Transdermal therapeutic systems containing silicone polymers for transdermal delivery of guanfacine

Abstract

The present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising: A) a backing layer; and B) a guanfacine-containing layer; wherein the transdermal therapeutic system comprises at least one silicone polymer.

Description

Field of the Invention

[0001] The present invention relates to a transdermal therapeutic system (TTS) for transdermal administration of guanfacine to the systemic circulation, and methods of manufacture, treatment and use thereof. Background of the Invention

[0003] Guanfacine (also known as N-(aminoiminomethyl)-2,6-dichloro-phenylacetamide, C9H9Cl2N3O, CAS No. 29110-47-2) is a sympatholytic drug used to treat hypertension and attention deficit hyperactivity disorder (ADHD). It is a centrally acting α(2)-adrenergic receptor agonist. It has the following chemical formula.

[0004]

[0005] Guanfacine is currently commercially available, for example in the form of immediate release or controlled release tablets containing 1-4 mg of guanfacine. The tablets are suitable for once-daily administration.

[0006] However, oral administration of active agents has disadvantages, for example in terms of patient compliance. In addition, it is not possible to terminate the treatment quickly, for example, in view of an overdose or the appearance of intolerance signs once the sustained-release tablets have been ingested.

[0007] Therefore, there is a need for a transdermal therapeutic system for transdermal administration of guanfacine. In particular, there is a need for a TTS that is suitable for multi-day therapy with a single application, thereby improving patient compliance. Summary of the invention

[0008] It is therefore an object of the present invention to provide a TTS for transdermal administration of guanfacine. In particular, it is an object of the present invention to provide a TTS for transdermal administration of guanfacine that provides a skin penetration rate sufficient to achieve a therapeutically effective dose.

[0009] Another object of the present invention is to provide a TTS for transdermal administration of guanfacine, which provides a therapeutically effective amount of guanfacine for at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours. In particular, it is an object of the present invention to provide a therapeutically effective amount over a period of time, wherein the TTS is applied to the skin, and a round-the-clock treatment is provided by replacing the TTS after a certain application time, such as at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.

[0010] Another object of the present invention is to provide a TTS for transdermal administration of guanfacine wherein fluctuations in guanfacine plasma concentrations are reduced compared to oral administration, particularly at steady state.

[0011] Another object of the present invention is to provide a TTS for transdermal administration of guanfacine which has a high utilization rate of the active ingredient.

[0012] Another object of the present invention is to provide a TTS for transdermal administration of guanfacine which meets the requirements of convenient application in terms of size and thickness and / or is easy and inexpensive to manufacture.

[0013] These and other objects are achieved by the present invention, which, according to one aspect, relates to a transdermal therapeutic system for transdermal administration of guanfacine, the transdermal therapeutic system comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising:

[0014] A) a backing layer; and

[0015] B) layer containing guanfacine;

[0016] Therein the transdermal therapeutic system comprises at least one silicone polymer.

[0017] It has been found that the TTS comprising silicone polymers according to the present invention 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 over a period of at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.

[0018] According to some embodiments, the present invention also relates to a transdermal therapeutic system for transdermal administration of guanfacine as described above, wherein the guanfacine-containing layer is a guanfacine-containing matrix layer comprising:

[0019] i) guanfacine, and

[0020] ii) at least one silicone polymer.

[0021] In some preferred embodiments, the guanfacine-containing layer structure further comprises at least one additive selected from the group consisting of a dispersant, a penetration enhancer, and a solubilizer.

[0022] According to a specific aspect, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure comprises:

[0023] A) a backing layer; and

[0024] B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer, comprising:

[0025] i) an amount of guanfacine ranging from 3 to 13 weight percent based on the total weight of the guanfacine-containing layer;

[0026] ii) at least one silicone polymer present in an amount of 35-90 weight percent based on the total weight of the guanfacine-containing layer;

[0027] iii) at least one dispersing agent present in an amount of 2 to 6 weight percent based on the total weight of the guanfacine-containing layer;

[0028] iv) at least one penetration enhancer present in an amount of 2% to 10% by weight of the total guanfacine-containing layer

[0029] weight; and

[0030] v) optionally at least one solubilizing agent in an amount of 0.5 to 4 weight percent based on the total weight of the guanfacine-containing layer.

[0031] According to some embodiments of the present invention, the transdermal therapeutic system according to the present invention is used in a method of treating a human patient, preferably in a method of treating a human patient aged 6 to 17 years. In particular, the transdermal therapeutic system according to the present invention is used in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient, preferably in a human patient aged 6 to 17 years and / or as an adjunct therapy to irritant drugs. With regard to these medical uses, the TTS according to the present invention is preferably applied to the patient's skin for at least 24 hours, more preferably for at least 72 hours, and most preferably for about 84 hours.

[0032] According to some embodiments, the present invention also relates to a method for treating a human patient, preferably a human patient aged 6 to 17 years, by applying a transdermal therapeutic system according to the invention to the patient's skin. In particular, the present invention relates to a method for treating hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient, preferably a human patient aged 6 to 17 years, by applying a transdermal therapeutic system according to the invention to the patient's skin. With regard to these methods, preferably the TTS according to the invention is applied to the patient's skin for at least 24 hours, more preferably for at least 72 hours, most preferably for about 84 hours.

[0033] According to another aspect, the present invention relates to a method for producing a guanfacine-containing layer for a transdermal therapeutic system according to the invention, the method comprising the following steps:

[0034] 1) Combine at least the following components:

[0035] i) guanfacine; and

[0036] ii) at least one silicone polymer;

[0037] to obtain a coating composition;

[0038] 2) applying the coating composition onto a backing layer or a release liner to obtain a coated coating composition; and

[0039] 3) Drying the applied coating composition to form a guanfacine-containing layer.

[0040] Preferably, the silicone polymer is provided in the form of a solution, wherein the solvent is ethyl acetate or n-heptane, preferably ethyl acetate.

[0041] According to another aspect, the present invention relates to a transdermal therapeutic system obtainable by the process according to the invention.

[0042] definition

[0043] Within the meaning of the present invention, the term "transdermal therapeutic system" (TTS) refers to a system for administering an active agent (e.g., guanfacine) to the systemic circulation by transdermal delivery, and refers to the entire individual dosage unit applied to the patient's skin after removing the optional release liner, which contains a therapeutically effective amount of the active agent in the layer structure containing the active agent, and optionally contains an additional adhesive cover (adhesive overlay) on top of the layer structure containing the active agent. The layer structure containing the active agent can be located on a release liner (a detachable protective layer), and therefore, the TTS can further include a release liner. Within the meaning of the present invention, the term "TTS" refers in particular to a system that provides transdermal delivery, excluding active delivery, such as via iontophoresis or microporation. A transdermal therapeutic system may also be referred to as a transdermal drug delivery system (TDDS) or a transdermal delivery system (TDS).

[0044] Within the meaning of the present invention, the term "guanfacine-containing layer structure" refers to a layer structure which contains a therapeutically effective amount of guanfacine and comprises a backing layer and at least one guanfacine-containing layer. Preferably, the guanfacine-containing layer structure is a guanfacine-containing self-adhesive layer structure.

[0045] Within the meaning of the present invention, the term "therapeutically effective amount" refers to the amount of active agent in a TTS that, if administered to a patient via the TTS, is sufficient to treat, prevent or alleviate hypertension or attention deficit hyperactivity disorder (ADHD) or to be used as an adjunct to stimulant medications in human patients. A TTS typically contains more active agent in the system than is actually provided to the skin and systemic circulation. This excess active agent is typically required to provide sufficient driving force for delivery from the TTS to the systemic circulation.

[0046] Within the meaning of the present invention, the terms "active substance", "active agent" and the like, as well as the term "guanfacine" refer to guanfacine in any pharmaceutically 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, 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 and the like, as well as guanfacine in the form of particles that may be micronized, crystalline and / or amorphous, and any mixtures of the above forms. The guanfacine, when contained in a medium such as a solvent, is preferably present in dispersed form.

[0047] When it is mentioned that guanfacine is used in the manufacture of a TTS in a specific form, this does not exclude interactions between this form of guanfacine and other components of the layer structure containing guanfacine, such as salt formation or complexation in the final TTS. This means that even if guanfacine is included in its free base form, it may be present in the final TTS in a 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, part of it may be present in the final TTS in the form of a free base. Unless otherwise stated, the amount of guanfacine in the layer structure relates to the amount of guanfacine contained in the TTS during the manufacture of the TTS and is calculated based on the form of guanfacine free base. For example, when 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 the manufacture, the content 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.

[0048] The guanfacine starting material included in the TTS during the manufacture of the TTS may be in particulate form.Guanfacine may be present in particulate form, for example, in the active agent-containing layer structure, preferably uniformly dispersed within the active agent-containing layer structure.

[0049] Within the meaning of the present invention, the term "particle" refers to a solid particulate material comprising individual particles, the size of which is negligible compared to the material. In particular, the particle is a solid, including a plastic / deformable solid, including amorphous and crystalline materials.

[0050] Within the meaning of the present invention, the term "dispersion" refers to a step or combination of steps in which the starting material (e.g., guanfacine) is not dissolved or is not completely dissolved. Within the meaning of the present invention, dispersion includes the dissolution of a portion of the material (e.g., guanfacine particles) depending on the solubility of the material (e.g., the solubility of guanfacine in the coating composition).

[0051] There are two main types of TTS for active agent delivery, namely matrix-type TTS and reservoir-type TTS. The release of the active agent in the matrix-type TTS is mainly controlled by the matrix including the active agent itself. In contrast, the reservoir-type TTS usually requires a rate-controlling membrane to control the release of the active agent. In principle, the matrix-type TTS can also include a rate-controlling membrane. However, the advantage of the matrix-type TTS is that, compared with the reservoir-type TTS, a rate-determining membrane is usually not required, and dose dumping will not occur due to membrane rupture. In short, the manufacturing complexity of the matrix-type transdermal therapeutic system (TTS) is low and the patient is easy to use.

[0052] Within the meaning of the present invention, "matrix-type TTS" refers to a system or structure in which an active agent is uniformly dissolved and / or dispersed in a polymer carrier, i.e., a matrix, which forms a matrix layer with the active agent and optional remaining ingredients. In such a system, the matrix layer controls the release of the active agent from the TTS. Preferably, the matrix layer has sufficient cohesion to be self-supporting, so that no sealing between other layers is required. Therefore, in one embodiment of the present invention, the layer containing the active agent can be a matrix layer containing the active agent, wherein the active agent is uniformly distributed in the polymer matrix. In some embodiments, the matrix layer containing the active agent can include two matrix layers containing the active agent that can be laminated together. The matrix-type TTS can be in particular in the form of a "drug in adhesive" type TTS, which refers to a system in which the active agent is uniformly dissolved and / or dispersed in a pressure-sensitive adhesive matrix. In this regard, the matrix layer containing the active agent can also be referred to as a pressure-sensitive adhesive layer containing the active agent or a pressure-sensitive adhesive matrix layer containing the active agent. According to the present invention, a TTS containing an active agent dissolved and / or dispersed in a polymer gel, such as a hydrogel, is also considered to be of the matrix type.

[0053] A TTS with a reservoir containing a liquid active agent 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. Therefore, in one embodiment, the layer containing the active agent can be a reservoir layer containing the active agent, which preferably comprises a liquid reservoir containing the active agent. In addition, the reservoir-type TTS generally also comprises a skin contact layer, wherein the reservoir layer and the skin contact layer can be separated by a rate-controlling membrane. In the storage layer, the active agent is preferably dissolved in a solvent such as ethanol or water or in silicone oil. The skin contact layer generally has adhesive properties.

[0054] In the meaning of the present invention, reservoir type TTS should not be understood as matrix type. However, micro-reservoir TTS (a two-phase system with a sediment (such as sphere, droplet) of an internal active ingredient phase dispersed in an external polymer phase) is considered in the art as a mixed form of matrix type TTS and reservoir type TTS, which is different from uniform single-phase matrix type TTS and reservoir type TTS in the concept of drug transport and drug delivery, and is considered to be matrix type in the sense of the present invention. The size of micro-reservoir droplets can be determined by optical microscope measurement (for example, by including a Leica MZ16 of a camera, such as Leica DSC320) by taking pictures of micro-reservoirs in different positions with an enhancement factor between 10 and 400 times (specifically depending on the required detection limit). By using imaging analysis software, the size of the micro-reservoir can be determined.

[0055] Within the meaning of the present invention, the term "active agent-containing layer" refers to a layer that contains an active agent and provides a release area. The term encompasses a matrix layer containing an active agent and a reservoir layer containing an active agent. If the layer containing an active agent is a matrix layer containing an active agent, the 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, an additional skin contact layer can be present as an adhesive layer, and / or an adhesive covering is provided. Typically, the additional skin contact layer is made to be free of active agents. However, due to the concentration gradient, over time, the active agent will migrate from the matrix layer to the additional skin contact layer until equilibrium is reached. The additional skin contact layer can be present on the matrix layer containing an active agent or separated from the matrix layer containing an active agent by a membrane, preferably a rate-controlling membrane. Preferably, the matrix layer containing an active agent has sufficient adhesiveness, so that there is no additional skin contact layer. If the layer containing an active agent is a reservoir layer containing an active agent, the layer is present in a reservoir-type TTS, and the layer contains an active agent in a liquid reservoir. In addition, an 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 does not contain an active agent or contains an active agent. If the additional skin contact layer does not contain an active agent, the active agent will migrate from the reservoir layer to the skin contact layer over time due to the concentration gradient until equilibrium is reached. In addition, an adhesive covering can be provided.

[0056] As used herein, the layer containing active agent is preferably a matrix layer containing active agent, and it is referred to as the final solidified layer. Preferably, after coating and drying the solvent-containing coating composition as described herein, a matrix layer containing active agent is obtained. Alternatively, a matrix layer containing active agent is obtained after melt coating and cooling. The matrix layer containing active agent can also be manufactured by laminating two or more such solidified layers (e.g., dried or cooled layers) with the same composition to provide the required area 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 a pressure-sensitive adhesive to provide enough viscosity. Preferably, the matrix layer is a pressure-sensitive adhesive matrix layer. Optionally, an adhesive covering can be present.

[0057] Within the meaning of the present invention, the term "pressure-sensitive adhesive" (also abbreviated as "PSA") refers to a material which adheres, is permanently tacky, exerts a strong holding force and should be removable from a smooth surface without residue, especially under finger pressure. When the pressure-sensitive adhesive layer is in contact with the skin, it is "self-adhesive", i.e., provides adhesion to the skin, and therefore generally does not require further assistance to be fixed on the skin. The "self-adhesive" layer structure comprises a pressure-sensitive adhesive layer for skin contact, which can be provided in the form of a pressure-sensitive adhesive matrix layer or in the form of an additional layer, i.e., a pressure-sensitive adhesive skin contact layer. Adhesive coverings can still be used to promote adhesion. The pressure-sensitive adhesive properties of the pressure-sensitive adhesive depend on the polymer or polymer composition used.

[0058] Within the meaning of the present invention, the term "silicone acrylic hybrid polymer" refers to a polymerization product comprising repeating units of a silicone subspecies and an acrylic subspecies. Therefore, the silicone acrylic hybrid polymer comprises a silicone phase and an acrylic phase. Preferably, the silicone acrylic hybrid polymer comprises a silicone phase and an acrylic phase, i.e., a silicone subspecies and an acrylic subspecies, in a certain weight ratio (e.g., 60:40 to 40:60). The term "silicone acrylic hybrid" is intended to mean more than a simple blend of a silicone-based subspecies and an acrylic-based subspecies. On the contrary, the term represents a polymerized hybrid species, which includes a silicone-based subspecies and an acrylic-based subspecies that have been polymerized together. The silicone acrylic hybrid polymer may also be referred to as a "silicone acrylate hybrid polymer" because in the context of the hybrid polymer used in the present invention, the terms acrylate and acrylic are generally used interchangeably.

[0059] Within the meaning of the present invention, the term "silicone acrylic hybrid pressure-sensitive adhesive" refers to a silicone acrylic hybrid polymer in the form of a pressure-sensitive adhesive. Silicone acrylic hybrid pressure-sensitive adhesives are described, for example, in EP 2 599 847 and WO 2016 / 130408. Examples of silicone acrylic hybrid pressure-sensitive adhesives include PSA series 7-6100 and 7-6300 (7-610X and 7-630X; X=1 based on n-heptane / X=2, based on ethyl acetate) produced and provided by Dow Corning in n-heptane or ethyl acetate. It has been found that, depending on the solvent in which the silicone acrylic hybrid PSA is provided, the arrangement of the silicone phase and acrylic phase providing a silicone or acrylic continuous external phase and a corresponding discontinuous internal phase is different. If the silicone acrylic hybrid PSA is provided in n-heptane, the composition comprises a continuous silicone external phase and a discontinuous acrylic internal phase. If the silicone acrylic hybrid PSA composition is provided in ethyl acetate, the composition comprises a continuous acrylic outer phase and a discontinuous silicone inner phase.

[0060] Within the meaning of the present invention, the term "non-hybrid polymer" is used synonymously for a polymer that does not comprise a hybrid substance. Preferably, the non-hybrid polymer is a pressure-sensitive adhesive (eg a silicone or acrylic based pressure-sensitive adhesive).

[0061] Within the meaning of the present invention, the term "silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups" includes the condensation reaction product of a silicone resin, a silicone polymer, and a silicon-containing capping agent providing the acrylate or methacrylate functional groups. It should be understood that the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups may include only acrylate functional groups, only methacrylate functional groups, or both acrylate functional groups and methacrylate functional groups.

[0062] As used herein, the matrix layer containing active agent is a layer containing an active agent dissolved or dispersed in at least one polymer or a layer containing a solvent dissolved to form an active agent-solvent mixture, which is dispersed in the form of a deposit (particularly droplets) in at least one polymer. Preferably, at least one polymer is a polymer-based pressure-sensitive adhesive (e.g., a silicone pressure-sensitive adhesive). Within the meaning of the present invention, the term "pressure-sensitive adhesive layer" refers to a pressure-sensitive adhesive layer obtained from a solvent-containing adhesive coating composition after coating and evaporating the solvent on the film.

[0063] Within the meaning of the present invention, the term "skin contact layer" refers to a layer contained in a layer structure containing an active agent that is in direct contact with the patient's skin during administration. It can be a layer containing an active agent. When the TTS includes an additional skin contact layer, the other layers of the layer structure containing the active agent do not contact the skin and do not necessarily have self-adhesive properties. As mentioned above, the additional skin contact layer attached to the layer containing the active agent 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 layer containing the active agent is usually coextensive and corresponds to the release area. However, the area of ​​the additional skin contact layer can also be greater than the area of ​​the layer containing the active agent. In this case, the release area still refers to the area of ​​the layer containing the active agent.

