Transdermal therapeutic system for transdermal administration of guanfacine containing a silicone polymer - Patent Application 20070123633

Abstract

To provide a transdermal therapeutic system for the transdermal administration of guanfacine comprising a guanfacine-containing layer structure.SOLUTION: A guanfacine-containing layer structure comprises: A) a backing layer; and B) a guanfacine-containing layer; wherein the transdermal therapeutic system comprises at least one silicone polymer.SELECTED DRAWING: Figure 1

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

[0002] The active agent guanfacine (N-(aminoiminomethyl)-2,6-dichloro-benzeneacetamide, C 9 H 9 Cl 2 N 3 O, also known as CAS 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] Guanfacine is currently commercially available in the form of immediate or controlled release tablets, e.g., 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 an extended release tablet is taken orally, it is not possible to quickly stop treatment, for example in light of signs of overdosing or intolerance.

[0005] Therefore, 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 in a single application, thereby improving patient compliance. Summary of the Invention [Problem to be solved by the invention]

[0006] It is therefore an object of the present invention to provide a TTS for the transdermal administration of guanfacine, in particular a TTS for the transdermal administration of guanfacine that provides a skin permeation rate that is sufficient 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 the entire time period, where the TTS is applied to the skin and allows 24-hour treatment by replacing the TTS after a certain application time, for example 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 blood plasma concentrations, especially when compared to oral administration at steady state.

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

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

[0011] These and other objects are achieved, according to one embodiment, by 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; and B) guanfacine-containing layer; This is achieved by the present invention with respect to a transdermal therapeutic system comprising at least one silicone polymer.

[0012] It has been found that the TTS according to the present invention comprising silicone polymer provides advantageous properties in terms of constant and continuous guanfacine delivery.In particular, the TTS according to the present invention provides a suitable permeation rate and a suitable permeation amount of guanfacine for a time period of at least 24 hours, preferably at least 72 hours, more preferably about 84 hours.

[0013] According to one particular embodiment, the present invention provides a guanfacine-containing layer comprising: i) guanfacine, and ii) at least one silicone polymer The present invention also relates to a transdermal therapeutic system for transdermal administration of guanfacine as described above, wherein the guanfacine-containing matrix layer comprises

[0014] In certain preferred embodiments, the guanfacine-containing layer structure further comprises at least one additive selected from the group consisting of dispersants, penetration enhancers, and solubilizers.

[0015] According to one particular embodiment, the present invention provides 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; and B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer, comprising: i) guanfacine in an amount of 3% to 13% by weight based on the total weight of the guanfacine-containing layer; ii) at least one silicone polymer in an amount of 35% to 90% by weight based on the total weight of the guanfacine-containing layer; iii) at least one dispersing agent in an amount of 2% to 6% by weight based on the total weight of the guanfacine-containing layer; iv) at least one penetration enhancer in an amount of 2% to 10% by weight based on the total weight of the guanfacine-containing layer; and v) optionally, at least one solubilizer in an amount of 0.5% to 4% by weight based on the total weight of the guanfacine-containing layer; The present invention relates to a transdermal therapeutic system comprising:

[0016] According to one 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 a method of treating a human patient between 6 and 17 years of age. In particular, the transdermal therapeutic system according to the invention is for use in a method for treating hypertension or attention deficit hyperactivity disorder (ADHD) and / or as an adjunct treatment to stimulant therapy in a human patient, preferably in a human patient aged between 6 and 17 years. In connection with these medical uses, the TTS according to the invention is applied to the patient's skin for at least 24 hours, more preferably at least 72 hours, and most preferably about 84 hours.

[0017] According to certain embodiments, the present invention further 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 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 between 6 and 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 at least 72 hours, and most preferably about 84 hours.

[0018] According to another aspect, the present invention provides a method for producing a method of making a digital camera comprising: 1) At least one component i) guanfacine; and ii) at least one silicone polymer; to obtain a coating composition; 2) coating the coating composition onto a backing layer or release liner to obtain a coated coating composition; and 3) A step of drying the coated coating composition to form a guanfacine-containing layer. The present invention relates to a process for producing a guanfacine-containing layer for use in a transdermal therapeutic system according to the present invention, comprising:

[0019] Preferably, the silicone polymer is provided as a solution, wherein the solvent is ethyl acetate or n-heptane, preferably ethyl acetate.

[0020] According to yet another aspect, the present invention relates to a transdermal therapeutic system obtainable by the process according to the invention.

[0021] definition Within the meaning of this invention, the term "transdermal therapeutic system" (TTS) refers to a system in which an active agent (e.g., guanfacine) is administered to the systemic circulation via transdermal delivery, and refers to the entire individual dosage unit that is applied to the patient's skin after removing a release liner that is optionally present, which includes a therapeutically effective amount of active agent in an active agent-containing layer structure, and optionally an additional adhesive overlay on top of the active agent-containing layer structure. The active agent-containing layer structure can be located on a release liner (a removable protective layer), and therefore the TTS can further include a release liner. Within the meaning of this invention, the term "TTS" refers in particular to a system that provides transdermal delivery that excludes active delivery, for example, via iontophoresis or microporation. Transdermal therapeutic systems can also be referred to as transdermal drug delivery systems (TDDS) or transdermal delivery systems (TDS).

[0022] Within the meaning of this invention, the term "guanfacine-containing layer structure" refers to a layer structure containing a therapeutically effective amount of guanfacine, and includes a backing layer and at least one guanfacine-containing layer. Preferably, the guanfacine-containing layer structure is a guanfacine-containing self-adhesive layer structure.

[0023] Within the meaning of this invention, the term "therapeutically effective amount" refers to the quantitative amount of active agent in TTS, which is sufficient to treat, prevent or reduce hypertension or attention deficit hyperactivity disorder (ADHD) in human patients when administered to the patient by TTS, or is sufficient as adjunctive treatment to stimulant therapy.TTS usually contains more active agent in its system than is actually provided to skin and systemic circulation.This excess amount of active agent is usually necessary to provide sufficient driving force for delivery from TTS to systemic circulation.

[0024] Within the meaning of this invention, terms such as "active" and "active agent", as well as the term "guanfacine", refer to guanfacine in any pharma- ceutically acceptable chemical and morphological form and physical state. These forms include, but are not limited to, guanfacine in its free base form, protonated or partially protonated guanfacine, guanfacine salts, and in particular acid addition salts formed by addition of inorganic or organic acids, such as guanfacine hydrochloride or guanfacine tartrate, solvates, hydrates, clathrates, cocrystals, complexes, as well as guanfacine in the form of particles, which may be micronized, crystalline and / or amorphous, and any mixture of the forms described above. When guanfacine is contained in a medium such as a solvent, it is preferably present in a dispersed form.

[0025] When it is stated that guanfacine is used in a particular form in the preparation of TTS, this does not exclude the interaction between this form of guanfacine and other components of the guanfacine-containing layer structure, such as salt formation or complexation, in the final TTS.This means that even if guanfacine is included in its free base form, it can be present in the final TTS in protonated or partially protonated 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 can be present as free base in the final TTS.Unless otherwise indicated, the amount of guanfacine in particular layer structure relates to the amount of guanfacine included in TTS during the preparation of TTS, and is calculated based on guanfacine in the form of free base. For example, if a) 0.1 mmol (equal to 24.61 mg) of guanfacine base or b) 0.1 mmol (equal to 27.71 mg) of guanfacine hydrochloride is included in the TTS during preparation, the amount of guanfacine in the layer structure, within the meaning of the present invention, is in both cases 24.06 mg, i.e. 0.1 mmol.

[0026] The guanfacine starting material contained in the TTS during the preparation of the TTS may be in the form of particles. The guanfacine may be present in the active agent-containing layer structure, for example, in the form of particles that are preferably homogeneously dispersed within the active agent-containing layer structure.

[0027] Within the meaning of this invention, the term "particle" refers to a solid particulate material comprising individual particles, the dimensions of which are negligible compared to the material. In particular, the particles are solids, including plastic / deformable solids, including amorphous and crystalline materials.

[0028] Within the meaning of this invention, the term "dispersing" refers to a step or combination of steps in which the starting material (e.g., guanfacine) is not dissolved or is not completely dissolved. Dispersing in the sense of this 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).

[0029] 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 a matrix-type TTS is controlled primarily by the matrix, including the active agent itself. In contrast, a reservoir-type TTS typically requires a rate-controlling membrane to control the release of the active agent. In principle, The TTS of the matrix type can also contain a rate-controlling membrane. However, compared with the TTS of the reservoir type, the TTS of the matrix type has an advantage in that a rate-determining membrane is usually not required and dose dumping does not occur due to membrane rupture. Thus, the TTS of the matrix type is less complicated to manufacture and easier and more convenient to use by patients.

[0030] Within the meaning of this invention, "matrix-type TTS" refers to a system or structure in which the active is homogeneously dissolved and / or dispersed in a polymeric carrier, i.e., a matrix in which the active and optionally the remaining components form a matrix layer. In such a system, the matrix layer controls the release of the active from the TTS. Preferably, the matrix layer has sufficient adhesion to be self-supporting, so that sealing between other layers is not required. Thus, the active agent-containing layer may be an active agent-containing matrix layer in one embodiment of the present invention, in which the active 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 can be laminated together. The 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 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 includes an active agent dissolved and / or dispersed in a polymeric gel, e.g., a hydrogel, is also considered to be a matrix type according to the present invention.

[0031] A TTS having a liquid active agent-containing reservoir is referred to by the term "reservoir-type TTS". In such a system, the release of the active agent is preferably controlled by a rate-controlling membrane. In particular, the reservoir is sealed between a backing layer and a rate-controlling membrane. Thus, the active agent-containing layer may in one embodiment be an active agent-containing reservoir layer, which preferably comprises a liquid reservoir containing an active agent. Furthermore, a reservoir-type TTS typically additionally comprises a skin contact layer, where the reservoir layer and the skin contact layer can be separated by a rate-controlling membrane. In the reservoir layer, the active agent is preferably dissolved in a solvent such as ethanol or water or in silicone oil. The skin contact layer typically has adhesive properties.

[0032] Reservoir type TTS should not be understood as matrix type within the meaning of the present invention. However, microreservoir TTS (two-phase system with deposits (e.g., spheres, droplets) of an internal active-containing phase dispersed in an external polymer phase) which is considered in the art to be a mixed form of matrix type TTS and reservoir type TTS, different from homogeneous single-phase matrix type TTS and reservoir type TTS in the concept of drug transport and drug delivery, is considered to be matrix type within the meaning of the present invention. The size of the microreservoir droplets can be determined by optical microscopy measurement (e.g., by a camera, e.g., Leica MZ16, including Leica DSC320) by taking pictures of the microreservoir at different positions with an enhancement between 10 times and 400 times depending on the required detection limit. The size of the microreservoir can be determined by using imaging analysis software.

[0033] Within the meaning of this invention, the term "active agent-containing layer" refers to a layer that contains an active agent and provides a release area. The term encompasses active agent-containing matrix layers and active agent-containing reservoir layers. If the active agent-containing layer is an active agent-containing matrix layer, said layer is present in a matrix-type TTS. If the polymer is a pressure-sensitive adhesive, the matrix layer can also represent the adhesive layer of the TTS, so that there is no additional skin contact layer. Alternatively, the additional skin contact layer can be present as an adhesive layer and / or or an adhesive overlay is provided. The additional skin contact layer is typically manufactured so that it is active agent free. However, due to a concentration gradient, the active agent migrates from the matrix layer to the additional skin contact layer over time until equilibrium is reached. The additional skin contact layer can be on the active agent-containing matrix layer or can 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 no additional skin contact layer is present. If the active agent-containing layer is an active agent-containing reservoir layer, said layer is present in a reservoir-type TTS, which layer contains the active agent in a liquid reservoir. In addition, the additional skin contact layer is preferably present to provide adhesive properties. Preferably, a rate-controlling membrane separates the reservoir layer from the additional skin contact layer. The additional skin contact layer can be manufactured so that it is active agent free or active agent-containing. If the additional skin contact layer is active agent free, the active agent migrates due to a concentration gradient from the reservoir layer to the skin contact layer over time until equilibrium is reached. Additionally, an adhesive overlay may be provided.

[0034] As used herein, the active agent-containing layer is preferably an active agent-containing matrix layer, which refers to 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 can also be produced by laminating two or more such solidified layers (e.g., dried or cooled layers) of the same composition to provide the desired areal weight. The matrix layer can be self-adhesive (in the form of a pressure-sensitive adhesive matrix layer), or the TTS can include an additional skin-contact layer of pressure-sensitive adhesive to provide sufficient adhesion. Preferably, the matrix layer is a pressure-sensitive adhesive matrix layer. Optionally, an adhesive overlay can be present.

[0035] Within the meaning of this invention, the term "pressure sensitive adhesive" (also abbreviated as "PSA") refers to a material that should adhere, especially with finger pressure, be permanently tacky, exert strong holding power and be removable from smooth surfaces without leaving residue. The pressure sensitive adhesive layer is "self-adhesive" when in contact with the skin, i.e. provides adhesion to the skin, so that typically no further auxiliary is required for fixation on the skin. The "self-adhesive" layer structure comprises a pressure sensitive adhesive layer for skin contact, i.e. a pressure sensitive adhesive skin contact layer, which can be provided in the form of a pressure sensitive adhesive matrix layer or in the form of an additional layer. Adhesive overlays can also be used to improve adhesion. The pressure sensitive adhesive properties of the pressure sensitive adhesive depend on the polymer or polymer composition used.

[0036] Within the meaning of this invention, the term "silicone acrylic hybrid polymer" refers to a polymerization product that includes repeat units of silicone subspecies and acrylate subspecies. Silicone acrylic hybrid polymers therefore include a silicone phase and an acrylic phase. Preferably, silicone acrylic hybrid polymers include a silicone phase and an acrylate phase, i.e., silicone subspecies and acrylate subspecies, in a certain weight ratio, for example, 60:40 to 40:60. The term "silicone acrylic hybrid" is intended to indicate more than a simple blend of silicone-based subspecies and acrylate-based subspecies. Instead, the term indicates a polymerized hybrid species that includes silicone-based subspecies and acrylate-based subspecies polymerized together. Silicone acrylic hybrid polymers can also be referred to as "silicone acrylate hybrid polymers", since the terms acrylate and acrylic are generally used interchangeably in the context of hybrid polymers used in the present invention.

[0037] Within the meaning of this invention, the term "silicone acrylic hybrid pressure sensitive adhesive" is used. The term 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 manufactured and supplied in n-heptane or ethyl acetate by Dow Corning (7-610X and 7-630X; X=1 n-heptane based / X=2 ethyl acetate based). It has been found that depending on the solvent in which the silicone acrylic hybrid PSA is supplied, the arrangement of the silicone phase and the acrylic phase is different, providing a silicone or acrylic continuous external phase and a corresponding discontinuous internal phase. If the silicone acrylic hybrid PSA is supplied in n-heptane, the composition contains a continuous silicone external phase and a discontinuous acrylic internal phase. If 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.

[0038] Within the meaning of this invention, the term "non-hybrid polymer" is used synonymously with a polymer that does not contain a hybrid species. Preferably, the non-hybrid polymer is a pressure sensitive adhesive (e.g., a silicone-based or acrylate-based pressure sensitive adhesive).

[0039] Within the meaning of this invention, the term "silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality" includes the condensation reaction product of a silicone resin, a silicone polymer, and a silicon-containing capping agent that provides said acrylate or methacrylate functionality. It should be understood that a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality can contain only acrylate functionality, only methacrylate functionality, or both acrylate and methacrylate functionality.

[0040] As used herein, active agent-containing matrix layer is a layer that contains active agent dissolved or dispersed in at least one polymer or dissolved in a solvent, so as to form an active agent-solvent mixture that is dispersed in the form of deposit (particularly droplets) in at least one polymer.Preferably, at least one polymer is a polymer-based pressure-sensitive adhesive (e.g. silicone pressure-sensitive adhesive).Within the meaning of this invention, the term "pressure-sensitive adhesive layer" refers to the pressure-sensitive adhesive layer obtained from a solvent-containing adhesive coating composition after coating and evaporating the solvent onto the film.

[0041] Within the meaning of this invention, the term "skin contact layer" refers to the layer included in the active agent-containing layer structure that directly contacts the patient's skin during administration. This may be the active agent-containing layer. If the TTS includes an additional 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 can absorb part of the active agent over time. The additional skin contact layer can be used to enhance adhesion. The size of the additional skin contact layer and the active agent-containing layer is usually coextensive and corresponds to the release area. However, the area of ​​the additional skin contact layer may be larger than the area of ​​the active agent-containing layer. In such cases, the release area also refers to the area of ​​the active agent-containing layer.

