13, 2004) carried out using 7.0 mL Franz diffusion cells. Split-thickness Gottinger miniature pig skin (female) was used. A dermatome was used to prepare skin with intact epidermis for all TTS at a thickness of 800 μm. 2 Die cuts with a release area of ​​were punched out of the TTS. The amount of guanfacine permeation in the receptor medium (0.9% sodium chloride solution containing 0.1% sodium azide as antimicrobial agent) in Franz diffusion cells at a temperature of 32±1°C was measured, and the corresponding cumulative amount of permeation was calculated.

[0381] The results are shown in Tables 4.3 and 4.4 and 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 below in Tables 5.1, 5.2, 5.3 and 5.4. The % solids values ​​refer to the amount in % by weight (Amt).

[0385] [Table 26]

[0386] [Table 27]

[0387] [Table 28]

[0388] [Table 29]

[0389] Preparation of the Coating Composition A premix of guanfacine base and pimelic acid was prepared. The premix was prepared according to the milling method by milling the mixture of guanfacine base and pimelic acid with zirconium oxide milling beads (bead size 3 mm, in a Retsch mixer mill MM500) at 35 Hz for about 10 minutes. The guanfacine base and pimelic acid were present in a 1:1 ratio. To prepare the coating composition, the premix and the accelerator used were dispersed in ethyl acetate solvent and 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 with a dissolver stirrer at 2000 rpm for 10 minutes. For Comparative Example 5F, a premix 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 the coating composition Considering the desired coating dry weight, according to the solids content of the mixture, the resulting guanfacine-containing coating composition was coated onto a polyethylene terephthalate film (Scotchpak 9755, which can serve as a release liner) using, for example, an Erichsen film applicator and dried for about 10 minutes at about 50° C. Depending on the target area weight, the corresponding film applicator gap will be between 300 and 525 μm.

[0391] By selecting the coating thickness, the areal weight of the guanfacine-containing layer upon removal of the solution was about 90 (Comparative Example 5A) g / m 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 The dried film was then 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-1D.

[0393] Measurement of skin permeability The permeation amount of the TTS prepared according to Comparative Examples 5A-F was measured according to the OECD guidelines (adopted on April 13, 2004) carried out using 7.0 mL Franz diffusion cells. Split-thickness Gottinger miniature pig skin (female) was used. A dermatome was used to prepare skin with intact epidermis for all TTS at a thickness of 800 μm. 2 Die cuts with a release area of ​​were punched out of the TTS. The amount of guanfacine permeation in the receptor medium (0.9% sodium chloride solution containing 0.1% sodium azide as antimicrobial agent) in Franz diffusion cells at a temperature of 32±1°C was measured, and the corresponding cumulative amount of permeation was calculated.

[0394] The results are shown in Tables 5.5 and 5.6, and 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 and Comparative Example 6 are summarized in Table 6.1 below. The % solids values ​​refer to the amount in % by weight (Amt).

[0398] [Table 32]

[0399] Preparation of the Coating Composition The guanfacine / sorbic acid premix of Example 6 and the guanfacine / glutaric acid premix of Comparative Example 6 were prepared according to the slurry method, i.e., according to the following general procedure. Guanfacine free base and each acid were weighed in equimolar amounts. A solvent, such as 1 mL of DCM or 2 mL of ethyl acetate, was added and the mixture was stirred at room temperature using a magnetic stir bar for at least 1 day. 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 compositions, the guanfacine / sorbic acid premix or guanfacine / glutaric acid premix, the accelerator used, and the adhesive were dispersed in ethyl acetate solvent and the mixture was homogenized using a dissolver stirrer at 1400 rpm for approximately 15 minutes.

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

[0402] By selecting the coating thickness, the areal weight of the guanfacine-containing layer upon removal of the solution was about 89 (Example 6) g / m 2 and 94 (Comparative Example 6) g / m 2 The dried film was then 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-1D.