[0064] Within the meaning of the present invention, the term "area weight" refers to the dry weight of a particular layer, such as a substrate layer, in g / m 2 Due to manufacturing variability, the area weight values ​​have a tolerance of ±10%, preferably ±7.5%.

[0065] Unless otherwise indicated, "%" means weight % (% wt).

[0066] In the meaning of the present invention, the term "polymer" refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, and includes homopolymers consisting of one monomer and copolymers consisting of two or more types of monomers. The polymer can be of any structure, such as linear polymers, star polymers, comb polymers, brush polymers, and in the case of copolymers, any monomer arrangement (such as alternating, statistical, block copolymers or grafted polymers). The minimum molecular weight varies depending on the polymer type and is known to the technician. The polymer can have, for example, a molecular weight greater than 2000, preferably greater than 5000, more preferably greater than 10,000 daltons. Accordingly, compounds with a molecular weight lower than 2000, preferably lower than 5000 or more preferably lower than 10,000 daltons are generally referred to as oligomers.

[0067] Within the meaning of the present invention, the term "crosslinking agent" refers to a substance capable of crosslinking the functional groups contained in the polymer.

[0068] Within the meaning of the present invention, the term "adhesive overlay" refers to a self-adhesive layer structure that does not contain an active agent and has a larger area than a structure containing an active agent and provides an additional area for adhesion to the skin, but does not have an area for releasing the active agent. Therefore, it enhances the overall adhesive properties of the TTS. The adhesive overlay comprises a backing layer that can provide occlusive or non-occlusive properties and an adhesive layer. Preferably, the backing layer of the adhesive overlay provides non-occlusive properties.

[0069] In the meaning of the present invention, the term "backing layer" refers to a layer supporting a layer containing an active agent or forming a backing of an adhesive covering. During storage and administration, at least one backing layer in the TTS, typically a backing layer containing an active agent layer, is substantially impermeable to the active agent contained in the layer, thereby preventing loss of active substances or cross contamination according to regulatory requirements. Preferably, the backing layer is also occlusive, meaning substantially impermeable to water and water vapor. Suitable materials for backing layers include polyethylene terephthalate (PET), polyethylene (PE), ethylene vinyl acetate copolymer (EVA), polyurethane and mixtures thereof. Therefore, suitable backing layers are, for example, PET laminates, EVA-PET laminates and PE-PET laminates. In a preferred embodiment, the backing layer is a siliconized PET foil. Woven or nonwoven backing materials are also suitable.

[0070] The TTS according to the invention can be characterized by several parameters measured in an in vitro skin penetration test.

[0071] Typically, in vitro permeation tests are performed in Franz diffusion cells using EVA membranes (e.g. 9% vinyl acetate and 50 μm thickness, preferably provided by 3M) and using phosphate buffer at pH 5.5 or 7.4 as receptor medium (32°C with 0.1% azide saline).

[0072] Furthermore, in vitro permeation tests can be performed in Franz diffusion cells using human or animal skin, and preferably dermatomed split-thickness human skin with a thickness of 800 μm and an intact epidermis, and with phosphate buffer at pH 5.5 or 7.4 as receptor medium (32° C. with 0.1% saline azide), with or without the addition of up to 40% by volume of organic solvents, such as ethanol, acetonitrile, isopropanol, dipropylene glycol, PEG 400, so that the receptor medium can, for example, contain 60% by volume of phosphate buffer at pH 5.5, 30% by volume of dipropylene glycol and 10% by volume of acetonitrile.

[0073] In vitro permeation tests were carried out with human skin of 800 μm thickness and intact epidermis, and using phosphate buffer at pH 5.5 as receptor medium (32° C. with 0.1% saline azide), unless otherwise stated. The amount of active substance permeated into the receptor medium was determined at regular intervals by taking a sample volume using a validated HPLC method and a UV photometric detector. When taking a sample volume, the receptor medium was completely or partially replaced by fresh culture medium, and the measured amount of active substance permeated relates to the amount permeated between the two last sampling points and not to the total amount permeated so far.

[0074] Therefore, within the meaning of the present invention, the parameter "permeability" is expressed in μg / cm 2 is provided and relates to the amount of active substance permeated in a sampling interval at a certain elapsed time. For example, in an in vitro permeation test as described above, in which the amount of active substance permeated into the receptor medium has been measured, for example, at 0, 2, 4, 8, 12 and 24 hours, the "permeated amount" of active substance may be given, for example, for the sampling interval from the 8th hour to the 12th hour and corresponds to the measurement at the 12th hour, in which the receptor medium has been completely replaced at the 8th hour.

[0075] The amount permeated can also be given as a "cumulative permeation", corresponding to the cumulative amount of active substance permeated at a certain point in time. For example, in an in vitro permeation test as described above, in which the amount of active substance permeated into the receptor medium has been measured, for example, at 0, 2, 4, 8, 12 and 24 hours, the "cumulative permeation" of active substance at hour 12 corresponds to the sum of the permeations from hour 0 to hour 2, hour 2 to hour 4, hour 4 to hour 8 and hour 8 to hour 12.

[0076] Within the meaning of the present invention, the parameter "skin permeation rate" is expressed in μg / (cm 2 *h) and were reported as μg / cm by in vitro permeation testing as described above. 2 The amount of permeation measured in said sampling interval is calculated by dividing the amount of permeation measured in said sampling interval by the number of hours in said sampling interval. For example, in the skin permeation rate in an in vitro permeation test as described above, where the amount of active substance permeated into the receptor medium has been measured, for example, at 0, 2, 4, 8, 12 and 24 hours, the "skin permeation rate" at the 12th hour is calculated as the amount of permeation in the sampling interval from the 8th hour to the 12th hour divided by 4 hours.

[0077] The "cumulative skin permeation rate" can be calculated from each cumulative permeation amount by dividing the cumulative permeation amount by the elapsed time. For example, in an in vitro permeation test as described above, in which the amount of active substance permeated into the receptor medium has been measured, for example, at 0, 2, 4, 8, 12 and 24 hours, the "cumulative skin permeation rate" at the 12th hour is calculated as the cumulative permeation amount at the 12th hour (see above) divided by 12 hours.

[0078] Within the meaning of the present 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 3 in vitro permeation tests. Unless otherwise specified, the standard deviation (SD) of these average values ​​refers to the corrected sample standard deviation calculated using the following formula:

[0079]

[0080] where n is the sample size, {x1,x2,…x n} is the observed value and is the mean of the observations.

[0081] The TTS according to the invention can also be characterized by some parameters measured in in vivo clinical studies.

[0082] Within the meaning of the present invention, the parameter "mean release rate" refers to the average release rate in μg / h (μg / hour, μg / hr) or mg / day over the administration period (e.g., 1 to 7 days) at which the active agent is released through human skin into the systemic circulation, and this rate is based on the AUC obtained during said dosing period in clinical studies.

[0083] Within the meaning of the present 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 about 24 hours to about 168 hours or 1 to 7 days or about 24 hours to about 84 hours or 1 to 3.5 days.

[0084] For continuous drug treatment, the frequency of drug application is preferably kept high enough to maintain therapeutically effective plasma concentrations. In other words, the interval between two dosage form administrations, also referred to as the dosing interval, needs to be adjusted 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 time points at which the TTS is applied to the patient's skin. Once applied, the TTS is usually kept on the patient's skin during the entire dosing interval and is only removed at the end of the dosing interval, when a new TTS is applied to the skin. For example, if the dosing interval is 24 hours or 1 day, the TTS is applied to and kept 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. Therefore, a dosing interval of 24 hours or 1 day allows a daily TTS replacement pattern in a continuous treatment. The preferred dosing interval according to the present invention is at least 72 hours, preferably about 84 hours. It should be understood that the application time of the TTS on the patient's skin is preferably the same as the time of the dosing interval, which means that guanfacine is continuously administered when the TTS is replaced.

[0085] Within the meaning of the present invention, the term "room temperature" refers to the unaltered temperature found in a laboratory room where the experiments are performed, typically between 15 and 35°C, preferably about 18 to 25°C.

[0086] Within the meaning of the present invention, the term "patient" refers to a subject who has shown clinical manifestations indicating specific symptoms or symptoms requiring treatment, has been treated prophylactically or preventively for the disease or has been diagnosed with a disease to be treated. Preferably, the patient is 6 to 17 years old.

[0087] Within the meaning of the present invention, the term "pharmacokinetic parameter" refers to a parameter describing the plasma profile, such as C obtained in clinical studies. max , C t and AUC t1-t2 , for example, by single dose, multiple dose or steady state administration of a TTS containing an active agent (e.g., a TTS containing guanfacine) to healthy human subjects. Arithmetic and geometric means (e.g., mean C max , average AUC t and the average AUC INF ) and other statistical data (such as the respective standard deviation and standard error, the minimum, maximum and the middle value (median) when the values ​​are arranged in a list) to summarize the pharmacokinetic parameters of each subject. In the context of the present invention, a pharmacokinetic parameter, such as C max , C t and AUC t1-t2Refers to the geometric mean unless otherwise indicated. It cannot be excluded that the absolute mean values ​​obtained for a particular TTS in clinical studies vary to some extent from study to study. In order to compare the absolute mean values ​​between studies, a reference preparation (e.g., any future product based on the present invention) can be used as an internal standard. Comparison of the AUC of each release area of ​​the corresponding reference product in early and late studies can be used to obtain a correction factor to take into account the differences from study to study.

[0088] Clinical studies according to the present invention refer to studies conducted in full compliance with the International Conference on Harmonization of Clinical Trials (ICH), and all local Good Clinical Practice (GCP) and regulations are applicable.

[0089] Within the meaning of the present invention, the term "healthy human subject" refers to a male or female subject, whose body weight ranges from 55 kg to 100 kg and whose body mass index (BMI) ranges from 18 to 29.4, and who has normal physiological parameters, such as blood pressure, etc. Healthy human subjects for the purpose of the present invention are selected according to inclusion and exclusion criteria, which are based on and in accordance with the recommendations of ICH.

[0090] Within the meaning of the present invention, the term "population of subjects" refers to at least 5, preferably at least ten individual healthy human subjects.

[0091] Within the meaning of the present invention, the term "geometric mean" refers to the mean of log-transformed data back-transformed to the original scale.

[0092] Within the meaning of the present invention, the term "arithmetic mean" refers to the sum of all observed values ​​divided by the total number of observations.

[0093] Within the meaning of the present invention, the parameter "AUC" corresponds to the area under the plasma concentration-time curve. The AUC value is proportional to the amount of active agent absorbed into the blood circulation and is therefore a measure of the bioavailability.

[0094] Within the meaning of the present invention, the parameter "AUC t1-t2 " is provided in (ng / ml) h and relates to the area under the plasma concentration-time curve from t1 to t2 hours and is calculated by the linear trapezoidal method unless otherwise indicated. Other calculation methods are e.g. logarithmic and linear-log trapezoidal methods.

[0095] Within the meaning of the present invention, the parameter "C max ” is provided in (ng / ml) and relates to the maximum observed plasma concentration of the active agent.

[0096] Within the meaning of the present invention, the parameter "C t ” is provided in (ng / ml) and refers to the plasma concentration of the active agent observed at t hours.

[0097] Within the meaning of the present invention, the parameter "t max ” is expressed in h, and is consistent with reaching C max In other words, t max is the time point at which maximum plasma concentration is observed.

[0098] Within the meaning of the present invention, the term "mean plasma concentration" is provided in (ng / ml) and is the average of the individual plasma concentrations of the active agent (eg guanfacine) at each time point.

[0099] Within the meaning of the present invention, the term "coating composition" refers to a composition comprising all components of a matrix layer in a solvent, which can be coated on a backing layer or a release liner to form a matrix layer after drying.

[0100] Within the meaning of the present invention, the term "pressure-sensitive adhesive composition" refers to a pressure-sensitive adhesive mixed at least with a solvent, such as n-heptane or ethyl acetate.

[0101] Within the meaning of the present invention, the term "dissolution" refers to the process of obtaining a solution which is transparent and does not contain any particles visible to the naked eye.

[0102] Within the meaning of the present invention, the term "solvent" refers to any liquid substance, which is preferably a volatile organic liquid, such as methanol, ethanol, isopropanol, acetone, ethyl acetate, dichloromethane, hexane, n-heptane, toluene and mixtures thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0104] Figure 1 The guanfacine permeation of the TTS prepared according to Examples 1a-d and Comparative Example 1 is described.

[0105] Figure 2 The guanfacine permeation of the TTS prepared according to Examples 2a-b is described.

[0106] Figure 3 The guanfacine permeation of the TTS prepared according to Examples 3a-b is described.

[0107] Figure 4 The guanfacine permeation of the TTS prepared according to Comparative Examples 2a-b is described. DETAILED DESCRIPTION OF THE INVENTION

[0109] TTS Structure

[0110] The present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising a) a backing layer, and b) a guanfacine-containing layer, wherein the transdermal therapeutic system comprises at least one silicone polymer. The guanfacine-containing layer structure is preferably a guanfacine-containing self-adhesive layer structure and preferably does not comprise an additional skin contact layer. In particular, the silicone acrylic hybrid polymer present in the transdermal therapeutic system, preferably in the self-adhesive layer structure, preferably provides adhesive properties.

[0111] The TTS according to the present invention may be a matrix-type TTS or a reservoir-type TTS, and is preferably a matrix-type TTS.

[0112] In a matrix-type TTS according to the invention, guanfacine is preferably uniformly dispersed in a polymer carrier, i.e., a matrix, which forms a matrix layer with guanfacine and optionally the remaining ingredients. Therefore, in one embodiment of the invention, the guanfacine-containing layer can be a guanfacine-containing matrix layer, wherein guanfacine is uniformly dispersed in a polymer matrix. The polymer matrix preferably comprises at least one silicone polymer. Therefore, according to the invention, it is preferred that the guanfacine-containing matrix layer comprises guanfacine and at least one silicone polymer present in the TTS. In this regard, it is also preferred that the guanfacine-containing matrix layer is self-adhesive, so that no additional skin contact layer is present. If the guanfacine-containing matrix layer is prepared by laminating two guanfacine-containing matrix layers of substantially identical composition together, the resulting double layer is regarded as one guanfacine-containing matrix layer.

[0113] In the reservoir-type TTS according to the present invention, the guanfacine-containing layer is a guanfacine-containing reservoir layer, which preferably comprises a liquid reservoir containing guanfacine. The reservoir-type TTS generally further comprises a skin contact layer, wherein 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 to be guanfacine-free.

[0114] In a preferred embodiment of the present invention, the guanfacine-containing layer is a guanfacine-containing matrix layer comprising:

[0115] i) guanfacine, and

[0116] ii) at least one silicone polymer.

[0117] Thus, according to one embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising a layer structure containing guanfacine, the layer structure comprising:

[0118] A) a backing layer; and

[0119] B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer, comprising:

[0120] i) guanfacine, and

[0121] ii) at least one silicone polymer.

[0122] The guanfacine-containing layer structure is preferably a guanfacine-containing self-adhesive layer structure. In this regard, it is also preferred that the guanfacine-containing layer structure does not include an additional skin contact layer. Instead, it is preferred that the guanfacine-containing layer (which is preferably a guanfacine-containing matrix layer) is self-adhesive. Therefore, in a preferred embodiment, the guanfacine-containing layer structure is a guanfacine-containing self-adhesive layer structure and preferably does not include an additional skin contact layer. Alternatively or additionally, it is preferred that the guanfacine-containing layer is directly attached to the backing layer so that there is no additional layer between the backing layer and the guanfacine-containing layer. Therefore, a layer structure of low complexity is obtained, which is advantageous, for example, in terms of manufacturing costs.

[0123] In particular, it is preferred that the guanfacine-containing layer structure comprises no more than 3 layers, preferably no more than 2 layers, i.e. preferably only the backing layer and the guanfacine-containing layer. The guanfacine-containing layer, preferably the guanfacine-containing matrix layer, then provides sufficient adhesion between the guanfacine-containing self-adhesive layer structure and the patient's skin during administration. If an additional skin contact layer is present, for example as a third layer of the guanfacine-containing layer structure, the adhesive properties can be provided by the additional skin contact layer. However, according to the invention, preferably no additional skin contact layer is present.

[0124] 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. Therefore, in a preferred embodiment of the present invention, the at least one silicone polymer is a silicone pressure-sensitive adhesive. More details about the silicone polymer according to the present invention are provided further below.

[0125] It should be understood that the TTS, preferably the layer containing guanfacine, more preferably the matrix layer containing guanfacine, may also comprise two silicone polymers.

[0126] In addition, the TTS, preferably the layer containing guanfacine, more preferably the matrix layer containing guanfacine, may also contain at least one silicone polymer, and at least one other polymer selected from acrylic polymers, silicone acrylic hybrid polymers, polyisobutylene and styrene-isoprene-styrene block copolymers, preferably selected from acrylic polymers and silicone acrylic hybrid polymers.

[0127] For example, a first polymer, such as a silicone polymer, provides advantages in terms of high flux, while a second polymer, such as other silicone polymers or acrylic polymers or silicone acrylic hybrid polymers can be used to reduce and / or optimize the flux to obtain a continuous and constant flux. In addition, the viscosity of the TTS can be changed by using a combination of at least two polymers. More details about specific polymers are provided below.

[0128] It should be understood that the TTS according to the present invention comprises at least a therapeutically effective amount of guanfacine. Therefore, in a preferred embodiment of the present invention, the guanfacine-containing layer structure comprises a therapeutically effective amount of guanfacine. The guanfacine in the guanfacine-containing layer structure is preferably present in the form of a free base, which is preferably dispersed in the guanfacine-containing layer. Preferred embodiments of guanfacine in the TTS according to the present invention are further provided below.

[0129] According to the present invention, the release area of ​​TTS is preferably 1 to 100 cm 2 , preferably 2.5 to 50 cm 2 .

[0130] In a preferred embodiment of the invention, the backing layer is substantially impermeable to guanfacine. Furthermore, it is preferred that the backing layer is occlusive, as described above.

[0131] According to some embodiments of the present invention, the TTS may further include an adhesive covering. In particular, the area of ​​the adhesive covering is larger than the area of ​​the layer structure containing guanfacine, and is attached thereto to enhance the adhesive properties of the entire transdermal therapeutic system. The adhesive covering includes a backing layer and an adhesive layer. The adhesive covering provides an additional area for attachment to the skin, but does not increase the area of ​​guanfacine release. The adhesive covering layer includes a self-adhesive polymer or self-adhesive polymer mixture selected from the following: silicone acrylic hybrid polymers, acrylic polymers, silicone polymers, polyisobutylene, styrene-isoprene-styrene copolymers and mixtures thereof, which may be the same or different from any polymer or polymer mixture contained in the layer structure containing guanfacine.

