RU2792822C2 - Transdermal therapeutic system for transdermal injection of guanfacine, containing silicone polymer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to the field of medicine and describes a transdermal therapeutic system (hereinafter – TTS) for transdermal injection of guanfacine, containing a guanfacine-containing layered structure, wherein the specified guanfacine-containing layered structure contains: A) substrate; and B) a guanfacine-containing layer. Moreover, TTS contains at least one silicone polymer. The guanfacine-containing layer contains at least one silicone polymer in amount of 30-97%. The guanfacine-containing layer additionally contains at least two auxiliary substances selected from a group consisting of dispersing agents, permeability enhancers, and solubilizers, where each of at least two auxiliary substances is present in amount of 0.5-10% by weight per the total weight of the guanfacine-containing layer. The group of inventions also discloses the use of TTS in a method for the treatment of a human patient aged 6-17 years and the use of TTS in a method for the treatment of hypertension or attention deficit hyperactivity disorder (ADHD) and/or as additional therapy to stimulator drugs in a human patient aged 6-17 years.

EFFECT: increase in the efficiency of TTS for transdermal injection of guanfacine.

16 cl, 13 tbl, 4 dwg, 6 ex

Description

The field of technology to which the present invention relates

[0001] The present invention relates to a transdermal therapeutic system (TTS) for transdermal administration of guanfacine into the systemic circulation and to methods for its preparation, method of treatment and its uses.

Background of the Invention

[0002] The active agent guanfacine (also known as N-(aminoiminomethyl)-2,6-dichlorobenzeneacetamide, C ₉ H ₉ Cl ₂ N ₃ O, CAS No. 29110-47-2) is a sympatholytic drug, used to treat hypertension and attention deficit hyperactivity disorder (ADHD). It is a centrally acting alpha(2)-adrenergic receptor agonist. It is characterized by the following chemical formula:

[0003] Guanfacine is currently commercially available, for example, in the form of immediate or controlled release tablets containing 1 to 4 mg of guanfacine. The tablets are suitable for administration once a day.

[0004] However, oral administration of active agents has disadvantages, for example, in terms of patient compliance with the regimen and treatment regimen. Moreover, it is not possible to quickly stop therapy, for example, due to overdose or signs of intolerance after ingestion of an extended release tablet.

[0005] 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, single-use therapy, thereby improving patient compliance with the regimen and treatment regimen.

Objectives and Summary of the Present Invention

[0006] Therefore, the aim of the present invention is to obtain 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 percutaneous penetration rate that is sufficient to achieve a therapeutically effective dose.

[0007] It is a further object of the present invention to provide a TTS for transdermal administration of guanfacine that provides therapeutically effective amounts of guanfacine for at least 24 hours, preferably at least 72 hours, more preferably about 84 hours. In particular, it is an object of the present invention that therapeutically effective amounts are provided over the entire period of time that TTS is applied to the skin, providing around the clock treatment by replacing TTS after a certain application time of, for example, at least 24 hours, preferably at least at least 72 hours, more preferably about 84 hours.

[0008] It is a further object of the present invention to provide a TTS for transdermal administration of guanfacine, where the fluctuation in plasma concentration of guanfacine is reduced compared to oral administration, in particular at steady state.

[0009] An additional object of the present invention is to provide a TTS for transdermal administration of guanfacine with a high degree of active substance utilization.

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

[0011] These and other objects are carried out using the present invention, which according to one aspect relates to a transdermal therapeutic system for transdermal administration of guanfacine, containing a guanfacine-containing layered structure, and the specified guanfacine-containing layered structure contains:

A) substrate; And

B) guanfacine-containing layer;

moreover, the transdermal therapeutic system contains at least one silicone polymer.

[0012] It was found that the TTS according to the present invention, which contains a silicone polymer, provides favorable properties in relation to the constant and continuous delivery of guanfacine. In particular, the TTS of the present invention provides suitable permeation rates and appropriate permeated amounts of guanfacine over a time period of at least 24 hours, preferably at least 72 hours, more preferably about 84 hours.

[0013] In certain embodiments, the present invention also relates to a transdermal therapeutic system for transdermal administration of guanfacine as described above, wherein the guanfacine-containing layer is a guanfacine-containing matrix layer comprising:

i) guanfacine, and

ii) at least one silicone polymer.

[0014] According to certain preferred embodiments, the guanfacine-containing layer structure further comprises at least one adjuvant selected from the group consisting of dispersing agents, penetration enhancers, and solubilizers.

[0015] According to one specific aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine, comprising a guanfacine-containing layered structure, and the specified guanfacine-containing layered structure contains:

A) substrate; And

B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer, containing:

i) guanfacine in an amount of 3-13% by weight, based on the total weight of the guanfacine-containing layer;

ii) at least one silicone polymer in an amount of 35-90% by weight, based on the total weight of the guanfacine-containing layer;

iii) at least one dispersing agent in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer;

iv) at least one penetration enhancer in an amount of 2-10% by weight, based on the total weight of the guanfacine-containing layer; And

v) optionally at least one solubilizer in an amount of 0.5-4% by weight, based on the total weight of the guanfacine-containing layer.

[0016] According to certain embodiments of the present invention, the transdermal therapeutic system of the present invention is provided for use in a method of treating a human patient, preferably for use in a method of treating a human patient aged 6-17 years. In particular, the transdermal therapeutic system of the present invention is provided for use in a method for the treatment of hypertension or attention deficit hyperactivity disorder (ADHD) and/or as adjunctive therapy to stimulant drugs in a human patient, preferably in a human patient aged constituting 6-17 years. In connection with these medical applications, the TTS of the present invention is preferably applied to the patient's skin for at least 24 hours, more preferably at least 72 hours, most preferably about 84 hours.

[0017] According to certain embodiments, the present invention further relates to a method of treating a human patient, preferably a human patient aged 6-17 years, by applying the transdermal therapeutic system of the present invention to the patient's skin. In particular, the present invention relates to a method of treating hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient, preferably a human patient aged 6-17 years, by applying a transdermal therapeutic system according to the present invention to the patient's skin. In connection with these methods, it is preferred that the TTS of the present invention is applied to the patient's skin for at least 24 hours, more preferably at least 72 hours, most preferably about 84 hours.

[0018] According to another aspect, the present invention relates to a method for preparing a guanfacine-containing layer for use in a transdermal therapeutic system according to the present invention, comprising the steps of:

1) combining at least the following components:

i) guanfacine; And

ii) at least one silicone polymer

to obtain a coating composition;

2) applying the coating composition to a substrate or protective coating to obtain an applied coating composition; And

3) drying the applied coating composition to form a guanfacine-containing layer.

[0019] Preferably, the silicone polymer is in the form of a solution, the solvent being ethyl acetate or n-heptane, preferably ethyl acetate.

[0020] According to another aspect, the present invention relates to a transdermal therapeutic system obtained using the method according to the present invention.

Definitions

[0021] As used herein, the term "transdermal therapeutic system" (TTS) refers to a system by which an active agent (e.g., guanfacine) is introduced into the systemic circulation via transdermal delivery and refers to the entire individual dosage unit that is applied after removal an optionally present protective coating, on the skin of a patient, and which contains a therapeutically effective amount of the active agent in the layered structure containing the active agent and optionally an additional adhesive layer on top of the layered structure containing the active agent. The active agent-containing layered structure can be disposed on a protective coating (removable protective layer), thus the TTS may further comprise a protective coating. Used in the present invention, the term "TTS", in particular, refers to systems that provide transdermal delivery, excluding active delivery, for example, by iontophoresis or microporation. Transdermal therapeutic systems may also be referred to as transdermal drug delivery systems (TDDS) or transdermal delivery systems (TDS).

[0022] Used in the present invention, the term "guanfacine-containing layered structure" refers to a layered structure containing a therapeutically effective amount of guanfacine and containing a substrate and at least one guanfacine-containing layer. Preferably, the guanfacine-containing layer structure is a guanfacine-containing self-adhesive layer structure.

[0023] As used herein, the term "therapeutically effective amount" refers to the amount of active agent in the TTS which, when administered by the TTS to a patient, is sufficient to treat, prevent, or reduce hypertension or attention deficit hyperactivity disorder (ADHD) or which is sufficient for adjunctive therapy to stimulant drugs in a human patient. TTS typically contains more active agent in the system than is actually delivered to the skin and systemic circulation. This excess amount of active agent is generally necessary to provide sufficient momentum for delivery from the TTS to the systemic circulation.

[0024] Used in the present invention, the terms "active agent", "active agent" and the like, as well as the term "guanfacine" refers to guanfacine in any pharmaceutically acceptable chemical and morphological form and physical state. These forms include, without limitation, guanfacine in its free base form, protonated or partially protonated guanfacine, salts of guanfacine, and in particular acid addition salts formed by the addition of an inorganic or organic acid, such as guanfacine hydrochloride or guanfacine tartrate, solvates, hydrates, clathrates, co-crystals, complexes, etc., as well as particulate guanfacine, which may be micronized, crystalline and/or amorphous, and any mixtures of the aforementioned forms. Guanfacine, if contained in a medium such as a solvent, is preferably present in particulate form.

[0025] When it is mentioned that guanfacine is used in a specific form in the manufacture of TTS, this does not preclude interactions between that form of guanfacine and other ingredients of the guanfacine-containing layer structure, such as salt formation or complexation, in the final TTS. This means that even if guanfacine is included in its free base form, it may be present in the final TTS in protonated or partially protonated form or in acid addition salt form, or if it is included in salt form, portions of it may be present as free bases in the final TTS. Unless otherwise indicated, in particular, the amount of guanfacine in the layered structure refers to the amount of guanfacine included in the TTS during the manufacture of the TTS, and is calculated based on guanfacine in free base form. For example, when a) 0.1 mmol (equal to 24.61 mg) guanfacine base or b) 0.1 mmol (equal to 27.71 mg) guanfacine hydrochloride is included in the TTS at the time of manufacture, the amount of guanfacine in the layered structure is according to the present invention in both cases 24.06 mg, i.e. 0.1 mmol.

[0026] The starting material guanfacine included in the TTS during the manufacture of the TTS may be in particulate form. The guanfacine may, for example, be present in the layered structure containing the active agent, in the form of particles, which are preferably homogeneously dispersed in the layered structure containing the active agent.

[0027] Used in the present invention, the term "particles" refers to a solid powder material containing individual particles, the dimensions of which are insignificant compared to the material. In particular, the particles are solid, including plastic/deformable solids, including amorphous and crystalline materials.

[0028] In the meaning of this invention, the term "dispersion" refers to a step or combination of steps in which the starting material (eg, guanfacine) does not dissolve or does not dissolve completely. Dispersing according to the present invention involves dissolving a portion of the starting material (eg, guanfacine particles) depending on the solubility of the starting material (eg, the solubility of guanfacine in the coating composition).

[0029] There are two main types of TTS for delivering an active agent, ie. 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, a reservoir type TTS typically needs a rate controlling membrane that controls the release of the active agent. In principle, a matrix-type TTS may also contain a rate-controlling membrane. However, matrix-type TTS has the advantage that, compared to reservoir-type TTS, no rate-determining membranes are generally required and no dose dumping due to membrane rupture can occur. Thus, matrix-type transdermal therapeutic systems (TTS) are less complex to manufacture and simple and convenient to use by patients.

[0030] According to the present invention, "matrix-type TTS" refers to a system or structure in which the active agent is homogeneously dissolved and/or dispersed in a polymeric carrier, i.e. in a matrix which is formed with the active agent and optionally the remaining ingredients of the matrix layer. In such a system, the matrix layer controls the release of the active agent from the TTS. Preferably, the matrix layer has sufficient cohesion to be self-supporting so that sealing between other layers is not required. Accordingly, the active agent-containing layer according to one embodiment of the present invention may be an active agent-containing matrix layer, where the active agent is homogeneously distributed within the polymer matrix. In some embodiments, the active agent containing matrix layer may comprise two active agent containing matrix layers that can be laminated together. The matrix-type TTS may in particular be in the form of a drug-in-adhesive type TTS, referring to a system in which the active agent is homogeneously dissolved and/or dispersed in a pressure-sensitive adhesive matrix. In this regard, the active agent-containing matrix layer may also be referred to as an active agent-containing pressure-sensitive adhesive layer or an active agent-containing pressure-sensitive adhesive matrix layer. A TTS containing an active agent dissolved and/or dispersed in a polymer gel, eg a hydrogel, is also considered to be a matrix type TTS according to the present invention.

[0031] A TTS with a reservoir containing a liquid active agent is referred to as a "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 the substrate and the speed control membrane. Accordingly, the active agent-containing layer may, according to one embodiment, be an active agent-containing reservoir layer, which preferably comprises a liquid reservoir containing the active agent. In addition, the reservoir-type TTS typically further comprises a skin-contacting layer, wherein the reservoir layer and the skin-contacting layer can be separated by a rate control membrane. In the reservoir layer, the active agent is preferably dissolved in a solvent such as ethanol or water, or in silicone oil. The skin-contacting layer generally has adhesive properties.

[0032] Tank type TTS should not be understood as a matrix type within the meaning of the present invention. However, microreservoir TTSs (two-phase systems containing a depot (e.g., spheres, droplets) of an inner active-containing phase dispersed in an outer polymeric phase), considered in the present art to be a mixed form of matrix-type TTS and reservoir-type TTS, which differs from homogeneous single-phase matrix-type TTS and reservoir-type TTS in the concept of drug transport and drug delivery are considered to be matrix-type according to the present invention. Microreservoir droplet sizes can be determined by measuring with an optical microscope (e.g. Leica MZ16, including a camera, e.g. Leica DSC320) by shooting the microreservoirs in various positions at a magnification factor of 10 to 400 times, depending on the required detection limit. Using image analysis software, microreservoir dimensions can be determined.

[0033] As used in the present invention, the term "active agent-containing layer" refers to a layer containing an active agent and providing a release area. The term encompasses matrix layers containing an active agent and reservoir layers containing an active agent. If the active agent-containing layer is an active agent-containing matrix layer, said layer is present in the matrix-type TTS. If the polymer is a pressure-sensitive adhesive, the matrix layer may also be a TTS adhesive layer so that there is no additional skin-contacting layer. Alternatively, an additional skin contact layer may be present as an adhesive layer and/or an adhesive top layer may be present. The additional skin-contacting layer is generally made in such a way that it does not contain an active agent. However, due to the concentration gradient, the active agent migrates over time from the matrix layer to the additional skin contact layer until equilibrium is reached. The additional skin contact layer may be present on the active agent containing matrix layer or be separated from the active agent containing matrix layer by a membrane, preferably a rate controlling membrane. Preferably, the active agent-containing matrix layer has sufficient adhesive properties such that there is no additional skin-contacting layer. If the active agent-containing layer is an active agent-containing reservoir layer, said layer is present in the reservoir-type TTS and the layer contains the active agent in the liquid reservoir. In addition, an additional skin-contacting layer is preferably present to provide adhesive properties. Preferably, the rate controlling membrane separates the reservoir layer from the additional skin contact layer. The additional skin-contacting layer can be made so that it does not contain an active agent or contains an active agent. If the additional skin-contacting layer does not contain an active agent, the active agent will migrate due to the concentration gradient from the reservoir layer to the skin-contacting layer over time until equilibrium is reached. In addition, an adhesive top layer may be provided.

[0034] The active agent-containing layer used in the present invention is preferably an active agent-containing matrix layer and refers to the final cured layer. Preferably, the active agent-containing matrix layer is obtained after coating and drying the solvent-containing coating composition as described herein. Alternatively, the matrix layer containing the active agent is obtained after hot melt coating and cooling. The active agent-containing matrix layer can also be made by laminating two or more such cured layers (eg dried or cooled layers) of the same composition to provide the desired surface weight. The matrix layer may be self-adhesive (in the form of a pressure-sensitive adhesive matrix layer), or the TTS may comprise an additional skin-contacting layer of pressure-sensitive adhesive to provide sufficient tack. Preferably, the matrix layer is a pressure-sensitive adhesive matrix layer. An adhesive top layer may optionally be present.