[0042] Within the meaning of this invention, the term "areal weight" means g / m 2 areal weight values ​​are subject to an error of ±10%, preferably ±7.5%, due to manufacturing variations.

[0043] Unless otherwise indicated, "%" refers to weight percent (wt%).

[0044] Within the meaning of this 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 monomer. The polymer may be any architecture, such as linear polymers, star polymers, comb polymers, brush polymers, etc., of any monomer sequence in the case of copolymers, such as alternating copolymers, statistical copolymers, block copolymers, or graft polymers. The minimum molecular weight varies depending on the polymer type and is known to those skilled in the art. The polymer may have, for example, a molecular weight of more than 2000 Daltons, preferably more than 5000 Daltons, more preferably more than 10,000 Daltons. Accordingly, compounds having 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.

[0045] Within the meaning of this invention, the term "crosslinking agent" refers to a substance capable of crosslinking functional groups contained within a polymer.

[0046] Within the meaning of this invention, the term "adhesive overlay" refers to a self-adhesive layer structure that is free of active agent, has a larger area than the active agent-containing structure, and provides additional area for adhesion to the skin but does not provide an area for release of the active agent. Thereby, it enhances the overall adhesive properties of the TTS. The adhesive overlay includes a backing layer and an adhesive layer that can provide occlusive or non-occlusive properties. Preferably, the backing layer of the adhesive overlay provides non-occlusive properties.

[0047] Within the meaning of this 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, 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. Suitable backing layers are therefore, for example, PET laminates, EVA-PET laminates, and PE-PET laminates. In a preferred embodiment, the backing layer is a siliconized PET foil. Also suitable are woven or non-woven backing materials.

[0048] The TTS according to the present invention may be characterized by certain parameters that may be measured in an in vitro skin permeation test.

[0049] Generally, in vitro permeation tests are performed in Franz diffusion cells using an EVA membrane (e.g., 9% vinyl acetate and 50 μm thick, preferably provided by 3M) and phosphate buffer pH 5.5 or 7.4 as receptor medium (32° C. with 0.1% saline azide).

[0050] Furthermore, in vitro permeation tests can be carried out in Franz diffusion cells using human or animal skin, preferably using dermatomed split-thickness human skin with a thickness of 800 μm and intact epidermis, and in a concentration of up to 40 vol-% organic solvent, e.g. ethanol, such that the receptor medium can contain, for example, 60 vol-% phosphate buffer pH 5.5, 30 vol-% dipropylene glycol and 10 vol-% acetonitrile. , acetonitrile, isopropanol, dipropylene glycol, phosphate buffer pH 5.5 or 7.4 (32° C. with 0.1% saline azide) with or without the addition of PEG 400 may be used as the receptor medium.

[0051] Unless otherwise indicated, in vitro permeation tests are performed with dermatomed split-thickness human skin with a thickness of 800 μm and with intact epidermis, and with phosphate buffer pH 5.5 as receptor medium (32° C. with 0.1% saline azide). The amount of active permeated into the receptor medium is determined at regular intervals using a validated HPLC method with a UV photometric detector by taking sample volumes. The receptor medium is completely or partially replaced by fresh medium at the time of taking the sample volume, and the measured amount of active permeated relates to the amount permeated between the two last sampling points and not to the total amount permeated up to that point.

[0052] Within the meaning of this invention, the parameter "penetration amount" is therefore defined as μg / cm 2 and relates to the amount of active permeated in a sample interval at a particular time interval. For example, in an in vitro permeation test as described above, where the amount of active permeated into the receptor medium is measured, for example, at 0, 2, 4, 8, 12 and 24 hours, the "amount of permeation" of active can be given, for example, at a sample interval from 8 to 12 hours, corresponding to the measurement at 12 hours, where the receptor medium has been completely replaced at 8 hours.

[0053] The amount of permeation can also be indicated as a "cumulative permeation," which corresponds to the cumulative amount of active permeated at a particular time point. For example, in an in vitro permeation test as described above, where the amount of active permeated into a receptor medium is measured, for example, at 0, 2, 4, 8, 12 and 24 hours, the "cumulative permeation" of the active at 12 hours corresponds to the sum of the permeation amounts from 0 to 2 hours, from 2 to 4 hours, from 4 to 8 hours, and from 8 to 12 hours.

[0054] Within the meaning of this invention, the parameter "skin permeability" for a particular sample interval at a particular time elapsed is μg / (cm 2* h) the sample interval time, 2 For example, in an in vitro permeation test as described above, the skin permeation rate is calculated by measuring the amount of active permeated into the receptor medium at, for example, 0, 2, 4, 8, 12 and 24 hours, and the "skin permeation rate" at 12 hours is calculated as the amount of permeation in the sample interval from 8 to 12 hours divided by 4 hours.

[0055] The "cumulative skin permeation rate" can be calculated from each cumulative permeation rate by dividing the cumulative permeation rate by the elapsed time. For example, in an in vitro permeation test as described above, where the amount of active permeated into the receptor medium is measured, for example, at 0, 2, 4, 8, 12 and 24 hours, the "cumulative skin permeation rate" at 12 hours is calculated as the cumulative permeation rate for 12 hours (see above) divided by 12 hours.

[0056] Within the meaning of this invention, the above parameters "permeation amount" and "skin permeation rate" (as well as "cumulative permeation amount" and "cumulative skin permeation rate") refer to the average values ​​calculated from at least three in vitro permeation test experiments. If not otherwise indicated, the standard deviation (SD) of these average values ​​is calculated according to the formula:

number

number

[0057] The TTS according to the present invention may also be characterized by certain parameters as measured in in vivo clinical studies.

[0058] Within the meaning of this invention, the parameter "average release rate" refers to the average release rate in μg / h (μg / hour, μg / hour) or mg / day of an active agent released through human skin into the systemic circulation over an administration period (e.g., 1 to 7 days) and is based on the AUC obtained over said administration period in clinical studies.

[0059] Within the meaning of this invention, the term "extended period of time" relates to a period of at least or about 24 hours, at least or about 48 hours, at least or about 72 hours, at least or about 84 hours, at least or about 1 day, at least or about 2 days, or at least or about 3 days, or at least or about 3.5 days, or a period of from about 24 hours to about 168 hours, or from 1 to 7 day(s), or from about 24 hours to about 84 hours, or from 1 to 3.5 day(s).

[0060] For continuous drug treatment, the frequency of drug administration is preferably kept high enough to maintain a therapeutically effective blood plasma concentration. In other words, the interval between two dosage forms administrations, also called the dosing interval, needs to be adapted accordingly. Within the meaning of the present invention, the term "dosing interval" refers to the time period between two consecutive TTS administrations, i.e., the interval between two consecutive times when the TTS is applied to the patient's skin. Once applied, the TTS is usually maintained on the patient's skin for the entire 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 and maintained on the patient's skin 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 dosing interval of 24 hours or 1 day allows a daily TTS replacement mode in a 24-hour treatment. Preferred according to the present invention is a dosing interval of at least 72 hours, preferably about 84 hours. The time of application of the TTS to the patient's skin is preferably the same as the time of the dosing interval, which should be understood to mean that a constant administration of guanfacine is administered with alternating TTS.

[0061] Within the meaning of this invention, the term "room temperature" refers to the unaltered temperature found indoors in the laboratory where the experiment is performed, usually within 15°C to 35°C, preferably about 18°C ​​to 25°C.

[0062] Within the meaning of this invention, the term "patient" refers to a subject to be treated preventatively or prophylactically for a condition, exhibiting a clinical presentation of a particular symptom or symptoms indicating the need for treatment. The term "patient" refers to a subject who has been diagnosed with a disease or condition to be treated. Preferably, the patient is between 6 and 17 years of age.

[0063] Within the meaning of this invention, the term "pharmacokinetic parameters" refers to blood plasma curves, e.g., C, obtained in clinical studies by single-dose, multiple-dose 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 , mean AUCt and mean AUC INF , and additional statistics, such as the respective standard deviations and standard errors, minimum, maximum, and median values ​​(centers) when the list of values ​​is ranked. In the context of the present invention, pharmacokinetic parameters, such as C max , C t and AUC t1-t2 Refers to geometric mean value unless otherwise indicated. It cannot be excluded that the absolute mean value obtained for a certain TTS in clinical studies varies to some extent from study to study. To allow 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. Comparison of the AUC per release area of ​​each reference product in early and late studies can be used to obtain a correction factor to take into account the differences between studies.

[0064] Clinical research according to the present invention refers to research conducted in full compliance with the International Council on Harmonisation (ICH) and all applicable local Good Clinical Practices (GCP) and regulations.

[0065] Within the meaning of this invention, the term "healthy human subject" refers to a male or female subject with 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, etc. 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.

[0066] Within the meaning of this invention, the term "subject population" refers to at least 5, preferably at least 10 individual healthy human subjects.

[0067] Within the meaning of this invention, the term "geometric mean" refers to the mean of log-transformed data that has been transformed back to the original scale.

[0068] Within the meaning of this invention, the term "arithmetic mean" refers to the sum of all the values ​​of the observations divided by the total number of observations.

[0069] Within the meaning of this invention, the parameter "AUC" corresponds to the area under the plasma concentration-time curve. The AUC value is proportional to the amount of active drug absorbed into the blood circulation in total and is therefore a measure for bioavailability.

[0070] Within the meaning of this invention, "AUC t1-t2 The parameter " is provided in (ng / ml)h and is the area under the plasma concentration-time curve from time t1 to t2, calculated by the linear trapezoidal method unless otherwise indicated. Other calculation methods are, for example, the logarithmic and linear logarithmic trapezoidal methods.

[0071] Within the meaning of this invention, "C max The parameter " is provided in (ng / ml) and relates to the maximum observed blood plasma concentration of the active drug.

[0072] Within the meaning of this invention, "C t The parameter " is provided in (ng / ml) and relates to the observed blood plasma concentration of active drug at time t.

[0073] Within the meaning of this invention, max " parameters are provided in h and C max It relates to the time when a value is reached. In other words, t max is the time point of maximum observed plasma concentration.

[0074] Within the meaning of this invention, the term "mean plasma concentration" is given in (ng / ml) and is the average of the individual plasma concentrations of the active agent, for example guanfacine, at each time point.

[0075] Within the meaning of this invention, the term "coating composition" refers to a composition containing all the components of a matrix layer in a solvent, which can be coated onto a backing layer or release liner to form a matrix layer upon drying.

[0076] Within the meaning of this invention, the term "pressure-sensitive adhesive composition" refers to a pressure-sensitive adhesive in a mixture with at least a solvent, such as n-heptane or ethyl acetate.

[0077] Within the meaning of this invention, the term "dissolving" refers to the process of obtaining a solution that is clear and does not contain any particles visible to the naked eye.

[0078] Within the meaning of this 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. [Brief description of the drawings]

[0079] [Figure 1] FIG. 2 shows the amount of guanfacine permeated into the TTS prepared according to Examples 1a to 1d and Comparative Example 1. [Diagram 2] FIG. 2 shows the amount of guanfacine permeated into the TTS prepared according to Examples 2a-b. [Diagram 3] FIG. 2 shows the amount of guanfacine permeated into the TTS prepared according to Examples 3a-b. [Figure 4] FIG. 1 shows the amount of guanfacine permeated into the TTS prepared according to Comparative Examples 2a-b. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0080] TTS structure The present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising an amfacine-containing layer structure, said guanfacine-containing layer structure comprises a) a backing layer and b) a guanfacine-containing layer, and said transdermal therapeutic system comprises at least one silicone polymer.This guanfacine-containing layer structure is preferably a guanfacine-containing self-adhesive layer structure, and preferably does not comprise additional skin contact layer.In particular, the silicone acrylic hybrid polymer present in the transdermal therapeutic system, preferably present in the self-adhesive layer structure, preferably provides adhesive properties.

[0081] The TTS according to the present invention may be a matrix-type TTS or a reservoir-type TTS, preferably a matrix-type TTS.

[0082] In the matrix-type TTS according to the present invention, the guanfacine is preferably homogenously dispersed within the polymer carrier, i.e., the matrix that forms the matrix layer together with the guanfacine and optionally the remaining components. Thus, the guanfacine-containing layer may in one embodiment of the present invention be a guanfacine-containing matrix layer, in which the guanfacine is homogenously dispersed within the polymer matrix. The guanfacine-containing matrix layer preferably comprises at least one silicone polymer. Thus, the guanfacine-containing matrix layer preferably comprises guanfacine and at least one silicone polymer present in the TTS. In this connection, it is also preferred that there is no additional skin contact layer, since the guanfacine-containing matrix layer is self-adhesive. If the guanfacine-containing matrix layer is prepared by laminating together two guanfacine-containing matrix layers of substantially the same composition, the resulting bilayer should be considered as one guanfacine-containing matrix layer.

[0083] In the reservoir type TTS according to the present invention, the guanfacine-containing layer is preferably a guanfacine-containing reservoir layer that contains a liquid reservoir that contains guanfacine.T reservoir type TTS typically additionally contains a skin contact layer, where the reservoir layer and the skin contact layer are preferably separated by a rate-controlling membrane.The silicone acrylic hybrid polymer then provides adhesive properties.Preferably, the skin contact layer is manufactured so that it is guanfacine-free.

[0084] In a preferred embodiment of the present invention, the guanfacine-containing layer comprises: i) guanfacine; and ii) at least one silicone polymer A guanfacine-containing matrix layer comprising:

[0085] Thus, according to one embodiment, the present invention provides: A) a backing layer; and B) a guanfacine-containing layer, which is preferably a guanfacine-containing matrix layer comprising: i) guanfacine; and ii) at least one silicone polymer The present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising a guanfacine-containing layer structure comprising:

[0086] The guanfacine-containing layer structure is preferably a guanfacine-containing self-adhesive layer structure. In this connection, moreover, the guanfacine-containing layer structure is preferably not comprised of an additional skin contact layer. Instead, the guanfacine-containing layer, which is preferably a guanfacine-containing matrix layer, is preferably self-adhesive. Thus, in a preferred embodiment, the guanfacine-containing layer structure is a guanfacine-containing self-adhesive layer structure, which is preferably not comprised of an additional skin contact layer. Alternatively or additionally, the guanfacine-containing layer is preferably directly attached to the backing layer, so that there is no additional layer between the backing layer and the guanfacine-containing layer. As a result, a layer structure with low complexity is obtained, which is advantageous, for example, in terms of costs for production.

[0087] In particular, the guanfacine-containing layer structure preferably comprises no more than three layers, preferably only two layers, namely preferably a backing layer and a guanfacine-containing layer.The sufficient adhesion between the guanfacine-containing self-adhesive layer structure and the patient's skin during administration is then provided by the guanfacine-containing layer, which is preferably a 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 can 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.

[0088] The self-adhesive properties of the guanfacine-containing layer structure are preferably provided by at least one silicone polymer present in the TTS, preferably in the guanfacine-containing layer, more preferably in the guanfacine-containing matrix layer. In a preferred embodiment, the at least one silicone polymer is a silicone pressure sensitive adhesive. Further details regarding silicone polymers according to the present invention are provided further below.

[0089] It should be understood that the TTS, preferably the guanfacine-containing layer, more preferably the guanfacine-containing matrix layer, may also comprise two silicone polymers.

[0090] Furthermore, the TTS, preferably the guanfacine-containing layer, more preferably the guanfacine-containing matrix layer, may also comprise at least one silicone polymer and at least one further polymer selected from the group consisting of acrylate polymers, silicone acrylic hybrid polymers, polyisobutylene, and styrene-isoprene-styrene block copolymers, preferably selected from the group consisting of acrylate polymers, and silicone acrylic hybrid polymers.

[0091] For example, a first polymer, such as a silicone polymer, provides an advantage in terms of high flux, while a second polymer, such as an additional silicone polymer or an acrylate polymer or a silicone acrylic hybrid polymer, can be used to reduce and / or optimize the flux to obtain a continuous and constant flux. Furthermore, the tackiness of the TTS can be modified by using a combination of at least two polymers. Further details regarding specific polymers are provided below.

[0092] It should be understood that the TTS according to the present invention contains at least a therapeutically effective amount of guanfacine.Therefore, in a preferred embodiment of the present invention, the layer structure containing guanfacine contains a therapeutically effective amount of guanfacine.The guanfacine in the layer structure containing guanfacine is preferably present in the form of free base, which is preferably dispersed in the layer containing guanfacine.The preferred embodiment of guanfacine in the TTS according to the present invention is further provided below.

[0093] According to the present invention, the area of ​​emission of the TTS is 1 cm 2 From 100cm 2 , preferably 2.5 cm2 From 50cm 2 It is preferable that the range is set to be:

[0094] In a preferred embodiment of the invention, the backing layer is substantially impermeable to guanfacine. Moreover, the backing layer is preferably occlusive as outlined above.