[0132] The guanfacine-containing layer structure according to the invention, for example a guanfacine-containing self-adhesive layer structure, is usually located on a removable protective layer (release liner) from which it is removed immediately before application to the patient's skin surface. Therefore, the TTS may also contain a release liner. The TTS protected in this way is usually stored in a blister pack or a seam-sealed bag. The packaging can be child-resistant and / or elderly-friendly.

[0133] Guanfacine-containing layer

[0134] As outlined in more detail above, 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.

[0135] 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.

[0136] In one embodiment, the guanfacine-containing layer comprises:

[0137] i) guanfacine, preferably in free base form; and

[0138] ii) at least one silicone polymer.

[0139] It is to be understood that the at least one silicone polymer comprised in the guanfacine-containing layer is the at least one silicone polymer comprised in the TTS according to the present invention.

[0140] In a preferred embodiment, the guanfacine-containing layer is a guanfacine-containing matrix layer comprising

[0141] i) guanfacine, preferably in free base form; and

[0142] ii) at least one silicone polymer.

[0143] It is to be understood that the at least one silicone polymer comprised in the guanfacine-containing layer is the at least one silicone polymer comprised in the TTS according to the present invention.

[0144] In a preferred embodiment, the guanfacine-containing layer comprises at least one silicone polymer which is a silicone pressure-sensitive adhesive. Therefore, the guanfacine-containing layer is preferably a guanfacine-containing matrix layer, particularly preferably a guanfacine-containing pressure-sensitive adhesive matrix layer.

[0145] In one embodiment of the present invention, the guanfacine-containing layer can be obtained by dispersing guanfacine, preferably by dispersing guanfacine in the form of the free base. As a result, the guanfacine-containing layer of the TTS according to the present invention generally comprises guanfacine in the form of the free base. In addition, in some embodiments of the present invention, guanfacine may be partially present in protonated form. 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 the free base. In a particularly preferred embodiment, 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 the free base.

[0146] In one embodiment of the present invention, the guanfacine-containing layer structure, preferably the guanfacine-containing layer, more preferably the guanfacine-containing matrix layer of the transdermal therapeutic system according to the present invention contains guanfacine in an amount of 1 to 100 mg / TTS, preferably 8 to 72 mg / TTS. In a preferred embodiment, the guanfacine-containing layer structure, preferably the guanfacine-containing layer, more preferably the guanfacine-containing matrix layer, contains guanfacine in an amount of 8 to 30 mg / TTS, for example in an amount of 8 to 10 mg / TTS or 17 to 19 mg / TTS. In other words, the total amount of guanfacine in the guanfacine-containing layer structure is 1 to 100 mg / TTS, preferably 8 to 72 mg / TTS, more preferably 8 to 30 mg / TTS, for example 8 to 10 mg / TTS or 17 to 19 mg / TTS.

[0147] In another embodiment, the guanfacine loading in the guanfacine-containing layer structure is 0.2 to 1.6 mg / cm 2 , preferably 0.4 to 1.2 mg / cm 2 In addition, preferably, the release area of ​​TTS is 1 to 100 cm 2 , preferably 2.5 to 50 cm 2 .

[0148] In one embodiment of the present invention, the guanfacine-containing layer comprises guanfacine in an amount of 1 to 20 wt %, preferably 3 to 16 wt %, more preferably 3 to 14 wt %, and most preferably 3 to 13 wt %, based on the total weight of the guanfacine-containing layer. For example, the guanfacine-containing layer may comprise 3 to 8 wt %, preferably 3 to 5 wt % or 5 to 7 wt %, or 10 to 14 wt %, preferably 11 to 13 wt % of guanfacine, based on the total weight of the guanfacine-containing layer, depending on the desired dosage strength of the TTS.

[0149] The guanfacine-containing layer structure, and preferably, the guanfacine-containing layer comprises at least one silicone polymer. As used herein, the term "silicone polymer" refers to a silicone-based polymer or a polysiloxane-based polymer, which can preferably be obtained as outlined below. Preferably, the silicone polymer is a silicone-based pressure-sensitive adhesive polymer.

[0150] The at least one silicone polymer can be obtained by polycondensation of silanol-terminated polydimethylsiloxane and silicate resin. The end-capping group is preferably trimethylsilyl. Preferably, the at least one silicone polymer is an amine-compatible silicone polymer. Amine-compatible silicone polymers can be obtained by reacting silicone polymers with trimethylsilyl (e.g., hexamethyldisilazane) to reduce the silanol content of the polymer. Therefore, in the case of 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, end-capped with trimethylsiloxy groups.

[0151] The viscosity of the at least one silicone polymer can be varied by the ratio of resin to polymer, i.e., the ratio of silanol-terminated polydimethylsiloxane to silicic acid resin, which is preferably in the range of 70:30 to 50:50, preferably 65:35 to 55:45. As the amount of polymer relative to the resin increases, the viscosity will increase. A high viscosity silicone polymer preferably has a resin to polymer ratio of 55:45, a medium viscosity silicone polymer preferably has a resin to polymer ratio of 60:40, and a low viscosity silicone polymer preferably has a resin to polymer ratio of 65:35. The high viscosity silicone polymer preferably has a complex viscosity of 5x 10 at 0.01 rad / s and 30°C. 6 The complex viscosity of the medium viscous silicone polymer at 0.01 rad / s and 30°C is preferably 5 x 10 7 The low viscosity silicone polymer preferably has a complex viscosity of 5 x 10 at 0.01 rad / s and 30°C. 8 The complex viscosity of the high viscosity amine compatible silicone polymer at 0.01 rad / s and 30°C is preferably 5 x 10 6 The complex viscosity of the medium viscosity amine-compatible silicone polymer at 0.01 rad / s and 30°C is preferably 5×10 8 The complex viscosity of the low viscosity amine-compatible silicone polymer at 0.01 rad / s and 30°C is preferably 5×10 9 Preferred according to the invention are medium and high viscosity silicone polymers, in particular medium and high viscosity amine-compatible silicone polymers.

[0152] The at least one silicone polymer is preferably provided in the form of a solution, wherein the solvent is preferably n-heptane or ethyl acetate.

[0153] 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:

[0154]

[0155] Such silicone polymers are also referred to as standard silicone adhesives and can be obtained, for example, from Dow Corning under the trade names BIO-PSA 7-4401, BIO-PSA-7-4501 or BIO-PSA 7-4601, which are provided in n-heptane solvent (represented by the number "01"), or under the trade names BIO-PSA 7-4402, BIO-PSA 7-4502 and BIO 7-4602, which are provided in ethyl acetate solvent (represented by the number "02"). The typical solid content in the solvent is 60-75%. The number "44" represents a 65:35 ratio of resin to polymer, resulting in low viscosity, the number "45" represents a 60:40 ratio of resin to polymer, resulting in medium viscosity, and the number "46" represents a 55:45 ratio of resin to polymer, resulting in high viscosity.

[0156] 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:

[0157]

[0158] Such amine compatible silicone polymers are available from Dow Corning, for example, under the trade names BIO-PSA 7-4101, BIO-PSA-7-4201 or BIO-PSA 7-4301, provided in n-heptane solvent (indicated by the code "01"), or under the trade names BIO-PSA 7-4102, BIO-PSA 7-4202 and BIO 7-4302, provided in ethyl acetate solvent (indicated by the code "02"). Typical solids content in the solvent is 60-75%. Code "41" indicates a resin to polymer ratio of 65:35, resulting in low viscosity, code "42" indicates a resin to polymer ratio of 60:40, resulting in medium viscosity, and code "43" indicates a resin to polymer ratio of 55:45, resulting in high viscosity.

[0159] In one embodiment of the invention, the guanfacine-containing layer comprises at least one silicone polymer, preferably one or two silicone polymers.

[0160] The guanfacine-containing layer may further comprise at least one other polymer selected from the group consisting of acrylic polymers, silicone acrylic hybrid polymers, polyisobutylene and styrene-isoprene-styrene block copolymers, preferably selected from the group consisting of acrylic polymers and silicone acrylic hybrid polymers.

[0161] Acrylate polymers can be obtained from one or more monomers selected from the group consisting of acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, tert-octylacrylamide and vinyl acetate, preferably one or more monomers selected from the group consisting of ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate and vinyl acetate. Such acrylic polymers can be purchased, for example, from Henkel, as explained in more detail below.

[0162] The silicone acrylate hybrid polymer comprises a silicone phase and an acrylate phase, preferably in a weight ratio of 60:40 to 40:60, and most preferably in a weight ratio of 50:50. The silicone acrylate hybrid polymer generally comprises the reaction product of: (a) a silicone-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups, (b) an ethylenically unsaturated monomer; and (c) an initiator. More details about components (a), (b) and (c) are provided further below. It should be understood that component (a) primarily forms the silicone phase, while component (b) primarily forms the acrylate phase of the silicone acrylate hybrid polymer. The acrylate phase affects the tack and viscosity of the silicone acrylate hybrid polymer. Therefore, the ethylenically unsaturated monomers that preferably form the acrylate phase are a combination of 2-ethylhexyl acrylate and methyl acrylate, preferably in a ratio of 40:60 to 70:30. In terms of high viscosity, a ratio of 60:40 is preferred, although the viscosity is subsequently reduced. For high viscosity, a 50:50 ratio is preferred, despite the attendant reduction in tack. The silicone acrylic hybrid polymer in the guanfacine-containing layer preferably comprises a continuous acrylic outer phase and a discontinuous silicone inner phase.

[0163] In one embodiment of the invention, the guanfacine-containing layer comprises at least one silicone polymer in an amount of 20-99 wt %, preferably 30-97 wt %, most preferably 35-90 wt %, based on the total weight of the guanfacine-containing layer. The amounts given refer to the total amount of one or more, preferably one or two, silicone polymers in the guanfacine-containing layer. However, as mentioned above, the guanfacine-containing layer may additionally comprise at least one other polymer, such as an acrylic polymer or a silicone-acrylic hybrid polymer.

[0164] In a preferred embodiment, the guanfacine-containing layer comprises a first polymer that is a silicone polymer in an amount of 35 to 70 wt % of the total weight of the guanfacine-containing layer, and a second polymer selected from a silicone polymer, an acrylic polymer, and a silicone-acrylic hybrid polymer in an amount of 15 to 45 wt % of the total weight of the guanfacine-containing layer, respectively. Thus, the guanfacine-containing layer may comprise two different silicone polymers, a silicone polymer and an acrylic 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 wt % of the total weight of the guanfacine-containing layer, and a second silicone polymer in an amount of 15-25 wt % of the total weight of the guanfacine-containing layer.

[0165] In some preferred embodiments, the guanfacine-containing layer may further comprise a third polymer selected from the group consisting of silicone polymers, acrylic polymers, and silicone-acrylic hybrid polymers, preferably in an amount of 1-5 wt % of the total weight of the guanfacine-containing layer.

[0166] In one embodiment of the invention, the TTS according to the invention, in particular the guanfacine-containing layer, comprises at least one additive. Suitable additives are described in further detail below and are each preferably present in an amount of 0.5 to 10 wt.-% or 1 to 10 wt.-%, based on the total weight of the guanfacine-containing layer.

[0167] In a preferred embodiment, the guanfacine-containing layer comprises at least one additive selected from a dispersant, a penetration enhancer and a solubilizing agent. In a preferred embodiment, at least one additive, i.e., each individual additive, is present in an amount of 0.5 to 10 wt % or 1 to 10 wt % based on the total weight of the guanfacine-containing layer. In a preferred embodiment, at least one additive is a dispersant. In another preferred embodiment, at least one additive is a penetration enhancer. In another preferred embodiment, at least one additive is a solubilizing agent. In some preferred embodiments, combinations of the above additives are also preferred, for example, a combination of a dispersant and a penetration enhancer, or a combination of a dispersant and a solubilizing agent, or a combination of a penetration enhancer and a solubilizing agent, or a combination of a dispersant, a penetration enhancer and a solubilizing agent. The above additives have particular advantages for providing guanfacine in a uniformly dispersed and releasable form. It should be understood that a dispersant may also act as a penetration enhancer and vice versa. Similarly, a solubilizing agent may also act as a dispersant or a penetration enhancer in addition. In addition, a solubilizing agent may stabilize the guanfacine dispersion in the TTS and avoid crystallization. In addition, a solubilizing agent may help optimize the cohesion of the TTS. In some preferred embodiments, the guanfacine-containing layer comprises at least one dispersing agent and at least one penetration enhancer, and optionally also comprises at least one solubilizing agent.

[0168] In a preferred embodiment, at least one additive is a dispersant in an amount of 1 to 10 wt % based on the total weight of the guanfacine-containing layer. The dispersant is preferably present in an amount of 2 to 6 wt %, more preferably 3 to 5 wt %, based on the total weight of the guanfacine-containing layer.

[0169] In another preferred embodiment, at least one additive is a permeation enhancer in an amount of 1 to 10 wt % based on the total weight of the guanfacine-containing layer. Preferably, the permeation enhancer is present in an amount of 5 to 9 wt % based on the total weight of the guanfacine-containing layer.

[0170] In another embodiment, at least one additive is a solubilizer in an amount of 0.5 to 10 wt % based on the total weight of the guanfacine-containing layer. Preferably, the solubilizer is present in an amount of 0.5 to 4 wt %, more preferably 0.5 to 3 wt %, based on the total weight of the guanfacine-containing layer.

[0171] In one embodiment, the TTS according to the invention, in particular the guanfacine-containing layer, more particularly the guanfacine-containing matrix layer, comprises at least two additives selected from dispersants, penetration enhancers and solubilizers.

[0172] In a preferred embodiment, the transdermal therapeutic system, in particular the guanfacine-containing layer, more particularly the guanfacine-containing matrix layer, comprises at least two additives, wherein the first additive is a dispersant in an amount of 1-10% by weight of the total weight of the guanfacine-containing layer, and the second additive is a permeation enhancer in an amount of 1 to 10% by weight of the total weight of the guanfacine-containing layer. Preferably, the dispersant is present in an amount of 1 to 6% by weight, and the permeation enhancer is present in an amount of 3 to 9% by weight. More preferably, the dispersant is present in an amount of 3 to 5% by weight, and the permeation enhancer is present in an amount of 5 to 9% by weight.

[0173] 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, wherein the first additive is a dispersant in an amount of 1-10% by weight of the total weight of the guanfacine-containing layer, and the second additive is a solubilizer in an amount of 0.5-10% by weight of the total weight of the guanfacine-containing layer. Preferably, the dispersant is present in an amount of 1-6% by weight, and the solubilizer is present in an amount of 0.5-4% by weight. More preferably, the dispersant is present in an amount of 3-5% by weight, and the solubilizer is present in an amount of 0.5-3% by weight.

[0174] 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, wherein the first additive is a permeation enhancer in an amount of 1-10% by weight, based on the total weight of the guanfacine-containing layer, and the second additive is a solubilizer in an amount of 0.5-10% 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.

[0175] In one embodiment, the TTS according to the invention, in particular the layer containing guanfacine, more particularly the matrix layer containing guanfacine, comprises at least three additives selected from dispersants, penetration enhancers and solubilizers.

[0176] In one embodiment, the transdermal therapeutic system, in particular the guanfacine-containing layer, more particularly the guanfacine-containing matrix layer, comprises at least three additives, wherein the first additive is a dispersant in an amount of 1 to 10% by weight of the total weight of the guanfacine-containing layer, the second additive is a permeation enhancer in an amount of 1 to 10% by weight of the total weight of the guanfacine-containing layer, and the third additive is a solubilizer in an amount of 0.5 to 10% by weight of the total weight of the guanfacine-containing layer. Preferably, the dispersant is present in an amount of 1-6% by weight, the permeation enhancer is present in an amount of 3-9% by weight, and the solubilizer is present in an amount of 0.5-4% by weight. More preferably, the dispersant is present in an amount of 3-5% by weight, the permeation enhancer is present in an amount of 5-9% by weight, and the solubilizer is present in an amount of 0.5-3% by weight.

[0177] In conjunction with the above embodiments regarding the number of additives and the amount of additives in the TTS according to the present invention, particularly in the guanfacine-containing layer, more particularly in the guanfacine-containing matrix layer, the following specific additives are preferred.

[0178] In a preferred embodiment, the dispersant is selected from: esters of fatty acids and polyols, fatty alcohols, polyethylene glycols with a number average molecular weight of 300 to 400, polyethylene glycol alkyl ethers, wherein the dispersant is preferably polyethylene glycol C8-C6 with 2 to 10 EO units, preferably 2 to 6 EO units. 20 Alkyl ether. A particularly preferred dispersant is polyoxyethylene (4) lauryl ether (C 12 H 25 (OCH2CH2)4OH). The dispersant may be, for example, a commercially available agent named Brij Obtained from Merck.

[0179] 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, and is preferably oleyl alcohol. For example, oleyl alcohol can be obtained under the trade name OA was obtained from BASF.

[0180] In a preferred embodiment, the solubilizing agent is selected from the group consisting of copolymers derived from esters of acrylic acid and methacrylic acid, polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymers, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers. Preferably, the solubilizing agent is selected from the group consisting of polyvinyl pyrrolidone and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers. Particularly preferred solubilizing agents are polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers. Suitable polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers are available, for example, under the trade name Olefin® is available from BASF and preferably has the following structural formula, wherein l, m and n are selected such that the average molecular weight determined by gel permeation chromatography is in the range of 90,000 to 140,000 g / mol.

[0181]

[0182] In certain preferred embodiments, the guanfacine-containing layer comprises at least one dispersant in an amount of 2 to 6 wt % of the total weight of the guanfacine-containing layer, at least one permeation enhancer in an amount of 3 to 9 wt % of the total weight of the guanfacine-containing layer, and optionally at least one solubilizing agent in an amount of 0.5 to 4 wt % of 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 wt % of the total weight of the guanfacine-containing layer, at least one permeation enhancer in an amount of 5 to 9 wt % of the total weight of the guanfacine-containing layer, and optionally at least one solubilizing agent in an amount of 0.5 to 3 wt % of the total weight of the guanfacine-containing layer. With respect to the above preferred wt % amounts, the above preferred dispersants, permeation enhancers, and solubilizing agents are preferred.