[0035] As used in the present invention, the term "pressure-sensitive adhesive" (also abbreviated as "PSA") refers to a material that, in particular, adheres due to finger pressure, is permanently tacky, exerts a strong holding force, and must be removed from smooth surfaces without leaving marks. The pressure-sensitive adhesive layer is "self-adhesive" when in contact with the skin, i. provides adhesion to the skin, so additional assistance is usually not required for fixing to the skin. The "self-adhesive" laminate structure includes a pressure-sensitive adhesive layer for skin contact, which may be 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. An adhesive top coat can still be used to improve adhesion. The pressure-sensitive adhesive properties of the pressure-sensitive adhesive depend on the polymer or polymer composition used.

[0036] As used in the present invention, the term "silicone-acrylic hybrid polymer" refers to a polymerization product that includes repeating units of the silicone subspecies and acrylate subspecies. Thus, the silicone-acrylic hybrid polymer contains a silicone phase and an acrylic phase. Preferably, the silicone-acrylic hybrid polymer contains a silicone phase and an acrylate phase, i.e. silicone subspecies and acrylate subspecies in a certain weight ratio, for example, from 60:40 to 40:60. The term "silicone-acrylic hybrid" is intended to mean more than a simple mixture of silicone-based and acrylate-based subtypes. Instead, the term refers to polymerized hybrid species, which include silicone-based subspecies and acrylate-based subspecies that have been polymerized together. A silicone-acrylic hybrid polymer may also be referred to as a "silicone-acrylate hybrid polymer" since the terms acrylate and acrylic are usually used interchangeably in the context of the hybrid polymers used in the present invention.

[0037] As used in 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 2599847 and WO 2016/130408. Examples of silicone-acrylic hybrid pressure sensitive adhesives include PSA 7-6100 and 7-6300 series, manufactured and supplied in n-heptane or ethyl acetate by Dow Coining (7-610X and 7-630X; X=1 based on n- heptane/X=2 based on ethyl acetate). It has been found that depending on the solvent in which the silicone-acrylic hybrid PSA is supplied, the arrangement of the silicone phase and the acrylic phase to provide a continuous silicone or acrylic outer phase and a corresponding discontinuous inner phase is different. When the silicone-acrylic hybrid PSA is supplied in n-heptane, the composition contains a continuous silicone outer phase and a discrete acrylic inner phase. When the silicone-acrylic hybrid PSA composition is supplied in ethyl acetate, the composition contains a continuous acrylic outer phase and a discrete silicone inner phase.

[0038] Used in the present invention, the term "non-hybrid polymer" is used as a synonym for a polymer that does not include hybrid species. Preferably, the non-hybrid polymer is a pressure-sensitive adhesive (eg, silicone or acrylate-based pressure-sensitive adhesives).

[0039] As used in the present invention, the term "acrylate or methacrylate functional silicon-containing pressure-sensitive adhesive composition" comprises a condensation reaction product of a silicone resin, a silicone polymer, and a silicon-containing blocking agent that provides said acrylate or methacrylate functional group. It should be understood that a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group may include only an acrylate functional group, only a methacrylate functional group, or both an acrylate functional group and a methacrylate functional group.

[0040] As used herein, the term "active agent-containing matrix layer" is a layer containing an active agent dissolved or dispersed in at least one polymer, or containing an active agent dissolved in a solvent to form an active agent-solvent mixture that is dispersed in the form of a depot (in particular droplets) in at least one polymer. Preferably, at least one polymer is a polymer-based pressure-sensitive adhesive (eg, a silicone pressure-sensitive adhesive). As used in 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 the film and evaporating the solvents.

[0041] As used herein, the term "skin-contact layer" refers to the layer included in the active agent-containing layered structure that is in direct contact with the patient's skin during application. This may be an active agent-containing layer. When the TTS contains an additional skin-contacting layer, the other layers of the active agent-containing layer structure do not contact the skin and do not necessarily have self-adhesive properties. As stated above, the additional skin contact layer attached to the active agent-containing layer may absorb portions of the active agent over time. An additional skin contact layer can be used to improve adhesion. The dimensions of the additional skin-contacting layer and the active agent-containing layer are generally the same and correspond to the release area. However, the area of the additional skin-contacting layer may also be larger than the area of the active agent-containing layer. In such a case, the release area still refers to the area of the active agent-containing layer.

[0042] Used in the present invention, the term "area weight" refers to the dry weight of a particular layer, for example, the matrix layer, presented in g/m ² . The area mass values are tolerant of ±10%, preferably ±7.5%, due to manufacturing process variability.

[0043] Unless otherwise indicated, "%" refers to the mass. % (% by weight).

[0044] As used in the present invention, the term "polymer" refers to any substance consisting of so-called repeating units obtained by polymerization of one or more monomers, and includes homopolymers, which consist of one type of monomer, and copolymers, which consist of two or more types of monomers. The polymers may have any architecture such as linear polymers, star polymer, comb polymers, brush polymers, any arrangement of monomer groups in the case of copolymers, eg alternating, random, block or graft polymers. The minimum molecular weight varies depending on the type of polymer and is known to the person skilled in the art. The polymers may, for example, have a molecular weight greater than 2000, preferably greater than 5000 and more preferably greater than 10,000 daltons. Accordingly, compounds with a molecular weight below 2000, preferably below 5000, or more preferably below 10,000 daltons, are generally referred to as oligomers.

[0045] Used in the present invention, the term "cross-linking agent" refers to a substance that is capable of cross-linking the functional groups contained in the polymer.

[0046] As used in the present invention, the term "adhesive topsheet" refers to a self-adhesive layered structure that does not contain an active agent and is larger in area than the structure containing the active agent, and provides additional area to adhere to the skin, but not the area of release of the active agent . It thus enhances the general adhesive properties of the TTS. The adhesive top layer comprises a backing that can provide occlusive or non-occlusive properties and an adhesive layer. Preferably, the backing of the adhesive topsheet provides non-occlusive properties.

[0047] Used in the present invention, the term "substrate" refers to a layer that supports containing the active agent layer or forms the basis of the adhesive top layer. At least one support in the TTS, and typically the support of the active agent-containing layer, is substantially impervious to the active agent contained in the layer during the period of storage and administration, and thus prevents loss of the active agent or cross-contamination according to regulatory requirements. Preferably, the substrate is also occlusive, which means that it is substantially impervious to water and water vapor. Suitable substrate materials include polyethylene terephthalate (PET), polyethylene (PE), ethylene-vinyl acetate (EVA) copolymer, polyurethanes, and mixtures thereof. Suitable substrates are thus, for example, PET laminates, EVA-PET laminates and PE-PET laminates. According to a preferred embodiment, the substrate is a siliconized PET foil. Also suitable are woven or non-woven backing materials.

[0048] The TTS of the present invention may be characterized by certain parameters measured in an in vitro skin permeability test.

[0049] Typically, an in vitro permeation test is performed in a Franz diffusion cell, on an EVA membrane (e.g., 9% vinyl acetate and 50 µm thickness, preferably provided by 3M), and using phosphate buffer pH 5.5 or 7.4 in as receptor medium (32°C with 0.1% sodium azide).

[0050] In addition, an in vitro permeation test can be carried out in a Franz diffusion cell, on human or animal skin, and preferably on dermatome-thickened human skin with a thickness of 800 μm and intact epidermis, and using phosphate buffer pH 5 .5 or 7.4 as receptor medium (32°C with 0.1% sodium azide) with or without the addition of a maximum of 40 vol.% organic solvent, e.g. ethanol, acetonitrile, isopropanol, dipropylene glycol, PEG 400, so that the medium may, for example, contain 60 vol.% phosphate buffer pH 5.5, 30 vol.% dipropylene glycol and 10 vol.% acetonitrile.

[0051] Unless otherwise indicated, an in vitro permeation test is performed on 800 µm thick human skin separated by a dermatome and intact epidermis and with phosphate buffer pH 5.5 as receptor medium (32° C. with 0.1% sodium azide ). The amount of active agent penetrating the receptor medium is determined at regular intervals using a validated HPLC method with a UV photometric detector, taking a sample volume. The receptor medium is completely or partially replaced with fresh medium when the volume of the sample is taken, and the measured amount of active agent permeated refers to the amount permeated between the last two sampling points, and not to the total amount permeated to date.

[0052] Thus, according to the present invention, the parameter "penetrated amount" is represented in μg/cm ² and it refers to the amount of active agent that has penetrated in the sampling interval for a certain elapsed time. For example, in an in vitro permeation test as described above, where the amount of active agent permeated into the receptor medium was, for example, measured at the 0, 2, 4, 8, 12, and 24 hour points, the “permeated amount” of the active agent can be represented, for example, for a sampling interval of 8 to 12 hours and corresponds to the measurement at the 12 o'clock point, with the receptor medium being completely replaced at the 8 o'clock point.

[0053] The permeated amount can also be thought of as a "cumulative permeated amount" corresponding to the accumulated amount of active agent permeated at a given point in time. For example, in an in vitro permeation test as described above, where the amount of active agent permeated into the receptor medium was, for example, measured at the 0, 2, 4, 8, 12, and 24 hour points, the "cumulative permeate" of the active agent at the 12 o'clock point corresponds to the sum of the infiltrated amount from 0 hours to 2 hours, from 2 hours to 4 hours, from 4 hours to 8 hours and from 8 hours to 12 hours.

[0054] According to the present invention, the parameter "percutaneous penetration rate" for a certain sampling interval at a certain elapsed time is presented in µg/(cm ² *h) and is calculated from the amount penetrated in the specified sampling interval, as measured using an in vitro test for permeability, as described above, in µg/cm ² divided by the hours of the specified sampling interval. For example, the percutaneous penetration rate in an in vitro permeation test as described above, where the amount of active agent permeated into the receptor medium was, for example, measured at points 0, 2, 4, 8, 12 and 24 hours, "transdermal penetration rate at the 12 o'clock point is calculated as the amount penetrated in the sampling interval from 8 hours to 12 hours divided by 4 hours.

[0055] "Cumulative percutaneous penetration rate" can be calculated from the respective cumulative penetration rate by dividing the cumulative penetration rate by the elapsed time. For example, in the in vitro permeation test as described above, where the amount of active agent permeated into the receptor medium was, for example, measured at 0, 2, 4, 8, 12, and 24 hours, the "cumulative percutaneous permeation rate" in the 12 o'clock point is calculated as the cumulative penetration rate for the 12 o'clock point (see above) divided by 12 hours.

[0056] According to the present invention, the above parameters "penetrated amount" and "percutaneous penetration rate" (as well as "cumulative penetrated amount" and "cumulative percutaneous penetration rate") refer to the average values calculated from at least 3 experiments in vitro tests for permeability. Unless otherwise noted, the standard deviation (SD) of these means refers to the adjusted sample standard deviation calculated using the following formula:

представляет собой среднее значение наблюдаемых значений.where n is the sample size, {x ₁ , x ₂ , ... x _n } are the observed values, and

is the mean of the observed values.

[0057] The TTS of the present invention may also be characterized by certain parameters measured in an in vivo clinical study.

[0058] According to the present invention, the parameter "average release rate" refers to the average release rate in μg/h (μg/h) or mg/day over the period of administration (for example, 1-7 days), at which the active agent is released through human skin into the systemic circulation and is based on the AUC value obtained during the indicated administration period in a clinical study.

[0059] As used herein, the term "long period of time" refers 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 to a period of about 24 hours to about 168 hours, or 1-7 days, or approximately 24 hours - approximately 84 hours, or 1-3.5 days.

[0060] For continuous drug treatment, the frequency of drug administration is preferably maintained at a sufficiently high level so as to maintain a therapeutically effective plasma concentration. In other words, the interval between two administrations of the dosage form, also referred to as the interval between doses, must be adapted accordingly. According to the present invention, the term "interval between doses" refers to the period of time between two consecutive administrations of TTS, i.e. the interval between two consecutive time points when TTS is applied to the patient's skin. Once applied, the TTS typically remains on the patient's skin for the entire dosing interval and is removed only at the end of the dosing interval, after which a new TTS is applied to the skin. For example, if the interval between dosing is 24 hours or 1 day, TTS is applied and stored on the patient's skin for 24 hours or 1 day. After 24 hours or 1 day, the TTS is removed from the skin and a new TTS is applied. Thus, a dosing interval of 24 hours or 1 day provides a daily replacement TTS regimen for around the clock treatment. According to the present invention, a dosing interval of at least 72 hours, preferably about 84 hours, is preferred. It should be understood that the time of applying the TTS to the patient's skin is preferably identical to the time of the interval between dosing, which means that the constant administration of guanfacine takes place when replacing the TTS.

[0061] As used in the present invention, the term "room temperature" refers to the unchanged temperature found in the room of the laboratory where experiments are carried out, and, as a rule, it lies in the range from 15 to 35 ° C, preferably from about 18 to 25 ° C .

[0062] As used herein, the term "patient" refers to a subject who has a clinical manifestation of a specific symptom or symptoms indicative of a need for treatment, who is being treated preventively or prophylactically for a condition, or who has been diagnosed with a condition to be treated. Preferably the age of the patient is from 6 to 17 years.

[0063] Used in the present invention, the term "pharmacokinetic parameters" refers to parameters describing the curve of blood plasma, for example, C _max , C _t and AUC _t1-t2 obtained in a clinical study, for example, using a single dose, multiple doses or stationary administration of TTS containing the active agent, for example, guanfacine-containing TTS, to healthy subjects. Pharmacokinetic parameters of individual subjects are summarized using arithmetic and geometric means, for example, mean C _max , mean AUC _t , and mean AUC _INF , as well as additional statistics such as corresponding standard deviations and standard errors, minimum value, maximum value, and the average value when ranking the list of values (median). In the context of the present invention, pharmacokinetic parameters, for example, C _max , C _t and AUC _t1-t2 refer to the geometric mean values, unless otherwise indicated. It cannot be ruled out that the absolute mean values obtained for a particular TTS in a clinical study vary to some extent from study to study. A reference composition is used to compare absolute averages between studies, for example, in the future, any product based on the present invention can be used as an internal standard. A comparison of the AUC by area release of the respective reference product in the earlier and later study can be used to derive an adjustment factor to account for study-to-study differences.

[0064] Clinical studies according to the present invention refers to studies conducted in full compliance with the International Conference on the Harmonization of Clinical Trials (ICH) and all applicable local standards for good clinical practice (GCP) and regulations.

[0065] As used herein, the term "healthy human subject" refers to a male or female subject with a body weight in the range of 55 kg to 100 kg and a body mass index (BMI) in the range of 18 to 29.4 and normal physiological parameters such as blood pressure, etc. Subjects - healthy people for the purposes of the present invention are selected in accordance with the criteria for inclusion and exclusion in trials, which are based on and are in accordance with the recommendations of the ICH.

[0066] Used in the present invention, the term "subject population" refers to at least five, preferably at least ten individual subjects - healthy people.

[0067] Used in the present invention, the term "geometric mean" refers to the average of the log-transformed data, inversely transformed to the original scale.

[0068] As used herein, the term "arithmetic mean" refers to the sum of all observation values divided by the total number of observations.

[0069] According to the present invention, the parameter "AUC" corresponds to the area under the plasma concentration versus time curve. The AUC value is proportional to the amount of active agent absorbed into the bloodstream as a whole, and therefore is an indicator of bioavailability.

[0070] According to the present invention, the parameter "AUC _t1-t2 " is presented in (ng/ml) h and refers to the area under the plasma concentration versus time curve from the point t1 hours to t2 hours and is calculated by the linear trapezoidal method, unless indicated otherwise. Other calculation methods are, for example, the logarithmic and linear logarithmic trapezoid method.

[0071] According to the present invention, the parameter "C _max "is presented in (ng/ml) and refers to the maximum observed plasma concentration of the active agent.

[0072] According to the present invention, the parameter "C _t " is presented in (ng/ml) and refers to the plasma concentration of the active agent observed at the t point of the clock.

[0073] According to the present invention, the parameter "t _max " is presented in hours and refers to the point in time at which the value of C _max is reached. In other words, t _max is the point in time of the maximum observed plasma concentration.

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

[0075] As used in the present invention, the term "coating composition" refers to a composition containing all components of the matrix layer in a solvent, which can be applied to a substrate or protective coating to form the matrix layer after drying.

[0076] As used herein, the term "pressure-sensitive adhesive composition" refers to a pressure-sensitive adhesive at least mixed with a solvent (eg, n-heptane or ethyl acetate).

[0077] Used in the present invention, the term "dissolve" refers to the process of obtaining a solution that is transparent and does not contain any particles visible to the naked eye.