[0095] 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 attached thereto to enhance the adhesive properties of the overall transdermal therapeutic system. The adhesive overlay comprises a backing layer and an adhesive layer. The adhesive overlay provides additional area for attachment to the skin but does not increase the area of ​​release 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.

[0096] The guanfacine-containing layer structure according to the invention, such as the guanfacine-containing self-adhesive layer structure, is usually placed on a removable protective layer (release liner), from which it is removed immediately before application to the surface of the patient's skin. Thus, the TTS further comprises a release liner. TTS protected in this manner are typically stored in blister packs or seam-sealed pouches. The packaging can be child-resistant and / or elderly-friendly.

[0097] 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, more preferably a self-adhesive guanfacine-containing matrix layer.In a preferred embodiment, the guanfacine-containing layer comprises a therapeutically effective amount of guanfacine.

[0098] 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. The guanfacine-containing layer is preferably a guanfacine-containing matrix layer.

[0099] In one embodiment, the guanfacine-containing layer comprises: i) guanfacine, preferably in the form of the free base; and ii) at least one silicone polymer Includes. The at least one silicone polymer contained in the guanfacine-containing layer should be understood to be the at least one silicone polymer contained in the TTS according to the present invention.

[0100] In a preferred embodiment, the guanfacine-containing layer comprises: i) guanfacine, preferably in the form of the free base; and ii) at least one silicone polymer A guanfacine-containing matrix layer comprising: The at least one silicone polymer contained in the guanfacine-containing layer should be understood to be the at least one silicone polymer contained in the TTS according to the present invention.

[0101] In a preferred embodiment, the guanfacine-containing layer comprises at least one silicone polymer that is a silicone pressure-sensitive adhesive. The guanfacine-containing layer is therefore preferably a guanfacine-containing matrix layer, particularly preferably a guanfacine-containing pressure-sensitive adhesive matrix layer.

[0102] In one embodiment of the present invention, the guanfacine-containing layer is obtained by dispersing guanfacine preferably in the form of free base.As a result, the guanfacine-containing layer of the TTS according to the present invention typically contains guanfacine in the form of free base.In addition, guanfacine can be partially present in protonated form in certain embodiments of the present invention.However, it is preferred that at least 50 mol%, preferably at least 75 mol% of the guanfacine in the guanfacine-containing layer is present in the form of free base.In certain preferred embodiments, at least 90 mol%, preferably at least 95 mol%, more preferably at least 99 mol% of the guanfacine in the guanfacine-containing layer is present in the form of free base.

[0103] 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, is preferably 0.1 mg to 100 mg / TTS, more preferably 0.1 mg to 72 mg / TTS. Contains guanfacine. 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 8mg to 30mg / TTS, for example 8mg to 10mg / TTS, or 17mg to 19mg / TTS. In other words, the total amount of guanfacine in the guanfacine-containing layer structure ranges from 1mg to 100mg / TTS, preferably 8mg to 72mg / TTS, more preferably 8mg to 30mg / TTS, for example 8mg to 10mg / TTS, or 17mg to 19mg / TTS.

[0104] In another embodiment, the loading of guanfacine in the guanfacine-containing layered structure is from 0.2 mg to 1.6 mg / cm 2 , preferably 0.4 mg to 1.2 mg / cm 2 Furthermore, the area of ​​emission of TTS is 1 cm 2 From 100cm 2 , preferably 2.5 cm 2 From 50cm 2 It is preferable that the range is set to be:

[0105] In one embodiment of the present invention, the guanfacine-containing layer comprises guanfacine in an amount of 1% to 20% by weight, preferably 3% to 16% by weight, more preferably 3% to 14% by weight, and most preferably 3% to 13% by weight, based on the total weight of the guanfacine-containing layer. For example, the guanfacine-containing layer may comprise guanfacine in an amount of 3% to 8% by weight, preferably 3% to 5% by weight, or 5% to 7% by weight, or in an amount of 10% to 14% by weight, preferably 11% to 13% by weight, based on the total weight of the guanfacine-containing layer, depending on the desired dosage strength of the TTS.

[0106] The layer structure containing guanfacine, preferably the layer containing guanfacine, comprises at least one silicone polymer.As used herein, the term "silicone polymer" refers to the silicone-based polymer or polysiloxane-based polymer that can be preferably obtained as outlined below.Preferably, the silicone polymer is a silicone-based pressure-sensitive adhesive polymer.

[0107] The at least one silicone polymer is obtained by polycondensation of silanol endblocked polydimethylsiloxane with silicate resin. The endblocking group is preferably a trimethylsilyl group. Preferably, the at least one silicone polymer is an amine-compatible silicone polymer. The amine-compatible silicone polymer can be obtained by reacting the silicone polymer with trimethylsilyl (e.g., hexamethyldisilazane) to reduce the silanol content of the polymer. Thus, in the context of the at least one silicone polymer, it is preferred that the residual silanol functional groups of the at least one silicone polymer are at least partially, preferably mostly or completely, capped with trimethylsiloxy groups.

[0108] The tack of the at least one silicone polymer can be varied by the resin to polymer ratio, i.e., the ratio of silanol endblocked polydimethylsiloxane to silicate resin, preferably ranging from 70:30 to 50:50, preferably 65:35 to 55:45. Tack is increased with increasing amounts of polymer relative to the resin. High tack silicone polymers preferably have a resin to polymer ratio of 55:45, medium tack silicone polymers preferably have a resin to polymer ratio of 60:40, and low tack silicone polymers preferably have a resin to polymer ratio of 65:35. High tack silicone polymers preferably have a viscosity of 5×10 at 0.01 rad / s and 30° C. 6 The medium viscosity silicone polymer preferably has a complex viscosity of about 5×10 at 0.01 rad / s and 30° C. 7 The low tack silicone polymer preferably has a complex viscosity of 5×10 at 0.01 rad / s and 30° C. 8 The high tack amine compatible silicone polymer preferably has a complex viscosity of 5×10 at 0.01 rad / s and 30° C. 6 The medium tack amine compatible silicone polymer has a complex viscosity of 0.01 Poise. 5 × 10 at rad / s and 30°C 8The low tack amine compatible silicone polymer preferably has a complex viscosity of 5×10 at 0.01 rad / s and 30° C. 9 Having a complex viscosity of poise. Preferred according to the present invention are medium and high tack silicone polymers, especially medium and high tack amine-compatible silicone polymers.

[0109] The at least one silicone polymer is preferably provided in the form of a solution, the solvent being preferably n-heptane or ethyl acetate.

[0110] In a preferred embodiment, the at least one silicone polymer is a silicone polymer, preferably a silicone-based pressure sensitive adhesive obtained according to the following scheme: [ka]

[0111] These silicone polymers, also referred to as standard silicone adhesives, are available from Dow Corning, for example, under the trademarks BIO-PSA 7-4401, BIO-PSA-7-4501 or BIO-PSA 7-4601 (designated by the code "01") in the solvent n-heptane, or under the trademarks BIO-PSA 7-4402, BIO-PSA 7-4502 and BIO 7-4602 (designated by the code "02") in the solvent ethyl acetate. Typical solids in the solvent range from 60% to 75%. Code "44" indicates a resin to polymer ratio of 65:35, which results in low adhesion, code "45" indicates a resin to polymer ratio of 60:40, which results in medium adhesion, and code "46" indicates a resin to polymer ratio of 55:45, which results in high adhesion.

[0112] In a more preferred embodiment, the at least one silicone polymer is an amine-compatible silicone polymer, preferably an amine-compatible silicone-based pressure sensitive adhesive obtained according to the following scheme: [ka]

[0113] Such amine-compatible silicone polymers are available from Dow Corning, for example, under the trademarks BIO-PSA 7-4101, BIO-PSA-7-4201 or BIO-PSA 7-4301 (designated by the code "01") in the solvent n-heptane, or under the trademarks BIO-PSA 7-4102, BIO-PSA 7-4202 and BIO 7-4302 (designated by the code "02") in the solvent ethyl acetate. Typical solids in the solvent range from 60% to 75%. Code "41" indicates a resin to polymer ratio of 65:35, which results in low adhesion, code "42" indicates a resin to polymer ratio of 60:40, which results in medium adhesion, and code "43" indicates a resin to polymer ratio of 55:45, which results in high adhesion.

[0114] In one embodiment of the present invention, the guanfacine-containing layer comprises at least one silicone polymer, preferably one or two silicone polymers.

[0115] The guanfacine-containing layer may also comprise at least one additional polymer selected from the group consisting of acrylate polymers, silicone acrylic hybrid polymers, polyisobutylene, and styrene-isoprene-styrene block copolymers, preferably selected from the group consisting of acrylate polymers, and silicone acrylic hybrid polymers.

[0116] The acrylate polymer is obtained from one or more monomers selected from acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, t-octylacrylamide and vinyl acetate, preferably from one or more monomers selected from ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate and vinyl acetate. Such acrylate polymers are available, for example, from Henkel, as described in more detail below.

[0117] Silicone acrylic hybrid polymers preferably have a silicone phase and an acrylate phase in a weight ratio of 60:40 to 40:60, most preferably 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 provided further below. It should be understood that component (a) forms primarily the silicone phase, while component (b) forms primarily the acrylate phase of the silicone acrylic hybrid polymer. The acrylate phase affects the tack and viscosity of the silicone acrylic hybrid polymer. Therefore, the ethylenically unsaturated monomer forming the acrylate phase is preferably a combination of 2-ethylhexyl acrylate and methyl acrylate, preferably in a ratio of 40:60 to 70:30. A ratio of 60:40 is preferred from the standpoint of high tack, but the viscosity is therefore lower. A ratio of 50:50 is preferred from the standpoint of higher viscosity, but the tack is therefore reduced. The silicone acrylic hybrid polymer in the guanfacine-containing layer preferably contains a continuous outer acrylic phase and a discontinuous inner silicone phase.

[0118] In one embodiment of the present invention, the guanfacine-containing layer comprises at least one silicone polymer in an amount of 20% to 99% by weight, preferably 30% to 97% by weight, most preferably 35% to 90% by weight, based on the total weight of the guanfacine-containing layer.The amount given refers to the total amount of one or more, preferably one or two silicone polymers in the guanfacine-containing layer.However, as indicated above, the guanfacine-containing layer can additionally comprise at least one further polymer, such as acrylate polymer or silicone acrylic hybrid polymer.

[0119] In a preferred embodiment, the guanfacine-containing layer comprises a first polymer, which is a silicone polymer, in an amount of 35% to 70% by weight, and a second polymer, which is selected from the group consisting of silicone polymers, acrylate polymers, and silicone-acrylic hybrid polymers, in an amount of 15% to 45% by weight, in each case based on the total weight of the guanfacine-containing layer.Thus, the guanfacine-containing layer can comprise two different silicone polymers, a silicone polymer and an acrylate polymer, or a silicone polymer and a silicone-acrylic hybrid polymer.In a particularly preferred embodiment, the guanfacine-containing layer comprises a first silicone polymer in an amount of 50% to 70% by weight, based on the total weight of the guanfacine-containing layer, and a second silicone polymer in an amount of 15% to 25% by weight, based on the total weight of the guanfacine-containing layer.

[0120] In certain preferred embodiments, the guanfacine-containing layer may further comprise a third polymer selected from the group consisting of silicone polymers, acrylate polymers, and silicone-acrylic hybrid polymers, preferably in an amount of 1% to 5% by weight based on the total weight of the guanfacine-containing layer.

[0121] 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 more detail below, preferably each present in an amount of 0.5% to 10% by weight, or 1% to 10% by weight, based on the total weight of the guanfacine-containing layer.

[0122] In a preferred embodiment, the guanfacine-containing layer comprises at least one additive selected from the group consisting of dispersants, permeation enhancers and solubilizers. In a preferred embodiment, the at least one additive, i.e., each individual additive, is present in an amount of 0.5% to 10% by weight, or 1% to 10% by weight, based on the total weight of the guanfacine-containing layer. In one preferred embodiment, the at least one additive is a dispersant. Another preferred embodiment is In a preferred embodiment, at least one additive is a permeation enhancer. In yet another preferred embodiment, at least one additive is a solubilizer. In certain preferred embodiments, combinations of the additives described above are also preferred, such as a combination of a dispersant and a permeation enhancer, or a combination of a dispersant and a solubilizer, or a combination of a permeation enhancer and a solubilizer, or a combination of a dispersant, a permeation enhancer and a solubilizer. The additives described above are particularly advantageous for providing guanfacine in a homogeneously dispersed and releasable form. It should be understood that the dispersant can also act as a permeation enhancer, and vice versa. Similarly, the solubilizer can additionally act as a dispersant or a permeation enhancer. Furthermore, the solubilizer stabilizes the guanfacine dispersion in the TTS and avoids crystallization. Furthermore, the solubilizer can help optimize the adhesion of the TTS. In certain preferred embodiments, the guanfacine-containing layer comprises at least one dispersant and at least one permeation enhancer, and optionally also at least one solubilizer.

[0123] In a preferred embodiment, the at least one additive is a dispersant present in an amount of 1% to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the dispersant is present in an amount of 2% to 6% by weight, more preferably 3% to 5% by weight, based on the total weight of the guanfacine-containing layer.

[0124] In another preferred embodiment, the at least one additive is a permeation enhancer present in an amount of 1% to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the permeation enhancer is present in an amount of 5% to 9% by weight based on the total weight of the guanfacine-containing layer.

[0125] In another embodiment, the at least one additive is a solubilizer present in an amount of 0.5% to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the solubilizer is present in an amount of 0.5% to 4% by weight, more preferably 0.5% to 3% by weight, based on the total weight of the guanfacine-containing layer.

[0126] In one embodiment, the TTS according to the present invention, particularly the guanfacine-containing layer, more particularly the guanfacine-containing matrix layer, comprises at least two additives selected from the group consisting of dispersants, permeation enhancers and solubilizers.

[0127] In a preferred embodiment, the transdermal therapeutic system, particularly the guanfacine-containing layer, more particularly the guanfacine-containing matrix layer, comprises at least two additives, where the first additive is a dispersing agent present in an amount of 1% to 10% by weight based on the total weight of the guanfacine-containing layer, and the second additive is a permeation enhancer present in an amount of 1% to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the dispersing agent is present in an amount of 1% to 6% by weight, and the permeation enhancer is present in an amount of 3% to 9% by weight. More preferably, the dispersing agent is present in an amount of 3% to 5% by weight, and the permeation enhancer is present in an amount of 5% to 9% by weight.

[0128] 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, where the first additive is a dispersant present in an amount of 1% to 10% by weight based on the total weight of the guanfacine-containing layer, and the second additive is a solubilizer present in an amount of 0.5% to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the dispersant is present in an amount of 1% to 6% by weight, and the solubilizer is present in an amount of 0.5% to 4% by weight. More preferably, the dispersant is present in an amount of 3% to 5% by weight, and the solubilizer is present in an amount of 0.5% to 3% by weight.

[0129] 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, where the first additive is a permeation enhancer present in an amount of 1% to 10% by weight based on the total weight of the guanfacine-containing layer, and the second additive is a solubilizer present in an amount of 0.5% to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the permeation enhancer is present in an amount of 3% to 9% by weight, and the solubilizer is present in an amount of 0.5% to 4% by weight. Preferably, the permeation enhancer is present in an amount of 5% to 9% by weight, and the solubilizer is present in an amount of 0.5% to 3% by weight.

[0130] In one embodiment, the TTS according to the present invention, particularly the guanfacine-containing layer, more particularly the guanfacine-containing matrix layer, comprises at least three additives selected from the group consisting of dispersants, permeation enhancers and solubilizers.

[0131] In one embodiment, the transdermal therapeutic system, particularly the guanfacine-containing layer, more particularly the guanfacine-containing matrix layer, comprises at least three additives, where the first additive is a dispersant present in an amount of 1% to 10% by weight based on the total weight of the guanfacine-containing layer, the second additive is a permeation enhancer present in an amount of 1% to 10% by weight based on the total weight of the guanfacine-containing layer, and the third additive is a solubilizer present in an amount of 0.5% to 10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the dispersant is present in an amount of 1% to 6% by weight, the permeation enhancer is present in an amount of 3% to 9% by weight, and the solubilizer is present in an amount of 0.5% to 4% by weight. More preferably, the dispersant is present in an amount of 3% to 5% by weight, the permeation enhancer is present in an amount of 5% to 9% by weight, and the solubilizer is present in an amount of 0.5% to 3% by weight.

[0132] 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, and more particularly in the guanfacine-containing matrix layer, the following specific additives are preferred.