[0183] Therefore, in a particularly preferred embodiment, the guanfacine-containing layer comprises polyethylene glycol C8-C16-6 having 2 to 10 EO units in an amount of 2 to 6 wt % based on the total weight of the guanfacine-containing layer. 20Alkyl ether, preferably polyoxyethylene (4) lauryl ether, oleyl alcohol in an amount of 3 to 9 wt % based on the total weight of the guanfacine-containing layer, and optionally polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, preferably as described above, in an amount of 0.5 to 4 wt % based on the total weight of the guanfacine-containing layer. Most preferably, the guanfacine-containing layer comprises polyethylene glycol C8-C8 having 2 to 10 EO units in an amount of 3 to 5 wt % based on the total weight of the guanfacine-containing layer. 20 Alkyl ether, preferably polyoxyethylene (4) lauryl ether, oleyl alcohol in an amount of 5 to 9 weight percent based on the total weight of the guanfacine-containing layer, and optionally polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, preferably as described above, in an amount of 0.5 to 3 weight percent based on the total weight of the guanfacine-containing layer.

[0184] In one embodiment of the present invention, the area weight of the layer containing guanfacine is 40 to 250 g / m 2 , preferably 50 to 180 g / m 2 , more preferably 70 to 180 g / m 2 , for example 75 to 150 g / m 2 or 100 to 150g / m 2 In some preferred embodiments, the area weight is 80 to 120 g / m 2 , preferably 90 to 100 g / m 2 .

[0185] In view of the above, the present invention relates in one embodiment to a transdermal therapeutic system for transdermal administration of guanfacine, the transdermal therapeutic system comprising a layer structure containing guanfacine, the layer structure comprising:

[0186] A) a backing layer; and

[0187] B) a layer containing guanfacine, preferably a matrix layer containing guanfacine, which comprises

[0188] i) guanfacine in an amount of 3 to 13 wt % based on the total weight of the guanfacine-containing layer;

[0189] ii) at least one silicone polymer present in an amount of 35-90 wt % based on the total weight of the guanfacine-containing layer;

[0190] iii) at least one dispersing agent present in an amount of 2 to 6 weight % based on the total weight of the guanfacine-containing layer;

[0191] iv) at least one penetration enhancer present in an amount of 2% to 10% by weight based on the total weight of the guanfacine-containing layer; and

[0192] v) optionally at least one solubilizing agent in an amount of 0.5 to 4 wt % based on the total weight of the guanfacine-containing layer.

[0193] With regard to this embodiment, it is further preferred that the guanfacine-containing layer structure does not comprise an additional skin contact layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, preferably represents the skin contact layer and has pressure-sensitive adhesive properties due to the silicone polymer.

[0194] In a preferred embodiment, the guanfacine-containing layer is a guanfacine-containing matrix layer comprising i) guanfacine in an amount of 3 to 13 wt % based on the total weight of the guanfacine-containing layer;

[0195] ii) at least one silicone polymer present in an amount of 35-90 wt % based on the total weight of the guanfacine-containing layer;

[0196] iii) polyethylene glycol C8-C having 2 to 10 EO units 20 an alkyl ether in an amount of 2 to 6 weight percent based on the total weight of the guanfacine-containing layer;

[0197] iv) oleyl alcohol in an amount of 2 to 10 wt % based on the total weight of the guanfacine-containing layer; and

[0198] v) optional polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in an amount of 0.5 to 4 wt % based on the total weight of the guanfacine-containing layer.

[0199] Furthermore, the area weight of the guanfacine-containing layer is preferably Preferably

[0200] In a particularly preferred embodiment, the guanfacine-containing layer is a guanfacine-containing matrix layer comprising

[0201] i) guanfacine in an amount of 3 to 13 wt % based on the total weight of the guanfacine-containing layer;

[0202] ii) a first silicone polymer present in an amount of 50 to 70 weight percent of the total weight of the guanfacine-containing layer and a second silicone polymer present in an amount of 15 to 25 weight percent of the total weight of the guanfacine-containing layer;

[0203] iii) polyethylene glycol C8-C having 2 to 10 EO units 20 an alkyl ether, preferably polyoxyethylene (4) lauryl ether, in an amount of 3 to 5 wt % based on the total weight of the guanfacine-containing layer;

[0204] iv) oleyl alcohol in an amount of 5 to 9 weight % based on the total weight of the guanfacine-containing layer; and

[0205] v) optional polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in an amount of 0.5 to 3 wt % based on the total weight of the guanfacine-containing layer.

[0206] Furthermore, the area weight of the guanfacine-containing layer is preferably Preferably

[0207] Guanfacine

[0208] The TTS according to the present invention comprises a layer structure containing guanfacine, the layer structure containing guanfacine comprising A) a backing layer; and B) a layer containing guanfacine; wherein the transdermal therapeutic system comprises at least one silicone polymer. The layer containing guanfacine, preferably the matrix layer containing guanfacine, has been described in detail above.

[0209] In one embodiment of the present invention, the amount of guanfacine contained in the guanfacine-containing layer structure is 1 to 100 mg / TTS, preferably 8 to 72 mg / TTS, more preferably 8 to 30 mg / TTS, for example 8 to 10 mg / TTS or 17 to 19 mg / TTS. More details in this regard have been provided above.

[0210] 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 a free base.

[0211] 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 the free base. In a particularly preferred embodiment, 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 the free base. Thus, preferably at least 50 mol%, preferably at least 75 mol% of guanfacine in the guanfacine-containing layer is present in the form of the free base. In a particularly preferred embodiment, at least 90 mol%, preferably at least 95 mol%, more preferably at least 99 mol% of guanfacine in the guanfacine-containing layer is present in the form of the free base. In some embodiments, the guanfacine-containing layer does not contain a guanfacine salt.

[0212] In certain embodiments, the amount of guanfacine in the guanfacine-containing layer is 1 to 20 wt %, preferably 3 to 16 wt %, most preferably 3 to 14 wt %, for example, 11-13 wt %, 7-9 wt %, or 3-5 wt % of the total weight of the guanfacine-containing layer.

[0213] In one embodiment of the invention, the guanfacine-containing layer is obtainable by dispersing guanfacine in free base form. If the guanfacine-containing layer is a guanfacine-containing matrix layer, the layer is preferably obtainable by dispersing guanfacine in free base form in a polymer carrier, which particularly preferably comprises a silicone acrylic hybrid polymer and optionally comprises at least one additive as defined above, in particular at least one dispersant.

[0214] In one embodiment, the guanfacine-containing layer comprises a pharmaceutically acceptable salt of guanfacine, such as guanfacine hydrochloride or guanfacine tartrate, preferably guanfacine hydrochloride. However, according to the present invention, it is preferred that guanfacine in the guanfacine-containing layer is present in the form of a free base.

[0215] In certain embodiments, guanfacine has a purity of at least 95%, preferably at least 98%, more preferably at least 99% as determined by quantitative HPLC.Quantitative HPLC can be performed using reverse phase HPLC with UV detection.

[0216] Silicone acrylic hybrid polymer

[0217] The TTS according to the present invention may comprise a silicone acrylic hybrid polymer. The silicone acrylic hybrid polymer comprises a polymerized hybrid comprising a silicone-based subspecies and an acrylic-based subspecies that have been polymerized together. Thus, the silicone acrylic hybrid polymer comprises a silicone phase and an acrylic phase. Preferably, the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive.

[0218] Typically, the silicone acrylic hybrid pressure sensitive adhesive is provided and used in solvents such as n-heptane and ethyl acetate. The solid content of the pressure sensitive adhesive is typically between 30% and 80%. The skilled person will appreciate that the solid content can be varied by adding an appropriate amount of solvent.

[0219] Preferably, the weight ratio of silicone to acrylic acid 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 acrylic acid is about 50:50. Suitable silicone acrylic hybrid pressure sensitive adhesives having a weight ratio of silicone to acrylic acid of 50:50 are, for example, commercially available silicone acrylic hybrid pressure sensitive adhesives 7-6102, silicone / acrylic acid ratio of 50 / 50, and 7-6302, silicone / acrylic acid ratio of 50 / 50, provided by Dow Corning in ethyl acetate.

[0220] 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 3500 cP, particularly from about 1,000 cP to about 3,000 cP, more preferably from about 1200 cP to about 1800 cP, or most preferably from about 1500 cP or most preferably from about 2200 cP to about 2800 cP, or most preferably about 2500 cP at 25°C and about 50% solids in ethyl acetate, preferably measured using a Brookfield RVT viscometer equipped with a No. 5 spindle and a rotation speed of 50 RPM.

[0221] These silicone acrylic hybrid pressure sensitive adhesives are also characterized by a complex viscosity at 30°C, 0.1 rad / s 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 more preferably from about 2.0e6 poise to about 9.0e7 poise, or most preferably about 1.0e7 poise, preferably measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with an 8 mm plate and a zero gap.

[0222] To prepare samples for rheological behavior measurement using a Rheometrics ARES rheometer, between 2 and 3 grams of adhesive solution can be poured into a SCOTCH-PAK 1022 fluoropolymer release liner and left at ambient conditions for 60 minutes. To obtain essentially solvent-free adhesive films, they can be placed in an oven at 110°C + / - 10°C for 60 minutes. After being removed from the oven and allowed to equilibrate to room temperature. The film can be removed from the release liner and folded to form a square. To eliminate air bubbles, the film can be compressed using a Carver press. The sample can then be loaded between the plates and compressed to 1.5 + / - 0.1 mm at 30°C. Excess adhesive is trimmed and the final gap is recorded. A frequency sweep between 0.01 and 100 rad / s can be performed with the following settings: temperature = 30°C; strain = 0.5-1%, data collected at 3 points / decade.

[0223] Commercially available suitable silicone acrylic hybrid pressure sensitive adhesives include the PSA series 7-6100 and 7-6300 (7-610X and 7-630X; X=1 based on n-heptane / X=2 based on ethyl acetate) manufactured by Dow Corning and provided in n-heptane or ethyl acetate. For example, the 7-6102 silicone acrylic hybrid PSA with a silicone / acrylic ratio of 50 / 50 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 and 0.1 rad / s. The 7-6302 silicone acrylic hybrid PSA with a silicone / acrylic ratio of 50 / 50 has 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 and 0.1 rad / s.

[0224] Depending on the solvent providing the silicone acrylic hybrid pressure-sensitive adhesive, the arrangement of the silicone phase and acrylic phase providing a silicone or acrylic continuous outer phase and a corresponding discontinuous inner phase is different. If the silicone acrylic hybrid pressure-sensitive adhesive is provided in n-heptane, the composition comprises a continuous silicone outer phase and a discontinuous acrylic inner phase. If the silicone acrylic hybrid pressure-sensitive adhesive is provided in ethyl acetate, the composition comprises a continuous acrylic outer phase and a discontinuous silicone inner 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 corresponds to the phase arrangement of the adhesive coating composition containing the solvent. For example, in the absence of any substance that can cause the phase arrangement in the silicone acrylic hybrid pressure-sensitive adhesive composition to be reversed, the pressure-sensitive adhesive layer made of the silicone acrylic hybrid pressure-sensitive adhesive in n-heptane can provide a continuous silicone outer phase and a discontinuous acrylic inner phase, and the pressure-sensitive adhesive layer prepared by the silicone acrylic hybrid pressure-sensitive adhesive in ethyl acetate can provide a continuous acrylic outer phase and a discontinuous acrylic inner phase. The phase arrangement of the composition can be determined, for example, in a peel force test using a pressure-sensitive adhesive film or layer prepared by a silicone acrylic hybrid PSA composition attached to a siliconized release liner. If the siliconized release liner cannot or is difficult to be removed from the pressure-sensitive adhesive film (laminated to the backing film) due to the blocking of the two silicone surfaces, the pressure-sensitive adhesive film comprises a continuous silicone outer phase. The blocking is caused by the adhesion of two silicone layers with similar surface energies. Silicone adhesives show good spreadability on siliconized pads, so good adhesion can be produced to the pad. If the siliconized release liner can be easily removed, the pressure-sensitive adhesive film comprises a continuous acrylic outer phase. Acrylic adhesives do not have good spreadability due to different surface energies, so the adhesion to the siliconized pad is very low or almost absent.

[0225] According to a preferred embodiment of the present invention, the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure sensitive adhesive obtainable from a silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups. It should be understood that the silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups may comprise only acrylate functional groups, only methacrylate functional groups, or both acrylate functional groups and methacrylate functional groups.

[0226] According to some embodiments of the present invention, the silicone acrylic hybrid pressure-sensitive adhesive comprises the following reaction product: (a) a silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group; (b) an ethylenically unsaturated monomer, and (c) an initiator. That is, the silicone acrylic hybrid pressure-sensitive adhesive is the product of a chemical reaction between these reactants ((a), (b) and (c)). In particular, the silicone acrylic hybrid pressure-sensitive adhesive comprises the following reaction product: (a) a silicon-containing pressure-sensitive adhesive composition comprising an acrylate or methacrylate functional group; (b) a (meth)acrylate monomer; and (c) an initiator (i.e., in the presence of an initiator). That is, the silicone acrylic hybrid pressure-sensitive adhesive comprises the product of a chemical reaction between these reactants ((a), (b) and (c)).

[0227] The reaction product of (a) a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups, (b) an ethylenically unsaturated monomer, and (c) an initiator can contain a continuous silicone outer phase and a discontinuous acrylic inner phase or the reaction product of (a), (b) and (c) can contain a continuous acrylic outer phase and a discontinuous silicone inner phase.

[0228] The silicon-containing pressure sensitive adhesive composition (a) containing acrylate or methacrylate functional groups is generally present in the silicone acrylic hybrid pressure sensitive adhesive in an amount of 5-95 parts by weight, more typically 25-75 parts by weight, based on 100 parts by weight of the hybrid pressure sensitive adhesive.

[0229] The ethylenically unsaturated monomer (b) is generally present in the silicone acrylic hybrid pressure sensitive adhesive in an amount of 5 to 95, more typically 25 to 75 parts by weight, based on 100 parts by weight of the hybrid pressure sensitive adhesive.

[0230] The initiator (c) is generally present in the silicone acrylic hybrid pressure sensitive adhesive in an amount of 0.005 to 3, more typically 0.01 to 2 parts by weight, based on 100 parts by weight of the hybrid pressure sensitive adhesive.

[0231] According to some embodiments of the present invention, the silicon-containing pressure-sensitive adhesive composition (a) comprising acrylate or methacrylate functional groups comprises a condensation reaction product of (a1) silicone resin, (a2) silicone polymer and (a3) ​​a silicon-containing end-capping agent providing the acrylate or methacrylate functional groups. Silicone resin (a1) may also be referred to as silicic acid resin or silicon dioxide resin (silica resin). Preferably, silicone polymer (a2) is polysiloxane, preferably polydimethylsiloxane. It should be understood that (a1) and (a2) form a silicone-based pressure-sensitive adhesive by polycondensation, and acrylate or methacrylate functional groups are introduced by reacting with (a3).

[0232] According to certain embodiments of the present invention, the silicon-containing pressure-sensitive adhesive composition (a) comprising acrylate or methacrylate functional groups comprises the following condensation reaction product:

[0233] (a1) silicone resin,

[0234] (a2) silicone polymer, and

[0235] (a3) providing a silicon-containing end-capping agent for the acrylate or methacrylate functional group, wherein the silicon-containing end-capping agent has a general formula of XYR′ b SZ 3-b ,in

[0236] X is a monovalent group of the general formula AE-

[0237] Wherein E is -O- or -NH-, and A is an acryl group or a methacryl group,

[0238] Y is a divalent alkylene group having 1 to 6 carbon atoms,

[0239] R' is a methyl or phenyl group,

[0240] Z is a monovalent hydrolyzable organic group or a halogen, and

[0241] b is 0 or 1;

[0242] wherein the silicone resin and the silicone polymer react to form a pressure sensitive adhesive, wherein a silicon-containing capping agent is introduced before, during or after the reaction of the silicone resin and the silicone polymer, and wherein:

[0243] After the silicone resin and the silicone polymer are condensed to form the pressure-sensitive adhesive, the silicon-containing end-capping agent reacts with the pressure-sensitive adhesive; or

[0244] The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer.

[0245] According to some embodiments of the present invention, the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups comprises a pressure-sensitive adhesive and a condensation reaction product of a silicon-containing end-capping agent providing the acrylate or methacrylate functional groups. That is, the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups is substantially a pressure-sensitive adhesive capped (capped) or end-blocked (endblocked) by a silicon-containing end-capping agent provided with the acrylate or methacrylate functional groups, wherein the pressure-sensitive adhesive comprises a condensation reaction product of a silicone resin and a silicone polymer. Preferably, silicone resin reacts with an amount of 30 to 80 parts by weight to form a pressure-sensitive adhesive, and silicone polymer reacts with an amount of 20 to 70 parts by weight to form a pressure-sensitive adhesive, based on 100 parts by weight of a hybrid pressure-sensitive adhesive. Although not required, the pressure-sensitive adhesive may include a catalytic amount of a condensation catalyst. Various silicone resins and silicone polymers are suitable for constituting a pressure-sensitive adhesive.

[0246] According to some embodiments of the present invention, the silicone acrylic hybrid pressure sensitive adhesive is the reaction product of:

[0247] (a) A silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups, comprising the condensation reaction product of:

[0248] (a1) silicone resin,

[0249] (a2) silicone polymer, and

[0250] (a3) providing a silicon-containing end-capping agent for the acrylate or methacrylate functional group, wherein the silicon-containing end-capping agent has the general formula XYR′ b SZ 3-b ,in

[0251] X is a monovalent group of the general formula AE-

[0252] wherein E is -O- or -NH-, and A is acryloyl or methacryloyl,

[0253] Y is a divalent alkylene group having 1 to 6 carbon atoms,

[0254] R' is a methyl or phenyl group,

[0255] Z is a monovalent hydrolyzable organic group or a halogen, and

[0256] b is 0 or 1;

[0257] wherein the silicone resin and the silicone polymer react to form a pressure sensitive adhesive, wherein a silicon-containing capping agent is introduced before, during or after the reaction of the silicone resin and the silicone polymer, and wherein:

[0258] After the silicone resin and the silicone polymer are condensed to form the pressure-sensitive adhesive, the silicon-containing end-capping agent reacts with the pressure-sensitive adhesive; or

[0259] The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer.

[0260] (b) ethylenically unsaturated monomers; and

[0261] (c) Initiator.