[0078] As used in 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, methylene chloride, hexane, n-heptane, toluene, and mixtures thereof.

Brief description of graphic materials

[0079] FIG. 1 shows the permeated amount of guanfacine TTS prepared according to examples 1a-d and comparative example 1.

[0080] FIG. 2 shows the permeated amount of guanfacine TTS prepared according to examples 2a-b.

[0081] FIG. 3 shows the permeated amount of guanfacine TTS prepared according to examples 3a-b.

[0082] FIG. 4 shows the permeated amount of guanfacine TTS prepared according to Comparative Examples 2a-b.

Detailed disclosure of the present invention

TTS Structure

[0083] The present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising a guanfacine-containing layered structure, wherein said guanfacine-containing layered structure comprises: a) a support, and b) a guanfacine-containing layer, wherein the transdermal therapeutic system comprises at least at least one silicone polymer. This guanfacine-containing layer structure is preferably a guanfacine-containing self-adhesive layer structure and preferably does not contain an additional skin contact layer. In particular, the silicone-acrylic hybrid polymer which is present in the transdermal therapeutic system, preferably in a self-adhesive layer structure, preferably provides adhesive properties.

[0084] The TTS of the present invention may be a matrix type TTS or a reservoir type TTS, and is preferably a matrix type TTS.

[0085] In the matrix type TTS of the present invention, the guanfacine is preferably homogeneously dispersed in the polymeric carrier, i. e. a matrix that forms with guanfacine and optionally the remaining ingredients a matrix layer. Accordingly, the guanfacine-containing layer according to one embodiment of the present invention may be a guanfacine-containing matrix layer, wherein the guanfacine is homogeneously dispersed in the polymer matrix. The polymer matrix preferably contains at least one silicone polymer. Thus, according to the present invention, it is preferred that the guanfacine-containing matrix layer contains guanfacine and at least one silicone polymer that is present in the TTS. In this regard, it is also preferred that the guanfacine-containing matrix layer is self-adhesive, so that there is no additional skin-contacting layer. If a guanfacine-containing matrix layer is obtained by laminating together two guanfacine-containing matrix layers that have essentially the same composition, the resulting double layer should be considered as one guanfacine-containing matrix layer.

[0086] In the reservoir-type TTS according to the present invention, the guanfacine-containing layer is a guanfacine-containing reservoir layer, which preferably contains a liquid reservoir containing guanfacine. The reservoir-type TTS typically further comprises a skin-contacting layer, wherein the reservoir layer and the skin-contacting layer are preferably separated by a rate-controlling membrane. The silicone-acrylic hybrid polymer then provides adhesive properties. Preferably, the skin-contacting layer is made so that it does not contain guanfacine.

[0087] According to a preferred embodiment of the present invention, the guanfacine-containing layer is a guanfacine-containing matrix layer containing:

i) guanfacine, and

ii) at least one silicone polymer.

[0088] Thus, in one embodiment, the present invention relates to a transdermal therapeutic system for transdermal administration of guanfacine, which comprises a guanfacine-containing layered structure comprising:

A) substrate; And

B) a guanfacine-containing layer, which is preferably a guanfacine-containing matrix layer containing:

i) guanfacine, and

ii) at least one silicone polymer.

[0089] 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 contain an additional skin-contacting layer. Instead, it is preferred that the guanfacine-containing layer, which is preferably the guanfacine-containing matrix layer, is self-adhesive. Thus, according to a preferred embodiment, the guanfacine-containing layer structure is a guanfacine-containing self-adhesive layer structure and preferably does not contain an additional skin contact layer. Alternatively or additionally, it is preferred that the guanfacine-containing layer is directly attached to the substrate, so that there is no additional layer between the substrate and the guanfacine-containing layer. Therefore, a laminar structure of low complexity is obtained, which is advantageous, for example, in terms of manufacturing costs.

[0090] In particular, it is preferred that the guanfacine-containing layer structure contains no more than 3, preferably 2 layers, i. e. preferably only the substrate and the guanfacine-containing layer. Sufficient adhesion between the guanfacine-containing self-adhesive layer structure and the patient's skin during administration is in this case provided by a guanfacine-containing layer, which is preferably a guanfacine-containing matrix layer. If an additional skin-contacting layer is present, for example, as the third layer of the guanfacine-containing layer structure, adhesive properties can be provided by the additional skin-contacting layer. However, according to the present invention, it is preferred that there is no additional skin-contacting layer.

[0091] The self-adhesive properties of the guanfacine-containing layer structure are preferably provided by at least one silicone polymer that is present in the TTS, preferably in the guanfacine-containing layer, more preferably in the guanfacine-containing matrix layer. Thus, according to a preferred embodiment of the present invention, the at least one silicone polymer is a silicone pressure-sensitive adhesive. Additional details regarding the silicone polymer of the present invention are provided further below.

[0092] It should be understood that the TTS, preferably the guanfacine-containing layer, more preferably the guanfacine-containing matrix layer, may also contain two silicone polymers.

[0093] Moreover, the TTS, preferably the guanfacine-containing layer, more preferably the guanfacine-containing matrix layer, may also contain at least one silicone polymer, and at least one additional polymer selected from the group consisting of: acr regular polymers , silicone-acrylic hybrid polymers, polyisobutylenes and styrene-isoprene-styrene block copolymers, preferably selected from the group consisting of acrylate polymers and silicone-acrylic hybrid polymers.

[0094] For example, the first polymer provides high flow advantages, while the second polymer, for example, an additional silicone polymer or an acrylate polymer or a silicone-acrylic hybrid polymer, can be used to reduce and/or optimize the flow to obtain a continuous and constant flow . Moreover, the tackiness of TTS can be modified by using a combination of at least two polymers. Additional details regarding specific polymers are provided further below.

[0095] It should be understood that the TTS of the present invention contains at least a therapeutically effective amount of guanfacine. Thus, according to a preferred embodiment of the present invention, the guanfacine-containing layered structure contains 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 for guanfacine in TTS according to the present invention are provided further below.

[0096] According to the present invention, it is preferred that the TTS release area is in the range of 1 to 100 cm ² , preferably 2.5 to 50 cm ² .

[0097] According to a preferred embodiment of the present invention, the substrate is substantially impermeable to guanfacine. Moreover, it is preferred that the substrate is occlusive as described above.

[0098] According to certain embodiments of the present invention, the TTS may further comprise an adhesive top layer. This adhesive topsheet, in particular, has a larger area than the guanfacine-containing layered structure, and is attached to it to enhance the adhesive properties of the entire transdermal therapeutic system. Said adhesive top layer comprises a substrate and an adhesive layer. The adhesive top layer provides additional bonding area to the skin, but does not add guanfacine release area. The adhesive top layer contains a self-adhesive polymer or a mixture of self-adhesive polymers selected from the group consisting of: silicone-acrylic hybrid polymers, acrylate polymers, silicone polymers, polyisobutylenes, styrene-isoprene-styrene copolymers and mixtures thereof, which may be the same or different from any polymer or mixture of polymers included in the guanfacine-containing layered structure.

[0099] A guanfacine-containing layer structure according to the present invention, such as a guanfacine-containing self-adhesive layer structure, is usually located on a removable protective layer (protective coating), from which it is removed immediately before application to the patient's skin surface. Thus, the TTS may further comprise a protective coating. TTS protected in this way is usually stored in a blister pack or sealed bag. The packaging may be child resistant and/or easy to handle for the elderly.

Guanfacine-containing layer

[0100] As described in more detail above, the TTS according to the present invention contains a guanfacine-containing layered structure containing a guanfacine-containing layer. Preferably, the guanfacine-containing layer structure is a guanfacine-containing self-adhesive layer structure. Accordingly, 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. According to a preferred embodiment, the guanfacine-containing layer contains a therapeutically effective amount of guanfacine.

[0101] According to one embodiment of the present invention, the guanfacine-containing layer is a guanfacine-containing matrix layer. According to another embodiment, the guanfacine-containing layer is a guanfacine-containing reservoir layer. It is preferred that the guanfacine-containing layer is a guanfacine-containing matrix layer.

[0102] In one embodiment, the guanfacine-containing layer comprises:

i) guanfacine, preferably in free base form; And

ii) at least one silicone polymer.

It should be understood that at least one silicone polymer, which is at least one silicone polymer, which is contained in the TTS according to the present invention.

[0103] In a preferred embodiment, the guanfacine-containing layer is a guanfacine-containing matrix layer comprising:

i) guanfacine, preferably in free base form; And

ii) at least one silicone polymer.

It should be understood that at least one silicone polymer, which is at least one silicone polymer, which is contained in the TTS according to the present invention.

[0104] In a preferred embodiment, the guanfacine-containing layer comprises at least one silicone polymer, which is a silicone pressure-sensitive adhesive. Thus, the guanfacine-containing layer is preferably a guanfacine-containing matrix layer, and particularly preferably a guanfacine-containing pressure-sensitive adhesive matrix layer.

[0105] According to one embodiment of the present invention, the guanfacine-containing layer can be obtained by dispersing guanfacine, preferably in the form of a free base. As a result, the guanfacine-containing TTS layer according to the present invention typically contains guanfacine in free base form. In addition, guanfacine, according to certain embodiments of the present invention, may be partially present in protonated form. However, it is preferred that at least 50 mol%, preferably at least 75 mol% of guanfacine in the guanfacine-containing layer is present in free base form. According to a specific 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 free base form.

[0106] According to one embodiment of the present invention, the guanfacine-containing layer structure, preferably the guanfacine-containing layer, more preferably the guanfacine-containing matrix layer of the transdermal therapeutic system according to the present invention contains guanfacine in an amount of 1-100 mg/TTS, preferably 8-72 mg /TTS. According to 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 8-30 mg/TTS, for example, in an amount of 8-10 mg/TTS or 17-19 mg/ TTS. In other words, the total amount of guanfacine in the guanfacine-containing layer structure is in the range from 1 to 100 mg/TTS, preferably from 8 to 72 mg/TTS, more preferably from 8 to 30 mg/TTS, for example, from 8 to 10 mg/ TTS or 17 to 19 mg/TTS.

[0107] According to another embodiment, the loading of guanfacine in the guanfacine-containing layer structure is in the range of 0.2 to 1.6 mg/cm ² , preferably 0.4 to 1.2 mg/cm ² . Moreover, it is preferred that the TTS release area is in the range of 1 to 100 cm ² , preferably 2.5 to 50 cm ² .

[0108] According to one embodiment of the present invention, the guanfacine-containing layer contains guanfacine in an amount of 1-20% by weight, preferably 3-16% by weight, more preferably 3-14% by weight, most preferably 3-13% by weight in calculated on the total weight of the guanfacine-containing layer. For example, the guanfacine-containing layer may contain guanfacine in an amount of 3-8% by weight, preferably 3-5 or 5-7% by weight, or in an amount of 10-14% by weight, preferably 11-13% by weight, based on the total weight of the guanfacine-containing layer, depending on the required dosage of TTS.

[0109] Guanfacine-containing layer structure and preferably guanfacine-containing layer contains at least one silicone polymer. As used in the present invention, the term "silicone polymer" refers to a silicone-based polymer or a polysiloxane-based polymer, which can preferably be obtained as described herein below. Preferably, the silicone polymer is a silicone-based pressure-sensitive adhesive polymer.

[0110] At least one silicone polymer can be obtained by polycondensation of polydimethylsiloxane with blocked terminal silanol groups with a silicate resin. The terminal blocking group is preferably a trimethylsilyl group. Preferably at least one silicone polymer is an amine compatible silicone polymer. Amino compatible silicone polymers can be prepared by reacting the silicone polymer with trimethylsilyl (eg, hexamethyldisilazane) to reduce the silanol content of the polymer. Thus, in the context of at least one silicone polymer, it is preferred that the residual silanol functional group of the at least one silicone polymer is at least partially, preferably mostly or completely blocked by trimethylsiloxy groups.

[0111] The tackiness of at least one silicone polymer can be modified by the ratio of resin to polymer, i. ratio of silanol-terminated polydimethylsiloxane to silicate resin, which is preferably in the range of 70:30-50:50, preferably 65:35-55:45. Tackiness will increase with increasing amounts of polymer relative to resin. High tack silicone polymers preferably have a resin to polymer ratio of 55:45, medium tack silicone polymers preferably have a resin to polymer ratio of 60:40, and low tack silicone polymers preferably have a resin to polymer ratio of 65: 35. High tack silicone polymers preferably have a complex viscosity at 0.01 rad/s and 30°C of 5×10 ⁶ P, medium tack silicone polymers preferably have a complex viscosity at 0.01 rad/s and 30°C of 5×10 ⁷ P, and low tack silicone polymers preferably have a complex viscosity at 0.01 rad/s and 30°C of 5×10 ⁸ P. Amino compatible silicone polymers with high tack preferably have a complex viscosity at 0.01 rad /s and 30°C, which is 5×10 ⁶ P, amino-compatible silicone polymers with medium tack are preferably characterized by a complex viscosity at 0.01 rad/s and 30°C, which is 5×10 ⁸ P, and amino-compatible silicone polymers with low tack preferably have a complex viscosity at 0.01 rad/s and 30° C. of 5×10 ⁹ P. Preferred according to the present invention are medium to high silicone polymers. and tackiness, in particular amine-compatible silicone polymers with medium to high tackiness.

[0112] The at least one silicone polymer is preferably provided in the form of a solution, the solvent being preferably n-heptane or ethyl acetate.

[0113] According to a preferred embodiment, the at least one silicone polymer is a silicone polymer, preferably a silicone-based pressure-sensitive adhesive, which is prepared according to the following scheme:

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

[0114] In a more preferred embodiment, the at least one silicone polymer is an amino-compatible silicone polymer, preferably an amino-compatible silicone-based pressure-sensitive adhesive prepared according to the following scheme:

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

[0115] According to one embodiment of the present invention, the guanfacine-containing layer comprises at least one silicone polymer, preferably one or two silicone polymers.

[0116] The guanfacine-containing layer may also contain at least one additional polymer selected from the group consisting of: acrylate polymers, silicone-acrylic hybrid polymers, polyisobutylenes, and styrene-isoprene-styrene block copolymers, preferably selected from the group consisting of from acrylate polymers and silicone-acrylic hybrid polymers.

[0117] Acrylate polymers can be made from one or more monomers selected from: acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, t-octylacrylamide and vinyl acetate, preferably from one or more monomers selected from : ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate and vinyl acetate. Such acrylate polymers are available, for example, from Henkel, as explained in more detail below.

[0118] Silicone-acrylic hybrid polymers contain a silicone phase and an acrylate phase, preferably in a weight ratio of 60:40 to 40:60, most preferably in a weight ratio of 50:50. The silicone-acrylic hybrid polymer typically contains the reaction product of the following: (a) a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, (b) an ethylenically unsaturated monomer; and (c) initiator. Additional details regarding components (a), (b) and (c) are provided further below. It should be understood that component (a) mainly forms the silicone phase, while component (b) mainly forms the acrylate phase of the silicone-acrylic hybrid polymer. The acrylate phase affects the tackiness and viscosity of the silicone-acrylic hybrid polymer. Therefore, it is preferred that the ethylenically unsaturated monomer forming the acrylate phase is a combination of 2-ethylhexyl acrylate and methyl acrylate, preferably in a ratio of 40:60 to 70:30. A ratio of 60:40 is preferred from a high tack point of view, although the viscosity is lower. A ratio of 50:50 is preferred in terms of increased viscosity, although tackiness is reduced. The silicone-acrylic hybrid polymer in the guanfacine-containing layer preferably contains a continuous, acrylic outer phase and a discontinuous, silicone inner phase.

[0119] According to one embodiment of the present invention, the guanfacine-containing layer contains at least one silicone polymer in an amount of 20-99%, preferably 30-97%, most preferably 35-90% by weight, based on the total weight of the guanfacine-containing layer . The amounts shown 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 further comprise at least one additional polymer, such as an acrylate polymer or a silicone-acrylic hybrid polymer.