[0404] Measurement of skin permeability The permeation amount of the TTS prepared according to Example 6 and Comparative Example 6 was measured according to the OECD guidelines (adopted on April 13, 2004) carried out using a 7.0 mL Franz diffusion cell. Split-thickness Gottinger mini pig skin was used. A dermatome was used to prepare skin with intact epidermis for all TTS at a thickness of 800 μm. 2 Die cuts with a release area of ​​were punched out of the TTS. The amount of guanfacine permeation in the receptor medium (0.9% sodium chloride solution containing 0.1% sodium azide as antimicrobial agent) in Franz diffusion cells at a temperature of 32±1°C was measured, and the corresponding cumulative amount of permeation was calculated.

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

[0406] [Table 33]

[0407] The 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, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer comprising guanfacine and a monocarboxylic acid; The transdermal therapeutic system comprising:

[0408] 2. The guanfacine-containing layer comprises: i) guanfacine and a monocarboxylic acid; ii) at least one polymer; and 2. The transdermal therapeutic system of claim 1, wherein the guanfacine-containing matrix layer comprises:

[0409] 3. 3. The transdermal therapeutic system of claim 1 or 2, wherein the monocarboxylic acid is sorbic acid.

[0410] 4. 4. The transdermal therapeutic system according to any one of 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. 5. The transdermal therapeutic system of any one of 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 polymers, or Acrylic polymers containing -OH groups The transdermal therapeutic system according to any one of clauses 1 to 5,

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

[0414] 8. The transdermal therapeutic 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, the silicone acrylic hybrid pressure sensitive adhesive comprising: (a) a silicone-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups; (b) an ethylenically unsaturated monomer; (c) an initiator; and The transdermal therapeutic system according to any one of clauses 5 to 8, comprising a reaction product of:

[0416] 10. The silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups is (a1) a silicone resin; (a2) a silicone polymer; (a3) a silicon-containing sealant containing acrylate or methacrylate functionality; and and the silicon-containing sealant 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 or 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 a halogen, and b is 0 or 1; the silicone resin and the silicone polymer are reacted to form a pressure sensitive adhesive, and the silicon-containing sealant is introduced prior to, during, or after reacting the silicone resin and the silicone polymer; The transdermal therapeutic system of clause 9, wherein the silicon-containing sealant reacts with the pressure-sensitive adhesive after the silicone resin and the silicone polymer condense to form the pressure-sensitive adhesive, or the silicon-containing sealant reacts in situ with the silicone resin and the silicone polymer.

[0417] 11. The transdermal therapeutic system according to any one of clauses 9 or 10, wherein the ethylenically unsaturated monomer is selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates, cycloaliphatic methacrylates, and combinations thereof, each of said 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 containing acrylate or methacrylate functional groups; and (b2) the ethylenically unsaturated monomer; (b3) the initiator; and 12. The transdermal therapeutic system of any one of claims 9 to 11, wherein the reaction product contains a continuous acrylic external phase and a discontinuous silicone internal phase.

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

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

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

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

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

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

[0425] 19. 18. The transdermal therapeutic system according to any one of clauses 1 to 17, wherein the guanfacine-containing layer comprises a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60 to 90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1 to 20% by weight, in each case based on the total weight of the guanfacine-containing layer, 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.

[0426] 20. 18. The transdermal therapeutic system of any one of clauses 1 to 17, wherein the guanfacine-containing layer comprises a mixture of two silicone-based polymers, the first silicone-based polymer being present in an amount of 20-55% by weight and the second silicone-based polymer being present in an amount of 20-55% by weight, based on the total weight of the guanfacine-containing layer.

[0427] twenty one. 21. The transdermal therapeutic system according to any one of 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 dispersing agents, 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 glycols having a number average molecular weight of 300 to 400, and polyethylene glycol alkyl ethers. The dispersant is preferably a polyethylene glycol C8-C10 having 2 to 10 EO units. 20 - alkyl ether,

[0429] twenty three. 23. The transdermal therapeutic system according to clause 21 or 22, wherein said permeation enhancer is selected from the group consisting of diethylene glycol monoethyl ether (Transcutol), oleic acid, levulinic acid, caprylic / capric triglyceride, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, triacetin, dimethylpropylene urea, oleyl alcohol, oleoyl macrogol-6 glycerides (labrafil MS 1944), lauroglycol, said permeation enhancer being preferably oleyl alcohol, lauroglycol, or oleoyl macrogol-6 glycerides (labrafil MS 1944).