[0262] The silicone acrylic hybrid composition used in the present invention can be prepared by a method comprising the following steps:

[0263] (i) providing a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups, which comprises the following condensation reaction product:

[0264] Silicone resin,

[0265] Silicone polymers, and

[0266] A silicon-containing end-capping agent for the acrylate or methacrylate functional group is provided, wherein the silicon-containing end-capping agent has the general formula XYR′ b SZ 3-b ,in

[0267] X is a monovalent group of the general formula AE-

[0268] wherein E is -O- or -NH-, and A is acryloyl or methacryloyl,

[0269] Y is a divalent alkylene group having 1 to 6 carbon atoms,

[0270] R' is a methyl or phenyl group,

[0271] Z is a monovalent hydrolyzable organic group or a halogen, and

[0272] b is 0 or 1;

[0273] wherein the silicone resin and the silicone polymer react to form a pressure sensitive adhesive, wherein a silicon-containing capping agent is introduced before, during or after the reaction of the silicone resin and the silicone polymer, and wherein:

[0274] After the silicone resin and the silicone polymer are condensed to form the pressure-sensitive adhesive, the silicon-containing end-capping agent reacts with the pressure-sensitive adhesive; or

[0275] The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer.

[0276] (ii) polymerizing the ethylenically unsaturated monomer and the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups of step (i) in the presence of an initiator, optionally at a temperature of 50° C. to 100° C. or 65° C. to 90° C., to form a silicone acrylic hybrid composition.

[0277] In the polymerization process of ethylenically unsaturated monomers and silicon-containing pressure-sensitive adhesive compositions containing acrylate or methacrylate functional groups, the ratio of silicone to acrylic acid can be controlled and optimized as needed. The ratio of silicone to acrylic acid can be controlled by various mechanisms in the process of the method and the method. An exemplary example of such a mechanism is to add one or more ethylenically unsaturated monomers to the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups in a controlled manner. In some applications, it may be desirable that the silicone content based on the subspecies or total silicone content exceeds the acrylic acid content based on the subspecies or total acrylic acid content. In other applications, the opposite may be desired. Regardless of the final application, as described above, it is generally preferred that the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups is preferably present in the silicone acrylic hybrid composition in an amount of about 5 to about 95 parts by weight, more preferably about 25 to about 75 parts by weight, and more preferably about 40 to about 60 parts by weight, based on 100 parts by weight of the silicone acrylic hybrid composition.

[0278] According to some embodiments of the present invention, the silicone acrylic hybrid composition used in the present invention can be prepared by a method comprising the following steps:

[0279] (i) providing a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups, which comprises the following condensation reaction product:

[0280] Silicone resin,

[0281] Silicone polymers, and

[0282] A silicon-containing end-capping agent for the acrylate or methacrylate functional group is provided, wherein the silicon-containing end-capping agent has the general formula XYR′ b SZ 3-b ,in

[0283] X is a monovalent group of the general formula AE-

[0284] wherein E is -O- or -NH-, and A is acryloyl or methacryloyl,

[0285] Y is a divalent alkylene group having 1 to 6 carbon atoms,

[0286] R' is a methyl or phenyl group,

[0287] Z is a monovalent hydrolyzable organic group or a halogen, and

[0288] b is 0 or 1;

[0289] wherein the silicone resin and the silicone polymer react to form a pressure sensitive adhesive, wherein a silicon-containing capping agent is introduced before, during or after the reaction of the silicone resin and the silicone polymer, and wherein:

[0290] After the silicone resin and the silicone polymer are condensed to form the pressure-sensitive adhesive, the silicon-containing end-capping agent reacts with the pressure-sensitive adhesive; or

[0291] The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer.

[0292] (ii) polymerizing the ethylenically unsaturated monomer and the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups of step (i) in a first solvent at a temperature of 50° C. to 100° C. in the presence of an initiator to form a silicone acrylic hybrid composition;

[0293] (iii) removing the first solvent; and

[0294] (iv) adding a second solvent to form a silicone acrylic hybrid composition, wherein the phase arrangement of the silicone acrylic hybrid composition is selectively controlled by selecting the second solvent.

[0295] The silicone acrylic hybrid PSA composition used in the present invention can also be prepared by a method comprising the following steps:

[0296] (i) providing a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups, which comprises the following condensation reaction product:

[0297] Silicone resin,

[0298] Silicone polymers, and

[0299] A silicon-containing end-capping agent for the acrylate or methacrylate functional group is provided, wherein the silicon-containing end-capping agent has the general formula XYR′ b SZ 3-b ,in

[0300] X is a monovalent group of the general formula AE-

[0301] wherein E is -O- or -NH-, and A is acryloyl or methacryloyl,

[0302] Y is a divalent alkylene group having 1 to 6 carbon atoms,

[0303] R' is a methyl or phenyl group,

[0304] Z is a monovalent hydrolyzable organic group or a halogen, and

[0305] b is 0 or 1;

[0306] wherein the silicone resin and the silicone polymer react to form a pressure sensitive adhesive, wherein a silicon-containing capping agent is introduced before, during or after the reaction of the silicone resin and the silicone polymer, and wherein:

[0307] After the silicone resin and the silicone polymer are condensed to form the pressure-sensitive adhesive, the silicon-containing end-capping agent reacts with the pressure-sensitive adhesive; or

[0308] The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer.

[0309] (ii) polymerizing the ethylenically unsaturated monomer and the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups of step (i) in a first solvent at a temperature of 50° C. to 100° C. in the presence of an initiator to form a silicone acrylic hybrid composition;

[0310] (iii) adding a treatment solvent, wherein the boiling point of the treatment solvent is higher than the boiling point of the first solvent, and

[0311] (iv) applying heat at a temperature of 70° C. to 150° C. to selectively remove a majority of the first solvent;

[0312] (v) removing the process solvent; and

[0313] (vi) adding a second solvent to form a silicone acrylic hybrid composition, wherein the phase arrangement of the silicone acrylic hybrid composition is selectively controlled by selecting the second solvent.

[0314] The silicone resin of the preceding paragraph may include a silicone resin having the formula R X 3SiO 1 / 2 The copolymer of triorganosiloxy units and the formula SiO 4 / 2 The ratio of triorganosiloxy units to each tetrafunctional siloxy unit is 0.1 to 0.9, preferably about 0.6 to 0.9. Preferably, each R X independently represents a monovalent hydrocarbon group having 1 to 6 carbon atoms, a vinyl group, a hydroxyl group or a phenyl group.

[0315] The silicone polymer of the preceding paragraph may comprise at least one polydiorganosiloxane and is preferably capped (terminated) with a functional group selected from the group consisting of hydroxyl, alkoxy, hydride, vinyl, or mixtures thereof. The diorgano substituent may be selected from the group consisting of dimethyl, methylvinyl, methylphenyl, diphenyl, methylethyl, (3,3,3-trifluoropropyl)methyl, and mixtures thereof. Preferably, the diorgano substituent comprises only methyl. The molecular weight of the polydiorganosiloxane is typically from about 50,000 to about 1,000,000, preferably from about 80,000 to about 300,000. Preferably, the polydiorganosiloxane comprises a polydiorganosiloxane terminated with TR X ASiO 1 / 2 AR with terminal unit X SiO units, wherein the polydiorganosiloxane has a viscosity of about 100 centipoise to about 30,000,000 centipoise at 25°C, and each A group is independently selected from R having 1 to 6 carbon atoms. X or a halogenated hydrocarbon group, each T group is independently selected from: R X , OH, H or OR Y , and each R Y The groups are independently alkyl groups having 1 to 4 carbon atoms.

[0316] As an example of the form using the preferred silicone resin and the preferred silicone polymer, a method of preparing a pressure sensitive adhesive is:

[0317] (i) 30 to 80 parts by weight of at least one compound containing silicon-bonded hydroxyl groups and consisting essentially of R X 3SiO 1 / 2 Unit and SiO 4 / 2 The resin copolymer consists of units with a molar ratio of each SiO 4 / 2 Unit 0.6 to 0.9 R X 3SiO 1 / 2 units, (ii) about 20 to about 70 parts by weight of at least one compound comprising a TR end-capping X ASiO 1 / 2 Unit is the terminal AR X SiO units, wherein the viscosity of the polydiorganosiloxane at 25° C. is from about 100 centipoise to about 30,000,000 centipoise and each R X is a monovalent organic group selected from a hydrocarbon group of 1 to 6 carbon atoms, each A group being independently selected from R X or a halogenated hydrocarbon group having 1 to 6 carbon atoms, each T group being independently selected from: R X , OH, H or OR Y , and each R Yis independently an alkyl group having 1 to 4 carbon atoms; a sufficient amount of (iii) at least one silicon-containing capping agent (hereinafter also referred to as a capping agent) described below, which is capable of providing a silanol content or concentration of 5,000 to 15,000, more typically 8,000 to 13,000 ppm; if necessary, an additional catalytic amount of (iv) a mild silanol condensation catalyst (in the case where (ii) is not provided); and if necessary, an effective amount of (v), which is an organic solvent inert relative to (i), (ii), (iii) and (iv) to reduce the viscosity of the mixture of (i), (ii), (iii) and (iv), and condense the mixture of (i), (ii), (iii) and (iv), at least until a large amount of the one or more silicon-containing capping agents react with the silicon-bonded hydroxyl groups and T groups of (i) and (ii). Additional organosilicon capping agents can be used in combination with the one or more silicon-containing capping agents (iii) of the present invention.

[0318] The silicon-containing capping agent according to the previous paragraph may be selected from the group consisting of acrylate-functional silanes, acrylate-functional silazanes, acrylate-functional disilazanes, acrylate-functional disiloxanes, methacrylate-functional silanes, methacrylate-functional silazanes, methacrylate-functional disilazanes, methacrylate-functional disiloxanes, and combinations thereof, and may be described as having the general formula XYR′ b SZ 3-b, wherein X is a monovalent group of the general formula AE-, wherein E is -O- or -NH-, A is acryloyl or methacryloyl, Y is a divalent alkylene group having 1 to 6 carbon atoms, R' is methyl or phenyl, Z is a monovalent hydrolyzable organic group or halogen, and b is 0, 1 or 2. Preferably, the monovalent hydrolyzable organic group has the general formula R"0- wherein R" is an alkylene group. Most preferably, the specific end-capping agent is selected from the group consisting of: 3-methacryloxypropyldimethylchlorosilane, 3-methacryloxypropyldichlorosilane, 3-methacryloxypropyltrichlorosilane, 3-methacryloxypropyldimethylmethoxysilane, 3-methacryloxypropylmethyldimethoxysilane, 3-methacryloxypropyltrimethoxysilane, 3-methacryloxypropyldimethylethoxysilane, 3-methacryloxypropylmethyldiethoxysilane, 3-methacryloxypropyltriethoxysilane, (methacryloxymethyl)dimethylmethoxysilane, (methacryloxymethyl)methyldimethoxysilane, (methacryloxypropyl)methyl

[0013] The invention further comprises the following: (1-(2-acryloxymethyl)trimethoxysilane, (methacryloxymethyl)dimethylethoxysilane, (methacryloxymethyl)methyldiethoxysilane, methacryloxymethyltriethoxysilane, methacryloxypropyltriisopropoxysilane, 3-methacryloxypropyldimethylsilazane, 3-acryloxypropyldimethylchlorosilane, 3-acryloxypropyldichlorosilane, 3-acryloxypropyltrichlorosilane, 3-acryloxypropyldimethylmethoxysilane, 3-acryloxypropylmethyldimethoxysilane, 3-acryloxypropyltrimethoxysilane, 3-acryloxypropyl-dimethylsilazane, and combinations thereof.

[0319] The ethylenically unsaturated monomer according to the preceding paragraph may be any monomer having at least one carbon-carbon double bond. Preferably, the ethylenically unsaturated monomer according to the preceding paragraph may be a compound selected from the following: aliphatic acrylates, aliphatic methacrylates, alicyclic acrylates, alicyclic methacrylates and combinations thereof. It should be understood that each compound, aliphatic acrylates, aliphatic methacrylates, alicyclic acrylates and alicyclic methacrylates, contains an alkyl group. The alkyl groups of these compounds may contain up to 20 carbon atoms. The aliphatic acrylate that may be selected as one of the ethylenically unsaturated monomers is selected from the group consisting of: methyl acrylate, ethyl acrylate, propyl acrylate, n-butyl acrylate, isobutyl acrylate, tert-butyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, isononyl acrylate, isopentyl acrylate, tridecyl acrylate, octadecyl 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, isobutyl methacrylate, tert-butyl methacrylate, hexyl methacrylate, 2-ethylhexyl methacrylate, isooctyl methacrylate, isononyl methacrylate, isoamyl methacrylate, tridecyl methacrylate, octadecyl 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.

[0320] It should be understood that the ethylenically unsaturated monomers used to prepare the 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, with a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups and an initiator. According to some embodiments of the present invention, the silicone acrylic hybrid pressure-sensitive adhesive is prepared by using at least two different ethylenically unsaturated monomers, and the ethylenically unsaturated monomers are preferably selected from 2-ethylhexyl acrylate and methyl acrylate, more preferably 2-ethylhexyl acrylate in a ratio of 50% and 50% methyl acrylate, or 2-ethylhexyl acrylate in a ratio of 60% and 40% methyl acrylate as acrylic monomers.

[0321] The initiator according to the preceding paragraph may be any substance suitable for initiating the polymerization of the silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups and ethylenically unsaturated monomers to form a silicone acrylic hybrid. For example, a free radical initiator selected from peroxides, azo compounds, redox initiators and photoinitiators may be used.

[0322] Other suitable silicone resins, silicone polymers, silicon-containing end-capping agents, ethylenically unsaturated monomers and initiators that can be used according to the preceding paragraphs are described in detail in WO 2007 / 145996, EP 2 599 847 A1 and WO 2016 / 130408.

[0323] According to some embodiments of the invention, the silicone acrylic hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin and an acrylic polymer, wherein the acrylic polymer is covalently self-crosslinked and covalently bonded to the silicone polymer and / or silicone resin.

[0324] According to another embodiment of the present invention, the silicone acrylic hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin and an acrylic polymer, wherein the silicone resin comprises a triorganosiloxy unit R3SiO 1 / 2 , where R is an organic group and a tetrafunctional siloxy unit SiO 4 / 2 , and the molar ratio of each SiO 4 / 2 There are 0.1 to 0.9 R3SiO 1 / 2 .

[0325] The acrylic polymer may comprise at least an alkoxysilyl functional monomer, a polysiloxane-containing monomer, a halosilyl functional monomer or an alkoxyhalosilyl functional monomer. Preferably, the acrylic polymer is prepared from an alkoxysilyl functional monomer selected from the group consisting of trialkoxysilyl (meth)acrylates, dialkoxyalkylsilyl (meth)acrylates and mixtures thereof, or comprises an end-capped alkoxysilyl functional group. The alkoxysilyl functional group may preferably be selected from the group consisting of trimethoxysilyl, dimethoxymethylsilyl, triethoxysilyl, diethoxymethylsilyl and mixtures thereof.

[0326] The acrylic polymer may also be prepared from a mixture comprising polysiloxane-containing monomers, preferably from a mixture comprising polydimethylsiloxane mono(meth)acrylate.

[0327] The silyl functional monomer is generally used in an amount of 0.2 to 20 weight percent based on the weight of the acrylic polymer, more preferably the silyl functional monomer is used in an amount of about 1.5 to about 5 weight percent based on the weight of the acrylic polymer.

[0328] The polysiloxane-containing monomer is generally used in an amount of 1.5 to 50 wt % based on the weight of the acrylic polymer, more preferably the amount of the polysiloxane-containing monomer is 5 to 15 wt % based on the weight of the acrylic polymer.

[0329] Alternatively, the acrylic polymer comprises a block or graft copolymer of acrylic acid and polysiloxane. An example of a polysiloxane block copolymer is a polydimethylsiloxane-acrylic acid block copolymer. The preferred amount of siloxane block is 10 to 50% by weight of the entire block polymer.

[0330] The acrylic polymer comprises 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 alkyl acrylates having a homopolymer glass transition temperature (Tg) of less than about 0°C have about 4 to about 10 carbon atoms in the alkyl group and include butyl acrylate, pentyl 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 may further comprise a (meth)acrylate monomer having a high Tg, such as methyl acrylate, ethyl acrylate, methyl methacrylate, and isobutyl methacrylate.

[0331] The acrylic polymer component may further comprise polyisobutylene groups to improve the cold flow properties of the resulting adhesive.

[0332] The acrylic polymer component may contain nitrogen-containing polar monomers. Examples include N-vinyl pyrrolidone, N-vinyl caprolactam, N-tert-octylacrylamide, dimethylacrylamide, diacetoneacrylamide, N-tert-butylacrylamide, N-isopropylacrylamide, cyanoethyl acrylate, N-vinylacetamide, and N-vinylformamide.

[0333] The acrylic polymer component may include one or more hydroxyl-containing monomers, such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, hydroxypropyl acrylate, and / or hydroxypropyl methacrylate.

[0334] If desired, the acrylic polymer component may contain carboxylic acid-containing monomers. Useful carboxylic acids preferably contain from about 3 to about 6 carbon atoms, and include, among others, acrylic acid, methacrylic acid, itaconic acid, β-carboxyethyl acrylate, and the like. Acrylic acid is particularly preferred.

[0335] Other useful well-known comonomers include vinyl acetate, styrene, cyclohexyl acrylate, alkyl di(meth)acrylates, glycidyl methacrylate and allyl glycidyl ether, and macromonomers such as poly(styryl)methacrylate.

[0336] One acrylic polymer component useful in the practice of the present invention is an acrylic polymer comprising from about 90 to about 99.5 weight percent butyl acrylate and from about 0.5 to about 10 weight percent dimethoxymethylsilyl methacrylate.

[0337] According to certain embodiments of the present invention, a silicone acrylic hybrid polymer may be prepared by a) reacting a silicone polymer with a silicone resin to form a resulting product, and b) reacting the resulting product of a) with an acrylic polymer containing reactive functional groups, wherein the components are reacted in an organic solvent.

[0338] According to certain embodiments of the present invention, a silicone acrylic hybrid polymer may be prepared by a) reacting a silicone resin with an acrylic polymer comprising reactive functional groups to form a resulting product, b) reacting the resulting product of a) with a silicone polymer, wherein the components react in an organic solvent.

[0339] According to certain embodiments of the present invention, a silicone acrylic hybrid polymer may be prepared by a) reacting a silicone polymer with an acrylic polymer comprising reactive functional groups to form a resulting product, and b) reacting the resulting product of a) with a silicone resin, wherein the components are reacted in an organic solvent.

[0340] Other suitable acrylic polymers, silicone resins and silicone polymers that can be used to chemically react silicone polymers, silicone resins and acrylic polymers together to provide silicone acrylic hybrid polymers according to the preceding paragraphs are described in detail in WO2010 / 124187.

[0341] 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., silicone or acrylic based pressure sensitive adhesives).

[0342] Non-hybrid polymer

[0343] The TTS according to the invention comprises at least one silicone polymer and optionally at least one other polymer, which may be a non-hybrid polymer, such as an acrylic polymer.