[0120] According to a preferred embodiment of the present invention, the guanfacine-containing layer contains a first polymer, which is a silicone polymer, in an amount of 35-70% by weight, and a second polymer, which is selected from the group consisting of silicone polymers, acrylate polymers and silicone -acrylic hybrid polymers, in an amount of 15-45% by weight, in each case based on the total weight of the guanfacine-containing layer. Thus, the guanfacine-containing layer may comprise two different silicone polymers, a silicone polymer and an acrylate polymer, or a silicone polymer and a silicone-acrylic hybrid polymer. According to a particularly preferred embodiment, the guanfacine-containing layer comprises a first silicone polymer in an amount of 50-70% by weight, based on the total weight of the guanfacine-containing layer, and a second silicone polymer in an amount of 15-25% by weight, based on the total weight of guanfacine- containing layer.

[0121] According to certain preferred embodiments, the guanfacine-containing layer may further comprise a third polymer selected from the group consisting of silicone polymers, acrylate polymers, and silicone-acrylic hybrid polymers, preferably in an amount of 1-5% by weight based on the total weight guanfacine-containing layer.

[0122] According to one embodiment of the present invention, the TTS according to the present invention, and in particular the guanfacine-containing layer, contains at least one auxiliary substance. Suitable adjuvants are described in more detail below, and are each preferably present in an amount of 0.5-10% by weight or 1-10% by weight, based on the total weight of the guanfacine-containing layer.

[0123] According to a preferred embodiment of the present invention, the guanfacine-containing layer contains at least one auxiliary substance selected from the group consisting of dispersing agents, penetration enhancers, and solubilizers. According to one preferred embodiment, at least one excipient, i. each individual adjuvant is present in an amount of 0.5-10% by weight or 1-10% by weight, based on the total weight of the guanfacine-containing layer. According to one preferred embodiment, at least one adjuvant is a dispersing agent. According to another preferred embodiment, the at least one adjuvant is a penetration enhancer. According to another preferred embodiment, at least one excipient is a solubilizer. According to a certain preferred embodiment, combinations of the aforementioned adjuvants are also preferred, for example, a combination of a dispersing agent and a penetration enhancer, or a combination of a dispersing agent and a solubilizer, or a combination of a penetration enhancer and a solubilizer, or a combination of a dispersing agent, a penetration enhancer and a solubilizer. The aforementioned excipients have the particular advantage of providing guanfacine in a homogeneously dispersed and releasable form. It should be understood that the dispersing agent can also act as a penetration enhancer and vice versa. Likewise, the solubilizer may also additionally act as a dispersing agent or penetration enhancer. Moreover, the solubilizer can stabilize the dispersion of guanfacine in TTS and prevent crystallization. Moreover, the solubilizer may be useful in optimizing the cohesion of the TTS. According to certain preferred embodiments, the guanfacine-containing layer contains at least one dispersing agent and at least one penetration enhancer, and optionally also at least one solubilizer.

[0124] According to one preferred embodiment, the at least one adjuvant is a dispersing agent that is present in an amount of 1-10% by weight, based on the total weight of the guanfacine-containing layer. Preferably, the dispersing agent is present in an amount of 2-6% by weight, more preferably 3-5% by weight, based on the total weight of the guanfacine-containing layer.

[0125] According to another preferred embodiment, the at least one adjuvant is a penetration enhancer that is present in an amount of 1-10% by weight, based on the total weight of the guanfacine-containing layer. Preferably, the penetration enhancer is present in an amount of 5-9% by weight, based on the total weight of the guanfacine-containing layer.

[0126] According to another embodiment, the at least one adjuvant is a solubilizer that is present in an amount of 0.5-10% by weight, based on the total weight of the guanfacine-containing layer. Preferably, the solubilizer is present in an amount of 0.5-4% by weight, more preferably 0.5-3% by weight, based on the total weight of the guanfacine-containing layer.

[0127] According to one embodiment, the TTS according to the present invention, and in particular the guanfacine-containing layer, more specifically the guanfacine-containing matrix layer, contains at least two auxiliary substances selected from the group consisting of dispersing agents, penetration enhancers, and solubilizers.

[0128] According to one preferred embodiment, the transdermal therapeutic system, and in particular the guanfacine-containing layer, more specifically the guanfacine-containing matrix layer, contains at least two adjuvants, the first adjuvant being a dispersing agent, which is present in an amount of 1 -10% by weight based on the total weight of the guanfacine-containing layer, and the second auxiliary substance is a penetration enhancer, which is present in an amount of 1-10% by weight, based on the total weight of the guanfacine-containing layer. Preferably, the dispersing agent is present in an amount of 1-6% by weight and the penetration enhancer is present in an amount of 3-9% by weight. More preferably, the dispersing agent is present in an amount of 3-5% by weight, and the penetration enhancer is present in an amount of 5-9% by weight.

[0129] According to another preferred embodiment, the transdermal therapeutic system, and in particular the guanfacine-containing layer, more specifically the guanfacine-containing matrix layer, contains at least two adjuvants, the first adjuvant being a dispersing agent, which is present in an amount of 1 -10% by weight based on the total weight of the guanfacine-containing layer, and the second auxiliary substance is a solubilizer, which is present in an amount of 0.5-10% by weight, based on the total weight of the guanfacine-containing layer. Preferably, the dispersing agent 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 dispersing agent is present in an amount of 3-5% by weight, and the solubilizer is present in an amount of 0.5-3% by weight.

[0130] According to another preferred embodiment, the transdermal therapeutic system, and in particular the guanfacine-containing layer, more specifically the guanfacine-containing matrix layer, contains at least two adjuvants, the first adjuvant being a penetration enhancer, which is present in an amount of 1 -10% by weight based on the total weight of the guanfacine-containing layer, and the second auxiliary substance is a solubilizer, which is present in an amount of 0.5-10% by weight, based on the total weight of the guanfacine-containing layer. Preferably, the penetration 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. Preferably, the penetration 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.

[0131] According to one embodiment, the TTS according to the present invention, and in particular the guanfacine-containing layer, more specifically the guanfacine-containing matrix layer, contains at least three auxiliary substances selected from the group consisting of dispersing agents, penetration enhancers, and solubilizers.

[0132] According to one embodiment, the transdermal therapeutic system, and in particular the guanfacine-containing layer, more specifically the guanfacine-containing matrix layer, contains at least three adjuvants, with the first adjuvant being a dispersing agent that is present in an amount of 1- 10% by weight based on the total weight of the guanfacine-containing layer, the second auxiliary substance is a penetration enhancer, which is present in an amount of 1-10% by weight, based on the total weight of the guanfacine-containing layer, and the third auxiliary substance is a solubilizer, which is present in an amount of 0.5-10% by weight based on the total weight of the guanfacine-containing layer. Preferably, the dispersing agent is present in an amount of 1-6% by weight, the penetration 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 dispersing agent is present in an amount of 3-5% by weight, the penetration 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.

[0133] In connection with the above embodiments regarding the number of adjuvants and the amounts of adjuvants in the TTS according to the present invention, and in particular in the guanfacine-containing layer, more specifically the guanfacine-containing matrix layer, the following specific adjuvants are preferred.

[0134] In a preferred embodiment, the dispersing agent is selected from the group consisting of: fatty acid esters of polyhydric alcohols, fatty alcohols, polyethylene glycols having a number average molecular weight of 300-400, polyethylene glycol alkyl esters, wherein the dispersing agent is preferably C ₈ -C ₂₀ polyethylene glycol alkyl ether containing 2-10 EO units, preferably 2-6 EO units. A particularly preferred dispersing agent is polyoxyethylene (4) lauryl ether (C ₁₂ H ₂₅ (OCH ₂ CH ₂ ) ₄ OH). This dispersing agent, for example, is available from Merck under the trademark Brij L4®.

[0135] According to a preferred embodiment, the penetration enhancer is selected from the group consisting of: diethylene glycol monoethyl ether (transcutol), oleic acid, levulinic acid, caprylic/capric acid triglycerides, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, triacetin, dimethylpropylene urea, and oleyl alcohol, and preferably is oleyl alcohol. Oleyl alcohol, for example, is available from BASF under the trademark Kollicream® OA.

[0136] According to a preferred embodiment, the solubilizer is selected from the group consisting of: copolymers derived from esters of acrylic and methacrylic acid, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers. Preferably the solubilizer is selected from polyvinylpyrrolidone and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers. Particularly preferred solubilizers are polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers. Suitable polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, for example, are available from BASF under the trademark Soluplus®, and are preferably characterized by the following structural formula, where l, m and n are chosen such that the average molecular weight, determined by gel permeation chromatography, is in the range from 90,000 to 140,000 g/mol.

[0137] In certain preferred embodiments, the guanfacine-containing layer comprises at least one dispersing agent in an amount of 2-6% by weight, at least one penetration enhancer in an amount of 2-9% by weight, and optionally at least one solubilizer in an amount of 0.5-4% by weight, in each case based on the total weight of the guanfacine-containing layer. Preferably, the guanfacine-containing layer contains at least one dispersing agent in an amount of 3-5% by weight, at least one penetration enhancer in an amount of 3-5% by weight, and optionally at least one solubilizer in an amount of 0.5-3 % by weight, in each case based on the total weight of the guanfacine-containing layer. In connection with the above preferred wt.% amounts, the above preferred dispersing agents, penetration enhancers and solubilizers are preferred.

[0138] Accordingly, according to a particularly preferred embodiment, the guanfacine-containing layer contains a C ₈ -C ₂₀ -alkyl ether of polyethylene glycol, characterized by 2-10 EO units, preferably polyoxyethylene (4) lauryl ether, in an amount of 2-6% by weight, oleyl alcohol in an amount of 3-9% by weight, and optionally a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, preferably as above, in an amount of 0.5-4% by weight, in each case based on the total weight of the guanfacine-containing layer. Most preferably, the guanfacine-containing layer contains a C ₈ -C ₂₀ polyethylene glycol alkyl ether characterized by 2-10 EO units, preferably polyoxyethylene (4) lauryl ether in an amount of 3-5% by weight, oleyl alcohol in an amount of 5-9% by weight. by weight, and optionally a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, preferably as above, in an amount of 0.5-3% by weight, in each case based on the total weight of the guanfacine-containing layer.

[0139] According to one embodiment of the present invention, the area weight of the guanfacine-containing layer is in the range of 40 to 250 g/m ² , preferably 50 to 180 g/m ² , more preferably 70 to 180 g/m ² , for example, from 75 to 150 g/m ² or from 100 to 150 g/m ² . According to certain preferred embodiments, the area weight is in the range of 80 to 120 g/m ² , preferably 90 to 100 g/m ² .

[0140] In view of the foregoing, the present invention according to one embodiment relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising a guanfacine-containing layered structure, said layered structure comprising:

A) substrate; And

B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer, containing:

i) guanfacine in an amount of 3-13% by weight, based on the total weight of the guanfacine-containing layer;

ii) at least one silicone polymer in an amount of 35-90% by weight, based on the total weight of the guanfacine-containing layer;

iii) at least one dispersing agent in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer;

iv) at least one penetration enhancer in an amount of 2-10% by weight, based on the total weight of the guanfacine-containing layer; And

v) optionally at least one solubilizer in an amount of 0.5-4% by weight, based on the total weight of the guanfacine-containing layer.

In connection with this embodiment, it is further preferred that the guanfacine-containing layer structure does not comprise an additional skin-contacting layer. Thus, the guanfacine-containing layer, preferably the guanfacine-containing matrix layer, is preferably a skin-contacting layer and has pressure-sensitive adhesive properties due to the silicone polymer.

[0141] According to a preferred embodiment, the guanfacine-containing layer is a guanfacine-containing matrix layer that contains:

i) guanfacine in an amount of 3-13% by weight, based on the total weight of the guanfacine-containing layer;

ii) at least one silicone polymer in an amount of 35-90% by weight, based on the total weight of the guanfacine-containing layer;

iii) C ₈ -C ₂₀ polyethylene glycol alkyl ether having 2-10 EO units in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer;

iv) oleyl alcohol in an amount of 2-10% by weight, based on the total weight of the guanfacine-containing layer; And

v) optionally a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in an amount of 0.5-4% by weight, based on the total weight of the guanfacine-containing layer.

Moreover, it is preferred that the area weight of the guanfacine-containing layer is in the range of 80 to 120 g/m ² , preferably 90 to 120 g/m ² .

[0142] According to a particularly preferred embodiment, the guanfacine-containing layer is a guanfacine-containing matrix layer that contains:

i) guanfacine in an amount of 3-13% by weight, based on the total weight of the guanfacine-containing layer;

ii) a first silicone polymer in an amount of 50-70% by weight, based on the total weight of the guanfacine-containing layer, and a second silicone polymer in an amount of 15-25% by weight, based on the total weight of the guanfacine-containing layer;

iii) C ₈ -C ₂₀ polyethylene glycol alkyl ether having 2-10 EO units, preferably polyoxyethylene lauryl ether (4), in an amount of 3-5% by weight based on the total weight of the guanfacine-containing layer;

iv) oleyl alcohol in an amount of 5-9% by weight, based on the total weight of the guanfacine-containing layer; And

v) optionally a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in an amount of 0.5-3% by weight, based on the total weight of the guanfacine-containing layer.

Moreover, it is preferred that the area weight of the guanfacine-containing layer is in the range of 80 to 120 g/m ² , preferably 90 to 120 g/m ² .

Guanfacine

[0143] The TTS of the present invention comprises a guanfacine-containing layer structure, said guanfacine-containing layer structure comprising: A) a substrate; and B) a guanfacine-containing layer; moreover, the transdermal therapeutic system contains at least one silicone polymer. The guanfacine-containing layer, which is preferably the guanfacine-containing matrix layer, has been described in more detail above.

[0144] According to one embodiment of the present invention, the amount of guanfacine contained in the guanfacine-containing layer structure is in the range from 1 to 100 mg/TTS, preferably 8-72 mg/TTS, more preferably 8-30 mg/TTS, for example, 8-10 mg/TTS or 17-19 mg/TTS. Additional details in this regard have been provided above.

[0145] According to one embodiment of the present invention, the guanfacine-containing layered structure preferably contains a therapeutically effective amount of guanfacine. More preferably, a 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 free base form.

[0146] According to one embodiment of the present invention, at least 50 mol%, preferably at least 75 mol% of the total amount of guanfacine in TTS is present in free base form. According to a specific preferred embodiment, at least 90 mol%, preferably at least 95 mol%, more preferably at least 99 mol% of the total amount of guanfacine in TTS is present in free base form. Thus, it is preferred that at least 50 mol%, preferably at least 75 mol% of guanfacine in the guanfacine-containing layer is present in free base form. According to a specific 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 free base form. In certain embodiments, the guanfacine-containing layer does not contain guanfacine salts.

[0147] In certain embodiments, the amount of guanfacine in the guanfacine-containing layer is in the range of 1-20% by weight, preferably 3-16% by weight, most preferably 3-14% by weight, such as 11-13% by weight, or 7-9% by weight or 3-5% by weight based on the total weight of the guanfacine-containing layer.

[0148] According to one embodiment of the present invention, the guanfacine-containing layer can be obtained by dispersing guanfacine in free base form. If the guanfacine-containing layer is a guanfacine-containing matrix layer, said layer can preferably be obtained by dispersing guanfacine in free base form in a polymer carrier, which particularly preferably contains a silicone-acrylic hybrid polymer, and optionally at least one auxiliary substance, as defined above, in particular at least one dispersing agent.

[0149] In one embodiment, the guanfacine-containing layer contains 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 the guanfacine in the guanfacine-containing layer is present in the form of a free base.

[0150] In certain embodiments, the guanfacine is at least 95% pure, preferably at least 98%, and more preferably at least 99% pure, as determined by quantitative HPLC. Quantitative HPLC can be performed using reverse phase HPLC with UV detection.

Silicone-acrylic hybrid polymer

[0151] The TTS of the present invention may comprise a silicone-acrylic hybrid polymer. The silicone-acrylic hybrid polymer contains a polymerized hybrid species that includes a silicone-based subtype and an acrylate-based subtype that have been polymerized together. The silicone-acrylic hybrid polymer thus contains a silicone phase and an acrylic phase. Preferably, the silicone-acrylic hybrid polymer is a silicone-acrylic hybrid pressure-sensitive adhesive.

[0152] Silicone-acrylic hybrid pressure-sensitive adhesives are typically supplied and used in solvents such as n-heptane and ethyl acetate. The solids content of pressure-sensitive adhesives is typically between 30% and 80%. The person skilled in the art is aware that the solids content can be modified by adding a suitable amount of solvent.