[0133] 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, polyethylene glycol alkyl ethers, where the dispersant is preferably a polyethylene glycol C having 2 to 10 EO units, preferably 2 to 6 EO units. 8 ~C 20 A particularly preferred dispersant is polyoxyethylene (4) lauryl ether (C 12 H 25 (OCH 2 CH 2 ) 4 OH). This dispersant is available, for example, from Merck under the trademark Brij L4®.

[0134] In a preferred embodiment, the penetration 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 and oleyl alcohol, preferably oleyl alcohol, which is available, for example, from BASF under the trademark Kollicream® OA.

[0135] 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 copolymer, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. Preferably, the solubilizer is polyvinylpyrrolidone and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The solubilizer is preferably selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers. A particularly preferred solubilizer is polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. Suitable polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers are available, for example, from BASF under the trademark Soluplus® and preferably have the following structural formula, where l, m and n are selected such that the average molecular weight, as determined by gel permeation chromatography, is in the range of 90000 g / mol to 140000 g / mol. [ka]

[0136] In certain preferred embodiments, the guanfacine-containing layer comprises at least one dispersant in an amount of 2% to 6% by weight, at least one permeation enhancer in an amount of 3% to 9% by weight, and optionally at least one solubilizer in an amount of 0.5% to 4% 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 3% to 5% by weight, at least one permeation enhancer in an amount of 5% to 9% by weight, and optionally at least one solubilizer in an amount of 0.5% to 3% by weight, in each case based on the total weight of the guanfacine-containing layer.In relation to the above preferred weight percentage amounts, the above preferred dispersants, permeation enhancers and solubilizers are preferred.

[0137] Thus, in a particularly preferred embodiment, the guanfacine-containing layer is made of polyethylene glycol C 2 O having 2 to 10 EO units, in each case based on the total weight of the guanfacine-containing layer. 8 ~C 20 -alkyl ether, preferably polyoxyethylene (4) lauryl ether, in an amount of 2% to 6% by weight, oleyl alcohol in an amount of 3% to 9% by weight, and optionally, preferably polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specified above in an amount of 0.5% to 4% by weight. Most preferably, the guanfacine-containing layer comprises a polyethylene glycol C having 2 to 10 EO units, in each case based on the total weight of the guanfacine-containing layer. 8 ~C 20 -alkyl ether, preferably polyoxyethylene (4) lauryl ether, in an amount of 3% to 5% by weight, oleyl alcohol in an amount of 5% to 9% by weight, and optionally, preferably a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as specified above in an amount of 0.5% to 3% by weight.

[0138] In one embodiment of the present invention, the area weight of the guanfacine-containing layer is 40 g / m2 from 250g / m 2 , preferably 50 g / m 2 From 180 g / m 2 , more preferably 70 g / m 2 From 180 g / m 2 , e.g. 75g / m 2 From 150 g / m 2 , or 100 g / m 2 From 150 g / m 2 In one particularly preferred embodiment, the area weight is in the range of 80 g / m 2 From 120 g / m 2 , preferably 90 g / m 2 From 100g / m 2 The range is.

[0139] In view of the above, the present invention in one embodiment provides a transdermal therapeutic system for transdermal administration of guanfacine comprising a guanfacine-containing layer structure, the layer structure comprising: A) a backing layer; and B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer, comprising: i) guanfacine in an amount of 3% to 13% by weight based on the total weight of the guanfacine-containing layer; ii) at least one silicone polymer in an amount of 35% to 90% by weight based on the total weight of the guanfacine-containing layer; iii) at least one dispersing agent in an amount of 2% to 6% by weight based on the total weight of the guanfacine-containing layer; iv) at least one permeation enhancer in an amount of 2% to 10% by weight based on the total weight of the guanfacine-containing layer; and v) optionally, at least one solubilizer in an amount of 0.5% to 4% by weight based on the total weight of the guanfacine-containing layer; The present invention relates to a transdermal therapeutic system comprising: In connection with this embodiment, it is further preferred that the guanfacine-containing layer structure does not include an additional skin contact layer.Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents the skin contact layer and has pressure-sensitive adhesive properties due to the silicone polymer.

[0140] In a preferred embodiment, the guanfacine-containing layer comprises: i) guanfacine in an amount of 3% to 13% by weight based on the total weight of the guanfacine-containing layer; ii) at least one silicone polymer in an amount of 35% to 90% by weight based on the total weight of the guanfacine-containing layer; iii) polyethylene glycol C having 2 to 10 EO units in an amount of 2% to 6% by weight based on the total weight of the guanfacine-containing layer. 8 ~C 20 - alkyl ethers; iv) oleyl alcohol in an amount of 2% to 10% by weight based on the total weight of the guanfacine-containing layer; and v) optionally, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in an amount of 0.5% to 4% by weight based on the total weight of the guanfacine-containing layer; A guanfacine-containing matrix layer comprising: Furthermore, the area weight of the guanfacine-containing layer is 80 g / m 2 From 120 g / m 2 , preferably 90 g / m 2 From 120 g / m 2 It is preferable that the range is set to be:

[0141] In a particularly preferred embodiment, the guanfacine-containing layer comprises: i) guanfacine in an amount of 3% to 13% by weight based on the total weight of the guanfacine-containing layer; ii) a first silicone polymer in an amount of 50% to 70% by weight based on the total weight of the guanfacine-containing layer, and a second silicone polymer in an amount of 15% to 25% by weight based on the total weight of the guanfacine-containing layer; iii) polyethylene glycol C having 2 to 10 EO units in an amount of 3% to 5% by weight based on the total weight of the guanfacine-containing layer. 8 ~C 20 - alkyl ethers, preferably polyoxyethylene(4) lauryl ether; iv) oleyl alcohol in an amount of 5% to 9% by weight based on the total weight of the guanfacine-containing layer; and v) optionally, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in an amount of 0.5% to 3% by weight based on the total weight of the guanfacine-containing layer; A guanfacine-containing matrix layer comprising: Furthermore, the area weight of the guanfacine-containing layer is 80 g / m 2 From 120 g / m 2 , preferably 90 g / m 2 From 120 g / m 2 It is preferable that the range is set to be:

[0142] 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; wherein the transdermal therapeutic system comprises at least one silicone polymer. The guanfacine-containing layer, which is preferably a guanfacine-containing matrix layer, has been described in detail above.

[0143] In one embodiment of the present invention, the amount of guanfacine contained in the guanfacine-containing layer structure ranges from 1 mg to 100 mg / TTS, preferably from 8 mg to 72 mg / TTS, more preferably from 8 mg to 30 mg / TTS, such as from 8 mg to 10 mg / TTS, or from 17 mg to 19 mg / TTS. Further details on this have been provided above.

[0144] In one 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. Preferably, the guanfacine in the guanfacine-containing layer structure is present in the form of free base.

[0145] In one embodiment of the present invention, at least 50 mol%, preferably at least 75 mol%, of the total amount of guanfacine in the TTS is present in the form of free base.In certain preferred embodiments, at least 90 mol%, preferably at least 95 mol%, more preferably at least 99 mol%, of the total amount of guanfacine in the TTS is present in the form of free base.Therefore, it is preferred that at least 50 mol%, preferably at least 75 mol%, of the guanfacine in the guanfacine-containing layer is present in the form of free base.In certain preferred embodiments, at least 90 mol%, preferably at least 95 mol%, more preferably at least 99 mol%, of the guanfacine in the guanfacine-containing layer is present in the form of free base.In certain embodiments, the guanfacine-containing layer is free of guanfacine salt.

[0146] In certain embodiments, the amount of guanfacine in the guanfacine-containing layer ranges from 1% to 20% by weight, preferably from 3% to 16% by weight, most preferably from 3% to 14% by weight, such as from 11% to 13% by weight, or from 7% to 9% by weight, or from 3% to 5% by weight, based on the total weight of the guanfacine-containing layer.

[0147] In one embodiment of the present invention, the guanfacine-containing layer is obtained by dispersing guanfacine in the form of the free base. If the guanfacine-containing layer is a guanfacine-containing matrix layer, said layer, which particularly preferably comprises a silicone-acrylic hybrid polymer and, optionally, at least one additive as defined above, in particular at least one dispersing agent, is preferably obtained by dispersing guanfacine in the form of the free base in a polymer carrier. Obtained by dispersing fascin.

[0148] In one embodiment, the guanfacine-containing layer comprises a pharma- ceutically acceptable salt of guanfacine, such as guanfacine hydrochloride or guanfacine tartrate, preferably guanfacine hydrochloride. However, according to the present invention, it is preferred that the guanfacine in the guanfacine-containing layer is present in the form of the free base.

[0149] In certain embodiments, the guanfacine has a purity of at least 95%, preferably at least 98%, more preferably at least 99% as determined by quantitative HPLC, which can be performed by reverse-phase HPLC with UV detection.

[0150] Silicone Acrylic Hybrid Polymer The TTS according to the present invention can comprise 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 that are polymerized together. The silicone acrylic hybrid polymer thus comprises a silicone phase and an acrylic phase. Preferably, the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive.

[0151] 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 can be modified by adding an appropriate amount of solvent.

[0152] 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 Dow Corning.

[0153] Preferred silicone acrylic hybrid pressure sensitive adhesives according to the present invention are characterized by a solution viscosity of greater than about 400 cP, or from about 500 cP to about 3,500 cP, particularly from about 1,000 cP to about 3,000 cP, more preferably from about 1,200 cP to about 1,800, 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 at 25° C. and about 50% solids in ethyl acetate, preferably using a Brookfield RVT Viscometer equipped with spindle number 5 at 50 RPM.

[0154] These silicone acrylic hybrid pressure sensitive adhesives may also be characterized by a complex viscosity of 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 at 30° C. at 0.1 rad / s, preferably using a Rheometrics ARES rheometer where the rheometer is equipped with 8 mm plates and a zeroed gap.

[0155] To prepare samples for measuring rheological behavior using the Rheometrics ARES rheometer, between 2 and 3 grams of adhesive solution are poured onto a SCOTCH-PAK 1022 fluoropolymer release liner and left for 60 minutes under ambient conditions. To achieve an essentially solvent-free film of adhesive, they are placed in an oven at 110°C + / - 10°C for 60 minutes. After removal from the oven and equilibrating to room temperature, the film can be removed from the release liner and folded over to form a square. To expel air bubbles, the film can be compressed using a Carver press. The sample is then filled between the plates and compressed to 1.5 + / - 0.1 mm at 30°C. Excess adhesive is removed and the final gap is recorded. A frequency sweep between 0.01 rad / s and 100 rad / s can be performed with the following settings: temperature = 30°C; strain = 0.5-1%, and data collected at 3 time points / decade.

[0156] Suitable commercially available silicone acrylic hybrid pressure sensitive adhesives include PSA series 7-6100 and 7-6300 manufactured and supplied by Dow Corning in n-heptane or ethyl acetate (7-610X and 7-630X; X=1 n-heptane based / X=2 ethyl acetate based). For example, 7-6102 silicone acrylic hybrid PSA with a 50 / 50 silicone / acrylate ratio is characterized by a solution viscosity of 2,500 cP at 25°C and about 50% solids in ethyl acetate and a complex viscosity of 1.0e7 poise at 30°C at 0.1 rad / s. 7-6302 silicone acrylic hybrid PSA with a 50 / 50 silicone / acrylate ratio is characterized by a solution viscosity of 1,500 cP at 25°C and about 50% solids in ethyl acetate and a complex viscosity of 4.0e6 poise at 30°C at 0.1 rad / s.

[0157] Depending on the solvent in which the silicone acrylic hybrid pressure sensitive adhesive is provided, the silicone phase and acrylic phase arrangement will be different, providing a silicone or acrylic continuous external phase and a corresponding discontinuous internal phase. If 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. If 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 any substance that can induce the inversion of the phase arrangement in the silicone acrylic hybrid pressure sensitive adhesive composition, the pressure sensitive adhesive layer prepared from the silicone acrylic hybrid pressure sensitive adhesive in n-heptane will provide a continuous silicone external phase and a discontinuous acrylic internal phase, and the pressure sensitive adhesive layer prepared from the silicone acrylic hybrid pressure sensitive adhesive in ethyl acetate will provide a continuous acrylic external phase and a discontinuous silicone internal phase. The phase sequence 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. If the siliconized release liner cannot or hardly can be removed from the pressure-sensitive adhesive film (laminated to a backing film) due to the blockage of the two silicone surfaces, the pressure-sensitive adhesive film contains a continuous silicone outer phase. The blockage is due to the adhesion of two silicone layers with similar surface energies. The silicone adhesive shows good spreading on the siliconized liner and can therefore create good adhesion to the liner. If the siliconized release liner can be easily removed, the pressure-sensitive adhesive film contains a continuous acrylic outer phase. The acrylic adhesive does not have good spreading due to the different surface energies and therefore cannot be easily attached to the siliconized liner. Has low or almost no adhesion.

[0158] According to a preferred embodiment of the present invention, the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive obtained from the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional group.It should be understood that the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional group can contain only acrylate functional group, only methacrylate functional group, or both acrylate functional group and methacrylate functional group.

[0159] According to a certain embodiment of the present invention, the silicone acrylic hybrid pressure-sensitive adhesive comprises the reaction product of (a) a silicon-containing pressure-sensitive adhesive composition comprising 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 the chemical reaction between these reactants ((a), (b) and (c)). In particular, the silicone acrylic hybrid pressure-sensitive adhesive comprises the reaction product (i.e., in the presence of the initiator) of (a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups, (b) a (meth)acrylate monomer, and (c) an initiator. That is, the silicone acrylic hybrid pressure-sensitive adhesive comprises the product of the chemical reaction between these reactants ((a), (b) and (c)).

[0160] The reaction product of (a) the silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups, (b) the ethylenically unsaturated monomer, and (c) the initiator can contain a continuous silicone external phase and a discontinuous acrylic internal phase, or the reaction product of (a), (b) and (c) can contain a continuous acrylic external phase and a discontinuous silicone internal phase.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] According to a particular embodiment of the present invention, the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional group (a) comprises the condensation reaction product of (a1) silicone resin, (a2) silicone polymer, and (a3) ​​silicon-containing capping agent providing said acrylate or methacrylate functional group. Silicone resin (a1) can also be referred to as silicate resin or silica resin. Preferably, silicone polymer (a2) is a polysiloxane, preferably polydimethylsiloxane. It should be understood that (a1) and (a2) form a silicone-based pressure-sensitive adhesive by polycondensation, and that acrylate or methacrylate functional group is introduced by reaction with (a3).

[0165] According to one particular embodiment of the present invention, the polymer comprises an acrylate or methacrylate functional group. The silicon-containing pressure sensitive adhesive composition (a) comprises: (a1) a silicone resin, (a2) a silicone polymer, and (a3) a silicon-containing capping agent that provides the acrylate or methacrylate functionality, wherein the silicon-containing capping agent has the general formula XYR′ b SiZ 3-b where: X is a monovalent group of the 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; b is 0 or 1; and wherein a silicone resin and a silicone polymer are reacted to form a pressure sensitive adhesive, and a silicon-containing capping agent is introduced before, during or after the silicone resin and the silicone polymer are reacted: the silicon-containing capping agent reacts with the pressure sensitive adhesive after the silicone resin and silicone polymer have been condensed to form the pressure sensitive adhesive; or The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer.

[0166] According to a particular embodiment of the present invention, the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups comprises a condensation reaction product of a pressure-sensitive adhesive and a silicon-containing capping agent that provides said acrylate or methacrylate functional groups. That is, the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups is essentially a pressure-sensitive adhesive that is capped or endblocked with a silicon-containing capping agent that provides said acrylate or methacrylate functional groups, where 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 parts by weight to 80 parts by weight to form the pressure-sensitive adhesive, and the silicone polymer is reacted in an amount of 20 parts by weight to 70 parts by weight to form the pressure-sensitive adhesive. Both of these parts by weight are based on 100 parts by weight of the pressure-sensitive adhesive. Although not required, the pressure-sensitive adhesive can include a catalytic amount of a condensation catalyst. A variety of silicone resins and silicone polymers are suitable for forming the pressure-sensitive adhesive.