[0344] Non-hybrid polymers (e.g. non-hybrid pressure-sensitive adhesives) are polymers (e.g. polymer-based pressure-sensitive adhesives) that do not include hybrid substances. Preferred are non-hybrid polymers (e.g. non-hybrid pressure-sensitive adhesives) based on polysiloxane, acrylic acid, polyisobutylene or styrene-isoprene-styrene block copolymers.

[0345] The non-hybrid polymer (eg, non-hybrid pressure sensitive adhesive) may be included in the active agent-containing layer structure and / or in the adhesive cover.

[0346] Non-hybrid pressure-sensitive adhesives are usually provided and used in solvents such as n-heptane and ethyl acetate. The solid content of pressure-sensitive adhesives is usually between 30% and 80%.

[0347] Suitable non-hybrid polymers according to the invention are commercially available, for example under the trade names: BIO-PSAs (polysiloxane-based pressure-sensitive adhesives), Oppanol TM (polyisobutylene), JSR-SIS (styrene-isoprene-styrene copolymer) or Duro-Tak TM (Acrylic polymers).

[0348] Polymers based on polysiloxanes can also be referred to as polymers based on silicone or silicone polymers or silicones (silicones). Pressure-sensitive adhesives based on polysiloxanes can also be referred to as pressure-sensitive adhesives based on silicone or silicone pressure-sensitive adhesives. These pressure-sensitive adhesives based on polysiloxanes can provide suitable viscosity and quickly adhere to various skin types (comprising moist skin), provide suitable adhesion and cohesion, lasting adhesion to skin, high flexibility, moisture permeability and compatibility with many active substances and film substrates. Sufficient amine resistance can be provided for them, and therefore enhance stability in the presence of amine. Such pressure-sensitive adhesives are based on the concept of resins in polymers, wherein, by the condensation reaction of silanol-terminated polydimethylsiloxane and silicic acid resin (also referred to as silicon dioxide resin), pressure-sensitive adhesives based on polysiloxanes are prepared, wherein in order to keep the stability of amine, remaining silanol functional groups are additionally terminated with trimethylsiloxy. The silanol-terminated polydimethylsiloxane content contributes to the viscoelastic behavior of the viscous component and affects the wetting and spreading of the adhesive. The resin acts as a tackifying and reinforcing agent and participates in the elastic component. The proper balance between the silanol-terminated polydimethylsiloxane and the resin provides the appropriate adhesive properties.

[0349] In view of the above, silicone-based polymers, especially silicone-based pressure-sensitive adhesives, can generally be obtained by polycondensation of silanol-terminated polydimethylsiloxane with silicic acid resins. Amine-compatible silicone-based polymers, especially amine-compatible silicone-based pressure-sensitive adhesives, can be obtained by reacting silicone-based polymers, especially silicone-based pressure-sensitive adhesives, with trimethylsilyl groups (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, terminated by trimethylsiloxy groups.

[0350] As described above, the viscosity of the silicone-based polymer can be varied by the ratio of resin to polymer, i.e., the ratio of silanol-terminated polydimethylsiloxane to silicic acid resin, which is preferably in the range of 70:30 to 50:50, preferably 65:35 to 55:45. As the amount of polydimethylsiloxane increases relative to the resin, the viscosity will increase. The resin to polymer ratio of the high viscosity silicone-based polymer is preferably 55:45, the resin to polymer ratio of the medium viscosity silicone-based polymer is preferably 60:40, and the resin to polymer ratio of the low viscosity silicone-based polymer is preferably 65:35. The complex viscosity of the high viscosity silicone-based polymer at 0.01 rad / s and 30°C is preferably about 5x 10 6 The complex viscosity of the medium-viscosity silicone-based polymer at 0.01 rad / s and 30°C is preferably about 5×10 7 The complex viscosity of the low-viscosity silicone-based polymer at 0.01 rad / s and 30°C is preferably about 5×10 8 The complex viscosity of the high viscosity amine compatible silicone based polymer at 0.01 rad / s and 30°C is preferably about 5 x 10 6 The complex viscosity of the medium viscosity amine compatible silicone based polymer at 0.01 rad / s and 30°C is preferably about 5 x 10 8 The complex viscosity of the low viscosity amine compatible silicone based polymer at 0.01 rad / s and 30°C is preferably about 5 x 10 9 moor.

[0351] Examples of commercially available silicone-based PSA compositions include the standard BIO-PSA series (7-4400, 7-4500 and 7-4600 series), the amine-compatible (end-capped) BIO-PSA series (7-4100, 7-4200 and 7-4300 series), made by Dow Corning and typically supplied in n-heptane or ethyl acetate, and the Soft Skin Adhesives series (7-9800) produced by Dow Corning and typically supplied solvent-free. For example, BIO-PSA 7-4201 is characterized by a solution viscosity of 450 mPa s at 25° C. and a solids content of about 73% in heptane and a complex viscosity of 1×10 8 The solution viscosity of BIO-PSA 7-4301 at 25°C and a solid content of about 73% in heptane is 500 mPa s and the complex viscosity at 30°C and 0.01 rad / s is 5×10 6 moor.

[0352] The silicone polymer is provided and used in a solvent such as n-heptane, ethyl acetate or other volatile silicone fluids. For the present invention, n-heptane is preferred. The solid content of the silicone polymer in the solvent is generally 60 to 80%, preferably 70 to 80% or 60 to 70%. The skilled person will appreciate that the solid content can be varied by adding an appropriate amount of solvent.

[0353] Preferred silicone-based pressure-sensitive adhesives according to the present 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 at 25° C. and 60% solids in n-heptane, preferably measured using a Brookfield RVT viscometer equipped with a No. 5 spindle at 50 rpm. These are also characterized by a complex viscosity of less than about 1×10 9 poise or about 1×10 5 About 9×10 8 moor.

[0354] Suitable polyisobutylenes according to the invention are available under the trade name Commercially available. Combinations of high molecular weight polyisobutylene (B100 / B80) and low molecular weight polyisobutylene (B10, B11, B12, B13) can be used. Suitable ratios of low molecular weight polyisobutylene to high molecular weight polyisobutylene are 100:1 to 1:100, preferably 95:5 to 40:60, more preferably 90:10 to 80:20. A preferred example of a polyisobutylene combination is B10 / B100 in a ratio of 85 / 15. The viscosity average molecular weight of B100 is M v The weight average molecular weight M is 1,110,000. w 1,550,000, average molecular weight distribution M w / M n is 2.9. The viscosity average molecular weight of B10 is M v The weight average molecular weight M is 40,000. w The average molecular weight distribution is 53,000. w / M n is 3.2. In certain embodiments, polybutene can be added to polyisobutylene. The solid content of polyisobutylene in the solvent is generally 30 to 50%, preferably 35 to 40%. The skilled person knows that the solid content can be changed by adding an appropriate amount of solvent.

[0355] Acrylic acid-based pressure-sensitive adhesives may also be referred to as acrylate pressure-sensitive adhesives. Acrylic acid-based pressure-sensitive adhesives may have a solid content preferably between 30% and 60%. Such acrylic acid-based pressure-sensitive adhesives may or may not contain functional groups, such as hydroxyl groups, carboxylic acid groups, neutralized carboxylic acid groups, and mixtures thereof. Therefore, the term "functional group" refers in particular to hydroxyl and carboxylic acid groups, and deprotonated carboxylic acid groups.

[0356] Corresponding commercial products are available, for example from Henkel under the trade name Duro Such acrylic-based pressure-sensitive adhesives are based on one or more monomers selected from the group consisting of acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, tert-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.

[0357] Specific acrylic-based pressure-sensitive adhesives include the following:

[0358] -Duro-Tak TM 387-2287 or Duro-Tak TM 87-2287 (copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate, supplied as a solution in ethyl acetate, no crosslinker required),

[0359] -Duro-Tak TM 387-2516 or Duro-Tak TM 87-2516 (copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate, supplied as a solution in ethyl acetate, ethanol, n-heptane and methanol, using a titanium crosslinker),

[0360] -Duro-Tak TM 387-2051 or Duro-Tak TM 87-2051 (a copolymer based on acrylic acid, butyl acrylate, 2-ethylhexyl acrylate and vinyl acetate, supplied as a solution in ethyl acetate and heptane),

[0361] -Duro-Tak TM 387-2353 or Duro-Tak TM87-2353 (copolymer based on acrylic acid, 2-ethylhexyl acrylate, glycidyl methacrylate and methyl acrylate, supplied as a solution in ethyl acetate and hexane),

[0362] -Duro-Tak TM 87-4098 (based on a copolymer of 2-ethylhexyl acrylate and vinyl acetate, supplied as a solution in ethyl acetate).

[0363] Additional polymers may also be added to enhance cohesion and / or adhesion.

[0364] Certain polymers particularly reduce cold flow and are therefore particularly suitable as additional polymers. A polymer matrix may exhibit cold flow because, despite very high viscosity, such polymer compositions generally exhibit very slow flow capabilities. Thus, during storage, the matrix may flow to a certain extent over the edges of the backing layer. This is a storage stability problem and can be prevented by adding certain polymers. Basic acrylic polymers (e.g., E100) can be used, for example, to reduce cold flow. Therefore, in certain embodiments, the matrix layer composition further comprises a basic polymer, in particular an amine-functional acrylate, such as E100. E100 is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate in 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 E100 is about 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 used to increase the dryness of the adhesive (eg, matrix layer).

[0365] Other additives

[0366] The TTS according to the invention, in particular the guanfacine-containing layer, may further comprise at least one additive or excipient. Particularly preferred additives according to the invention include dispersants, penetration enhancers and solubilizers. Details in this regard are provided above. However, the TTS according to the invention, in particular the guanfacine-containing layer, may also comprise other additives or excipients.

[0367] Typically, additives or excipients are preferably selected from dispersants, solubilizers, penetration enhancers, film formers, softeners / plasticizers, viscosity enhancers, skin care substances, pH adjusters, preservatives, stabilizers and fillers. Such additives may be present in the guanfacine-containing layer in an amount of 0.001 wt % to 15 wt %, such as 0.5-10 wt % or 1-10 wt %, based on the total weight of the guanfacine-containing layer, and wherein the wt % amounts refer to a single additive.

[0368] It should be noted that in pharmaceutical preparations, the formulation ingredients are classified according to their physicochemical and physiological properties and their functions. This means in particular that it is not excluded that a substance or compound belonging to one category belongs to another category of formulation ingredients. For example, a polymer can be both a film former and a tackifier. For example, some substances may be a typical softener, but at the same time a penetration enhancer. The technician can determine which or more formulation components a certain substance or compound belongs to based on his common sense. In the following, details about excipients and additives are provided, but these details should not be understood as exclusive. According to the present invention, other substances not explicitly listed in this specification may also be used, and according to the intention of the present invention, it is not excluded that substances and / or compounds explicitly listed for one formulation component category are used as another formulation component.

[0369] In one embodiment, the guanfacine-containing layer comprises a dispersant as defined above, preferably selected from the following dispersants: esters of fatty acids and polyols, fatty alcohols, polyethylene glycols with a number average molecular weight of 300 to 400, polyethylene glycol alkyl ethers. As mentioned above, the dispersant is preferably polyethylene glycol C8-C8 with 2 to 10 EO units. 20 Alkyl ethers, in particular polyoxyethylene (4) lauryl ether. Alternatively or additionally, silicone polyethers may be used as dispersants. Dispersants help to evenly disperse guanfacine in the layer containing guanfacine, in particular in the matrix layer containing guanfacine, thereby improving the release properties of the TTS.

[0370] In one embodiment, the guanfacine-containing layer comprises a solubilizing agent. The solubilizing agent preferably improves the dispersibility of guanfacine in the guanfacine-containing layer and stabilizes the guanfacine-containing layer. In addition, the solubilizing agent can positively affect cohesion. Preferred solubilizers include, for example, glycerol esters, polyglycerol esters, propylene glycol esters and polyoxyethylene esters of medium-chain and / or long-chain fatty acids, such as monolinolein, medium-chain glycerides and medium-chain triglycerides, nonionic solubilizers prepared by reacting castor oil with ethylene oxide, and any mixtures thereof which may further contain fatty acids or fatty alcohols; cellulose and methylcellulose and their derivatives, such as hydroxypropyl cellulose and hydroxypropyl methylcellulose acetate succinate; various cyclodextrins and their derivatives; nonionic triblock copolymers having a hydrophobic central chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, known as poloxamers; water-soluble derivatives of vitamin E; pharmaceutically graded or agglomerated spherical isomalt; a graft copolymer based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam, also abbreviated as PVAc-PVCap-PEG, also known as Vinylpyrrolidone-vinyl acetate copolymers, e.g. VA64; purified grade natural castor oil, polyethylene glycol 400, polyoxyethylene sorbitan monooleate (e.g. polysorbate 80) or propylene glycol; diethylene glycol monoethyl ether; glucono-δ-lactone; corn and potato starch; and any soluble polyvinyl pyrrolidone mentioned below, as well as insoluble / cross-linked polyvinyl pyrrolidone, such as crospovidone.

[0371] However, the penetration enhancers mentioned below can also be used as solubilizers. In addition, the film formers mentioned below can also be used as solubilizers at the same time, and vice versa.

[0372] In one embodiment, the layer containing guanfacine comprises a penetration enhancer. Preferences in this regard are provided above. A penetration enhancer is a substance that affects the barrier properties of the stratum corneum in the sense of increasing the permeability of the active agent. Some examples of penetration enhancers are polyols, 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, methylcetyl sulfoxide, dimethyllaurylamine, dodecylpyrrolidone, isosorbide, dimethylacetonide, dimethyl sulfoxide, decylmethyl sulfoxide and dimethylformamide; 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, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate and isopropyl palmitate. If the guanfacine-containing layer comprises a permeation enhancer, the permeation enhancer is preferably selected from the group consisting of diethylene glycol monoethyl ether (transcutol), oleic acid, levulinic acid, caprylic / capric triglyceride, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, triacetin, dimethylpropylene urea and oleyl alcohol, and is preferably oleyl alcohol.

[0373] In one embodiment, the guanfacine-containing layer further comprises a film former. It should be understood that the above-mentioned solubilizing agent, e.g. It can also be used as a film former and control cohesion. Suitable examples of other film formers include polyvinyl pyrrolidone, vinyl acetate / vinyl pyrrolidone copolymers and cellulose derivatives, preferably polyvinyl pyrrolidone, more preferably soluble polyvinyl pyrrolidone.

[0374] If the layer containing guanfacine is required to have self-adhesiveness, and one / more polymers that cannot provide enough self-adhesiveness are selected, a tackifier is added. Preferred tackifiers include Miglyol, which is a liquid wax ester of long-chain unsaturated even-numbered fatty acids and long-chain unsaturated even-numbered fatty alcohols and polyethylene glycol based on plant sources. In particular, the tackifier can be selected from polyvinyl pyrrolidone (due to its ability to absorb water, the adhesive properties of the matrix layer can be maintained, so it can be regarded as a tackifier in a broad sense), triglycerides, polyethylene glycol, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethyl polysiloxanes and polybutenes, preferably polyvinyl pyrrolidone, more preferably soluble polyvinyl pyrrolidone. Preferably, the tackifier can be selected from polyvinyl pyrrolidone, triglycerides, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethyl polysiloxanes and polybutenes, preferably polyvinyl pyrrolidone, more preferably soluble polyvinyl pyrrolidone.

[0375] The term "soluble polyvinyl pyrrolidone" refers to polyvinyl pyrrolidone, also known as povidone, which is soluble in at least 10% in ethanol, 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-butylene glycol, glycerol, triethanolamine, propionic acid and acetic acid. Examples of commercially available polyvinyl pyrrolidone include povidone K90F supplied by BASF or povidone K90F 12PF, 17PF, 25. 30 and 90F. Different grades are defined according to the K value which reflects the average molecular weight of the polyvinyl pyrrolidone grade. The K value range of 12PF is 10.2 to 13.8, and the corresponding nominal K value is 12. The K value range of 17PF is 15.3 to 18.4, corresponding to a nominal K value of 17. 25 is characterized by a K value range of 22.5 to 27.0, corresponding to a nominal K value of 25, The K value range of 30 is 27.0 to 32.4, corresponding to a nominal K value of 30. The K value range of 90F is 81.0 to 97.2, corresponding to a nominal K value of 90. Rated as 12PF, 30 and 90 F. Within the meaning of the present invention, the term "K value" refers to the value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the European Pharmacopoeia (Ph. Eur) and the USP monograph on "Polyvidone".

[0376] In one embodiment, the guanfacine-containing layer further comprises a softener / plasticizer. Exemplary softeners / plasticizers include linear or branched, saturated or unsaturated alcohols having 6 to 20 carbon atoms, triglycerides, and polyethylene glycols.

[0377] In one embodiment, the guanfacine-containing layer further comprises a stabilizer. Stabilizers include tocopherol and its ester derivatives and ascorbic acid and its ester derivatives. Other stabilizers include sodium metabisulfite, ascorbic acid esters of fatty acids, such as ascorbyl palmitate, ascorbic acid, butylated hydroxytoluene, tocopherol, tocopheryl acetate, and tocopheryl linoleate.

[0378] In one embodiment, the guanfacine-containing layer further comprises a pH adjuster. Suitable pH adjusters include weak acids and bases, including amine derivatives, inorganic base derivatives, and polymers having basic or acidic functional groups.

[0379] In one embodiment, the guanfacine-containing layer further comprises a preservative. Suitable preservatives include parabens, formaldehyde releasers, isothiazolinones, phenoxyethanol, and organic acids such as benzoic acid, sorbic acid, levulinic acid, and anisic acid.

[0380] In one embodiment, the guanfacine-containing layer further comprises a substance for skin care. Such substances can be used to avoid or reduce skin irritation, as detected by skin reaction scoring. Substances suitable for skin care include sterol compounds, such as cholesterol, dexpanthenol, alpha-disaccharide alcohols, and antihistamines.

[0381] 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 cohesion and adhesive strength, in a desired manner.

[0382] Release Features

[0383] The TTS according to the invention is designed for transdermal administration of guanfacine to the systemic circulation for a predetermined extended period of time, preferably at least 24 hours, more preferably at least 72 hours, in particular about 84 hours.

[0384] In one embodiment, the TTS according to the present invention provides a mean plasma concentration of guanfacine of 1 to 20 ng / ml, preferably 1 to 15 ng / ml, more preferably 1 to 10 ng / ml, by transdermal delivery at steady state.

[0385] Preferably, the TTS provides a therapeutically effective plasma concentration of guanfacine in less than 8 hours, preferably less than 6 hours, and more preferably less than 4 hours after the TTS is applied to the skin. In addition, the therapeutically effective plasma concentration is preferably maintained throughout the administration period of at least 24 hours, preferably at least 72 hours, and more preferably about 84 hours.