[0430] twenty four. 24. The transdermal therapeutic system according to any one of clauses 21 to 23, wherein the solubilizer is selected from the group consisting of copolymers derived from esters of acrylic and methacrylic acid, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer and polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, preferably polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer.

[0431] twenty five. 25. The transdermal therapeutic system according to any one of clauses 21 to 24, wherein the guanfacine-containing layer comprises two additives selected from a dispersing agent and a permeation enhancer.

[0432] 26. The area weight of the guanfacine-containing layer is 40 to 250 g / m 2 , preferably 50 to 180 g / m 2 and / or the emission area is in the range of 1 to 100 cm 2 , preferably 2.5 to 50 cm 2 The transdermal therapeutic system according to any one of clauses 1 to 25, wherein the range is

[0433] 27. The guanfacine loading of the transdermal therapeutic system is 0.4-2 mg / cm 2 , preferably 0.4 to 0.85 mg / cm 2 The transdermal therapeutic system according to any one of clauses 1 to 26, wherein the range is

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

[0435] 29. AUC of about 10 to 600 ng*h / ml, preferably about 20 to 400 ng*h / ml 0-24hand / 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 C of less than 3.5 max C 84 and / or has a C ratio of less than 3.0 max C 72 and / or has a C ratio of less than 2.0 max C 24 29. The transdermal therapeutic system according to any one of clauses 1 to 28, having a ratio of:

[0436] 30. Franz diffusion cell measurements using explanted minipig skin showed a mean concentration of 0.01 μg / (cm) in the first 24 hours. 2 *h)~8μg / (cm 2 *h), and 0.05 μg / (cm) from 24 hours to 88 hours 2 *h)~10μg / (cm 2 *h) A transdermal therapeutic system according to any one of clauses 1 to 29, providing a skin permeability rate of guanfacine of the following:

[0437] 31. 0.01 mg / cm over an 88 hour period as measured in Franz diffusion cells using explanted minipig skin 2 ~0.7mg / cm 2 , preferably 0.05 mg / cm 2 ~0.6mg / cm 2 , more preferably 0.10 mg / cm 2 ~0.5mg / cm 2 31. The transdermal therapeutic system according to any one of clauses 1 to 30, providing a cumulative permeation amount of guanfacine of.

[0438] 32. 32. The transdermal therapeutic system according to any one of clauses 1 to 31 for use in a method for treating a human patient, preferably a human patient aged between 6 and 17 years.

[0439] 33. 32. A transdermal therapeutic system according to any one of clauses 1 to 31 for use in a method for treating hypertension or attention deficit hyperactivity disorder (ADHD) and / or for use as an adjunct therapy to stimulant medication in a human patient, preferably a human patient aged between 6 and 17 years.

[0440] 34. A transdermal therapeutic system for use according to clause 32 or 33, wherein the transdermal therapeutic system is applied to the skin of the patient for at least 24 hours, preferably at least 72 hours, more preferably about 84 hours.

[0441] 35. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of an acrylic polymer and at least one silicone-based polymer, the acrylic polymer being present in an amount of 20-55% by weight and the at least one silicone-based polymer being present in an amount of 20-55% by weight, based on the total weight of the guanfacine-containing layer; iii) at least one dispersing agent in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) at least one permeation enhancer in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

[0442] 36. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case based on the total weight of the guanfacine-containing layer; iii) at least one dispersing agent in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) at least one permeation enhancer in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

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

[0444] 38. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) an acrylic polymer in an amount of 65 to 95% by weight based on the total weight of the guanfacine-containing layer; iii) at least one dispersing agent in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) at least one permeation enhancer in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

[0445] 39. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) an acrylic polymer containing -OH groups in an amount of 65 to 95% by weight based on the total weight of the guanfacine-containing layer; iii) at least one dispersing agent in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) at least one permeation enhancer in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

[0446] 40. 36. The transdermal therapeutic system according to claim 35, comprising a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of an acrylic polymer and at least one silicone-based polymer, the acrylic polymer being present in an amount of 20-55% by weight and the at least one silicone-based polymer being present in an amount of 20-55% by weight, based on the total weight of the guanfacine-containing layer; iii) polyethylene glycol C8-C10 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, iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