[0167] According to one particular embodiment of the present invention, the silicone acrylic hybrid pressure sensitive adhesive comprises: (a) a silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functionality comprising the condensation reaction product of: (a1) a silicone resin, (a2) a silicone polymer, and (a3) a silicon-containing capping agent that provides the acrylate or methacrylate functionality, wherein the silicon-containing capping agent has the general formula XYR′ b SiZ 3-b where: X is a monovalent group of the 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; b is 0 or 1; wherein a silicone resin and a silicone polymer are reacted to form a pressure sensitive adhesive, and a silicon-containing capping agent is introduced before, during or after the silicone resin and the silicone polymer are reacted: The silicon-containing capping agent reacts with the pressure sensitive adhesive after the silicone resin and silicone polymer have been condensed to form the pressure sensitive adhesive; or The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer; (b) ethylenically unsaturated monomers; and (c) Initiator It is the reaction product of

[0168] The silicone acrylic hybrid composition used in the present invention comprises: (i) providing a silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functionality comprising the condensation reaction product of: Silicone resin, Silicone polymers, and a silicon-containing capping agent providing said acrylate or methacrylate functionality, said silicon-containing capping agent having the general formula XYR' b SiZ 3-b where: X is a monovalent group of the 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; b is 0 or 1; wherein a silicone resin and a silicone polymer are reacted to form a pressure sensitive adhesive, and a silicon-containing capping agent is introduced before, during or after the silicone resin and the silicone polymer are reacted: The silicon-containing capping agent reacts with the pressure sensitive adhesive after the silicone resin and silicone polymer have been condensed to form the pressure sensitive adhesive; or The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer; (ii) polymerizing the ethylenically unsaturated monomer and the silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups of step (i) in the presence of an initiator, optionally at a temperature of from 50° C. to 100° C., or from 65° C. to 90° C., to form a silicone acrylic hybrid composition. The compound can be described by being prepared by a method comprising:

[0169] During polymerization of silicon-containing pressure-sensitive adhesive compositions containing ethylenically unsaturated monomers and acrylate or methacrylate functional groups, the silicone to acrylic ratio can be controlled and optimized as desired.The silicone to acrylic ratio can be controlled by a variety of mechanisms in and during the process.An illustrative example of one such mechanism is the rate-controlled addition of an ethylenically unsaturated monomer or monomers to silicon-containing pressure-sensitive adhesive compositions containing acrylate or methacrylate functional groups.In certain applications, it may be desirable to have a silicone-based subspecies or overall silicone content that exceeds the acrylate-based subspecies or overall acrylic content.In other applications, it may be desirable for the opposite to be true.Regardless of the end use, generally, the silicone to acrylic ratio can be controlled by a variety of mechanisms in and during the process.An illustrative example of one such mechanism is the rate-controlled addition of an ethylenically unsaturated monomer or monomers to silicon-containing pressure-sensitive adhesive compositions containing acrylate or methacrylate functional groups.In certain applications, it may be desirable to have a silicone-based subspecies or overall silicone content that exceeds the acrylate-based subspecies or overall acrylic content.In other applications, it may be desirable for the opposite to be true.In general, the silicone to acrylic ratio can be controlled by a variety of mechanisms in and during the process.The ... The isopropyl-containing pressure sensitive adhesive composition is preferably present in the silicone acrylic hybrid composition in an amount of from about 5 to about 95 parts by weight, more preferably from about 25 to about 75 parts by weight, and even more preferably from about 40 to about 60 parts by weight, based on 100 parts by weight of the silicone acrylic hybrid composition.

[0170] According to one particular embodiment of the present invention, the silicone acrylic hybrid composition used in the present invention comprises: (i) providing a silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functionality comprising the condensation reaction product of: Silicone resin, Silicone polymers, and a silicon-containing capping agent providing said acrylate or methacrylate functionality, said silicon-containing capping agent having the general formula XYR' b SiZ 3-b where: X is a monovalent group of the 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; b is 0 or 1; wherein a silicone resin and a silicone polymer are reacted to form a pressure sensitive adhesive, and a silicon-containing capping agent is introduced before, during or after the silicone resin and the silicone polymer are reacted: The silicon-containing capping agent reacts with the pressure sensitive adhesive after the silicone resin and silicone polymer have been condensed to form the pressure sensitive adhesive; or The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer; (ii) polymerizing the ethylenically unsaturated monomer and the silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups of step (i) in the presence of an initiator in a first solvent at a temperature of 50° C. to 100° C. to form a silicone acrylic hybrid composition; (iii) removing the first solvent; and (iv) forming a silicone acrylic hybrid composition by adding a second solvent, where the phase sequence of the silicone acrylic hybrid composition is selectively controlled by the selection of the second solvent. The compound can be described by being prepared by a method comprising:

[0171] The silicone acrylic hybrid PSA composition used in the present invention comprises: (i) providing a silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functionality comprising the condensation reaction product of: Silicone resin, Silicone polymers, and a silicon-containing capping agent providing said acrylate or methacrylate functionality, said silicon-containing capping agent having the general formula XYR' b SiZ 3-b where: X is a monovalent group of the 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; b is 0 or 1; wherein a silicone resin and a silicone polymer are reacted to form a pressure sensitive adhesive, and a silicon-containing capping agent is introduced before, during or after the silicone resin and the silicone polymer are reacted: The silicon-containing capping agent reacts with the pressure sensitive adhesive after the silicone resin and silicone polymer have been condensed to form the pressure sensitive adhesive; or The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer; (ii) polymerizing the ethylenically unsaturated monomer and the silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups of step (i) in a first solvent in the presence of an initiator at a temperature of 50° C. to 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; and (iv) applying heat at a temperature of from 70° C. to 150° C. such that a majority of the first solvent is selectively removed; (v) removing the processing solvent; and (vi) forming a silicone acrylic hybrid composition by adding a second solvent, where the phase sequence of the silicone acrylic hybrid composition is selectively controlled by the selection of the second solvent. It can also be described by being prepared by a method comprising:

[0172] The silicone resin according to the previous paragraph has the formula R X 3 SiO 1 / 2 and triorganosiloxy units of the formula SiO 4 / 2 In the present invention, the copolymer may contain tetrafunctional siloxy units of from 0.1 to 0.9, preferably about 0.6 to 0.9, triorganosiloxy units for each tetrafunctional siloxy unit. X independently represent a monovalent hydrocarbon group having 1 to 6 carbon atoms, a vinyl group, a hydroxyl group, or a phenyl group.

[0173] The silicone polymer according to the previous paragraph may comprise at least one polydiorganosiloxane, preferably endcapped (endblocked) with a functional group selected from the group consisting of hydroxyl, alkoxy, hydride, vinyl, or mixtures thereof. The diorgano substituents may be selected from the group consisting of dimethyl, methylvinyl, methylphenyl, diphenyl, methylethyl, (3,3,3-trifluoropropyl)methyl, and mixtures thereof. Preferably, the diorgano substituents contain only methyl groups. The molecular weight of the polydiorganosiloxane typically ranges from about 50,000 to about 1,000,000, preferably from about 80,000 to about 300,000. Preferably, the polydiorganosiloxane is ... X ASiO 1 / 2 AR terminated with unit X SiO units, where the poly-diorganosiloxane has a viscosity of about 100 centipoise to about 30,000,000 centipoise at 25° C., and each A group is 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 is independently selected from the group consisting of Y is independently an alkyl group having 1 to 4 carbon atoms.

[0174] As an example of using the preferred silicone resin and preferred silicone polymer morphology, one type of pressure sensitive adhesive is made by: (i) each SiO 2 present that contains silicon-bonded hydroxyl groups; 4 / 2 R of 0.6 to 0.9 for units X 3 SiO 1 / 2 The unit is mole ratio, R X 3 SiO 1 / 2 Units and SiO 4 / 2 At least 30 parts by weight to 80 parts by weight, inclusive, as required by the unit (ii) a resin copolymer, endblocked by TRX ASiO 1 / 2 AR terminated with unit X Between about 20 parts by weight and about 70 parts by weight of at least one polydiorganosiloxane containing SiO units, where the polydiorganosiloxane has a viscosity of about 100 centipoise to about 30,000,000 centipoise at 25° C., and each R X is a monovalent organic radical selected from the group consisting of hydrocarbon radicals of 1 to 6 carbon atoms, inclusive; each A group is R X or a halohydrocarbon group having 1 to 6 carbon atoms, inclusive; each T group is independently selected from R X , OH, H or OR Y and each R is independently selected from the group consisting of Y are independently, inclusively, an alkyl group of 1 to 4 carbon atoms; (iii) thereon a sufficient amount of at least one of the silicon-containing capping agents, referred to throughout and described below as endblocking agents, capable of providing a silanol content or concentration in the range of 5,000 ppm to 15,000 ppm, more typically 8,000 ppm to 13,000 ppm, and, if desired, (iv) an additional catalytic amount of a mild silanol condensation catalyst if none is provided by (ii), and, if necessary, (v) mixing an effective amount of an organic solvent inert with respect to (i), (ii), (iii) and (iv) to reduce the viscosity of the mixture of (i), (ii), (iii) and (iv), and condensing the mixture of (i), (ii), (iii) and (iv) until at least a substantial amount of the silicon-containing capping agent or agents has reacted with the silicon-bonded hydroxyl groups and T groups of (i) and (ii). Additional organosilicon endblocking agents may be used in conjunction with the silicon-containing capping agent or agent (iii) of the present invention.

[0175] The silicon-containing capping agent according to the previous paragraph can 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 can be represented by the general formula XYR′ b SiZ 3-bwhere X is a monovalent group 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, 1 or 2. Preferably, the monovalent hydrolyzable organic group is of the general formula R"0-, where R" is an alkylene group. Most preferably, the 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)trimethyl ...

[0043] The compound is selected from the group consisting of acryloxysilane, (methacryloxymethyl)dimethylethoxysilane, (methacryloxymethyl)methyldiethoxysilane, methacryloxymethyltriethoxysilane, methacryloxy-propyltriisopropoxysilane, 3-methacryloxypropyldimethylsilazane, 3-acryloxy-propyldimethylchlorosilane, 3-acryloxypropyldichlorosilane, 3-acryloxypropyl-trichlorosilane, 3-acryloxypropyldimethylmethoxysilane, 3-acryloxy-propylmethyldimethoxysilane, 3-acryloxypropyltrimethoxysilane, 3-acryloxypropyldimethylsilazane, and combinations thereof.

[0176] The ethylenically unsaturated monomer according to the previous paragraph may be any monomer having at least one carbon-carbon double bond. Preferably, the ethylenically unsaturated monomer according to the previous paragraph may be a compound selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates, cycloaliphatic methacrylates, and combinations thereof. The compound Each of the aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates and cycloaliphatic methacrylates should be understood to include an alkyl group. The alkyl groups of these compounds can include up to 20 carbon atoms. The aliphatic acrylates that can be selected as one of the ethylenically unsaturated monomers are selected from the group consisting of methyl acrylate, ethyl acrylate, propyl acrylate, n-butyl acrylate, iso-butyl acrylate, tert-butyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, iso-octyl acrylate, iso-nonyl acrylate, iso-pentyl acrylate, tridecyl acrylate, stearyl acrylate, lauryl acrylate, and mixtures thereof. The aliphatic methacrylate that can 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 can be selected as one of the ethylenically unsaturated monomers is cyclohexyl acrylate, and the alicyclic methacrylate that can be selected as one of the ethylenically unsaturated monomers is cyclohexyl methacrylate.

[0177] It should be understood that the ethylenically unsaturated monomer used to prepare silicone acrylic hybrid pressure sensitive adhesive can be more than one ethylenically unsaturated monomer.That is, a combination of ethylenically unsaturated monomers can be polymerized, more specifically copolymerized together with the silicon-containing pressure sensitive adhesive composition that comprises acrylate or methacrylate functional group and initiator.According to a certain embodiment of the present invention, silicone acrylic hybrid pressure sensitive adhesive is prepared by using at least two different ethylenically unsaturated monomers as acrylic monomers, preferably selected from the group of 2-ethylhexyl acrylate and methyl acrylate, 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.

[0178] The initiator according to the previous paragraph can 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 of peroxides, azo compounds, redox initiators and photoinitiators can be used.

[0179] Further suitable silicone resins, silicone polymers, silicon-containing capping agents, ethylenically unsaturated monomers and initiators that can be used in accordance with the preceding paragraph are detailed in WO2007 / 145996, EP2599847A1 and WO2016 / 130408.

[0180] According to certain 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, where the acrylic polymer is covalently self-crosslinked and covalently bonded to the silicone polymer and / or the silicone resin.

[0181] According to certain other 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, wherein the silicone resin comprises triorganosiloxy units R, where R is an organic group. 3 SiO 1 / 2 , and the tetrafunctional siloxy unit SiO 4 / 2 Each SiO 4 / 2 0.1 to 0 R of .9 3 SiO 1 / 2 The molar ratio of each component is expressed as:

[0182] 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 comprises an alkoxysilyl-functional group prepared from or end-capped with an alkoxysilyl-functional monomer selected from the group consisting of trialkoxysilyl (meth)acrylate, dialkoxyalkylsilyl (meth)acrylate, and mixtures thereof.The alkoxysilyl-functional group may preferably be selected from the group consisting of trimethoxylsilyl, dimethoxymethylsilyl, triethoxylsilyl, diethoxymethylsilyl, and mixtures thereof.

[0183] Acrylic polymers can also be prepared from mixtures that include polysiloxane-containing monomers, preferably polydimethylsiloxane mono(meth)acrylate.

[0184] The silyl-functional monomer is typically used in an amount of from 0.2% to 20% by weight of the acrylic polymer, and more preferably, the amount of silyl-functional monomer ranges from about 1.5% to about 5% by weight of the acrylic polymer.

[0185] The amount of polysiloxane-containing monomer is typically used in an amount of from 1.5% to 50% by weight of the acrylic polymer, and more preferably the amount of polysiloxane-containing monomer ranges from 5% to 15% by weight of the acrylic polymer.

[0186] Alternatively, the acrylic polymer comprises a block or grafted 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% by weight of the total block polymer.

[0187] 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 with homopolymer Tg 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. Particularly preferred are butyl acrylate, 2-ethylhexyl acrylate, and isooctyl acrylate. The acrylic polymer component can further include (meth)acrylate monomers with high Tg, such as methyl acrylate, ethyl acrylate, methyl methacrylate, and isobutyl methacrylate.

[0188] The acrylic polymer component may further include polyisobutylene groups to improve the low temperature flow properties of the resulting adhesive.

[0189] The acrylic polymer component may include nitrogen-containing polar monomers, examples of which include N-vinylpyrrolidone, N-vinylcaprolactam, N-tertiary octyl acrylamide, dimethylacrylamide, diacetone acrylamide, N-tertiary butyl acrylamide, N-isopropyl acrylamide, cyanoethyl acrylate, N-vinyl acetamide, and N-vinyl formamide.

[0190] The acrylic polymer component may be 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, hydroxypropyl acrylate and / or hydroxypropyl The polymer may include one or more hydroxyl-containing monomers, such as dimethacrylate.

[0191] The acrylic polymer component can include carboxylic acid-containing monomers, if desired. Useful carboxylic acids preferably contain from about 3 to about 6 carbon atoms and include acrylic acid, methacrylic acid, itaconic acid, and β-carboxyethyl acrylate, among others. Acrylic acid is particularly preferred.

[0192] 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.

[0193] One acrylic polymer component that can be used in the practice of the present invention is an acrylic polymer that includes about 90% to about 99.5% by weight butyl acrylate and about 0.5% to about 10% by weight dimethoxymethylsilyl methacrylate.

[0194] In accordance with certain embodiments of the present invention, a silicone acrylic hybrid polymer can 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 the components are reacted in an organic solvent.

[0195] According to certain embodiments of the present invention, a silicone acrylic hybrid polymer can 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, wherein the components are reacted in an organic solvent.

[0196] According to certain embodiments of the present invention, a silicone acrylic hybrid polymer can 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 the components are reacted in an organic solvent.

[0197] 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.

[0198] According to certain embodiments of the present invention, the silicone acrylic hybrid polymer used in the TTS is blended with one or more non-hybrid polymers, preferably the silicone acrylic hybrid polymer is blended with one or more non-hybrid pressure sensitive adhesives (e.g., polysiloxane or acrylate based pressure sensitive adhesives).

[0199] Non-hybrid polymers The TTS according to the present invention comprises at least one silicone polymer and, optionally, at least one further polymer, which may be a non-hybrid polymer, such as an acrylate polymer.

[0200] A non-hybrid polymer (e.g., a non-hybrid pressure sensitive adhesive) is a polymer (e.g., a polymer-based pressure sensitive adhesive) that does not contain a hybrid species. Preferred are non-hybrid polymers (e.g., non-hybrid pressure sensitive adhesives) based on polysiloxanes, acrylates, polyisobutylene, or styrene-isoprene-styrene block copolymers.

[0201] Non-hybrid polymers (eg, non-hybrid pressure sensitive adhesives) can be included in the active agent-containing layer structure and / or in the adhesive overlay.