[0153] Preferably, the weight ratio of silicone to acrylate in the silicone-acrylic hybrid pressure sensitive adhesive is 5:95 to 95:5 or 20:80 to 80:20, more preferably 40:60 to 60:40, and most preferably the ratio of silicone to acrylate is approximately 50:50. Suitable silicone-acrylic hybrid pressure-sensitive adhesives having a silicone to acrylate weight ratio of 50:50 are, for example, commercially available silicone-acrylic hybrid pressure-sensitive adhesives 7-6102, silicone to acrylate ratio 50/50, and 7-6302, 50/50 silicone to acrylate, available in Dow Coining ethyl acetate.

[0154] The preferred silicone-acrylic hybrid pressure-sensitive adhesives of the present invention have a solution viscosity at 25°C and about 50% solids in ethyl acetate of greater than about 400 cps, or from about 500 cps to about 3500 cps, in in particular from about 1000 cP to about 3000 cP, more preferably from about 1200 cP to about 1800, or most preferably about 1500 cP, or alternatively more preferably from about 2200 cP to about 2800 cP, or most preferably about 2500 cP, preferably as measured using a Brookfield RVT viscometer equipped with a #5 measuring tip at 50 rpm.

[0155] These silicone-acrylic hybrid pressure-sensitive adhesives may also have a complex viscosity at 0.1 rad/s at 30°C of less than about 1.0e9 P (poise), or from about 1.0e5 P to about 9.0e8 P, or more preferably from about 9.0e5 P to about 1.0e7 P, or most preferably about 4.0e6 P, or alternatively more preferably from about 2.0e6 P to about 9.0e7 P, or most preferably approximately 1.0e7 P, preferably as measured using a Rheometrics ARES rheometer, with the rheometer fitted with 8 mm plates and zero clearance.

[0156] To prepare rheological samples using the Rheometrics ARES rheometer, 2 to 3 g of adhesive solution can be poured onto a protective coating of SCOTCH-PAK 1022 fluoropolymer and allowed to settle for 60 minutes at ambient conditions. To obtain practically solvent-free adhesive films, they can be placed in an oven at 110°C+/-10°C for 60 minutes. Remove from oven and allow to equilibrate to room temperature. The films can be removed from the protective cover and folded to form a square. Films can be compressed using a Carver press to eliminate air bubbles. Samples can then be loaded between plates and compressed to 1.5+/- 0.1mm at 30°C. Excess adhesive is trimmed off and the final gap recorded. Frequency swing from 0.01 to 100 rad/s can be done with the following settings: temperature = 30°C; strain = 0.5-1% and data collected at 3 points per decade.

[0157] Suitable silicone-acrylic hybrid pressure-sensitive adhesives that are commercially available include PSA series 7-6100 and 7-6300, manufactured and supplied in n-heptane or ethyl acetate by Dow Corning (7-610X and 7- 630X; X=1 - based on n-heptane / X=2 - based on ethyl acetate). For example, the silicone-acrylic hybrid PSA series 7-6102, which has a silicone to acrylate ratio of 50/50, has a solution viscosity at 25°C and approximately 50% solids content in ethyl acetate of 2500 cps and a complex viscosity at 0. 1 rad/s at 30°C of 1.0e7 P. Series 7-6302 silicone-acrylic hybrid PSA, featuring a 50/50 silicone to acrylate ratio, has a solution viscosity at 25°C and approximately 50% solids content in ethyl acetate, which is 1500 cP, and a complex viscosity at 0.1 rad/s at 30°C, which is 4.0e6 P.

[0158] Depending on the solvent in which the silicone-acrylic hybrid pressure-sensitive adhesive is supplied, the arrangement of the silicone phase and the acrylic phase providing the silicone or acrylic continuous outer phase and the corresponding discontinuous inner phase is different. When the silicone-acrylic hybrid pressure-sensitive adhesive is provided in n-heptane, the composition contains a continuous, silicone outer phase and a discrete, acrylic inner phase. When the silicone-acrylic hybrid pressure-sensitive adhesive is supplied in ethyl acetate, the composition contains a continuous, acrylic outer phase and a discrete, silicone inner phase. After evaporation of the solvent in which the silicone-acrylic hybrid pressure-sensitive adhesive is supplied, the phase arrangement of the resulting pressure-sensitive adhesive film or layer corresponds to the phase arrangement of the solvent-containing adhesive coating composition. For example, in the absence of any substance that can induce a phase inversion in a silicone-acrylic hybrid pressure-sensitive adhesive composition, a pressure-sensitive adhesive layer made from a silicone-acrylic hybrid pressure-sensitive adhesive in n-heptane provides continuous silicone an outer phase and a discrete acrylic inner phase, a pressure-sensitive adhesive layer made from a silicone-acrylic hybrid pressure-sensitive adhesive in ethyl acetate provides a continuous acrylic outer phase and a discrete silicone inner phase. The phase positions of the compositions can, for example, be determined in peel strength tests with pressure-sensitive adhesive films or layers made from silicone-acrylic hybrid PSA compositions that are affixed to a siliconized backsheet. The pressure-sensitive adhesive film contains a continuous, silicone outer phase if the siliconized protective coating cannot be removed or is only difficult to remove from the pressure-sensitive adhesive film (laminated on the outer film) due to the blocking of the two silicone surfaces. Blocking is the result of the adhesion of two silicone layers that contain similar surface energy. The silicone adhesive exhibits good flow on the siliconized coating and therefore can form good adhesion to the coating. While the siliconized protective coating can be easily removed, the pressure-sensitive adhesive film contains a continuous acrylic outer phase. The acrylic adhesive does not flow well due to varying surface energies and thus exhibits little or no adhesion to the siliconized coating.

[0159] According to a preferred embodiment of the present invention, the silicone-acrylic hybrid polymer is a silicone-acrylic hybrid pressure-sensitive adhesive obtained from a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group. It should be understood that a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group may include only an acrylate functional group, only a methacrylate functional group, or both an acrylate functional group and a methacrylate functional group.

[0160] According to certain embodiments of the present invention, the silicone-acrylic hybrid pressure-sensitive adhesive comprises the reaction product of: (a) a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, (b) an ethylenically unsaturated monomer, and (c) an initiator . In other words, the silicone-acrylic hybrid pressure-sensitive adhesive is the product of a chemical reaction between these reagents ((a), (b) and (c)). Specifically, the silicone-acrylic hybrid pressure-sensitive adhesive includes the reaction product of: (a) a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, (b) a (meth)acrylate monomer, and (c) an initiator ( i.e. in the presence of the initiator). In other words, the silicone-acrylic hybrid pressure sensitive adhesive includes the product of a chemical reaction between these reactants ((a), (b) and (c)).

[0161] The reaction product of (a) a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, (b) an ethylenically unsaturated monomer, and (c) an initiator may contain a continuous silicone external phase and a discrete acrylic internal phase or reaction product ( a), (b) and (c) may contain a continuous acrylic outer phase and a discrete silicone inner phase.

[0162] A silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group (a) is typically present in the silicone-acrylic hybrid pressure-sensitive adhesive in an amount of 5-95, more typically 25-75 parts by weight based on 100 parts by weight of the hybrid pressure-sensitive adhesive.

[0163] The ethylenically unsaturated monomer (b) is typically present in the silicone-acrylic hybrid pressure-sensitive adhesive in an amount of 5-95, more typically 25-75 parts by weight based on 100 parts by weight of the hybrid pressure-sensitive adhesive.

[0164] The initiator (c) is typically present in the silicone-acrylic hybrid pressure-sensitive adhesive in an amount of 0.005-3, more typically 0.01-2 parts by weight based on 100 parts by weight of the hybrid pressure-sensitive adhesive.

[0165] According to certain embodiments of the present invention, a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group (a) contains a condensation reaction product: (a1) a silicone resin, (a2) a silicone polymer, and (a3) a silicon- containing a blocking agent that provides the specified acrylate or methacrylate functional group. Silicone resin (a1) may also be referred to as silicate resin or silica gel resin. Preferably the silicone polymer (a2) is a polysiloxane, preferably a polydimethylsiloxane. It should be understood that (a1) and (a2) form a silicone-based pressure-sensitive adhesive by polycondensation, and that an acrylate or methacrylate functional group is introduced by reaction with (a3).

[0166] According to certain embodiments of the present invention, the silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group (a) contains a condensation reaction product:

(a1) silicone resin,

(a2) silicone polymer, and

(a3) a silicon-containing blocking agent that provides the specified acrylate or methacrylate functional group, and the specified silicon-containing blocking agent is characterized by the General formula XYR' _b SiZ _3-b where

X is a monovalent radical according to the general formula AE-

where E represents -O- or -NH-, and A represents an acrylic group or a methacrylic group,

Y is a divalent alkylene radical with 1-6 carbon atoms,

R' is a methyl or phenyl radical,

Z is a monovalent hydrolyzable organic radical or halogen, and

b is 0 or 1;

wherein the silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, wherein the silicon-containing blocking agent is added before, during, or after the reaction of the silicone resin and the silicone polymer, and wherein:

the silicon-containing blocking agent reacts with the pressure-sensitive adhesive after the silicone resin and the silicone polymer have undergone a condensation reaction to form the pressure-sensitive adhesive; or

the silicon-containing blocking agent reacts in situ with the silicone resin and the silicone polymer.

[0167] According to certain embodiments of the present invention, a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group contains a condensation reaction product of a pressure-sensitive adhesive and a silicon-containing blocking agent that provides the specified acrylate or methacrylate functional group. In other words, a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group is essentially a pressure-sensitive adhesive that has been blocked at the ends with a silicon-containing blocking agent that provides the specified acrylate or methacrylate functional group, wherein the pressure-sensitive adhesive comprises a condensation reaction product of a silicone resin and a silicone polymer. Preferably, the silicone resin is reacted in an amount of 30-80 parts by weight to form a pressure-sensitive adhesive, and the silicone polymer is reacted in an amount of 20-70 parts by weight to form a pressure-sensitive adhesive. In both cases, parts by weight are given per 100 parts by weight of the pressure-sensitive adhesive. Although not required, the pressure-sensitive adhesive may contain a catalytic amount of a condensation catalyst. A wide range of silicone resins and silicone polymers are suitable for making a pressure sensitive adhesive.

[0168] According to certain embodiments of the present invention, the silicone-acrylic hybrid pressure-sensitive adhesive is the reaction product of:

(a) a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, which contains a condensation reaction product:

(a1) silicone resin,

(a2) silicone polymer, and

(a3) a silicon-containing blocking agent that provides the specified acrylate or methacrylate functional group, and the specified silicon-containing blocking agent is characterized by the General formula XYR' _b SiZ _3-b where

X is a monovalent radical according to the general formula AE-

where E represents -O- or -NH-, and A represents an acrylic group or a methacrylic group,

Y is a divalent alkylene radical characterized by 1-6 carbon atoms,

R' is a methyl or phenyl radical,

Z is a monovalent hydrolyzable organic radical or halogen, and

b is 0 or 1;

wherein the silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, wherein the silicon-containing blocking agent is added before, during, or after the reaction of the silicone resin and the silicone polymer, and wherein:

the silicon-containing blocking agent reacts with the pressure-sensitive adhesive after the silicone resin and the silicone polymer have undergone a condensation reaction to form the pressure-sensitive adhesive; or

the silicon-containing blocking agent reacts in situ with the silicone resin and the silicone polymer;

(b) an ethylenically unsaturated monomer; And

(c) initiator.

[0169] The silicone-acrylic hybrid composition used in the present invention can be described by its preparation using a method comprising the following steps:

(i) obtaining a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, which contains a condensation reaction product:

silicone resin,

silicone polymer, and

a silicon-containing blocking agent that provides the specified acrylate or methacrylate functional group, and the specified silicon-containing blocking agent is characterized by the General formula XYR' _b SiZ _3-b where

X is a monovalent radical according to the general formula AE-

where E represents -O- or -NH-, and A represents an acrylic group or a methacrylic group,

Y is a divalent alkylene radical characterized by 1-6 carbon atoms,

R' is a methyl or phenyl radical,

Z is a monovalent hydrolyzable organic radical or halogen, and

b is 0 or 1;

wherein the silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, wherein the silicon-containing blocking agent is added before, during, or after the reaction of the silicone resin and the silicone polymer, and wherein:

the silicon-containing blocking agent reacts with the pressure-sensitive adhesive after the silicone resin and the silicone polymer have undergone a condensation reaction to form the pressure-sensitive adhesive; or

the silicon-containing blocking agent reacts in situ with the silicone resin and the silicone polymer;

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

[0170] During the polymerization of the ethylenically unsaturated monomer and the silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, the ratio of silicone to acrylic can be controlled and optimized as needed. The ratio of silicone to acrylic can be controlled by a wide variety of mechanisms during and during the process. An illustrative example of one such mechanism is the rate-controlled addition of an ethylenically unsaturated monomer or monomers to a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group. In certain applications, it may be desirable that the silicone-based subtype, or total silicone content, exceed the acrylate-based subtype, or total acrylic content. In other applications, it may be desirable for the opposite to take place. Regardless of the end use, it is generally preferred, as already described above, that the silicone-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group is preferably present in the silicone-acrylic hybrid composition in an amount of from about 5 to about 95 parts by weight, more preferably from about 25 to about 75 parts by weight, and even more preferably from about 40 to about 60 parts by weight, based on 100 parts by weight of the silicone-acrylic hybrid composition.

[0171] According to certain embodiments of the present invention, the silicone-acrylic hybrid composition used in the present invention can be described by its preparation using a method comprising the following steps:

(i) obtaining a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, which contains a condensation reaction product:

silicone resin,

silicone polymer, and

a silicon-containing blocking agent that provides the specified acrylate or methacrylate functional group, and the specified silicon-containing blocking agent is characterized by the General formula XYR' _b SiZ _3-b where

X is a monovalent radical according to the general formula AE-

where E represents -O- or -NH-, and A represents an acrylic group or a methacrylic group,

Y is a divalent alkylene radical characterized by 1-6 carbon atoms,

R' is a methyl or phenyl radical,

Z is a monovalent hydrolyzable organic radical or halogen, and

b is 0 or 1;

wherein the silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, wherein the silicon-containing blocking agent is added before, during, or after the reaction of the silicone resin and the silicone polymer, and wherein:

the silicon-containing blocking agent reacts with the pressure-sensitive adhesive after the silicone resin and the silicone polymer have undergone a condensation reaction to form the pressure-sensitive adhesive; or

the silicon-containing blocking agent reacts in situ with the silicone resin and the silicone polymer;

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

(iii) removing the first solvent; And

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

[0172] The silicone-acrylic hybrid PSA composition used in the present invention can be described by its preparation using a method comprising the following steps:

(i) obtaining a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group, which contains a condensation reaction product:

silicone resin,

silicone polymer, and

a silicon-containing blocking agent that provides the specified acrylate or methacrylate functional group, and the specified silicon-containing blocking agent is characterized by the General formula XYR' _b SiZ _3-b where

X is a monovalent radical according to the general formula AE-

where E represents -O- or -NH-, and A represents an acrylic group or a methacrylic group,

Y is a divalent alkylene radical characterized by 1-6 carbon atoms,

R' is a methyl or phenyl radical,

Z is a monovalent hydrolyzable organic radical or halogen, and

b is 0 or 1;

wherein the silicone resin and the silicone polymer react to form a pressure-sensitive adhesive, wherein the silicon-containing blocking agent is added before, during, or after the reaction of the silicone resin and the silicone polymer, and wherein:

the silicon-containing blocking agent reacts with the pressure-sensitive adhesive after the silicone resin and the silicone polymer have undergone a condensation reaction to form the pressure-sensitive adhesive; or

the silicon-containing blocking agent reacts in situ with the silicone resin and the silicone polymer;

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

(iii) adding a treatment solvent, wherein the treatment solvent has a higher boiling point than the first solvent, and

(iv) applying heat at a temperature of from 70°C to 150°C, so that the main part of the first solvent is selectively removed;

(v) removing the processing solvent; And

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

[0173] The silicone resin according to the previous paragraphs may contain a copolymer containing triorganosiloxy units according to the formula R ^X ₃ SiO _1/2 and tetrafunctional siloxy units according to the formula SiO _4/2 in a ratio of 0.1-0.9, preferably approximately 0.6-0.9 triorganosiloxy units for each tetrafunctional siloxy unit. Preferably, each R ^X independently represents a monovalent hydrocarbon radical containing 1-6 carbon atoms, vinyl, hydroxyl or phenyl groups.