[0447] 41. 37. The transdermal therapeutic system according to claim 36, comprising a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case based on the total weight of the guanfacine-containing layer; iii) polyethylene glycol C8-C10 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, iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

[0448] 42. 38. The transdermal therapeutic system according to claim 37, comprising a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-based polymers, the first silicone-based polymer being present in an amount of 20-55% by weight and the second silicone-based polymer being present in an amount of 20-55% by weight, based on the total weight of the guanfacine-containing layer; iii) polyethylene glycol C8-C10 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, iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

[0449] 43. 39. The transdermal therapeutic system according to claim 38, comprising a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) an acrylic polymer in an amount of 65 to 95% by weight based on the total weight of the guanfacine-containing layer; iii) polyethylene glycol C8-C10 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, iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

[0450] 44. 40. The transdermal therapeutic system according to claim 39, comprising a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine in an amount of 3 to 16% by weight and sorbic acid in an amount of 1 to 7.2% by weight based on the total weight of the guanfacine-containing layer; ii) an acrylic polymer containing -OH groups in an amount of 65 to 95% by weight based on the weight of the guanfacine-containing layer; iii) polyethylene glycol C8-C10 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, iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

[0451] 45. 1. A method for producing an active agent-containing layer for use in a transdermal therapeutic system, comprising: 1) At least one ingredient (i) a pharma- ceutical active agent; and (ii) at least one monocarboxylic acid; to obtain a premix; 2) (i) the premix of step 1); (ii) at least one polymer; to obtain a coating composition; 3) coating the coating composition onto a backing layer or release liner to obtain a coated coating composition; 4) drying the coated coating composition to form the active agent-containing layer; The method comprising:

[0452] 46. 46. ​​The process according to clause 45, wherein the pre-mixture according to process step 1) is obtained by combining (i) and (ii) by a dry grinding process and / or a slurry process.

[0453] 47. 47. The method of claim 45 or 46, wherein the slurry process comprises 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. 48. The method according to any one of clauses 45 to 47, wherein said slurry method further comprises a step of stirring the solution obtained in step 1) for 24 to 36 hours.

[0455] 49. The method of claim 48, wherein the solution is preferably stirred for 24 hours.

[0456] 50. The active agent-containing layer comprises: i) a pharma- ceutical active agent and a monocarboxylic acid; ii) at least one polymer; and 50. The method according to any one of clauses 45 to 49, wherein the active agent-containing matrix layer comprises

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

[0458] 52. 52. The method of any one of clauses 45 to 51, wherein the pharma- ceutical active agent is guanfacine.

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

[0460] 54. 54. The method of any one of clauses 45-53, 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 polymers, or Acrylic polymers containing -OH groups 55. The method according to any one of clauses 45 to 54, wherein

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

[0463] 57. 57. The method according to any one of clauses 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, the silicone acrylic hybrid pressure sensitive adhesive comprising: (a) a silicone-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups; (b) an ethylenically unsaturated monomer; (c) an initiator; and 58. The method of any one of clauses 45 to 57, comprising the reaction product of

[0465] 59. The silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups is (a1) a silicone resin; (a2) a silicone polymer; (a3) a silicon-containing sealant containing acrylate or methacrylate functionality; and and the silicon-containing sealant 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 or 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 a halogen, and b is 0 or 1; the silicone resin and the silicone polymer are reacted to form a pressure sensitive adhesive, and the silicon-containing sealant is introduced prior to, during, or after reacting the silicone resin and the silicone polymer; 59. The method of claim 58, wherein the silicon containing sealant reacts with the pressure sensitive adhesive after the silicone resin and the silicone polymer condense to form the pressure sensitive adhesive or the silicon containing sealant reacts in situ with the silicone resin and the silicone polymer.

[0466] 60. 60. The method of claim 58 or 59, wherein the ethylenically unsaturated monomer is selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates, cycloaliphatic methacrylates, and combinations thereof, each of said 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 containing acrylate or methacrylate functional groups; and (b2) the ethylenically unsaturated monomer; (b3) the initiator; and 61. The method of any one of clauses 58-60, wherein the reaction product contains a continuous acrylic external phase and a discontinuous silicone internal phase.