[0202] Non-hybrid pressure sensitive adhesives are typically supplied and used in solvents such as n-heptane and ethyl acetate. The solids content of pressure sensitive adhesives is typically between 30% and 80%.

[0203] Suitable non-hybrid polymers according to the invention are commercially available, for example, under the trade names BIO-PSA (polysiloxane-based pressure-sensitive adhesives), Oppanol™ (polyisobutylene), JSR-SIS (styrene-isoprene-styrene copolymer) or Duro-Tak™ (acrylic polymer).

[0204] The polysiloxane-based polymer can also be called silicone-based polymer or silicone polymer or silicone. The polysiloxane-based pressure-sensitive adhesive can also be called silicone-based pressure-sensitive adhesive or silicone pressure-sensitive adhesive. These polysiloxane-based pressure-sensitive adhesives provide suitable adhesion and rapid bonding to various skin types, including wet skin, suitable adhesive and adhesion qualities, long-lasting adhesion to skin, high degree of flexibility, moisture permeability, and compatibility with many actives and film substrates. They can provide sufficient amine resistance and therefore enhanced stability in the presence of amines. These pressure-sensitive adhesives are based on the resin-in-polymer concept, where the polysiloxane-based pressure-sensitive adhesive is prepared by the condensation reaction of silanol endblocked polydimethylsiloxane with silicate resin (also called silica resin), where 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 visco-elastic behavior and influences the wetting and spreading properties of the adhesive. The resin acts as a tackifier and reinforcing agent and participates in the elastic component. The corrective balance between the silanol endblocked polydimethylsiloxane and the resin provides the corrective adhesive properties.

[0205] In view of the above, silicone-based polymers, particularly silicone-based pressure-sensitive adhesives, are generally obtained by polycondensation of silanol endblocked polydimethylsiloxanes with silicate resins. 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, the remaining silanol functional groups are at least partially, preferably mostly or completely capped with trimethylsiloxy groups.

[0206] As indicated above, the tack of the silicone-based polymers can be modified by the resin to polymer ratio, i.e., the ratio of silanol endblocked polydimethylsiloxane to silicate resin, which preferably ranges from 70:30 to 50:50, preferably 65:35 to 55:45. Tack is increased with increasing amounts of polydimethylsiloxane relative to resin. High tack silicone-based polymers are preferably obtained with a resin to polymer ratio of 55:45. The medium tack silicone-based polymer preferably has a resin to polymer ratio of 60:40, and the low tack silicone-based polymer preferably has a resin to polymer ratio of 65:35. The high tack silicone-based polymer preferably has a viscosity of about 5×10 at 0.01 rad / s and 30° C. 6 The medium viscosity silicone-based polymer has a complex viscosity of about 5×10 at 0.01 rad / s and 30° C. 7 The low tack silicone-based polymer preferably has a complex viscosity of about 5×10 at 0.01 rad / s and 30° C. 8 The highly tacky, amine-compatible silicone-based polymer preferably has a complex viscosity of about 5×10 at 0.01 rad / s and 30° C. 6 A moderately viscous, amine-compatible silicone-based polymer having a complex viscosity of poise is preferably about 5×10 at 0.01 rad / s and 30° C. 8 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 has a complex viscosity in poise.

[0207] Examples of commercially available silicone-based PSA compositions include the standard BIO-PSA series (7-4400, 7-4500 and 7-4600 series) manufactured and typically delivered by Dow Corning in n-heptane or ethyl acetate, the amine-compatible (end-capped) BIO-PSA series (7-4100, 7-4200 and 7-4300 series), and the Soft Skin Adhesives series (7-9800) manufactured and typically delivered by Dow Corning solvent-free. For example, BIO-PSA 7-4201 has a solution viscosity of 450 mPa s at 25°C and about 73% solids in heptane and a viscosity of 1 x 10 at 30°C at 0.01 rad / s. 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 approximately 73% solids in heptane, and a complex viscosity of 5 × 10 at 30 °C at 0.01 rad / s. 6 It has a complex viscosity in poise.

[0208] Silicone polymer is supplied and used in a solvent such as n-heptane, ethyl acetate or other volatile silicone fluid. For the present invention, n-heptane is preferred. The solid content of silicone polymer in the solvent is usually between 60% and 80%, preferably between 70% and 80%, or between 60% and 70%. Those skilled in the art know that the solid content can be modified by adding an appropriate amount of solvent.

[0209] Preferred pressure sensitive adhesives based on polysiloxanes according to the invention are characterized by a solution viscosity of greater than about 150 mPa s, or from about 200 mPa s to about 700 mPa s, as measured at 25° C. and 60% solids in n-heptane, preferably at 50 rpm using a Brookfield RVT viscometer equipped with spindle number 5. These have a viscosity of about 1×10 at 30° C. at 0.01 rad / s. 9 Less than poise, or about 1 x 10 5 From about 9 × 10 8 It may also be characterized as a complex viscosity in poise.

[0210] Suitable polyisobutylenes according to the invention are available under the trade name Oppanol®. Combinations of high molecular weight polyisobutylene (B100 / B80) and low molecular weight polyisobutylene (B10, B11, B12, B13) may be used. Suitable ratios of low molecular weight polyisobutylene to high molecular weight polyisobutylene range from 100:1 to 1:100, preferably from 95:5 to 40:60, more preferably from 90:10 to 80:20. A preferred example for a polyisobutylene combination is B10 / B100 in a ratio of 85 / 15. Oppanol® B100 has a viscosity average molecular weight M of 1,110,000. v , and a weight average molecular weight M of 1,550,000 w , and an average molecular weight distribution M of 2.9 w / M n Oppanol® B10 has a viscosity average molecular weight M of 40,000. v , and a weight average molecular weight M of 53,000 w , and the average molecular weight distribution M of 3.2 w / M n In certain embodiments, polybutene can be added to polyisobutylene. The solids content of polyisobutylene in the solvent is typically 3 It is between 0% and 50%, preferably between 35% and 40%. Those skilled in the art know that the solid content can be modified by adding an appropriate amount of solvent.

[0211] The acrylate-based pressure-sensitive adhesive may also be referred to as an acrylate-based pressure-sensitive adhesive or an acrylate pressure-sensitive adhesive. The acrylate-based pressure-sensitive adhesive may preferably have a solids content between 30% and 60%. Such 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 in particular to hydroxy and carboxylic acid groups, as well as deprotonated carboxylic acid groups.

[0212] Corresponding commercial products are available, for example, from Henkel under the trademark 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, 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.

[0213] Specific acrylate-based pressure sensitive adhesives are: - 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 crosslinking agent), - 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 (copolymer based on acrylic acid, butyl acrylate, 2-ethylhexyl acrylate and vinyl acetate, provided as a solution in ethyl acetate and heptane), Duro-Tak® 387-2353 or Duro-Tak® 87-2353 (copolymer 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) It is available as:

[0214] Additional polymers may also be added to enhance cohesion and / or adhesion.

[0215] Certain polymers in particular reduce cold flow and are therefore particularly suitable as additional polymers. Polymeric matrices can exhibit cold flow because such polymer compositions often exhibit the ability to flow very slowly despite very high viscosity. Thus, during storage, the matrix can flow to some extent around the edges of the backing layer. This is a storage stability issue that can be prevented by the addition of certain polymers. Basic acrylate polymers (e.g., based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate) are preferred. Eudragit® E100, a copolymer based on dimethylaminoethyl methacrylate, can be used, for example, to reduce cold flow. Thus, in certain embodiments, the matrix layer composition additionally comprises a basic polymer, in particular an amine-functional acrylate, such as Eudragit® E100. Eudragit® E100 is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate with a ratio of 2:1:1. The monomers are randomly distributed along the copolymer chain. Based on the SEC method, the weight-average molar mass (Mw) of Eudragit® E100 is approximately 47,000 g / mol. In addition, polymers such as Plastoid B, acrylic polymers such as Eudragits, chitosan, cellulose and its derivatives, and polystyrene can be useful to increase the dryness of the adhesive (e.g., matrix layer).

[0216] Further Additives The TTS according to the present invention, particularly the layer containing guanfacine, can 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 subject are provided above.However, the TTS according to the present invention, particularly the layer containing guanfacine, can also comprise further additives or excipients.

[0217] In general, additives or excipients are preferably selected from the group consisting of dispersants, solubilizers, penetration enhancers, film formers, softeners / plasticizers, tackifiers, skincare substances, pH adjusters, preservatives, stabilizers and fillers.These additives can be present in the guanfacine-containing layer in an amount of 0.001% to 15% by weight, for example 0.5% to 10% by weight, or 1% to 10% by weight, based on the total weight of the guanfacine-containing layer, where the weight percent amount refers to a single additive.

[0218] It should be noted that in pharmaceutical formulations, formulation components are categorized according to their physicochemical and physiological properties and according to their functions. This means in particular that a substance or compound that falls into one category is not excluded from being included in another category of formulation components. For example, a certain polymer is a film-forming agent, but can also be a tackifier. Some substances, for example, are typical softeners, but can simultaneously act as penetration enhancers. A person skilled in the art can determine based on his general knowledge in which category or categories of formulation components a certain substance or compound belongs. In the following, details regarding excipients and additives are provided, which, however, should not be understood as being exclusive. Other substances not expressly listed in this description can be used in the same way according to the present invention, and substances and / or compounds that are expressly listed for one category of formulation components are not excluded from being used as another formulation component in the sense of the present invention.

[0219] In one embodiment, the guanfacine-containing layer comprises a dispersing agent as defined above, preferably 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. As explained above, the dispersing agent is preferably a polyethylene glycol C having 2 to 10 EO units. 8 ~C 20 -alkyl ethers, in particular polyoxyethylene (4) lauryl ether. Alternatively or additionally, silicone polyethers can be used as dispersants. The dispersants serve to homogeneously disperse guanfacine in the guanfacine-containing layer, in particular in the guanfacine-containing matrix layer, thereby improving the release characteristics of the TTS.

[0220] In one embodiment, the guanfacine-containing layer comprises a solubilizer. The solubilizer is preferably improves the dispersibility of guanfacine in the guanfacine-containing layer and stabilizes the guanfacine-containing layer. In addition, the solubilizer can positively affect adhesion. 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 which may further contain fatty acids or fatty alcohols; cellulose and methylcellulose and derivatives thereof, such as hydroxypropyl cellulose and hypromellose acetate succinate; various cyclodextrins and derivatives thereof; non-ionic tri-block copolymers with a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, known as poloxamers; water-soluble derivatives of vitamin E; Pharmaceutical grade or agglomerated spherical isomalt; polyethylene 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, of polyethylene glycol 400, of polyoxyethylene sorbitan monooleate (such as Polysorbate 80) or of propylene glycol; diethylene glycol monoethyl ether; glucono-delta-lactone; corn and potato starch; and any of the soluble polyvinylpyrrolidones described below as well as insoluble / crosslinked polyvinylpyrrolidones, such as crospovidone.

[0221] However, the penetration enhancers described below can also act as solubilizers, and the film-forming agents described below can simultaneously act as solubilizers, and vice versa.

[0222] In one embodiment, the guanfacine-containing layer comprises a permeation enhancer. The preferences in this regard are given above. Permeation enhancers are substances that affect the barrier properties of the stratum corneum in the sense of increasing active agent permeability. 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, dimethyl aurylamine, dodecyl pyrrolidone, isosorbitol, dimethyl acetonide, dimethyl sulfoxide, decyl methyl sulfoxide and dimethyl formamide; salicylic acid; amino acids; benzyl nicotinate; and higher molecular weight aliphatic surfactants, such as lauryl sulfate. Other agents include oleic and linoleic acid, ascorbic acid, panthenol, butylhydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate and isopropyl palmitate.If the guanfacine-containing layer includes a penetration enhancer, the penetration 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 and oleyl alcohol, preferably oleyl alcohol.

[0223] In one embodiment, the guanfacine-containing layer further comprises a film-forming agent. It should be understood that the solubilizers described above, such as Soluplus®, can act as film-forming agents and also control adhesion. Suitable examples of additional film-forming agents include polyvinylpyrrolidone, vinyl acetate / vinylpyrrolidone copolymers, and cellulosic acid copolymers. Examples of the polyvinylpyrrolidone include cellulose derivatives, preferably polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone.

[0224] If the layer containing guanfacine is required to have self-adhesive properties and one or more polymers are selected that provide / do not provide sufficient self-adhesive properties, a tackifier is added.Preferred tackifiers include Miglyol, a liquid wax ester based on long-chain unsaturated even-numbered fatty acids and long-chain unsaturated even-numbered fatty alcohols of vegetable origin, and polyethylene glycol.In particular, the tackifier can 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), triglycerides, polyethylene glycol, dipropylene glycol, resins, resin esters, terpenes and their derivatives, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes, 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, preferably polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone.

[0225] The term "soluble polyvinylpyrrolidone" refers to polyvinylpyrrolidone, also known as povidone, which is soluble at more than 10% in at least ethanol, and preferably 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, glycerin, triethanolamine, propionic acid and acetic acid. Commercially available examples of polyvinylpyrrolidone include Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® 25, Kollidon® 30 and Kollidon® 90 F, or Povidone K90F, supplied by BASF. The different grades of Kollidon® are defined in terms of K values, which reflect the average molecular weight of the polyvinylpyrrolidone grade. Kollidon® 12 PF is characterized by a K-value range of 10.2 to 13.8, corresponding to a nominal K-value of 12. Kollidon® 17 PF is characterized by a K-value range of 15.3 to 18.4, corresponding to a nominal K-value of 17. Kollidon® 25 is characterized by a K-value range of 22.5 to 27.0, corresponding to a nominal K-value of 25, and Kollidon® 30 is characterized by a K-value range of 27.0 to 32.4, corresponding to a nominal K-value of 30. Kollidon® 90 F is characterized by a K-value range of 81.0 to 97.2, corresponding to a nominal K-value of 90. Preferred Kollidon® grades are Kollidon® 12 PF, Kollidon® 30 and Kollidon® 90 F. Within the meaning of this 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".

[0226] In one embodiment, the guanfacine-containing layer further comprises a softener / plasticizer. Illustrative softeners / plasticizers include linear or branched, saturated or unsaturated alcohols having from 6 to 20 carbon atoms, triglycerides, and polyethylene glycols.

[0227] In one embodiment, the guanfacine-containing layer further comprises a stabilizer. The stabilizers include tocopherol and its ester derivatives, and ascorbic acid and its ester derivatives. Further stabilizers include sodium metabisulfite, ascorbyl esters of fatty acids, such as ascorbyl palmitate, ascorbic acid, butylhydroxytoluene, tocopherol, tocopheryl acetate, and tocopheryl linoleate. Examples include:

[0228] In one embodiment, the guanfacine-containing layer further comprises a pH adjusting agent. Suitable pH adjusting agents include mild acids and bases, including amine derivatives, inorganic alkali derivatives, and polymers with basic or acidic functionality.

[0229] In one embodiment, the guanfacine-containing layer further comprises a preservative. Suitable preservatives include parabens, formaldehyde-releasing agents, isothiazolinones, phenoxyethanol, and organic acids, such as benzoic acid, sorbic acid, levulinic acid, and anisic acid.

[0230] In one embodiment, the guanfacine-containing layer further comprises a skin care substance. Such substances can be used to avoid or reduce skin irritation, as detectable by the skin response score. Suitable skin care substances include sterol compounds, such as cholesterol, dexpanthenol, alpha-bisabolol, and antihistamines.

[0231] In one embodiment, the guanfacine-containing layer further comprises a filler. Fillers such as silica gel, titanium dioxide and zinc oxide can be used in conjunction with the polymer to affect certain physical parameters, such as adhesion and bond strength, in a desired manner.

[0232] Emission Characteristics The TTS according to the invention is designed to administer guanfacine transdermally into the systemic circulation for a predefined extended period of time, preferably at least 24 hours, more preferably at least 72 hours, especially about 84 hours.

[0233] In one embodiment, the TTS according to the present invention provides an average plasma concentration of guanfacine of 1 ng / ml to 20 ng / ml, preferably 1 ng / ml to 15 ng / ml, more preferably 1 ng / ml to 10 ng / ml at steady state via transdermal delivery.

[0234] Preferably, the TTS provides a therapeutically effective plasma concentration of guanfacine within 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.

[0235] In one embodiment, the TTS according to the present invention is administered in a concentration of 10 to 600 ng. * h / ml, preferably 20 to 400 ng * AUC of h / ml 0-24h In another embodiment, the TTS according to the present invention is provided in a concentration of 30 to 1800 ng. * h / ml, preferably 60 to 1200 ng * AUC of h / ml 0-72h In another embodiment, the TTS according to the present invention is provided in a concentration of 35 to 2100 ng. * h / ml, preferably 70 to 1400 ng * AUC of h / ml 0-84hIt should be understood that the AUC values ​​preferably refer to the AUC values ​​obtained at steady state.