[0174] The silicone polymer according to the preceding paragraphs may contain at least one polydiorganosiloxane and is preferably terminated with a functional group selected from the group consisting of: hydroxyl groups, alkoxy groups, hydride groups, vinyl groups, or mixtures thereof. The diorgano substituent may be selected from the group consisting of: dimethyl, methylvinyl, methylphenyl, diphenyl, methylethyl, (3,3,3-trifluoropropyl)methyl, and mixtures thereof. Preferably, the diorgano substituents contain only methyl groups. The molecular weight of the polydiorganosiloxane will typically be ⁱⁿ the range of from about 50,000 to about 1,000,000, preferably from ^about _80,000 to about 300,000. of approximately 100 cP - approximately 30,000,000 cP at 25°C, each radical A is independently selected from R ^X or halohydrocarbon radicals characterized by 1-6 carbon atoms, each radical T is independently selected from the group consisting of R ^X , OH, H or ORY , and each RY is independently an alkyl radical having 1-4 carbon atoms.

[0175] By way of example, using the forms of the preferred silicone resin and the preferred silicone polymer, one type of pressure-sensitive adhesive is prepared by: mixing: (i) 30-80 parts by weight, inclusive, of at least one resin copolymer containing silicone-bound hydroxyl radicals and consisting essentially of R ^X ₃ SiO _1/2 units and SiO _4/2 units in a molar ratio of 0.6-0.9 R ^X ₃ SiO _1/2 units for each SiO _4/2 unit present, ( ii) from about 20 to about 70 parts by weight of at least one polydiorganosiloxane containing AR ^X SiO units ending in TR ^X ASiO _1/2 terminal blocking units, wherein the polydiorganosiloxane has a viscosity of from about 100 cP to about 30,000,000 cP at 25 °C, and each R ^X is a monovalent organic radical selected from the group consisting of hydrocarbon radicals with 1-6 inclusive atom carbon atoms, each A radical is independently selected from ^RX or halocarbon radicals having 1-6 carbon atoms inclusive, each T radical is independently selected from the group consisting of R ^X , OH, H or OR ^Y , and each R ^Y is independently alkyl radical with 1-4 inclusive carbon atoms; a sufficient amount of: (iii) at least one of the silicon-containing blocking agents, also referred to herein as end blocking agents, which are described below and are capable of providing a content or concentration of silanol in the range of 5000-15000, more typically 8000-13000 ppm, if necessary, an additional catalytic amount (iv) of a mild silanol condensation catalyst in case none of them is provided in (ii), and if necessary, an effective amount (y) of an organic solvent which is inert with respect to ( i), (ii), (iii) and (iv), to reduce the viscosity of the mixture (i), (ii), (iii) and (iv), and condense the mixture (i), (ii), (iii) and (iv) at least until a significant amount of the silicon-containing blocking agent or agents reacts with the silicone-bound hydroxyl radicals and the T radicals in (i) and (ii). Additional organosilicon end blocking agents may be used in combination with the silicon containing blocking agent or agents (iii) of the present invention.

[0176] The silicon-containing blocking agent according to the preceding paragraphs can be selected from the following group: acrylate-functional silanes, acrylate-functional silazanes, acrylate-functional disilazanes, acrylate-functional disiloxanes, methacrylate-functional silanes, methacrylate-functional silanes functional group, methacrylate-functional disilazanes, methacrylate-functional disiloxanes, and combinations thereof, and can be described as having the general formula XYR' _b SiZ _3-b , where X is a monovalent radical according to the general formula AE-, where E is -O- or -NH-, and A is an acrylic group or a methacrylic group, Y is a divalent alkylene radical having 1-6 carbon atoms, R' is a methyl or phenyl radical, Z is a monovalent hydrolysable organic radical or halogen , and b with leaves 0, 1 or 2. Preferably, the monovalent hydrolyzable organic radical is characterized by the general formula R''0-, where R'' is an alkylene radical. Most preferably, this particular end blocking agent is selected from the following group: 3-methacryloxypropyldimethylchlorosilane, 3-methacryloxypropyldichlorosilane, 3-methacryloxypropyltrichlorosilane, 3-methacryloxypropylde and methylmethoxysilane, 3-methacryloxypropylmethylide and methoxysilane, 3-methacryloxypropyltrimethoxysilane, 3-methacryloxypropyldimethylethoxysilane, 3-methacryloxypropylmethoxypropylmethyl, (methacryloxymethyl)dimethylmethoxysilane, (methacryloxymethyl)methyldimethoxysilane, (methacryloxymethyl)trimethoxysilane, (methacryloxymethyl)dimethylethoxysilane, (methacryloxymethyl)methyldiethoxysilane, methacryloxymethyltriethoxysilane, methacryloxypropyltriisopropoxysilane, 3-methacryloxypropyldimethylsilazane, 3-acryloxypropyldimethylchlorosilane, propyl-3-dichloroacryloxy, propyl-3-dichloroacryloxy, -acryloxypropyl and methylmethoxysilane, 3-acryloxypropylmethyldimethoxysilane, 3-acryloxypropyltrimethoxysilane, 3-acryloxypropyldimethylsilazane, and combinations thereof.

[0177] The ethylenically unsaturated monomer according to the preceding paragraphs can be any monomer having at least one carbon-carbon double bond. Preferably, the ethylenically unsaturated monomer according to the preceding paragraphs may be a compound selected from the group consisting of the following: aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates, cycloaliphatic methacrylates, and combinations thereof. It should be understood that each of the following compounds: aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates and cycloaliphatic methacrylates, include an alkyl radical. The alkyl radicals of these compounds may include up to 20 carbon atoms. Aliphatic acrylates, which can be selected as one of the ethylenically unsaturated monomers, are selected from the group consisting of the following: methyl acrylate, ethyl acrylate, propylacrylate, n-butyl acrylate, isobutyl acrylate, t-butyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, isononyl acrylate, isopentyl acrylate, tridecyl acrylate , stearyl acrylate, lauryl acrylate and mixtures thereof. Aliphatic methacrylates, which can be selected as one of the ethylenically unsaturated monomers, are selected from the group consisting of the following: methyl methacrylate, ethyl methacrylate, propyl methacrylate, n-butyl methacrylate, isobutyl methacrylate, t-butyl methacrylate, hexyl methacrylate, 2-ethylhexyl methacrylate, isooctyl methacrylate, isononyl methacrylate, isopentyl methacrylate, , stearyl methacrylate, lauryl methacrylate and mixtures thereof. The cycloaliphatic acrylate, which can be selected as one of the ethylenically unsaturated monomers, is cyclohexyl acrylate, and the cycloaliphatic methacrylate, which can be selected as one of the ethylenically unsaturated monomers, is cyclohexyl methacrylate.

[0178] It should be understood that the ethylenically unsaturated monomer used to make the silicone-acrylic hybrid pressure-sensitive adhesive may be more than one ethylenically unsaturated monomer. In other words, the combination of ethylenically unsaturated monomers can be polymerized, more specifically copolymerized, together with a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group and an initiator. According to a specific embodiment of the present invention, the silicone-acrylic hybrid pressure-sensitive adhesive is prepared by using at least two different ethylenically unsaturated monomers, preferably selected from the group of 2-ethylhexyl acrylate and methyl acrylate, more preferably in a ratio of 50% 2-ethylhexyl acrylate and 50% methyl acrylate , or in a ratio of 60% 2-ethylhexyl acrylate and 40% methyl acrylate as the acrylic monomer.

[0179] The initiator according to the previous paragraphs can be any substance that is suitable for initiating the polymerization of a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group and an ethylenically unsaturated monomer to form a silicone-acrylic hybrid. For example, free radical initiators selected from the group of peroxides, azo compounds, redox initiators and photoinitiators can be used.

[0180] Additional suitable silicone resins, silicone polymers, silicon-containing blocking agents, ethylenically unsaturated monomers and initiators that can be used in accordance with the previous paragraphs are described in detail in WO 2007/145996, EP 2599847 A1 and WO 2016/130408.

[0181] According to a specific embodiment of the present invention, the silicone-acrylic hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin, and an acrylic polymer, wherein the acrylic polymer is covalently crosslinked to itself and covalently bonded to the silicone polymer and/or silicone resin.

[0182] According to a certain other 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 contains R ₃ SiO _1/2 triorganosiloxy units, where R is an organic group, and tetrafunctional siloxy units SiO _4/2 in a molar ratio of 0.1 to 0.9 R ₃ SiO _1/2 units for each SiO _4/2 unit.

[0183] The acrylic polymer may contain at least an alkoxysilyl-functional monomer, a polysiloxane-containing monomer, a halosilyl-functional monomer, or an alkoxyhalogensilyl-functional monomer. Preferably, the acrylic polymer is derived from alkoxysilyl-functionalized monomers selected from the group consisting of trialkoxysilyl (meth)acrylates, dialkoxyalkylsilyl (meth)acrylates, and mixtures thereof, or it contains terminated alkoxysilyl functional groups. Alkoxysilyl functional groups may preferably be selected from the group consisting of trimethoxysilyl groups, dimethoxymethylsilyl groups, triethoxysilyl groups, diethoxymethylsilyl groups, and mixtures thereof.

[0184] The acrylic polymer can also be obtained from a mixture containing polysiloxane-containing monomers, preferably from a mixture containing polydimethylsiloxane mono(meth)acrylate.

[0185] Silyl-functional monomers will generally be used in amounts ranging from 0.2 to 20% by weight of the acrylic polymer, more preferably the amount of silyl-functional monomers will be in the range of from about 1.5 to about 5 % by weight of acrylic polymer.

[0186] The amount of polysiloxane-containing monomer will typically be used in amounts ranging from 1.5 to 50% by weight of the acrylic polymer, more preferably the amount of polysiloxane-containing monomers will be in the range of 5-15% by weight of the acrylic polymer.

[0187] Alternatively, the acrylic polymer comprises a block or graft copolymer of acrylic and polysiloxane. An example of a polysiloxane block copolymer is a polydimethylsiloxane-acrylic block copolymer. The preferred amount of the siloxane block is 10-50% by weight of the entire block polymer.

[0188] The acrylic polymer contains alkyl(meth)acrylate monomers. Preferred alkyl (meth)acrylates that can be used have up to about 18 carbon atoms in the alkyl group, preferably 1 to about 12 carbon atoms in the alkyl group. Preferred low glass transition temperature (Tg) alkyl acrylates with a homopolymer Tg of less than about 0° C. have about 4 to about 10 carbon atoms in the alkyl group and include butyl acrylate, amyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, octylacrylate, isooctyl acrylate, decyl acrylate, their isomers and combinations thereof. Especially preferred are butyl acrylate, 2-ethylhexyl acrylate and isooctyl acrylate. The acrylic polymer components may further comprise high Tg (meth)acrylate monomers such as methyl acrylate, ethyl acrylate, methyl methacrylate, and isobutyl methacrylate.

[0189] The acrylic polymer component may further contain a polyisobutylene group to improve the flow of the adhesive from under the patch properties of the resulting adhesive.

[0190] The acrylic polymer components may contain nitrogen-containing polar monomers. Examples include N-vinylpyrrolidone, N-vinylcaprolactam, N-tertiary octylacrylamide, dimethylacrylamide, diacetonacrylamide, N-tertiary butylacrylamide, N-isopropylacrylamide, cyanoethyl acrylate, N-vinylacetamide, and N-vinylformamide.

[0191] The acrylic polymer component may contain one or more hydroxyl-containing monomers such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, hydroxypropylacrylate, and/or hydroxypropyl methacrylate.

[0192] The acrylic polymer components may optionally contain monomers containing carboxylic acids. 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.

[0193] Other applicable well-known comonomers include vinyl acetate, styrene, cyclohexyl acrylate, alkyl di(meth)acrylates, glycidyl methacrylate, and allyl glycidyl ether, as well as macromers such as, for example, poly(styryl) methacrylate.

[0194] One acrylic polymer component that can be used in the practice of the present invention is an acrylic polymer that contains from about 90 to about 99.5% by weight of butyl acrylate and from about 0.5 to about 10% by weight of dimethoxymethylsilyl methacrylate .

[0195] According to a certain embodiment of the present invention, a silicone-acrylic hybrid polymer can be prepared as follows: a) reacting a silicone polymer with a silicone resin to form a product obtained, b) reacting the product obtained from a) with an acrylic polymer containing a reactive functional group, wherein components react in an organic solvent.

[0196] According to a specific embodiment of the present invention, a silicone-acrylic hybrid polymer can be obtained as follows: a) reacting a silicone resin with an acrylic polymer containing a reactive functional group to form the resulting product, b) reacting the resulting product from a) with a silicone polymer, wherein the components react in an organic solvent.

[0197] According to a certain embodiment of the present invention, a silicone-acrylic hybrid polymer can be obtained as follows: a) reacting a silicone polymer with an acrylic polymer containing a reactive functional group to form a product obtained, b) reacting the product obtained from a) with a silicone resin, wherein components react in an organic solvent.

[0198] Additional suitable acrylic polymers, silicone resins, and silicone polymers that can be used to chemically react with the silicone polymer, silicone resin, and acrylic polymer to produce the silicone-acrylic hybrid polymer according to the previous paragraphs are detailed in International Patent Publication WO 2010/124187 .

[0199] According to certain embodiments of the present invention, the silicone-acrylic hybrid polymer used in 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., pressure-sensitive adhesives based on polysiloxane or acrylates).

non-hybrid polymers

[0200] The TTS of the present invention comprises at least one silicone polymer and optionally at least one additional polymer, which may be a non-hybrid polymer such as an acrylate polymer.

[0201] Non-hybrid polymers (eg, non-hybrid pressure-sensitive adhesives) are polymers (eg, polymer-based pressure-sensitive adhesives) that do not include a hybrid appearance. Preferred are non-hybrid polymers (eg non-hybrid pressure-sensitive adhesives) based on polysiloxanes, acrylates, polyisobutylenes or styrene-isoprene-styrene block copolymers.

[0202] Non-hybrid polymers (eg, non-hybrid pressure-sensitive adhesives) may be contained in the active agent-containing layer structure and/or in the adhesive top layer.

[0203] Non-hybrid pressure-sensitive adhesives are typically supplied and used in solvents such as n-heptane and ethyl acetate. The solids content of pressure-sensitive adhesives is typically between 30% and 80%.

[0204] Suitable non-hybrid polymers of the present invention are commercially available, for example, under the trademarks BIO-PSA (polysiloxane-based pressure-sensitive adhesives), Oppanol™ (polyisobutylenes), JSR-SIS (styrene-isoprene-styrene copolymer), or Duro -Tak™ (acrylic polymers).

[0205] Polysiloxane-based polymers may also be referred to as silicone-based polymers or silicone polymers, or silicones. Pressure-sensitive adhesives based on polysiloxanes may also be referred to as silicone-based pressure-sensitive adhesives or silicone pressure-sensitive adhesives. These polysiloxane-based pressure-sensitive adhesives provide suitable tack and fast adhesion to a variety of skin types, including wet skin, suitable adhesive and cohesive properties, long-term adhesion to the skin, a high degree of flexibility, moisture permeability, and compatibility with many active agents and substrate films. It is possible to provide them with sufficient amine resistance and hence increased stability in the presence of amines. Such pressure-sensitive adhesives are based on the resin-in-polymer concept where, by condensing a silanol-terminated polydimethylsiloxane and a silicate resin (also called silica gel resin), a polysiloxane-based pressure-sensitive adhesive is obtained, with residual silanol for amine resistance. the functional group is further blocked with trimethylsiloxy groups. The content of polydimethylsiloxane with a blocked terminal silanol group gives the viscous component viscoelastic properties, and affects the properties of wetting and spreading of the adhesive. The resin acts as a tackifier and reinforcing agent and participates in the elastic component. The right balance between the silanol-capped polydimethylsiloxane and the resin ensures the right adhesive properties.

[0206] In view of the foregoing, silicone-based polymers, and in particular silicone-based pressure-sensitive adhesives, can generally be prepared by polycondensation of a silanol-terminated polydimethylsiloxane and a silicate resin. Amino-compatible silicone-based polymers, and in particular amino-compatible silicone-based pressure-sensitive adhesives, can be prepared by reacting a silicone-based polymer, in particular a silicone-based pressure-sensitive adhesive, with trimethylsilyl (e.g., hexamethyldisilazane) to reduce the silanol content of the polymer. As a result, the residual silanol functional group is at least partially, preferably mostly or completely blocked by trimethylsiloxy groups.