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

[0469] 63. 63. The method according to any one of clauses 45-62, wherein the active drug containing layer comprises the pharma- ceutical active agent in an amount of 1-20 wt%, more preferably in an amount of 3-16 wt%, based on the total weight of the active drug containing layer.

[0470] 64. 64. The method according to any one of clauses 45 to 63, comprising equimolar amounts of said pharma- ceutical active agent and said monocarboxylic acid.

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

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

[0473] 67. 66. The method according to any one of clauses 45 to 65, wherein the active agent containing layer comprises a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60 to 90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1 to 20% by weight, in each case based on the total weight of the active agent containing layer, 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. 66. The method of any one of clauses 45-65, wherein the active agent-containing layer comprises a mixture of two silicone-based polymers, the first silicone-based polymer being present in an amount of 20-55% by weight and the second silicone-based polymer being present in an amount of 20-55% by weight, based on the total weight of the active agent-containing layer.

[0475] 69. 69. The method of any one of clauses 45-68, wherein said active drug containing layer further comprises at least one additive, preferably at least two additives selected from the group consisting of dispersing agents, permeation enhancers and solubilizers.

[0476] 70. The dispersant is selected from the group consisting of esters of fatty acids and polyols, aliphatic alcohols, polyethylene glycols having a number average molecular weight of 300 to 400, and polyethylene glycol alkyl ethers. The dispersant is preferably a polyethylene glycol C8-C10 having 2 to 10 EO units. 20 70. The method according to claim 69, wherein said alkyl ether is an alkyl ether.

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

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

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

[0480] 74. A transdermal therapeutic system obtainable by the method according to any one of clauses 45 to 73.

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

[0482] 76. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) 6-9% by weight of guanfacine and sorbic acid based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case based on the total weight of the guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

[0483] 77. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) 6-9% by weight of guanfacine and sorbic acid based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case based on the total weight of the guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) lauroglycol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

[0484] 78. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) 6-9% by weight of guanfacine and sorbic acid based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case based on the total weight of the guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) oleoyl macrogol-6 glyceride in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

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

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

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

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

[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, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer comprising guanfacine and a monocarboxylic acid; The transdermal therapeutic system comprising:

[0490] 2. The guanfacine-containing layer comprises: i) guanfacine and a monocarboxylic acid; ii) at least one polymer; and 2. The transdermal therapeutic system of claim 1, wherein the guanfacine-containing matrix layer comprises:

[0491] 3. 3. The transdermal therapeutic system of claim 1 or 2, wherein the monocarboxylic acid is sorbic acid.

[0492] 4. 4. The transdermal therapeutic system according to any one of 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. 5. The transdermal therapeutic system of any one of 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 polymers, or Acrylic polymers containing -OH groups The transdermal therapeutic system according to any one of clauses 1 to 5,

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

[0496] 8. The transdermal therapeutic 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, the silicone acrylic hybrid pressure sensitive adhesive comprising: (a) a silicone-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups; (b) an ethylenically unsaturated monomer; (c) an initiator; and The transdermal therapeutic system according to any one of clauses 5 to 8, comprising a reaction product of:

[0498] 10. The silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups is (a1) a silicone resin; (a2) a silicone polymer; (a3) a silicon-containing sealant containing acrylate or methacrylate functionality; and and the silicon-containing sealant 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 or 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 a halogen, and b is 0 or 1; the silicone resin and the silicone polymer are reacted to form a pressure sensitive adhesive, and the silicon-containing sealant is introduced prior to, during, or after reacting the silicone resin and the silicone polymer; The transdermal therapeutic system of clause 9, wherein the silicon-containing sealant reacts with the pressure-sensitive adhesive after the silicone resin and the silicone polymer condense to form the pressure-sensitive adhesive, or the silicon-containing sealant reacts in situ with the silicone resin and the silicone polymer.

[0499] 11. 11. The transdermal therapeutic system according to any one of items 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. 12. The transdermal therapeutic system according to any one of clauses 1 to 11, wherein said guanfacine-containing layer structure contains guanfacine in an amount of 1 to 100 mg / TTS, preferably 3 to 72 mg / TTS.

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

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

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

[0504] 16. 16. The transdermal therapeutic system according to any one of clauses 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 dispersing agents, permeation enhancers and solubilizers.