[0386] In one embodiment, the TTS according to the invention provides an AUC of 10 to 600 ng*h / ml, preferably 20 to 400 ng*h / ml. 0-24h In another embodiment, the TTS according to the present invention provides an AUC of 30-1800 ng*h / ml, preferably 60-1200 ng*h / ml. 0-72h In another embodiment, the TTS according to the invention provides an AUC of 35 to 2100 ng*h / ml, preferably 70 to 1400 ng*h / ml. 0-84h It should be understood that the AUC value preferably refers to the AUC value obtained at steady state.

[0387] In one embodiment, the TTS according to the present invention provides C max With C 84 In another embodiment, the TTS according to the present invention provides C max With C 72 In another embodiment, the TTS according to the present invention provides C max With C 24 The ratio is less than 2.0. These ratios indicate a flat plasma curve, which is advantageous in the continuous treatment of patients.

[0388] In one embodiment, a TTS according to the invention provides the following skin permeation rate of guanfacine as measured in a Franz diffusion cell of human skin harvested with a skin harvester:

[0389] In the first 24 hours, 0.01 μg / (cm 2 *h) to 8μg / (cm 2 *h),

[0390] From 24 hours to 72 hours, 0.05 μg / (cm 2 *h) to 10μg / (cm 2 *h).

[0391] In one embodiment, the TTS according to the present invention provides a guanfacine skin permeation rate of 0.05 mg / cm over a 72 hour period. 2 Up to 0.7mg / cm 2 , preferably 0.1 mg / cm 2Up to 0.6mg / cm 2 , as measured in a Franz diffusion cell of human skin harvested with a skin harvester.

[0392] In view of the above, the present invention also relates in one aspect to a transdermal therapeutic system for transdermal administration of guanfacine, comprising a layer structure containing guanfacine,

[0393] wherein the transdermal therapeutic system provides one or more pharmacokinetic parameters selected from the following via transdermal delivery:

[0394] AUC from 10 to 600 (ng / mL)h 0-24 ,

[0395] AUC from 30 to 1800 (ng / mL)h 0-72 ,

[0396] AUC from 35 to 2100 (ng / mL)h 0-84 ,

[0397] C max With C 24 The ratio is less than 2.0,

[0398] C max With C 72 The ratio is less than 3.0, and

[0399] C max With C 84 The ratio is less than 3.5.

[0400] In a preferred embodiment of the present invention, it relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising a layer structure containing guanfacine,

[0401] wherein the transdermal therapeutic system provides one or more pharmacokinetic parameters selected from the following via transdermal delivery:

[0402] AUC from 20 to 400 (ng / mL)h 0-24 ,

[0403] AUC 60 to 1200 (ng / mL)h 0-72 ,

[0404] AUC 70 to 1400 (ng / mL)h 0-84 ,

[0405] C max With C 24 The ratio is less than 1.5,

[0406] C max With C 72 The ratio is less than 2.5, and

[0407] C max With C 84 The ratio is less than 3.0.

[0408] Treatment methods / medical uses

[0409] 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 from 6 to 17 years. 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 in a human patient aged from 6 to 17 years and / or as an adjunct therapy to stimulant drugs.

[0410] In a preferred embodiment related to the above-mentioned medical use, the TTS is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, more preferably about 84 hours.

[0411] In one embodiment, the present invention relates to a method for treating a human patient, preferably a human patient aged 6 to 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 6 to 17 years, by applying to the patient's skin a transdermal therapeutic system according to the invention.

[0412] In a preferred embodiment of the above-described 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 for about 84 hours.

[0413] 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 6 to 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 used in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient and / or as an adjunct therapy to irritant drugs. In a more preferred embodiment, the transdermal therapeutic system is a transdermal therapeutic system according to the present invention, in particular a transdermal therapeutic system providing one or more pharmacokinetic parameters selected from the group consisting of:

[0414] AUC from 10 to 600 (ng / mL)h 0-24 ,

[0415] AUC from 30 to 1800 (ng / mL)h 0-72 ,

[0416] AUC from 35 to 2100 (ng / mL)h0-84 ,

[0417] C max With C 24 The ratio is less than 2.0,

[0418] C max With C 72 The ratio is less than 3.0, and

[0419] C max With C 84 The ratio is less than 3.5;

[0420] and is preferably selected from:

[0421] AUC from 20 to 400 (ng / mL)h 0-24 ,

[0422] AUC 60 to 1200 (ng / mL)h 0-72 ,

[0423] AUC 70 to 1400 (ng / mL)h 0-84 ,

[0424] C max With C 24 The ratio is less than 1.5,

[0425] C max With C 72 The ratio is less than 2.5, and

[0426] C max With C 84 The ratio is less than 3.0.

[0427] In another aspect, the present invention relates to guanfacine for use in a method of treating a human patient, preferably a human patient aged 6 to 17 years, by transdermal administration of guanfacine with a transdermal therapeutic system, 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, guanfacine is used in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient and / or as an adjunct therapy to stimulant drugs. In a more preferred embodiment, the transdermal therapeutic system is a transdermal therapeutic system according to the invention, in particular a transdermal therapeutic system providing one or more pharmacokinetic parameters selected from the group consisting of:

[0428] AUC from 10 to 600 (ng / mL)h 0-24 ,

[0429] AUC from 30 to 1800 (ng / mL)h 0-72 ,

[0430] AUC from 35 to 2100 (ng / mL)h 0-84 ,

[0431] C max With C 24 The ratio is less than 2.0,

[0432] C max With C 72 The ratio is less than 3.0, and

[0433] C max With C 84 The ratio is less than 3.5;

[0434] and is preferably selected from:

[0435] AUC from 20 to 400 (ng / mL)h 0-24 ,

[0436] AUC 60 to 1200 (ng / mL)h 0-72 ,

[0437] AUC 70 to 1400 (ng / mL)h 0-84 ,

[0438] C max With C 24 The ratio is less than 1.5,

[0439] C max With C 72 The ratio is less than 2.5, and

[0440] C max With C 84 The ratio is less than 3.0.

[0441] In another aspect, the present invention relates to a method for treating a human patient, preferably a human patient aged 6 to 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 method is used for treating hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient and / or as an adjunct therapy to stimulant drugs. In a more preferred embodiment, the transdermal therapeutic system is a transdermal therapeutic system according to the invention, in particular a transdermal therapeutic system providing one or more pharmacokinetic parameters selected from the group consisting of:

[0442] AUC from 10 to 600 (ng / mL)h 0-24 ,

[0443] AUC from 30 to 1800 (ng / mL)h 0-72 ,

[0444] AUC from 35 to 2100 (ng / mL)h 0-84 ,

[0445] C max With C 24 The ratio is less than 2.0,

[0446] C max With C 72 The ratio is less than 3.0, and

[0447] C max With C 84 The ratio is less than 3.5;

[0448] and is preferably selected from:

[0449] AUC from 20 to 400 (ng / mL)h 0-24 ,

[0450] AUC 60 to 1200 (ng / mL)h 0-72 ,

[0451] AUC 70 to 1400 (ng / mL)h 0-84 ,

[0452] C max With C 24 The ratio is less than 1.5,

[0453] C max With C 72 The ratio is less than 2.5, and

[0454] C max With C 84 The ratio is less than 3.0.

[0455] With regard to the above-mentioned uses and methods of treatment, the TTS according to the present invention is preferably applied to at least one body surface of a subject at a given dosing interval, the body surface being selected from the group consisting of the upper outer art, the upper chest, the upper back or the side of the chest.

[0456] 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 a new TTS can be optionally applied for around-the-clock treatment.

[0457] Manufacturing method

[0458] The present invention also relates to a method for producing a guanfacine-containing layer, preferably a guanfacine-containing matrix layer, for use in a transdermal therapeutic system.

[0459] According to the invention, the method for producing a guanfacine-containing layer for a transdermal therapeutic system according to the invention comprises the following steps:

[0460] 1) Combine at least the following components

[0461] i) guanfacine; and

[0462] ii) at least one silicone polymer;

[0463] to obtain a coating composition;

[0464] 2) applying the coating composition onto a backing layer or a release liner to obtain a coated coating composition; and

[0465] 3) Drying the applied coating composition to form a guanfacine-containing layer.

[0466] In step 1) of the above-mentioned manufacturing method, guanfacine is preferably dispersed in the polymer to obtain a uniform coating composition.

[0467] It should be understood that in step 1), further ingredients may also be added, preferably at least one further polymer and / or at least one additive as defined above.

[0468] 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 from non-alcoholic solvents, in particular ethyl acetate, hexane, heptane, petroleum ether, toluene and mixtures thereof, and more preferably from non-alcoholic solvents, most preferably ethyl acetate or n-heptane.

[0469] 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.

[0470] In step 2) of the method, the coating composition is applied to the backing layer or the release liner. As a result, a coated coating composition, ie, a coating composition coated on the backing layer or the release liner, is obtained.

[0471] After forming the guanfacine-containing layer in step 3), the method may further include a step of applying a release liner or a backing layer to the other side of the guanfacine-containing layer.

[0472] In step 3) of the above production method, drying is preferably performed at a temperature of 20 to 90° C., more preferably 40 to 70° C. Drying may preferably take at least 1 hour, preferably at least 8 hours, for example one day. Example

[0473] The present invention will now be described more fully with reference to the accompanying examples. However, it should be understood that the following description is illustrative only and should not limit the present invention in any way. The numerical values ​​of the amount or area weight of the components in the composition provided in the examples may vary slightly due to manufacturing differences.

[0474] Examples 1A-D

[0475] Coating composition

[0476] 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).

[0477] Table 1.1a

[0478]

[0479]

[0480] Table 1.1b

[0481]

[0482] Preparation of coating compositions

[0483] The drug and enhancer used are dispersed in the solvent ethyl acetate and subjected to ultrasound treatment for about 10 minutes. The binder is added. The two steps can also be carried out in the opposite order. The mixture is homogenized at 2000 rpm for 2 minutes with a dissolving stirrer. Soluplus is added and the material is stirred at 2000 rpm for another 2 minutes and further homogenized at 1500 rpm for at least 30 minutes.

[0484] In the case of composition 1b, the enhancers polyoxyethylene (4) lauryl ether and Soluplus were dispersed in the solvent ethanol and sonicated for 10 minutes. The drug and enhancer oleyl alcohol were added and the mixture was sonicated for another 10 minutes. The binder was added.

[0485] In the case of composition 1d, the drug and the enhancer used were dispersed in the solvent ethyl acetate and sonicated for 10 minutes. The binder and Soluplus were added. The mixture was homogenized with a dissolving stirrer at 2000 rpm for 2 minutes. The material was further stirred at 1500 rpm for at least 30 minutes.

[0486] Application of coating composition

[0487] The resulting guanfacine-containing coating composition is applied onto a polyethylene terephthalate film (Scotchpak 9755, which can be used as a release liner) using, for example, an Erichsen applicator, taking into account the desired dry coating weight, depending on the solid content of the mixture, and dried at about 50° C. for about 10 minutes. Depending on the target area weight, the corresponding applicator gap is between 150 and 350 μm.

[0488] The coating thickness was selected so that removal of the solution resulted in an area weight of the guanfacine-containing layer of about 100 (Example 1a), 91 (Example 1b), 106 (Example 1c), and 110 (Example 1d) g / m 2 The dried film was then laminated with a backing layer (PET 15 μm tsp, MN 19) to provide a guanfacine-containing self-adhesive layer structure.

[0489] Preparation of TTS (for all examples)

[0490] Individual systems (TTS) are then punched out from the guanfacine-containing self-adhesive layer structure obtained as described above. The TTS is then sealed in a bag of primary packaging material.

[0491] Measurement of skin penetration

[0492] The permeation of the TTS prepared according to Examples 1a-d was determined by experiments performed using a 10.0 mL Franz diffusion cell according to the OECD guidelines (approved on April 13, 2004). Split thickness human skin from cosmetic surgery (female abdomen, born in 1966) was used. The skin was prepared with a thickness of 500 μm using a skin extractor, and the epidermis for all TTS was intact. A release area of ​​1.188 cm was punched out from the TTS. 2 The permeation of guanfacine into the receptor medium of the Franz cell (phosphate buffer solution pH 5.5, containing 0.1% sodium azide as an antimicrobial agent) was measured at a temperature of 32±1°C, and the corresponding cumulative permeation was calculated.

[0493] The results are shown in Tables 1.2 and Figure 1 .

[0494] Table 1.2

[0495]

[0496]

[0497] Example 2A-B

[0498] Coating composition

[0499] The formulations of the guanfacine-containing coating compositions of Examples 2a-b are summarized in Table 2.1 below. The % values ​​refer to amounts in % by weight.

[0500] Table 2.1

[0501]

[0502] Preparation of coating compositions

[0503] The drug and enhancer used were dispersed in ethyl acetate and ultrasonicated for about 10 minutes. A binder was added. The two steps can also be performed in the opposite order. The mixture was homogenized with a dissolving stirrer at 2000 rpm for 2 minutes. The material was stirred again at 1000 rpm for 10 minutes.

[0504] Application of coating composition

[0505] See the coating method of Examples 1a-d. The coating thicknesses gave an area weight of the guanfacine-containing layer of 115 (Example 2a) and 113 (Example 2b) g / m 2 The dried film is laminated with a backing layer (eg, siliconized MN 19) to provide a guanfacine-containing self-adhesive layer structure.

[0506] Preparation of TTS

[0507] See Example 1.

[0508] Measurement of skin penetration

[0509] The permeation of the TTS prepared according to Examples 2a-b was determined as described in Examples 1a-d above. A release area of ​​1.188 cm was punched out of the TTS. 2 Die-cuttings.

[0510] The results are shown in Table 2.2 and Figure 2 shown.

[0511] Table 2.2

[0512]

[0513] Examples 3A-B

[0514] The formulations of the guanfacine-containing coating compositions of Examples 3a-b are summarized in Table 3.1 below. The % values ​​refer to amounts in % by weight.

[0515] Table 3.1

[0516]

[0517]

[0518] Preparation of coating compositions

[0519] The drug and enhancer used are dispersed in the solvent ethyl acetate and subjected to ultrasound treatment for about 10 minutes. The binder is added. The two steps can also be carried out in the opposite order. The mixture is homogenized at 2000 rpm for 2 minutes with a dissolving stirrer. Soluplus is added and the material is stirred at 2000 rpm for another 2 minutes and further homogenized at 1500 rpm for 30 minutes.

[0520] Application of coating composition

[0521] See the coating method of Examples 1a-d. The coating thickness gave an area weight of 106 (Example 3a) and 103 (Example 3b) g / m 2 The dried film is laminated with a backing layer (eg, siliconized MN 19) to provide a guanfacine-containing self-adhesive layer structure.

[0522] Preparation of TTS

[0523] See Example 1.

[0524] Measurement of skin penetration

[0525] The permeation of the TTS prepared according to Examples 3a-b was determined as described in Examples 1a-d above. A release area of ​​1.188 cm was punched out of the TTS. 2 Die-cuttings.

[0526] The results are shown in Table 3.2 and Figure 3 shown.

[0527] Table 3.2

[0528]

[0529]

[0530] Example 4A

[0531] The formulation of the guanfacine-containing coating composition of Example 4a is summarized in Table 4.1 below. The % values ​​refer to amounts in % by weight.

[0532] Table 4.1

[0533]

[0534] Preparation of coating compositions

[0535] The drug was dispersed in the solvent n-heptane and sonicated for about 45 minutes. The binder was added. The two steps can also be performed in the reverse order. The mixture was homogenized with a dissolving stirrer at 1000 rpm for 15 minutes.

[0536] Application of coating composition

[0537] See Example 1a-d for coating method. Coating thickness The resulting area weight of the guanfacine-containing layer is 100 (Example 4a). The dried film is laminated with a backing layer (eg Hostaphan 15 μm) to provide a guanfacine-containing self-adhesive layer structure.

[0538] Preparation of TTS

[0539] See Example 1.

[0540] Measurement of skin penetration

[0541] The permeation of the TTS prepared according to Example 4a was determined as described in Examples 1a-d above. A release area of ​​1.188 cm was punched out of the TTS. 2 Die-cuttings.

[0542] The results are shown in Table 4.2.

[0543] Table 4.2

[0544]

[0545] Comparative Example 1

[0546] Comparative Example 1 is a mixture of Oppanol B10 and Oppanol B100 in a ratio of 15 / 85 and guanfacine base. Table 4.1a below summarizes the formulation of the guanfacine-containing coating composition of Comparative Example 1. The % values ​​refer to the amount in weight %

[0547] Table 4.1a

[0548]

[0549] Preparation of coating compositions

[0550] The drug was dispersed in the solvent n-heptane and then ultrasonicated for 10 minutes. The adhesive mixture was then added. The two steps could also be performed in the opposite order. The mixture was homogenized at 100-500 rpm for 30 minutes using a dissolving stirrer.

[0551] Application of coating composition

[0552] See the coating method of Examples 1a-d. Coating thickness The area weight of the guanfacine-containing layer obtained was 91 g / m 2 The dried film was laminated with a backing layer (siliconized MN 19) to provide a guanfacine-containing self-adhesive layer structure.

[0553] Preparation of TTS

[0554] See Example 1.

[0555] Measurement of skin penetration

[0556] The permeation of the TTS prepared according to Comparative Example 1 was determined as described in Examples 1a-d above. A release area of ​​1.188 cm was punched out of the TTS. 2 Die-cuttings.

[0557] The results are shown in Table 4.2a and Figure 1 shown.

[0558] Table 4.2a

[0559]

[0560] *DL = Detection Limit

[0561] Comparative Examples 2A-B

[0562] Coating composition

[0563] The formulations of the guanfacine-containing coating compositions of Comparative Examples 2a-b are summarized in Table 5.1 below. The % values ​​refer to amounts in % by weight.

[0564] Table 5.1

[0565]

[0566] Preparation of coating compositions

[0567] The drug is dispersed in the solvent ethyl acetate and ultrasonicated for about 5 minutes. Then the binder is added. These two steps can also be performed in the opposite order. The mixture is homogenized at 500-800 rpm for about 10 minutes using a dissolving stirrer.

[0568] In the case of Comparative Example 2, the drug was directly dispersed in the binder. The mixture was stirred at 500 rpm for about 10 minutes.

[0569] Application of coating composition

[0570] See the coating method of Examples 1a-d. For Comparative Example 2b, the coating composition was coated on a PET 100 μm film. The coating thickness gave an area weight of 49 (Comparative Example 2a) and 50 (Comparative Example 2b) g / m 2 The dried film was laminated with a backing layer (PET 15 μm tsp) to provide a guanfacine-containing self-adhesive layer structure.