[0207] As noted above, the tackiness of at least one silicone-based polymer can be modified by the ratio of resin to polymer, i.e. ratio of silanol-terminated polydimethylsiloxane to silicate resin, which is preferably in the range of 70:30-50:50, preferably 65:35-55:45. The stickiness will increase with increasing amounts of polydimethylsiloxane relative to the resin. High tack silicone based polymers preferably have a resin to polymer ratio of 55:45, medium tack silicone based polymers preferably have a resin to polymer ratio of 60:40, and low tack silicone based polymers preferably have a resin to polymer ratio of to the polymer constituting 65:35. High tack silicone based polymers preferably have a complex viscosity at 0.01 rad/s and 30°C of 5×10 ⁶ P, medium tack silicone based polymers preferably have a complex viscosity at 0.01 rad/s and 30 °C of 5×10 ⁷ P and low tack silicone based polymers preferably have a complex viscosity at 0.01 rad/s and 30°C of 5×10 ⁸ P. Amino compatible silicone based polymers with high tack are preferably have a complex viscosity at 0.01 rad/s and 30°C of 5×10 ⁶ P, amino-compatible polymers based on silicone with medium tack preferably have a complex viscosity at 0.01 rad/s and 30°C of 5×10 ⁸ P, and low tack silicone-based amino-compatible polymers preferably have a complex viscosity at 0.01 rad/s and 30°C of 5×10 ⁹ P.

[0208] Examples of silicone-based PSA compositions that are commercially available include the standard BIO-PSA series (7-4400, 7-4500, and 7-4600 series), the amino-compatible (end-locked) BIO-PSA series ( 7-4100, 7-4200, and 7-4300), manufactured and typically supplied in n-heptane or ethyl acetate by Dow Corning, and the Delicate Skin Adhesive Series (7-9800), manufactured and typically supplied without solvent by Dow Corning. For example, BIO-PSA 7-4201 has a solution viscosity at 25°C and approximately 73% solids in heptane of 450 mPa.s and a complex viscosity at 0.01 rad/s at 30°C of 1×10 ⁸ P. BIO-PSA 7-4301 has a solution viscosity at 25°C and approximately 73% solids content in heptane of 500 mPa.s and a complex viscosity at 0.01 rad/s at 30°C of 5× 10 ⁶ P.

[0209] Silicone polymers are supplied and used in solvents such as n-heptane, ethyl acetate, or other volatile silicone fluids. For the present invention, n-heptane is preferred. The solids content of silicone polymers in solvents is generally 60 to 80%, preferably 70 to 80% or 60 to 70%. One skilled in the art will appreciate that the solids content can be modified by adding a suitable amount of solvent.

[0210] The preferred polysiloxane pressure-sensitive adhesives of the present invention have a solution viscosity at 25°C and 60% solids in n-heptane of greater than about 150 mPa.s, or about 200 mPa.s - about 700 mPa.s, preferably as measured using a Brookfield RVT viscometer equipped with a #5 measuring tip at 50 rpm. They may also have a complex viscosity at 0.01 rad/s at 30°C of less than about 1 x 10 ⁹ P or about 1 x 10 ⁵ to about 9 x 10 ⁸ P.

[0211] Suitable polyisobutylenes according to the present invention are available under the trademark Oppanol®. Combinations of high molecular weight polyisobutylenes (B100/B80) and low molecular weight polyisobutylenes (B10, B11, B12, B13) can be used. Suitable ratios of low molecular weight polyisobutylene to high molecular weight polyisobutylene are in the range of 100:1 to 1:100, preferably 95:5 to 40:60, more preferably 90:10 to 80:20. A preferred example of a combination of polyisobutylenes is B10/B100 in a ratio of 85/15. Oppanol® B100 has a viscosity average molecular weight M _v of 1,110,000 and a weight average molecular weight M _w of 1,550,000 and an average molecular weight distribution M _w /M _n of 2.9. Oppanol® B10 has a viscosity average molecular weight M _v of 40,000 and a weight average molecular weight M _w of 53,000 and an average molecular weight distribution M _w /M _n of 3.2. In certain embodiments, polybutene can be added to polyisobutylenes. The solids content of polyisobutylenes in solvents is generally 30-50%, preferably 35-40%. One skilled in the art will appreciate that the solids content can be modified by adding a suitable amount of solvent.

[0212] Acrylate-based pressure-sensitive adhesives may also be referred to as acrylate-based pressure-sensitive adhesives, or acrylate pressure-sensitive adhesives. Pressure-sensitive adhesives based on acrylates can have a solids content of preferably 30%-60%. Such acrylate-based pressure-sensitive adhesives may or may not contain functional groups such as hydroxy groups, carboxylic acid groups, neutralized carboxylic acid groups, and mixtures thereof. Thus, the term "functional groups" specifically refers to hydroxy and carboxylic acid groups, and deprotonated carboxylic acid groups.

[0213] Relevant commercial products are available, for example, from Henkel under the brand name Duro So®. Such acrylate-based pressure-sensitive adhesives are based on monomers selected from one or more of the following: acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, t-octylacrylamide, and vinyl acetate, and are supplied in ethyl acetate, heptanes, n-heptane, hexane, methanol, ethanol, isopropanol, 2,4-pentanedione, toluene or xylene, or mixtures thereof.

[0214] Specific acrylate-based pressure-sensitive adhesives are available as:

- Duro-Tak™ 387-2287 or Duro-Tak™ 87-2287 (a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate provided as a solution in ethyl acetate without a crosslinker) ,

- Duro-Tak™ 387-2516 or Duro-Tak™ 87-2516 (copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate provided as a solution in ethyl acetate, ethanol, n-heptane and methanol with titanium cross-linking agent),

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

- Duro-Tak™ 387-2353 or Duro-Tak™ 87-2353 (a copolymer based on acrylic acid, 2-ethylhexyl acrylate, glycidyl methacrylate and methyl acrylate provided as a solution in ethyl acetate and hexane),

- Duro-Tak™ 87-4098 (a copolymer based on 2-ethylhexyl acrylate and vinyl acetate provided as a solution in ethyl acetate).

[0215] Additional polymers can also be added to enhance cohesion and/or adhesion.

[0216] Certain polymers, in particular, reduce the leakage of the adhesive substance from under the patch and, thus, in particular, are suitable as an additional polymer. The polymer matrix may exhibit leakage of the adhesive from under the patch, since such polymer compositions often exhibit, in spite of their very high viscosity, the ability to flow very slowly. Thus, during storage, the matrix may leak out of the substrate to a certain extent. This is a storage stability problem and can be prevented by adding certain polymers. A base acrylate polymer (eg, Eudragit® E100), for example, can be used to reduce leakage of the adhesive from under the patch. Thus, in certain embodiments, the matrix layer composition further comprises a base polymer, in particular an amino-functional acrylate, such as Eudragit® E100. Eudragit® 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 (gel filtration) method, the weight average molar mass (M _w ) of Eudragit® E100 is approximately 47,000 g/mol. In addition, polymers such as Plastoid B, acrylic polymers such as Eudragit, chitosan, celluloses and their derivatives, and polystyrene can be used to increase the dryness of the adhesive (eg, matrix layer).

Additional excipients

[0217] The TTS of the present invention, and in particular the guanfacine-containing layer, may further comprise at least one adjuvant or adjuvant. Particularly preferred adjuvants according to the present invention include dispersing agents, penetration enhancers and solubilizers. Details in this regard are provided above. However, the TTS according to the present invention, and in particular the guanfacine-containing layer, may also include additional adjuvants or adjuvants.

[0218] In general, adjuvants or adjuvants are preferably selected from the group consisting of the following: dispersing agents, solubilizers, penetration enhancers, film forming agents, emollients/plasticizers, tackifiers, skin care agents, pH adjusters, preservatives, stabilizing agents and fillers. Such excipients may be present in the guanfacine-containing layer in an amount of 0.001%-15% by weight, for example, 0.5-10% by weight or 1-10% by weight, based on the total weight of the guanfacine-containing layer, and where wt The .% quantities refer to one excipient.

[0219] It should be noted that in pharmaceutical compositions, the components of the composition can be classified according to their physico-chemical and physiological properties, and according to their function. This means, in particular, that a substance or compound falling into one category is not excluded from another category of a composition component. For example, the particular polymer may be a film-forming agent, but also a tackifier. Some substances may, for example, represent a typical emollient, but at the same time act as a penetration enhancer. A person skilled in the art is able to determine, based on his general knowledge, which category or categories of composition components a particular substance or compound belongs to. The following are details with respect to adjuvants and excipients, which, however, should not be understood as exclusive. Other substances not expressly listed herein may also be used in accordance with the present invention, and it is possible that substances and/or compounds explicitly listed for one formulation component category may be used for another formulation component within the meaning of the present invention.

[0220] In one embodiment, the guanfacine-containing layer comprises a dispersing agent as defined above, preferably the dispersing agent is selected from the group consisting of the following: fatty acid esters with polyhydric alcohols, fatty alcohols, polyethylene glycols having a number average molecular weight of 300 -400, polyethylene glycol alkyl ethers. As explained above, the dispersing agent is preferably a C ₈ -C ₂₀ -alkyl ether of polyethylene glycol, characterized by 2-10 EO units, in particular polyoxyethylene lauryl ether (4). Alternatively or additionally, polyester silicones can be used as dispersing agents. The dispersing agent is useful in order to homogeneously disperse the guanfacine within the guanfacine-containing layer, in particular the guanfacine-containing matrix layer, thereby improving the release properties of the TTS.

[0221] According to one embodiment, the guanfacine-containing layer contains a solubilizer. The solubilizer preferably improves the dispersibility of guanfacine in the guanfacine-containing layer and stabilizes the guanfacine-containing layer. Moreover, the solubilizer can positively influence the cohesion. Preferred solubilizers include, for example, the following: esters of glycerol, polyglycerol, propylene glycol and polyoxyethylene and medium and/or long chain fatty acids such as glyceryl monolinoleate, medium chain glycerides and medium chain triglycerides, non-ionic solubilizers obtained the reaction of castor oil with ethylene oxide, and any mixtures thereof, which may additionally contain fatty acids or fatty alcohols; cellulose and methylcellulose and their derivatives such as hydroxypropylcellulose and hypromellose acetate succinate; various cyclodextrins and their derivatives; nonionic triblock copolymers characterized by a central hydrophobic polyoxypropylene chain flanked by two hydrophilic polyoxyethylene chains, known as poloxamers; water-soluble derivatives of vitamin E; pharmaceutical grade or agglomerated spherical isomalt; a graft copolymer based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam, also abbreviated as PVAc-PVCap-PEG and known as Soluplus®; vinylpyrrolidone-vinyl acetate copolymers such as Kollidon® VA64; refined grades of natural castor oil, polyethylene glycol 400, polyoxyethylene sorbitan monooleate (such as polysorbate 80), or propylene glycols; diethylene glycol monoethyl ether; glucono delta lactone; corn and potato starch; as well as any of the soluble polyvinyl pyrrolidones mentioned below, but also insoluble/cross-linked polyvinyl pyrrolidones such as crospovidones.

[0222] However, also the penetration enhancers mentioned below can act as solubilizers. Moreover, the film-forming agents described below can also act simultaneously as solubilizers and vice versa.

[0223] According to one embodiment, the guanfacine-containing layer contains a penetration enhancer. Preferred options in this regard are given above. Penetration enhancers are substances which affect the barrier properties of the stratum corneum in the sense of increasing the penetration of the active agent. Some examples of penetration enhancers are polyhydric alcohols such as dipropylene glycol, propylene glycol and polyethylene glycol; oils such as olive oil, squalene and lanolin; fatty esters 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, methylcetylsulfoxide, dimethylaurylamine, dodecylpyrrolidone, isosorbitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide and dimethylformamide; salicylic acid; amino acids; benzyl nicotinate; and higher molecular weight aliphatic surfactants such as lauryl sulfate salts. Other agents include oleic and linoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, and isopropyl palmitate. If the guanfacine-containing layer contains a permeation enhancer, the permeation enhancer is preferably selected from the group consisting of diethylene glycol monoethyl ether (transcutol), oleic acid, levulinic acid, caprylic/capric acid triglycerides, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, triacetin, dimethylpropylene urea, and oleyl urea. alcohol, and preferably it is oleyl alcohol.

[0224] According to one embodiment, the guanfacine-containing layer further comprises a film-forming agent. It should be understood that the solubilizers mentioned above, such as Soluplus®, can also act as film forming agents and control cohesion. Suitable examples of additional film forming agents include polyvinylpyrrolidone, vinyl acetate-vinylpyrrolidone copolymers and cellulose derivatives, preferably polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone.

[0225] If the guanfacine-containing layer is required to have self-adhesive properties and one or more polymers are selected that do not provide sufficient self-adhesive properties, a tackifier is added. Preferred tackifiers include miglyol, which is a liquid wax ester of even-numbered long-chain unsaturated fatty acids and even-numbered long-chain unsaturated fatty alcohols of plant origin, and polyethylene glycols. In particular, the tackifying agent can be selected from polyvinylpyrrolidone (which, due to its ability to absorb water, is able to maintain the adhesive properties of the matrix layer and thus can be considered as a tackifying agent in a broad sense), triglycerides, polyethylene glycols, dipropylene glycol, resins, complex resin esters, terpenes and their derivatives, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes, preferably polyvinylpyrrolidone and more preferably soluble polyvinylpyrrolidone. Preferably, the tackifying agent can be selected from polyvinylpyrrolidone, triglycerides, dipropylene glycol, resins, resin esters, terpenes and their derivatives, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes, preferably polyvinylpyrrolidone and more preferably soluble polyvinylpyrrolidone.

[0226] The term "soluble polyvinylpyrrolidone" refers to polyvinylpyrrolidone, also known as povidone, which is soluble with more than 10% in at least ethanol, preferably also in water, diethylene glycol, methanol, n-propanol, 2-propanol, n- butanol, chloroform, methylene chloride, 2-pyrrolidone, macrogol 400, 1,2-propylene glycol, 1,4-butanediol, glycerin, triethanolamine, propionic acid and acetic acid. Examples of polyvinylpyrrolidones that are commercially available include Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® 25, Kollidon® 30 and Kollidon® 90 F supplied by BASF, or povidone K90F. The various grades of Kollidon® are defined in terms of a K value reflecting the average molecular weight of the grades of polyvinylpyrrolidone. Kollidon® 12 PF has a K value range of 10.2 to 13.8, corresponding to a nominal K value of 12. Kollidon® 17 PF has a K value range of 15.3 to 18.4, corresponding to a nominal K value of 17. Kollidon® 25 has a K value range of 22.5 to 27.0, corresponding to a nominal K value of 25, Kollidon® 30 has a K value range of 27.0 to 32.4, corresponding to a nominal K value of 30. Kollidon® 90 F has a K value range of 81.0 to 97.2, corresponding to a nominal K value of 90. Kollidon® 12 PF, Kollidon® 30 and Kollidon® 90 F are preferred grades. In the invention, the term "K value" refers to a value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the monographs "Povidone" of the European Pharmacopoeia (Ph. Eur.) and the United States Pharmacopeia (USP).

[0227] According to one embodiment, the guanfacine-containing layer further comprises an emollient/plasticizer. Exemplary softeners/plasticizers include linear or branched, saturated or unsaturated alcohols having from 6 to 20 carbon atoms, triglycerides, and polyethylene glycols.

[0228] According to one embodiment, the guanfacine-containing layer further comprises a stabilizing agent. Stabilizing agents include tocopherol and its ester derivatives and ascorbic acid and its ester derivatives. Additional stabilizing agents include sodium metabisulfite, fatty acid ascorbyl esters such as ascorbyl palmitate, ascorbic acid, butylated hydroxytoluene, tocopherol, tocopheryl acetate, and tocopheryl linoleate.

[0229] In one embodiment, the guanfacine-containing layer further comprises a pH adjuster. Suitable pH adjusters include weak acids and bases, including amine derivatives, inorganic alkali derivatives, and basic or acid functional polymers.