[0505] 17. The area weight of the guanfacine-containing layer is 40 to 250 g / m 2 , preferably 50 to 180 g / m 2 and / or the emission area is in the range of 1 to 100 cm 2 , preferably 2.5 to 50 cm 2 The transdermal therapeutic system according to any one of clauses 1 to 16, wherein the range is

[0506] 18. 18. The transdermal therapeutic system according to any one of clauses 1 to 17 for use in a method for treating a human patient, preferably a human patient aged between 6 and 17 years.

[0507] 19. 18. A transdermal therapeutic system according to any one of clauses 1 to 17 for use in a method for treating hypertension or attention deficit hyperactivity disorder (ADHD) and / or for use as an adjunct therapy to stimulant medication in a human patient, preferably a human patient aged between 6 and 17 years.

[0508] 20. 20. A transdermal therapeutic system for use according to clause 18 or 19, wherein said transdermal therapeutic system is applied to the skin of said patient for at least 24 hours, preferably at least 72 hours, more preferably about 84 hours.

[0509] twenty one. 1. A method for producing an active agent-containing layer for use in a transdermal therapeutic system, comprising: 1) At least one ingredient (i) a pharma- ceutical active agent; and (ii) at least one monocarboxylic acid; to obtain a premix; 2) (i) the premix of step 1); (ii) at least one polymer; to obtain a coating composition; 3) coating the coating composition onto a backing layer or release liner to obtain a coated coating composition; 4) drying the coated coating composition to form the active agent-containing layer; The method comprising:

[0510] twenty two. 22. The method of clause 21, wherein the pharma- ceutical active agent is guanfacine.

[0511] twenty three. 23. The method according to clause 21 or 22, wherein the premix according to process step 1) is obtained by combining (i) and (ii) in a dry grinding and / or slurry process.

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

[0513] twenty five. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) 6-9% by weight of guanfacine and sorbic acid based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case based on the total weight of the guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

[0514] 26. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) 6-9% by weight of guanfacine and sorbic acid based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case based on the total weight of the guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) lauroglycol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

[0515] 27. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) 6-9% by weight of guanfacine and sorbic acid based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case based on the total weight of the guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; iv) macrogol-6 glyceride in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

Claims

1. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer comprising guanfacine and a monocarboxylic acid; The transdermal therapeutic system comprising:

2. The guanfacine-containing layer comprises: i) guanfacine and a monocarboxylic acid; ii) at least one polymer; and The transdermal therapeutic system according to claim 1, wherein the guanfacine-containing matrix layer comprises:

3. The transdermal therapeutic system according to claim 1 or 2, wherein the monocarboxylic acid is sorbic acid.

4. The transdermal therapeutic system according to any one of claims 1 to 3, wherein the guanfacine and the monocarboxylic acid in the guanfacine-containing layer are present in the form of a premixture.

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

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

7. The transdermal therapeutic system according to any one of claims 1 to 6, 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.

8. 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 - an acrylic polymer, or -Acrylic polymer containing -OH group The transdermal therapeutic system according to any one of claims 1 to 7,

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

10. The transdermal therapeutic system according to any one of claims 7 to 9, 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.

11. The silicone-acrylic hybrid polymer is a silicone acrylic hybrid pressure sensitive adhesive, the silicone acrylic hybrid pressure sensitive adhesive comprising: (a) a silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functionality; and (b) an ethylenically unsaturated monomer. (c) an initiator; and The transdermal therapeutic system according to any one of claims 7 to 10, comprising the reaction product of:

12. The silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups comprises (a1) a silicone resin; (a2) a silicone polymer; and (a3) a silicon-containing sealant containing an acrylate or methacrylate functional group; and and the silicon-containing sealant comprises a condensation reaction product of the general formula XYR′ ｂ SIZ ３－ｂ wherein X is a monovalent radical of the general formula AE, where E is -O- or -NH-, and A is an acrylic or methacrylic radical, and Y is a divalent alkylene radical having 1 to 6 carbon atoms. R′ is a methyl or phenyl group, Z is a monovalent hydrolyzable organic group or a halogen, and b is 0 or 1; the silicone resin and the silicone polymer are reacted to form a pressure sensitive adhesive, and the silicon-containing sealant is introduced prior to, during, or after reacting the silicone resin and the silicone polymer; The transdermal therapeutic system of claim 11, wherein the silicon-containing sealant reacts with the pressure-sensitive adhesive after the silicone resin and the silicone polymer condense to form the pressure-sensitive adhesive, or the silicon-containing sealant reacts in situ with the silicone resin and the silicone polymer.