[0236] In one embodiment, the TTS according to the present invention has a C of less than 3.5. 84 C against max In another embodiment, the TTS according to the present invention has a C ratio of less than 3.0. 72 C against max In another embodiment, the TTS according to the present invention provides a C ratio of less than 2.0. 24 C against max These ratios show a flat blood plasma curve which is advantageous in terms of the continuous treatment of the patient.

[0237] In one embodiment, the TTS according to the present invention comprises: 0.01μg / (cm for the first 24 hours 2* h) to 8μg / (cm 2* h). 0.05μg / (cm from 24 hours to 72 hours 2* h) to 10μg / (cm 2* h) 1 provides the skin permeation rate of guanfacine as measured in Franz diffusion cells using dermatomed human skin.

[0238] In one embodiment, the TTS according to the present invention is administered at a concentration of 0.05 mg / cm for a time period of 72 hours. 2 to 0.7 mg / cm 2 , preferably 0.1 mg / cm 2 to 0.6 mg / cm 2 1 provides the skin permeation rate of guanfacine as measured in Franz diffusion cells using dermatomed human skin.

[0239] In view of the above, the present invention provides, in one aspect, a transdermal therapeutic system for transdermal administration of guanfacine, comprising a guanfacine-containing layer structure, AUC from 10 to 600 (ng / mL) h 0-24 , AUC from 30 to 1800 (ng / mL) h 0-72 , AUC from 35 to 2100 (ng / mL) h 0-84 , Less than 2.0, C 24 C against max ratio, Less than 3.0, C 72 C against max Ratio, and Less than 3.5, C 84 C against max ratio The present invention also relates to a transdermal therapeutic system that provides one or more pharmacokinetic parameters selected from the group consisting of:

[0240] In a preferred embodiment, the present invention provides a transdermal therapeutic system for the transdermal administration of guanfacine, comprising a guanfacine-containing layer structure, AUC from 20 to 400 (ng / mL) h 0-24 , AUC from 60 to 1200 (ng / mL) h 0-72 , AUC from 70 to 1400 (ng / mL) h 0-84 , Less than 1.5, C 24 C against max ratio, Less than 2.5, C 72 C against max Ratio, and Less than 3.0, C 84 C against max ratio The present invention relates to a transdermal therapeutic system that provides one or more pharmacokinetic parameters selected from the group consisting of via transdermal delivery.

[0241] Method of Treatment / 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) in a human patient, preferably a human patient aged between 6 and 17 years old, and / or as an adjunct therapy to stimulant therapy.

[0242] In a preferred embodiment relating to said medical use, the TTS is applied to the patient's skin for a period of at least 24 hours, preferably at least 72 hours, more preferably about 84 hours.

[0243] 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 to the patient's skin a transdermal therapeutic system as defined in any one of items 1 to 37. 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 to the patient's skin a transdermal therapeutic system according to the present invention. .

[0244] 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.

[0245] In view of the above, the present invention relates in one aspect to a transdermal therapeutic system comprising guanfacine for use in a method of treating a human patient, preferably a human patient aged between 6 and 17 years, by transdermal administration of guanfacine, wherein 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. In a preferred embodiment, the transdermal therapeutic system is for use in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient and / or as an adjunct therapy to stimulant therapy. In a more preferred embodiment, the transdermal therapeutic system comprises a transdermal therapeutic system according to the invention, in particular AUC from 10 to 600 (ng / mL) h 0-24 , AUC from 30 to 1800 (ng / mL) h 0-72 , AUC from 35 to 2100 (ng / mL) h 0-84 , Less than 2.0, C 24 C against max ratio, Less than 3.0, C 72 C against max Ratio, and Less than 3.5, C 84 C against max ratio selected from the group consisting of; Preferably AUC from 20 to 400 (ng / mL) h 0-24 , AUC from 60 to 1200 (ng / mL) h 0-72 , AUC from 70 to 1400 (ng / mL) h 0-84 , Less than 1.5, C 24 C against max ratio, Less than 2.5, C 72 C against max Ratio, and Less than 3.0, C 84 C against max ratio The transdermal therapeutic system provides one or more of the pharmacokinetic parameters selected from the group consisting of:

[0246] In another aspect, the present invention relates to guanfacine for use in a method of treating a human patient, preferably a human patient aged between 6 and 17 years, by transdermal administration of guanfacine using a transdermal therapeutic system, 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 guanfacine is for use in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient and / or as an adjunct therapy to stimulant therapy. In a more preferred embodiment, the transdermal therapeutic system is a transdermal therapeutic system according to the present invention, in particular AUC from 10 to 600 (ng / mL) h 0-24 , AUC from 30 to 1800 (ng / mL) h 0-72 , AUC from 35 to 2100 (ng / mL) h 0-84 , Less than 2.0, C 24 C against max ratio, Less than 3.0, C 72 C against max Ratio, and Less than 3.5, C 84 C against max ratio selected from the group consisting of; Preferably AUC from 20 to 400 (ng / mL) h 0-24 , AUC from 60 to 1200 (ng / mL) h 0-72 , AUC from 70 to 1400 (ng / mL) h 0-84 , Less than 1.5, C 24 C against max ratio, Less than 2.5, C 72 C against max Ratio, and Less than 3.0, C 84 C against max ratio The transdermal therapeutic system provides one or more of the pharmacokinetic parameters selected from the group consisting of:

[0247] In another aspect, the present invention relates to a method for treating a human patient, preferably a human patient between 6 and 17 years of age, by transdermal administration of guanfacine, 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. In a preferred embodiment, the method is for treating hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient and / or as an adjunct therapy to stimulant therapy. In a more preferred embodiment, the transdermal therapeutic system comprises a transdermal therapeutic system according to the invention, in particular AUC from 10 to 600 (ng / mL) h 0-24 , AUC from 30 to 1800 (ng / mL) h 0-72 , AUC from 35 to 2100 (ng / mL) h 0-84 , Less than 2.0, C 24 C against max ratio, Less than 3.0, C 72 C against max Ratio, and Less than 3.5, C 84 C against max ratio selected from the group consisting of; Preferably AUC from 20 to 400 (ng / mL) h 0-24 , AUC from 60 to 1200 (ng / mL) h 0-72 , AUC from 70 to 1400 (ng / mL) h 0-84 , Less than 1.5, C 24 C against max ratio, Less than 2.5, C 72 C againstmax Ratio, and Less than 3.0, C 84 C against max ratio The transdermal therapeutic system provides one or more of the pharmacokinetic parameters selected from the group consisting of:

[0248] In relation to the above methods of use and treatment, the TTS according to the invention is preferably applied to at least one body surface on a subject selected from the upper outer arms, upper chest, upper back or lateral chest for a defined dosing interval.

[0249] 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 can be removed and optionally a new TTS can be applied to allow for 24 hour treatment.

[0250] Manufacturing Process The present invention further relates to a process for producing a guanfacine-containing layer, preferably a guanfacine-containing matrix layer, for use in a transdermal therapeutic system.

[0251] According to the invention, the process for producing a guanfacine-containing layer for use in a transdermal therapeutic system according to the invention comprises: 1) At least one component i) guanfacine; and ii) at least one silicone polymer; to obtain a coating composition; 2) Coating the coating composition onto a backing layer or release liner. obtaining a coated coating composition; and 3) A step of drying the coated coating composition to form a guanfacine-containing layer. Includes.

[0252] In step 1) of the above process of manufacture, guanfacine is preferably dispersed in the polymer to obtain a homogenous coating composition.

[0253] It should be understood that in step 1), further components as defined above, preferably at least one further polymer and / or at least one additive, can also be added.

[0254] Preferably, a solvent is added in step 1) of the process and / or is present because the one or more 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, more preferably selected from non-alcoholic solvents, most preferably ethyl acetate or n-heptane.

[0255] In a preferred embodiment, the at least one silicone polymer is provided as a solution having a solids content of 40% to 60% by weight.

[0256] In step 2) of the process, the coating composition is applied to a backing layer or release liner, resulting in a coated coating composition, i.e., a coating composition coated on a backing layer or release liner.

[0257] After the guanfacine-containing layer is formed in step 3), the process therefore further comprises the step of applying a release liner or backing layer to the other side of the guanfacine-containing layer.

[0258] In step 3) of the above process of manufacture, drying is preferably carried out at a temperature of from 20° C. to 90° C., more preferably from 40° C. to 70° C. Drying may preferably take at least 1 hour, preferably at least 8 hours, for example 1 day.

[0259] Working Example The present invention will now be described in more detail with reference to the accompanying examples.The following description should be understood to be illustrative only and should not be interpreted as the limitation of 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 variations.

[0260] Examples 1a to d Coating Composition The formulations of the guanfacine-containing coating compositions of Examples 1a-d are summarized in Tables 1.1a and 1.1b below. The % values ​​refer to the amount in % by weight (Amt).

[0261] [Table 1]

[0262] [Table 2]

[0263] Preparation of the Coating Composition The drug substance and enhancer used were dispersed in the solvent ethyl acetate and sonicated for approximately 10 minutes. The adhesive was added. These two steps can also be carried out in reverse order. The mixture was homogenized using a dissolving stirrer at 2000 rpm for 2 minutes. Soluplus was added, and the mass was stirred at 2000 rpm for another 2 minutes, and further homogenized at 1500 rpm for at least 30 minutes. In the case of composition 1b, the enhancer polyoxyethylene (4) lauryl ether and Soluplus were dispersed in the solvent ethanol and sonicated for 10 minutes. The drug substance and the enhancer oleyl alcohol were added and the mixture was sonicated for an additional 10 minutes. The adhesive was added. In the case of composition 1d, the drug substance and the enhancer used were dispersed in the solvent ethyl acetate and sonicated for 10 minutes. The adhesive and Soluplus were added. Dissolution The mixture was homogenized using a stirrer at 2000 rpm for 2 minutes. The mass was further stirred at 1500 rpm for at least 30 minutes.

[0264] Coating of the coating composition The resulting guanfacine-containing coating composition is applied, for example, using a film applicator from the company Erichsen, on a polyethylene terephthalate film (Scotchpak), according to the solids content of the mixture, taking into account the desired coating dry weight. 9755, which can act as a release liner) and dried for approximately 10 minutes at approximately 50° C. Depending on the target areal weight, the corresponding film applicator gap is between 150 and 350 μm.

[0265] Solution removal was approximately 100 (Example 1a), 91 (Example 1b), 106 (Example 1c), and 110 (Example 1d) g / m 2 The coating thickness was selected to result in an areal weight of the guanfacine-containing layer of: The dry film was then laminated with a backing layer (PET 15 μm tsp, MN19) to provide a guanfacine-containing self-adhesive layer structure.

[0266] Preparation of TTS (for all examples) Individual systems (TTS) were then extracted from the resulting guanfacine-containing self-adhesive layer structure as described above. The TTS were then sealed in pouches of primary packaging material.

[0267] Skin penetration measurements The permeation amount of the TTS prepared according to Examples 1a-d was determined by experiments carried out with 10.0 mL Franz diffusion cells according to OECD guidelines (adopted on April 13, 2004). Split-thickness human skin from a cosmetic surgery (e.g., female abdomen, birth date 1966) was used. Dermatomes were used to prepare skin to a thickness of 500 μm with intact epidermis for all TTS. 1.188 cm 2 Die cuts with a release area of ​​were extracted from the TTS. The amount of guanfacine permeation in the receptor medium (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacterial agent) of Franz diffusion cells at a temperature of 32±1° C. was measured and the corresponding cumulative amount of permeation was calculated.

[0268] The results are shown in Table 1.2a and Figure 1.

[0269] [Table 3]

[0270] Examples 2a-b Coating Composition The formulations of the guanfacine-containing coating compositions of Examples 2a-b are summarized in Table 2.1 below. The % values ​​refer to the amounts in % by weight.

[0271] [Table 4]

[0272] Preparation of the Coating Composition The drug substance and enhancer used were dispersed in the solvent ethyl acetate and sonicated for approximately 10 minutes. The adhesive was added. These two steps can also be carried out in reverse order. The mixture was homogenized using a dissolving stirrer at 2000 rpm for 2 minutes. The mass was stirred again at 1000 rpm for 10 minutes.

[0273] Coating of the coating composition For the coating process, see Examples 1a-d. The coating thickness was 115 (Example 2a) and 113 (Example 2b) g / m 2 The dry film was laminated with a backing layer (e.g. siliconized MN 19) to provide a guanfacine-containing self-adhesive layer structure.

[0274] Preparation of TTS See Example 1.

[0275] Skin penetration measurements The permeation volume of the TTS prepared according to Examples 2a-b was determined as described for Examples 1a-d above. 2 A die cut having an ejection area of ​​10 mm was removed from the TTS.

[0276] The results are shown in Table 2.2 and Figure 2.

[0277] [Table 5]

[0278] Examples 3a-b The formulations of the guanfacine-containing coating compositions of Examples 3a-b are summarized in Table 3.1 below. The % values ​​refer to the amounts in % by weight.

[0279] [Table 6]

[0280] Preparation of the Coating Composition The drug substance and the enhancer used were dispersed in the solvent ethyl acetate and sonicated for approximately 10 minutes. The adhesive was added. These two steps can also be carried out in reverse order. The mixture was homogenized using a dissolving stirrer at 2000 rpm for 2 minutes. Soluplus was added, and the mass was stirred at 2000 rpm for another 2 minutes, and further homogenized at 1500 rpm for 30 minutes.

[0281] Coating of the coating composition For the coating process, see Examples 1a-d. The coating thickness was 106 (Example 3a) and 103 (Example 3b) g / m 2 The dry film was laminated with a backing layer (e.g., siliconized MN 19) to provide a guanfacine-containing self-adhesive layer structure.

[0282] Preparation of TTS See Example 1.

[0283] Skin penetration measurements The permeation volume of the TTS prepared according to Examples 3a-b was determined as described for Examples 1a-d above. 2 A die cut having an ejection area of ​​10 mm was removed from the TTS.

[0284] The results are shown in Table 3.2 and Figure 3.

[0285] [Table 7]

[0286] Example 4a The formulation of the guanfacine-containing coating composition of Example 4a is summarized in Table 4.1 below, where the % values ​​refer to the amounts in % by weight.

[0287] [Table 8]

[0288] Preparation of the Coating Composition The drug substance was dispersed in the solvent n-heptane and sonicated for approximately 45 minutes. The adhesive was added. These two steps can also be performed in the reverse order. The mixture was homogenized using a dissolution stirrer at 1000 rpm for 15 minutes.

[0289] Coating of the coating composition See Examples 1a-d for the coating process. The coating thickness gave an areal weight of the guanfacine-containing layer of 100 (Example 4a). The dry film was laminated with a backing layer (e.g., Hostaphan 15 μm) to provide a guanfacine-containing self-adhesive layer structure.

[0290] Preparation of TTS See Example 1.

[0291] Skin penetration measurements The permeation volume of the TTS prepared according to Example 4a was determined as described for Examples 1a-d above. 2 A die cut having an ejection area of ​​10 mm was removed from the TTS.

[0292] The results are shown in Table 4.2.

[0293] [Table 9]

[0294] Comparative Example 1 Comparative Example 1 (Comp.-Ex.1) is a mixture of Oppanol B10 and Oppanol B100 with guanfacine base in a ratio of 15 / 85. The formulation of the guanfacine-containing coating composition of Comparative Example 1 is summarized in Table 4.1 below. The % values ​​refer to the amounts in weight %.

[0295] [Table 10]

[0296] Preparation of the Coating Composition The drug substance was dispersed in the solvent n-heptane and sonicated for 10 minutes. The adhesive mixture was then added. These two steps can also be performed in the reverse order. The mixture was homogenized for 30 minutes at 100-500 rpm using a dissolution stirrer.

[0297] Coating of the coating composition For the coating process, see Examples 1a-d. The coating thickness is 91 g / m 2 The dry film was laminated with a backing layer (siliconized MN 19) to provide a guanfacine-containing self-adhesive layer structure.

[0298] Preparation of TTS See Example 1.

[0299] Skin penetration measurements The permeation volume of the TTS prepared according to Comparative Example 1 was determined as described for Examples 1a-d above. 2 A die cut having an ejection area of ​​10 mm was removed from the TTS.

[0300] The results are shown in Table 4.2 and Figure 1.

[0301] [Table 11]

[0302] Comparative examples 2a-b Coating Composition The formulations of the guanfacine-containing coating compositions of Comparative Examples 2a-b are summarized in Table 5.1 below. The % values ​​refer to the amounts in % by weight.