[0571] Preparation of TTS

[0572] See Example 1.

[0573] Determination of skin penetration

[0574] The permeation of the TTS prepared according to Comparative Examples 2a-b was determined by experiments performed according to the OECD guidelines (approved on April 13, 2004) using a 10.0 mL Franz diffusion cell. Blade-thick Goettinger miniature pig skin (female) was used. The skin was prepared using a skin extractor with a thickness of 800 μm, and the epidermis for all TTS was intact. A 1.165 cm area was punched out from the TTS. 2 The permeation of guanfacine into the receptor medium of the Franz cell (phosphate buffer solution pH 5.5, containing 0.1% sodium azide as an antimicrobial agent) was measured at a temperature of 32±1°C, and the corresponding cumulative permeation was calculated.

[0575] The results are shown in Table 5.2 and Figure 4 middle.

[0576] Table 5.2

[0577]

[0578] The present invention particularly relates to the following other items:

[0579] 1. A transdermal therapeutic system for transdermal administration of guanfacine, comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure comprises:

[0580] A) a backing layer; and

[0581] B) layer containing guanfacine;

[0582] Therein the transdermal therapeutic system comprises at least one silicone polymer.

[0583] 2. The transdermal therapeutic system according to claim 1,

[0584] The guanfacine-containing layer is a matrix layer containing guanfacine, which comprises:

[0585] i) guanfacine; and

[0586] ii) at least one silicone polymer.

[0587] 3. The transdermal therapeutic system according to any one of items 1 or 2,

[0588] The layer structure containing guanfacine is self-adhesive and preferably does not comprise an additional skin contact layer.

[0589] 4. The transdermal therapeutic system according to any one of items 1 to 3,

[0590] At least one of the silicone polymers is a silicone pressure sensitive adhesive.

[0591] 5. The transdermal therapeutic system according to any one of items 1 to 4,

[0592] The guanfacine-containing layer structure contains a therapeutically effective amount of guanfacine.

[0593] 6. The transdermal therapeutic system according to any one of items 1 to 5,

[0594] Wherein the guanfacine in the guanfacine-containing layer structure is present in the form of a free base, it is preferably dispersed in the guanfacine-containing layer.

[0595] 7. The transdermal therapeutic system according to any one of items 1 to 6,

[0596] The guanfacine-containing layer structure contains guanfacine in an amount of 1 to 100 mg / TTS, preferably 8 to 72 mg / TTS.

[0597] 8. The transdermal therapeutic system according to any one of items 1 to 7,

[0598] The guanfacine-containing layer comprises guanfacine in an amount of 1 to 20 wt %, more preferably 3 to 16 wt %, based on the total weight of the guanfacine-containing layer.

[0599] 9. The transdermal therapeutic system according to any one of items 1 to 8,

[0600] The guanfacine-containing layer comprises the at least one silicone polymer in an amount of 20 to 99 wt %, preferably 30 to 97 wt %, and most preferably 35 to 90 wt % based on the total weight of the guanfacine-containing layer.

[0601] 10. The transdermal therapeutic system according to any one of items 1 to 9,

[0602] The at least one silicone polymer may be obtained by polycondensation of silanol-terminated polydimethylsiloxane and a silicic acid resin.

[0603] 11. The transdermal therapeutic system according to claim 10,

[0604] The residual silanol functional groups of at least one silicone polymer are terminated with trimethylsiloxy groups.

[0605] 12. Transdermal therapeutic system according to any one of items 1 to 11, wherein the guanfacine-containing layer comprises at least one other polymer selected from the group consisting of acrylic polymers, silicone acrylic hybrid polymers, polyisobutylene and styrene-isoprene-styrene block copolymers, preferably selected from the group consisting of acrylic polymers and silicone acrylic hybrid polymers.

[0606] 13. A transdermal therapeutic system according to any one of items 1 to 12, wherein the guanfacine-containing layer comprises a first polymer which is a silicone polymer, the content of which is 35-70 wt % of the total weight of the guanfacine-containing layer, and a second polymer which is selected from the group consisting of silicone polymers, acrylic polymers and silicone-acrylic hybrid polymers, the content of which is 15% to 45 wt % of the total weight of the guanfacine-containing layer.

[0607] 14. A transdermal therapeutic system according to any one of items 12 or 13, wherein the acrylic polymer is obtainable from one or more monomers selected from the group consisting of acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, tert-octylacrylamide and vinyl acetate, preferably obtainable from one or more monomers selected from the group consisting of ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate and vinyl acetate.

[0608] 15. Transdermal therapeutic system according to any one of items 12 to 14, wherein the silicone acrylic hybrid polymer comprises a silicone phase and an acrylic phase in a weight ratio of 60:40 to 40:60.

[0609] 16. The transdermal therapeutic system according to any one of items 12 to 15,

[0610] The silicone acrylic hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin and an acrylic polymer, wherein the acrylic polymer covalently self-crosslinks and covalently bonds to the silicone polymer and / or the silicone resin.

[0611] 17. The transdermal therapeutic system according to any one of items 12 to 15,

[0612] The silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive obtainable from:

[0613] (a) A silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups.

[0614] 18. Transdermal therapeutic system according to any one of items 12 to 15 or 17,

[0615] The silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure sensitive adhesive comprising the reaction product of:

[0616] (a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups;

[0617] (b) ethylenically unsaturated monomers; and

[0618] (c) Initiator.

[0619] 19. The transdermal therapeutic system according to any of items 17 or 18,

[0620] The silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups comprises the condensation reaction product of:

[0621] (a1) silicone resin, and

[0622] (a2) silicone polymer, and

[0623] (a3) Silicon-containing capping agents comprising acrylate or methacrylate functional groups.

[0624] 20. The transdermal therapeutic system according to any one of items 17 to 19,

[0625] The silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups comprises the condensation reaction product of:

[0626] (a1) silicone resin, and

[0627] (a2) silicone polymer, and

[0628] (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 SZ 3-b , wherein X is a monovalent group of the general formula AE, wherein E is -O- or -NH-, A is an acryloyl group or a methacryloyl group, Y is a divalent alkylene group having 1 to 6 carbon atoms, R' is a methyl group or a phenyl group, Z is a monovalent hydrolyzable organic group or a halogen, and b is 0 or 1;

[0629] wherein the silicone resin and the silicone polymer react to form a pressure sensitive adhesive, wherein a silicon-containing end-capping agent is introduced before, during or after the reaction of the silicone resin and the silicone polymer,

[0630] After the silicone resin and the silicone polymer undergo a condensation reaction to form a pressure-sensitive adhesive, the silicon-containing end-capping agent reacts with the pressure-sensitive adhesive, or the silicon-containing end-capping agent reacts with the silicone resin and the silicone polymer in situ.

[0631] 21. The transdermal therapeutic system according to any one of items 18 to 20,

[0632] The ethylenically unsaturated monomer is selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, alicyclic acrylates, alicyclic methacrylates and combinations thereof, each of the compounds having up to 20 carbon atoms in the alkyl group, and the ethylenically unsaturated monomer is preferably a combination of 2-ethylhexyl acrylate and methyl acrylate, particularly preferably in a ratio of 40:60 to 70:30.

[0633] 22. The transdermal therapeutic system according to any one of items 18 to 21,

[0634] The reaction product of (a), (b) and (c) comprises a continuous acrylic outer phase and a discontinuous silicone inner phase.

[0635] (a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functional groups;

[0636] (b) ethylenically unsaturated monomers; and

[0637] (c) Initiator.

[0638] 23. The transdermal therapeutic system according to any one of items 1 to 22,

[0639] 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.

[0640] 24. The transdermal therapeutic system according to claim 23, wherein 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, wherein the dispersant is preferably polyethylene glycol C8-C16 having 2 to 10 EO units. 20 Alkyl ether.

[0641] 25. A transdermal therapeutic system according to item 23 or 24, wherein the penetration enhancer is selected from: 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, and is preferably oleyl alcohol.

[0642] 26. A transdermal therapeutic system according to any one of items 23 to 25, wherein the solubilizer is selected from copolymers derived from esters of acrylic acid and methacrylic acid, polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymers and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, and is preferably a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0643] 27. The transdermal therapeutic system according to any one of items 23 to 26,

[0644] The at least one additive is present in an amount of 0.5 to 10 weight % or 1 to 10 weight % of the total weight of the guanfacine-containing layer.

[0645] 28. Transdermal therapeutic system according to any one of items 1 to 27,

[0646] The release area is 1 to 100 cm 2 , preferably 2.5 to 50 cm 2 and / or wherein the area weight of the layer containing guanfacine is 40 to 250 g / m 2 , preferably 50 to 150 g / m 2 .

[0647] 29. The transdermal therapeutic system according to any one of items 1 to 28,

[0648] The guanfacine loading of the transdermal therapeutic system is 0.2 to 2.4 mg / cm 2 , preferably 0.2 to 1.5 mg / cm 2 .

[0649] 30. Transdermal therapeutic system according to any one of items 1 to 29,

[0650] The transdermal therapeutic system provides a mean plasma concentration of guanfacine of 1 to 20 ng / ml, preferably 1 to 15 ng / ml, at steady state via transdermal delivery.

[0651] 31. Transdermal therapeutic system according to any one of items 1 to 30,

[0652] The skin permeation rate of guanfacine measured on human skin harvested by a skin harvester in a Franz diffusion cell is provided as:

[0653] In the first 24 hours, 0.01 μg / (cm 2 *h) to 8μg / (cm 2 *h),

[0654] From 24 hours to 72 hours, 0.05 μg / (cm 2 *h) to 10μg / (cm 2 *h).

[0655] 32. The transdermal therapeutic system according to any one of items 1 to 31,

[0656] The cumulative permeation of guanfacine measured on human skin harvested using a skin harvester in a Franz diffusion cell was provided as 0.05 mg / cm over a 72 hour period. 2 Up to 0.7mg / cm 2 , preferably 0.1 mg / cm 2 Up to 0.6mg / cm2 .

[0657] 33. Transdermal therapeutic system according to any of items 1 to 32, for use in a method of treating a human patient, preferably a human patient aged 6 to 17 years.

[0658] 34. Transdermal therapeutic system according to any one of items 1 to 32 for use in a method for the treatment of hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient, preferably in a human patient aged 6 to 17 years and / or as an adjunct therapy to stimulant drugs.

[0659] 35. Transdermal therapeutic system for use according to any 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.

[0660] 36. Method for treating a human patient, preferably a human patient aged 6 to 17 years, by applying to the patient's skin a transdermal therapeutic system as defined in any one of items 1 to 32.

[0661] 37. Method for treating hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient, preferably in a human patient aged 6 to 17 years, by applying a transdermal therapeutic system as defined in any one of items 1 to 32 to the skin of the patient.

[0662] 38. Method for treating a human patient according to any 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.

[0663] 39. A method for producing a guanfacine-containing layer for a transdermal therapeutic system according to any one of items 1 to 32, comprising the following steps:

[0664] 1) Combine at least the following components:

[0665] i) Guanfacine;

[0666] ii) at least one silicone polymer; and

[0667] to obtain a coating composition;

[0668] 2) applying the coating composition onto a backing layer or a release liner to obtain a coated coating composition; and

[0669] 3) Drying the applied coating composition to form a guanfacine-containing layer.

[0670] 40. The method for producing a guanfacine-containing layer according to item 39, wherein the silicone polymer is provided in the form of a solution, wherein the solvent is ethyl acetate or n-heptane.

[0671] 41. Transdermal therapeutic system obtainable by a process according to any of items 40 or 41.

[0672] 42. A transdermal therapeutic system for transdermal administration of guanfacine, comprising a guanfacine-containing layer structure, the guanfacine-containing layer structure comprising:

[0673] A) a backing layer; and

[0674] B) a layer containing guanfacine, preferably a matrix layer containing guanfacine, which comprises

[0675] i) an amount of guanfacine ranging from 3 to 13 weight percent based on the total weight of the guanfacine-containing layer;

[0676] ii) at least one silicone polymer present in an amount of 35-90 weight percent based on the total weight of the guanfacine-containing layer;

[0677] iii) at least one dispersing agent present in an amount of 2 to 6 weight percent based on the total weight of the guanfacine-containing layer;

[0678] iv) at least one penetration enhancer present in an amount of 2 to 10 weight percent based on the total weight of the guanfacine-containing layer; and

[0679] v) optionally at least one solubilizing agent in an amount of 0.5 to 4 weight percent based on the total weight of the guanfacine-containing layer.

[0680] 43. The transdermal therapeutic system according to item 42, wherein the layer containing guanfacine is a matrix layer containing guanfacine, which comprises

[0681] i) guanfacine in an amount of 3 to 13 wt % based on the total weight of the guanfacine-containing layer;

[0682] ii) at least one silicone polymer present in an amount of 35-90 wt % based on the total weight of the guanfacine-containing layer;

[0683] iii) polyethylene glycol C8-C having 2 to 10 EO units 20 an alkyl ether in an amount of 2 to 6 weight percent based on the total weight of the guanfacine-containing layer;

[0684] iv) oleyl alcohol in an amount of 2 to 10 wt % based on the total weight of the guanfacine-containing layer; and

[0685] v) optional polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in an amount of 0.5 to 4 wt % based on the total weight of the guanfacine-containing layer.

[0686] 44. The transdermal therapeutic system according to item 42 or 43, wherein the guanfacine-containing layer is a guanfacine-containing matrix layer comprising

[0687] i) guanfacine in an amount of 3 to 13 wt % based on the total weight of the guanfacine-containing layer;

[0688] ii) a first silicone polymer in an amount of 50 to 70 weight percent of the total weight of the guanfacine-containing layer, and a second silicone polymer in an amount of 15-25 weight percent of the total weight of the guanfacine-containing layer;

[0689] iii) polyethylene glycol C8-C having 2 to 10 EO units 20 an alkyl ether, preferably polyoxyethylene (4) lauryl ether, in an amount of 3 to 5 wt % based on the total weight of the guanfacine-containing layer;

[0690] iv) oleyl alcohol in an amount of 5 to 9 weight percent based on the total weight of the guanfacine-containing layer; and

[0691] v) optional polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in an amount of 0.5 to 3 wt % based on the total weight of the guanfacine-containing layer.

[0692] 45. Transdermal therapeutic system according to any one of items 42 to 44, wherein the area weight of the layer containing guanfacine is from 80 to 120 g / m 2 , preferably 90 to 120 g / m 2 .

Claims

1. A transdermal therapeutic system for transdermal administration of guanfacine, comprising a guanfacine-containing layer structure, wherein the guanfacine-containing layer structure comprises: A) backing layer; and B) Guanfacine-containing layer; wherein the transdermal therapeutic system comprises at least one silicone polymer; wherein the guanfacine-containing layer comprises at least one silicone polymer in an amount of 30 to 97 weight percent; and wherein the guanfacine-containing layer further comprises an additive, the additive being a combination of a dispersant and a penetration enhancer or a combination of a dispersant, a penetration enhancer and a solubilizer, wherein the dispersant is polyoxyethylene (4) lauryl ether, the penetration enhancer is oleyl alcohol and the solubilizer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, wherein the dispersant, the penetration enhancer or the solubilizer are each present in an amount of 0.5 to 10 wt % based on the total weight of the guanfacine-containing layer, and wherein the guanfacine-containing layer comprises guanfacine in an amount of 1 to 20 wt % based on the total weight of the guanfacine-containing layer.

2. The transdermal therapeutic system according to claim 1, The guanfacine-containing layer is a matrix layer containing guanfacine, which comprises: i) guanfacine; and ii) said at least one silicone polymer.

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

4. The transdermal therapeutic system according to claim 1, wherein the guanfacine in the guanfacine-containing layer structure is present in the form of a free base which is dispersed in the guanfacine-containing layer, and / or The guanfacine-containing layer structure contains guanfacine in an amount of 1 to 75 mg / TTS.

5. The transdermal therapeutic system according to claim 1, wherein the guanfacine-containing layer comprises guanfacine in an amount of 3 to 16 wt % based on the total weight of the guanfacine-containing layer.

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

7. The transdermal therapeutic system according to any one of claims 1 to 5, The at least one silicone polymer may be obtained by polycondensation of silanol-terminated polydimethylsiloxane and a silicic acid resin.

8. The transdermal therapeutic system according to any one of claims 1 to 5, The guanfacine-containing layer comprises a first polymer which is a silicone polymer, and its content is 35-70 weight % of the total weight of the guanfacine-containing layer, and a second polymer which is selected from one or more of a silicone polymer, an acrylic polymer and a silicone-acrylic hybrid polymer, and its content is 15 to 45 weight % of the total weight of the guanfacine-containing layer.

9. The transdermal therapeutic system according to claim 6, The guanfacine-containing layer comprises a first polymer which is a silicone polymer, and its content is 35-70 weight % of the total weight of the guanfacine-containing layer, and a second polymer which is selected from one or more of a silicone polymer, an acrylic polymer and a silicone-acrylic hybrid polymer, and its content is 15 to 45 weight % of the total weight of the guanfacine-containing layer.

10. The transdermal therapeutic system according to any one of claims 1 to 5, wherein the dispersant, penetration enhancer or solubilizer is each present in an amount of 1 to 10% by weight, based on the total weight of the guanfacine-containing layer.

11. The transdermal therapeutic system according to claim 6, wherein the dispersant, penetration enhancer or solubilizer is each present in an amount of 1 to 10% by weight, based on the total weight of the guanfacine-containing layer.

12. The transdermal therapeutic system according to claim 8, wherein the dispersant, penetration enhancer or solubilizer is each present in an amount of 1 to 10% by weight, based on the total weight of the guanfacine-containing layer.

13. The transdermal therapeutic system according to any one of claims 1 to 5, The area weight of the layer containing guanfacine is 40 to 250 g / m 2 , and / or The release area is 1 to 100 cm 2 .

14. Transdermal therapeutic system according to claim 1 for use in a method of treatment of human patients aged 6 to 17 years.

15. Transdermal therapeutic system according to claim 1 for use in a method for the treatment of hypertension or attention deficit hyperactivity disorder in human patients aged 6 to 17 years and / or as an adjunct therapy to stimulant drugs.

16. Transdermal therapeutic system according to any of Claims 14 or 15, wherein the transdermal therapeutic system is applied to the patient's skin for at least 24 hours.

17. Transdermal therapeutic system according to any of Claims 14 or 15, wherein the transdermal therapeutic system is applied to the patient's skin for at least 72 hours.

18. Transdermal therapeutic system according to any of Claims 14 or 15, wherein the transdermal therapeutic system is applied to the patient's skin for 84 hours.

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