13. The transdermal therapeutic system according to any one of claims 11 or 12, wherein the ethylenically unsaturated monomer is selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates, cycloaliphatic methacrylates, and combinations thereof, each of said 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.

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

15. The transdermal therapeutic system according to any one of claims 1 to 14, wherein the guanfacine-containing layer comprises 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.

16. A transdermal therapeutic system according to any one of claims 1 to 15, comprising guanfacine and said monocarboxylic acid in equimolar amounts.

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

18. The transdermal therapeutic system according to any one of claims 1 to 17, wherein the guanfacine-containing layer further comprises at least one additive, preferably at least two additives, selected from the group consisting of dispersing agents, permeation enhancers and solubilizers.

19. The area weight of the guanfacine-containing layer is 40 to 250 g / m ２ , preferably 50 to 180 g / m ２ and / or the emission area is in the range of 1 to 100 cm ２ , preferably 2.5 to 50 cm ２ The transdermal therapeutic system according to any one of claims 1 to 18, wherein the range is

20. A transdermal therapeutic system according to any one of claims 1 to 19 for use in a method for treating a human patient, preferably a human patient aged between 6 and 17 years.

21. A transdermal therapeutic system according to any one of claims 1 to 19 for use in a method for treating hypertension or attention deficit hyperactivity disorder (ADHD) and / or for use as an adjunct to stimulant medication in a human patient, preferably a human patient aged between 6 and 17 years.

22. The transdermal therapeutic system is to be applied to the patient's skin for at least 24 hours, preferably at least 22. A transdermal therapeutic system for use according to claim 20 or 21, wherein the therapeutic system is applied for at least 72 hours, more preferably for about 84 hours.

23. 1. A method for producing an active agent-containing layer for use in a transdermal therapeutic system, comprising: 1) At least one ingredient (i) a pharma- ceutical active agent; and (ii) at least one monocarboxylic acid; to obtain a premix; ２） (i) the premix of step 1); (ii) at least one polymer; and to obtain a coating composition; 3) coating the coating composition onto a backing layer or release liner to obtain a coated coating composition; 4) drying the coated coating composition to form the active agent-containing layer; and The method comprising:

24. 24. The method of claim 23, wherein the pharma- ceutical active agent is guanfacine.

25. 25. The method according to claim 23 or 24, wherein the premix according to process step 1) is obtained by combining (i) and (ii) in a dry grinding and / or slurry process.

26. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine and sorbic acid in a total amount of 6-9% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case based on the total weight of said guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight based on the total weight of said guanfacine-containing layer; iv) a permeation enhancer selected from oleyl alcohol, lauroglycol, and oleoyl macrogol-6 glyceride in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

27. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine and sorbic acid in a total amount of 6-9% by weight based on the total weight of the guanfacine-containing layer; ii) a first silicone layer, in each case based on the total weight of said guanfacine-containing layer; a mixture of two silicone-acrylic hybrid polymers, wherein 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) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight based on the total weight of said guanfacine-containing layer; iv) oleyl alcohol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

28. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine and sorbic acid in a total amount of 6-9% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case based on the total weight of said guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight based on the total weight of said guanfacine-containing layer; iv) lauroglycol in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

29. A transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer; wherein the layer comprises i) guanfacine and sorbic acid in a total amount of 6-9% by weight based on the total weight of the guanfacine-containing layer; ii) a mixture of two silicone-acrylic hybrid polymers, the first silicone-acrylic hybrid polymer being present in an amount of 60-90% by weight and the second silicone-acrylic hybrid polymer being present in an amount of 1-20% by weight, in each case based on the total weight of said guanfacine-containing layer; iii) polyoxyethylene (4) lauryl ether in an amount of 2-6% by weight based on the total weight of said guanfacine-containing layer; iv) oleoyl macrogol-6 glyceride in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system comprising:

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