[0303] [Table 12]

[0304] Preparation of the Coating Composition The drug substance was dispersed in the solvent ethyl acetate and sonicated for approximately 5 minutes. The adhesive was then added. These two steps can also be performed in the reverse order. The mixture was homogenized using a dissolving stirrer at 500-800 rpm for approximately 10 minutes. In the case of Comparative Example 2a, the drug substance was dispersed directly into the adhesive. The mixture was stirred at 400° C. for approximately 10 minutes.

[0305] Coating of the coating composition For the coating process, see Examples 1a-d. For Comparative Example 2b, the coating composition was coated onto a PET 100 μm film. The coating thickness was 49 (Comparative Example 2a) and 50 (Comparative Example 2b) g / m 2 The dry film was laminated with a backing layer (PET 15 μm tsp) to provide a guanfacine-containing self-adhesive layer structure.

[0306] Preparation of TTS See Example 1.

[0307] Skin permeability measurement The permeation amount of the TTS prepared according to Comparative Example 2a-b was determined by experiments according to OECD guidelines (adopted on April 13, 2004) carried out in a 10.0 ml Franz diffusion cell. Split thickness Goettingen miniature pig skin (female) was used. Dermatomes were used to prepare the skin to a thickness of 800 μm with intact epidermis for all TTS. 1.165 cm 2 Die cuts with a release area of ​​were extracted from the TTS. The amount of guanfacine permeation in the receptor medium (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacterial agent) of Franz diffusion cells at a temperature of 32±1° C. was measured and the corresponding cumulative amount of permeation was calculated.

[0308] The results are shown in Table 5.2 and Figure 4.

[0309] [Table 13]

[0310] The present invention relates in particular to the following further items: 1. 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) guanfacine-containing layer; Including, 1. A transdermal therapeutic system, comprising at least one silicone polymer. i) guanfacine; and ii) at least one silicone polymer; A guanfacine-containing matrix layer comprising A transdermal therapeutic system according to item 1. 3. The guanfacine-containing layer structure is self-adhesive and preferably does not include an additional skin-contact layer; A transdermal therapeutic system according to either one of items 1 or 2. 4. At least one silicone polymer is a silicone pressure sensitive adhesive; A transdermal therapeutic system according to any one of items 1 to 3. 5. The guanfacine-containing layer structure contains a therapeutically effective amount of guanfacine; A transdermal therapeutic system according to any one of items 1 to 4. 6. The guanfacine in the guanfacine-containing layer structure is present in the form of a free base, preferably dispersed in the guanfacine-containing layer; A transdermal therapeutic system according to any one of items 1 to 5. 7. The guanfacine-containing layer structure contains guanfacine in an amount of 1 mg to 100 mg / TTS, preferably 8 mg to 72 mg / TTS; A transdermal therapeutic system according to any one of items 1 to 6. 8. 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; A transdermal therapeutic system according to any one of items 1 to 7. 9. The guanfacine-containing layer comprises at least one silicone polymer in an amount of 20% to 99% by weight, preferably 30% to 97% by weight, most preferably 35% to 90% by weight, based on the total weight of the guanfacine-containing layer; A transdermal therapeutic system according to any one of items 1 to 8. 10. At least one silicone polymer is obtained by polycondensation of a silanol endblocked polydimethylsiloxane with a silicate resin; A transdermal therapeutic system according to any one of items 1 to 9. 11. The residual silanol functional groups of at least one silicone polymer are capped with trimethylsiloxy groups; A transdermal therapeutic system according to item 10. 12. The guanfacine-containing layer comprises at least one further polymer selected from the group consisting of acrylate polymers, silicone acrylic hybrid polymers, polyisobutylene, and styrene-isoprene-styrene block copolymers, preferably selected from the group consisting of acrylate polymers, and silicone acrylic hybrid polymers; A transdermal therapeutic system according to any one of items 1 to 11. 13. The guanfacine-containing layer comprises a first polymer which is a silicone polymer in an amount of 35% to 70% by weight, and a second polymer selected from the group consisting of silicone polymers, acrylate polymers, and silicone-acrylic hybrid polymers in an amount of 15% to 45% by weight, in each case based on the total weight of the guanfacine-containing layer; A transdermal therapeutic system according to any one of items 1 to 12. 14. The acrylate polymer is obtained from one or more monomers selected from acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, t-octylacrylamide and vinyl acetate, preferably from one or more monomers selected from ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate and vinyl acetate; Transdermal therapeutic systems according to item 12 or 13. 15. The silicone acrylic hybrid polymer comprises a silicone phase and an acrylate phase in a weight ratio of 60:40 to 40:60; A transdermal therapeutic system according to any one of items 12 to 14. 16. Silicone acrylic hybrid polymer is a silicone polymer, silicone resin and a reaction product of a silicone polymer and an acrylic polymer, wherein the acrylic polymer is self-crosslinked and covalently bonded to a silicone polymer and / or a silicone resin. A transdermal therapeutic system according to any one of items 12 to 15. 17. Silicone acrylic hybrid polymers are (a) a silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups A silicone acrylic hybrid pressure sensitive adhesive obtained from A transdermal therapeutic system according to any one of items 12 to 15. 18. Silicone acrylic hybrid polymers are (a) a silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups; (b) an ethylenically unsaturated monomer; and (c) Initiator A silicone acrylic hybrid pressure sensitive adhesive comprising the reaction product of A transdermal therapeutic system according to any one of items 12 to 15 or 17. 19. A silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups, (a1) a silicone resin, and (a2) a silicone polymer, and (a3) comprises a condensation reaction product of a silicon-containing capping agent containing an acrylate or methacrylate functionality; A transdermal therapeutic system according to any one of items 17 or 18. 20. A silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups, (a1) a silicone resin, and (a2) a silicone polymer, and (a3) a silicon-containing capping agent comprising an acrylate or methacrylate functional group, wherein the silicon-containing capping agent has 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 radical, Y is a divalent alkylene radical having 1 to 6 carbon atoms, R' is a methyl or phenyl radical, Z is a monovalent hydrolyzable organic radical or a halogen, and b is 0 or 1; and wherein a silicone resin and a silicone polymer are reacted to form a pressure sensitive adhesive, and a silicon-containing capping agent is introduced before, during or after the silicone resin and the silicone polymer are reacted; 20. The transdermal therapeutic system according to any one of items 17 to 19, wherein the silicon-containing capping agent reacts with the pressure sensitive adhesive after the silicone resin and the silicone polymer are condensed to form the pressure sensitive adhesive, or the silicon-containing capping agent reacts in situ with the silicone resin and the silicone polymer. 21. 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 radical, 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. A transdermal therapeutic system according to any one of items 18 to 20. twenty two. (a) a silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups; (b) an ethylenically unsaturated monomer; and (c) Initiator contains a continuous acrylic outer phase and a discontinuous silicone inner phase. A transdermal therapeutic system according to any one of items 18 to 21. 23. The guanfacine-containing layer further comprises at least one additive selected from the group consisting of a dispersant, a penetration enhancer and a solubilizer, or at least two additives selected from the group consisting of a dispersant, a penetration enhancer and a solubilizer, preferably a combination of a dispersant and a penetration enhancer, or a combination of a dispersant and a solubilizer, or a combination of a penetration enhancer and a solubilizer, or at least three additives selected from the group consisting of a dispersant, a penetration enhancer and a solubilizer, preferably a combination of a dispersant, a penetration enhancer and a solubilizer is present; A transdermal therapeutic system according to any one of items 1 to 22. 24. 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 polyethylene glycol C having 2 to 10 EO units. 8 ~C 20 - alkyl ether, Transdermal therapeutic systems according to item 23. 25. The transdermal therapeutic system according to item 23 or 24, wherein the penetration 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 and oleyl alcohol, preferably oleyl alcohol. 26. The transdermal therapeutic system according to any one of items 23 to 25, 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-polyvinyl acetate-polyethylene glycol graft copolymer, preferably polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. 27. At least one additive is present in an amount of 0.5% to 10% by weight, or 1% to 10% by weight, based on the total weight of the guanfacine-containing layer; A transdermal therapeutic system according to any one of items 23 to 26. 28. The emission area is 1 cm 2 From 100cm 2 , preferably 2.5 cm 2 From 50cm 2 and / or the areal weight of the guanfacine-containing layer is in the range of 40 g / m 2 from 250 g / m 2 , preferably 50 g / m 2 From 150 g / m 2 In the range A transdermal therapeutic system according to any one of items 1 to 27. 29. The loading of guanfacine in transdermal therapeutic systems ranges from 0.2 mg to 2.4 mg / cm 2 , preferably 0.2 mg to 1.5 mg / cm 2 In the range A transdermal therapeutic system according to any one of items 1 to 28. 30. Transdermal delivery provides an average plasma concentration of guanfacine of 1 to 20 ng / ml, preferably 1 to 15 ng / ml, at steady state; A transdermal therapeutic system according to any one of items 1 to 29. 31. 0.01μg / (cm for the first 24 hours 2* h) to 8μg / (cm 2* h). 0.05μg / (cm from 24 hours to 72 hours 2* h) to 10μg / (cm 2* h) 1 provides the skin permeation rate of guanfacine as measured in Franz diffusion cells using dermatomed human skin. A transdermal therapeutic system according to any one of items 1 to 30. 0.05 mg / cm over a time period of 32.72 hours 2 to 0.7 mg / cm 2 , good Preferably 0.1 mg / cm 2 to 0.6 mg / cm 2 1 provides the cumulative permeation amount of guanfacine as measured in Franz diffusion cells using dermatomed human skin. A transdermal therapeutic system according to any one of items 1 to 31. 33. A transdermal therapeutic system according to any one of items 1 to 32 for use in a method for treating a human patient, preferably a human patient aged between 6 and 17 years. 34. A transdermal therapeutic system according to any one of items 1 to 32 for use in a method for treating hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient, preferably in a human patient aged between 6 and 17 years, and / or as an adjunct therapy to stimulant therapy. 35. A transdermal therapeutic system for use according to any one of items 33 or 34, wherein 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. 36. 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 in any one of items 1 to 32 to the patient's skin. 37. 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 as defined in any one of items 1 to 32 to the patient's skin. 38. A method of treating a human patient according to any one of items 36 or 37, wherein 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. 39. A process for producing a guanfacine-containing layer for use in a transdermal therapeutic system according to any one of items 1 to 32, comprising: 1) At least one component i) guanfacine; and ii) at least one silicone polymer; to obtain a coating composition; 2) coating the coating composition onto a backing layer or release liner to obtain a coated coating composition; and 3) A step of drying the coated coating composition to form a guanfacine-containing layer. A process including. 40. A process for producing a guanfacine-containing layer according to item 39, wherein at least one silicone polymer is provided as a solution, wherein the solvent is ethyl acetate or n-heptane. 41. A transdermal therapeutic system obtained by a process according to any one of items 40 or 41. 42. 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; and B) i) guanfacine in an amount of 3% to 13% by weight based on the total weight of the guanfacine-containing layer; ii) at least one silicone polymer in an amount of 35% to 90% by weight based on the total weight of the guanfacine-containing layer; iii) at least one dispersing agent in an amount of 2% to 6% by weight based on the total weight of the guanfacine-containing layer; iv) at least one penetration enhancer in an amount of 2% to 10% by weight based on the total weight of the guanfacine-containing layer; and v) optionally, from 0.5% by weight to 4 times the total weight of the guanfacine-containing layer; At least one solubilizer in an amount of % by weight A guanfacine-containing layer, preferably a guanfacine-containing matrix layer, comprising A transdermal therapeutic system comprising: 43. The guanfacine-containing layer is i) guanfacine in an amount of 3% to 13% by weight based on the total weight of the guanfacine-containing layer; ii) at least one silicone polymer in an amount of 35% to 90% by weight based on the total weight of the guanfacine-containing layer; iii) polyethylene glycol C having 2 to 10 EO units in an amount of 2% to 6% by weight based on the total weight of the guanfacine-containing layer. 8 ~C 20 - alkyl ethers; iv) oleyl alcohol in an amount of 2% to 10% by weight based on the total weight of the guanfacine-containing layer; and v) optionally, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in an amount of 0.5% to 4% by weight based on the total weight of the guanfacine-containing layer; 44. The transdermal therapeutic system according to item 68, wherein the guanfacine-containing matrix layer comprises: i) guanfacine in an amount of 3% to 13% by weight based on the total weight of the guanfacine-containing layer; ii) a first silicone polymer in an amount of 50% to 70% by weight based on the total weight of the guanfacine-containing layer, and a second silicone polymer in an amount of 15% to 25% by weight based on the total weight of the guanfacine-containing layer; iii) polyethylene glycol C having 2 to 10 EO units in an amount of 3% to 5% by weight based on the total weight of the guanfacine-containing layer. 8 ~C 20 - alkyl ethers, preferably polyoxyethylene(4) lauryl ether; iv) oleyl alcohol in an amount of 5% to 9% by weight based on the total weight of the guanfacine-containing layer; and v) optionally, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in an amount of 0.5% to 3% by weight based on the total weight of the guanfacine-containing layer; 44. The transdermal therapeutic system according to item 42 or 43, wherein the guanfacine-containing matrix layer comprises 45. The area weight of the guanfacine-containing layer is 80 g / m 2 From 120 g / m 2 , preferably 90 g / m 2 From 120 g / m 2 A transdermal therapeutic system according to any one of items 42 to 44, ranging from

Claims

1. 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; and B) a guanfacine-containing layer; Including, The transdermal therapeutic system comprises at least one silicone polymer; the guanfacine-containing layer comprises at least one silicone polymer in an amount of 30% to 97% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system, wherein the guanfacine-containing layer further comprises at least one additive selected from the group consisting of dispersants, penetration enhancers and solubilizers, and the at least one additive is present in an amount of 0.5% to 10% by weight based on the total weight of the guanfacine-containing layer.

2. The guanfacine-containing layer comprises: i) guanfacine; and ii) at least one silicone polymer A guanfacine-containing matrix layer comprising The transdermal therapeutic system according to claim 1 .

3. The guanfacine-containing layer structure is self-adhesive and does not include an additional skin-contact layer; The transdermal therapeutic system according to claim 1 or 2.

4. the guanfacine in the guanfacine-containing layer structure is present in the form of a free base dispersed in the guanfacine-containing layer; and / or The guanfacine-containing layer structure contains guanfacine at 1 mg to 75 mg / TTS, or 3 mg to 30 mg / TTS, The transdermal therapeutic system according to any one of claims 1 to 3.

5. the guanfacine-containing layer comprises guanfacine in an amount of 1% to 20% by weight, or 3% to 16% by weight, based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system according to any one of claims 1 to 4.

6. the guanfacine-containing layer comprises at least one silicone polymer in an amount of 35% to 90% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system according to any one of claims 1 to 5.

7. At least one silicone polymer is obtained by polycondensation of a silanol endblocked polydimethylsiloxane with a silicate resin; The transdermal therapeutic system according to any one of claims 1 to 6.

8. the guanfacine-containing layer comprises a first polymer which is a silicone polymer in an amount of 35% to 70% by weight, and a second polymer selected from the group consisting of silicone polymers, acrylate polymers, and silicone-acrylic hybrid polymers in an amount of 15% to 45% by weight, in each case based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system according to any one of claims 1 to 7.

9. The transdermal therapeutic system according to any one of claims 1 to 8, wherein the dispersing agent 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.

10. The transdermal therapeutic system according to any one of claims 1 to 9, wherein the penetration 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 and oleyl alcohol.

11. The transdermal therapeutic system according to any one of claims 1 to 10, 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-polyvinyl acetate-polyethylene glycol graft copolymer.

12. The at least one additive is present in an amount of 1% to 10% by weight based on the total weight of the guanfacine-containing layer; The transdermal therapeutic system according to any one of claims 1 to 11.

13. The areal weight of the guanfacine-containing layer is 40 g / m 2 to 250 g / m 2 , or 50 g / m 2 to 150 g / m 2 and / or The emission area is 1 cm 2 From 100cm 2 , or 2.5 cm 2 From 50cm 2 The transdermal therapeutic system according to any one of claims 1 to 12, wherein the range is

14. A transdermal therapeutic system described in any one of claims 1 to 13 for use in a method for treating a human patient aged 6 to 17 years.

15. Hypertension or Attention Deficit Hyperactivity Disorder (ADHD) in a human patient between 6 and 17 years of age. A transdermal therapeutic system according to any one of claims 1 to 13 for use in a method for treating and / or as an adjunct therapy to stimulant therapy.

16. 16. A transdermal therapeutic system for use according to any one of claims 14 or 15, wherein the transdermal therapeutic system is applied to the skin of a patient for at least 24 hours, or at least 72 hours, or about 84 hours.

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