[0230] In one embodiment, the guanfacine-containing layer further comprises a preservative. Suitable preservatives include parabens, formaldehyde release agents, isothiazolinones, phenoxyethanol, and organic acids such as benzoic acid, sorbic acid, levulinic acid, and anisic acid.

[0231] According to one embodiment, the guanfacine-containing layer further comprises further comprises a skin care agent. Such substances can be used to prevent or reduce skin irritation as measured by the Skin Response Scale. Suitable skin care agents include sterol compounds such as cholesterol, dexpanthenol, alpha-bisabolol and antihistamines.

[0232] According to one embodiment, the guanfacine-containing layer further comprises a filler. Fillers such as silica gels, titanium dioxide and zinc oxide can be used in combination with the polymer to influence certain physical parameters such as cohesion and bond strength in the desired manner.

Release characteristics

[0233] The TTSs of the present invention are for transdermal administration of guanfacine into the systemic circulation over a predetermined extended period of time, preferably at least 24 hours, more preferably at least 72 hours, in particular about 84 hours.

[0234] In one embodiment, the TTS of the present invention provides, via steady state transdermal delivery, an average plasma concentration of guanfacine of 1-20 ng/mL, preferably 1-15 ng/mL, more preferably 1-10 ng/mL.

[0235] Preferably, TTS provides therapeutically effective plasma concentrations of guanfacine within less than 8 hours, preferably less than 6 hours, more preferably less than 4 hours after application of TTS to the skin. Moreover, therapeutically effective plasma concentrations are preferably maintained for an entire administration period of at least 24 hours, preferably at least 72 hours, more preferably about 84 hours.

[0236] According to one embodiment, the TTS according to the present invention provides an AUC _0-244 of 10-600 ng*h/ml, preferably 20

- 400 ng*h/ml. According to another embodiment, the TTS according to the present invention provides an AUC _0-724 of 30-1800 ng*h/ml, preferably 60

- 1200 ng*h/ml. According to another embodiment, the TTS according to the present invention provides an AUC _0-844 of 35-2100 ng*h/ml, preferably 70

- 1400 ng*h/ml. It should be understood that AUC values preferably refer to AUC values obtained at steady state.

[0237] In one embodiment, the TTS of the present invention provides a C _max to C ₈₄ ratio of less than 3.5. In another embodiment, the TTS of the present invention provides a C _max to C ₇₂ ratio of less than 3.0. In another embodiment, the TTS of the present invention provides a C _max to C ₂₄ ratio of less than 2.0. These ratios indicate a flat curve of plasma concentration, which is favorable from the point of view of continuous treatment of the patient.

[0238] According to one embodiment, the TTS of the present invention provides a percutaneous penetration rate of guanfacine, as measured in a Franz diffusion cell using dermatotomized human skin, of:

0.01 mcg / (cm ² * h) - 8 mcg / (cm ² * h) in the first 24 hours,

0.05 mcg / (cm ² * h) - 10 mcg / (cm ² * h) from 24 to 72 hours.

[0239] According to one embodiment, the TTS of the present invention provides a percutaneous penetration rate of guanfacine, as measured in a Franz diffusion cell using dermatotomized human skin, of 0.05 mg/cm ² - 0.7 mg/cm ² , preferably 0.1 mg/cm ² - 0.6 mg/cm ² over a period of 72 hours.

[0240] In view of the foregoing, the present invention according to one aspect also relates to a transdermal therapeutic system for transdermal administration of guanfacine, comprising a guanfacine-containing layered structure,

wherein the transdermal therapeutic system provides, via transdermal delivery, one or more pharmacokinetic parameters selected from the group consisting of the following:

AUC _0-24 10-600 (ng/ml)⋅h,

AUC _0-72 30-1800 (ng/ml)⋅h,

AUC _0-84 35-2100 (ng/ml)⋅h,

the ratio of C _max to C ₂₄ that is less than 2.0,

a C _max to C ₇₂ ratio of less than 3.0, and

a C _max to C ₈₄ ratio of less than 3.5.

[0241] According to a preferred embodiment of the present invention relates to a transdermal therapeutic system for the transdermal administration of guanfacine, comprising a guanfacine-containing layered structure,

wherein the transdermal therapeutic system provides, via transdermal delivery, one or more pharmacokinetic parameters selected from the group consisting of the following:

AUC _0-24 20-400 (ng/ml)⋅h,

AUC _0-72 60-1200 (ng/ml)⋅h,

AUC _0-84 70-1400 (ng/ml)⋅h,

a ratio of C _max to C ₂₄ that is less than 1.5,

a C _max to C ₇₂ ratio of less than 2.5, and

a C _max to C ₈₄ ratio of less than 3.0.

Method of treatment/medical use

[0242] According to one embodiment of the present invention, the TTSs of the present invention are suitable for use in a method of treating a human patient, preferably a patient aged 6-17 years. In particular, the TTSs of the present invention are suitable for use in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD) and/or as adjunctive therapy to stimulant drugs in a human patient, preferably in a human patient aged 6-17 years old.

[0243] In a preferred embodiment, in connection with the above medical uses, TTS is applied to the skin of a patient for at least 24 hours, preferably at least 72 hours, more preferably about 84 hours.

[0244] According to one embodiment, the present invention relates to a method of treating a human patient, preferably a human patient aged 6-17 years, by applying a transdermal therapeutic system, as defined in one of items 1-37, to the patient's skin. In particular, the present invention relates to a method of treating hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient, preferably a human patient aged 6-17 years, by applying a transdermal therapeutic system according to the present invention to the patient's skin.

[0245] According to a preferred embodiment of the above treatment methods, 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.

[0246] In view of the foregoing, the present invention according to one aspect relates to a transdermal therapeutic system containing guanfacine, for use in a method of treating a human patient, preferably a human patient aged 6-17 years, by transdermal administration of guanfacine, and transdermal the 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 provided for use in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD) and/or as adjunctive therapy to stimulant drugs in a human patient. According to 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 the following:

AUC _0-24 10-600 (ng/ml)⋅h,

AUC _0-72 30-1800 (ng/ml)⋅h,

AUC _0-84 35-2100 (ng/ml)⋅h,

the ratio of C _max to C ₂₄ that is less than 2.0,

a C _max to C ₇₂ ratio of less than 3.0, and

the ratio of C _max to C ₈₄ that is less than 3.5;

and preferably selected from the group consisting of the following:

AUC _0-24 20-400 (ng/ml)⋅h,

AUC _0-72 60-1200 (ng/ml)⋅h,

AUC _0-84 70-1400 (ng/ml)⋅h,

a ratio of C _max to C ₂₄ that is less than 1.5,

a C _max to C ₇₂ ratio of less than 2.5, and

a C _max to C ₈₄ ratio of less than 3.0.

[0247] According to another aspect, the present invention relates to guanfacine for use in a method of treating a human patient, preferably a human patient aged 6-17 years, by transdermal administration of guanfacine using a transdermal therapeutic system, and the transdermal therapeutic system is applied to the skin patient for at least 24 hours, preferably at least 72 hours, more preferably about 84 hours. In a preferred embodiment, guanfacine is provided for use in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD) and/or as adjunctive therapy to stimulant drugs in a human patient. According to 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 the following:

AUC _0-24 10-600 (ng/ml)⋅h,

AUC _0-72 30-1800 (ng/ml)⋅h,

AUC _0-84 35-2100 (ng/ml)⋅h,

the ratio of C _max to C ₂₄ that is less than 2.0,

a C _max to C ₇₂ ratio of less than 3.0, and

the ratio of C _max to C ₈₄ that is less than 3.5;

and preferably selected from the group consisting of the following:

AUC _0-24 20-400 (ng/ml)⋅h,

AUC _0-72 60-1200 (ng/ml)⋅h,

AUC _0-84 70-1400 (ng/ml)⋅h,

a ratio of C _max to C ₂₄ that is less than 1.5,

a C _max to C ₇₂ ratio of less than 2.5, and

a C _max to C ₈₄ ratio of less than 3.0.

[0248] According to another aspect, the present invention relates to a method of treating a human patient, preferably a human patient aged 6-17 years, by transdermal administration of guanfacine, and the transdermal therapeutic system is applied to the skin of the patient for at least 24 hours, preferably at least 72 hours, more preferably about 84 hours. According to a preferred embodiment, the method is provided for the treatment of hypertension or attention deficit hyperactivity disorder (ADHD) and/or as adjunctive therapy to stimulant drugs in a human patient. According to 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 the following:

AUC _0-24 10-600 (ng/ml)⋅h,

AUC _0-72 30-1800 (ng/ml)⋅h,

AUC _0-84 35-2100 (ng/ml)⋅h,

the ratio of C _max to C ₂₄ that is less than 2.0,

a C _max to C ₇₂ ratio of less than 3.0, and

the ratio of C _max to C ₈₄ that is less than 3.5;

and preferably selected from the group consisting of the following:

AUC _0-24 20-400 (ng/ml)⋅h,

AUC _0-72 60-1200 (ng/ml)⋅h,

AUC _0-84 70-1400 (ng/ml)⋅h,

a ratio of C _max to C ₂₄ that is less than 1.5,

a C _max to C ₇₂ ratio of less than 2.5, and

a C _max to C ₈₄ ratio of less than 3.0.

[0249] In connection with the above uses and methods of treatment, TTS according to the present invention is preferably applied to at least one surface of the subject's body, selected from the upper outer region, upper chest, upper back, or lateral chest, during certain intervals between injections doses.

[0250] The preferred application time of the TTS according to the present invention is at least 24 hours (1 day), preferably at least 72 hours (3 days), more preferably about 84 hours (3.5 days). After this time, the TTS can be removed and optionally a new TTS can be applied to provide around the clock treatment.

How to obtain

[0251] The present invention further relates to a method for preparing a guanfacine-containing layer, preferably a guanfacine-containing matrix layer, for use in a transdermal therapeutic system.

[0252] According to the present invention, a method for producing a guanfacine-containing layer for use in a transdermal therapeutic system according to the present invention includes the following steps:

1) combining at least the following components:

i) guanfacine; And

ii) at least one silicone polymer; and to obtain a coating composition;

2) applying the coating composition to a substrate or protective coating to obtain an applied coating composition; And

3) drying the applied coating composition to form a guanfacine-containing layer.

[0253] In step 1) of the above production process, guanfacine is preferably dispersed in the polymer to obtain a homogeneous coating composition.

[0254] It should be understood that additional ingredients can also be added in step 1), preferably at least one additional polymer and/or at least one auxiliary substance, as defined above.

[0255] Preferably, the solvent is added in step 1) of the process and/or the solvent 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 selected from non-alcoholic solvents, and most preferably is ethyl acetate or n-heptane.

[0256] According to a preferred embodiment, at least one silicone polymer is provided as a solution with a solids content of 40-60% by weight.

[0257] In step 2) of the process, the coating composition is applied to a substrate or protective coating. The result is an applied coating composition, i. e. a coating composition applied to a substrate or protective coating.

[0258] Thereafter, the guanfacine-containing layer is formed in step 3), the method thus may further comprise a step in which a protective coating or substrate is applied to the other side of the guanfacine-containing layer.

[0259] In step 3) of the above production method, drying is carried out preferably at a temperature of 20-90°C, more preferably 40-70°C. Drying may preferably take at least 1 hour, preferably at least 8 hours, such as one day.

EXAMPLES

[0260] The present invention will now be more fully described with reference to the accompanying examples. However, it should be understood that the following description is illustrative only and should in no way be construed as limiting the present invention. The numerical values given in the examples in relation to the number of ingredients in the composition or the mass of the area may vary slightly due to the variability of the manufacturing process.

EXAMPLE 1A-D

Coating composition

[0261] The compositions of the guanfacine-containing coating compositions according to examples 1a-d are summarized in Tables 1.1a and 1.1b below. Values in % refer to amounts (number) in % by weight.

Preparation of the coating composition

The active pharmaceutical ingredient and the enhancers used were dispersed in an ethyl acetate solvent and sonicated for approximately 10 minutes. Added adhesives. These two steps can also be carried out in reverse order. Using a dissolution stirrer, the mixture was homogenized at 2000 rpm for 2 minutes. Soluplus was added and the mass was stirred for an additional 2 minutes at 2000 rpm and further homogenized at 1500 rpm for at least 30 minutes.

In the case of composition 1b, polyoxyethylene lauryl ether enhancer (4) and Soluplus were dispersed in ethanol solvent and sonicated for 10 minutes. The active pharmaceutical ingredient and oleyl alcohol enhancer were added and the mixture was sonicated for an additional 10 minutes. Added adhesives.

In the case of composition 1d, the active pharmaceutical ingredient and the enhancers used were dispersed in the solvent ethyl acetate and sonicated for 10 minutes. Added adhesives and Soluplus. Using a dissolution stirrer, the mixture was homogenized at 2000 rpm for 2 minutes. The mass was further stirred at 1500 rpm for at least 30 minutes.

Application of the coating composition

[0264] The resulting guanfacine-containing coating composition was applied to a polyethylene terephthalate film (Scotchpak 9755, which can function as a protective coating) using, for example, a film applicator from Erichsen, according to the solids content of the mixture in question with the desired dry weight of the coating and dried at approximately 50°C for approximately 10 minutes. Depending on the target area weight, the appropriate film applicator gap is 150-350 µm.

[0265] The thickness of the coating was chosen such that removal of the solution results in an area weight of the guanfacine-containing layer of approximately 100 (Example 1a), 91 (Example 1b), 106 (Example 1c), 110 (Example 1d) g/m ² . The dried film was then laminated with a substrate (PET, 15 µm, transparent, MN 19) to obtain a guanfacine-containing self-adhesive layer structure.

Get TTS (applies to all examples)

[0266] Separate systems (TTS) were then obtained by stamping from the guanfacine-containing self-adhesive layered structure obtained as described above. Then, the TTS were sealed in bags from the primary packaging material.

Skin permeability measurement

[0267] the Penetrated amount of TTS obtained according to examples 1a-d, was determined using experiments in accordance with the guidelines of the OECD (adopted April 13, 2004) was carried out using a 10.0 ml Franz diffusion cell. Thickness-divided human skin obtained from cosmetic surgery (eg, woman's abdomen, date of birth 1966) was used. A dermatome was used to obtain skin with a thickness of 500 μm with intact epidermis for all TTSs. Sections with a release area of 1.188 cm ² were obtained by stamping from TTS. The permeated amount of guanfacine in the receptor medium of the Franz diffusion cell (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacterial agent) was measured at a temperature of 32±1° C. and the corresponding cumulative permeated amount was calculated.

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

EXAMPLE 2A-B

Coating composition

[0270] The compositions of guanfacine-containing coating compositions according to examples 2a-b are summarized in table 2.1. Values in % refer to amounts in % by weight.

Preparation of the coating composition

[0272] The active pharmaceutical ingredient and the enhancers used were dispersed in the solvent ethyl acetate and sonicated for about 10 minutes. Added adhesives. These two steps can also be carried out in reverse order. Using a dissolution stirrer, the mixture was homogenized at 2000 rpm for 2 minutes. The mass was stirred again for 10 minutes at 1000 rpm.

Application of the coating composition

[0273] See Example 1a-d for the coating process. The coating thickness gave the area weight of the guanfacine-containing layer of 115 (example 2a) and 113 (example 2b) g/m ² . The dried film was laminated with a substrate (eg, siliconized MN 19) to obtain a guanfacine-containing self-adhesive layer structure.

Receiving TTS

[0274] See example 1.

Skin permeability measurement

[0275] the Penetrated amount of TTS obtained according to examples 2a-b was determined as described for examples 1a-d above. Sections with a release area of 1.188 cm ² were obtained by stamping from TTS.

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

EXAMPLE 3A-B

[0278] The compositions of the guanfacine-containing coating compositions according to examples 3a-b are summarized in table 3.1 below. Values in % refer to amounts in % by weight.

Preparation of the coating composition

[0280] The active pharmaceutical ingredient and the enhancers used were dispersed in the solvent ethyl acetate and sonicated for about 10 minutes. Added adhesives. These two steps can also be carried out in reverse order. Using a dissolution stirrer, the mixture was homogenized at 2000 rpm for 2 minutes. Soluplus was added and the mass was stirred for an additional 2 minutes at 2000 rpm and further homogenized at 1500 rpm for 30 minutes.

Application of the coating composition

[0281] See Example 1a-d for the coating process. The coating thickness gave the area weight of the guanfacine-containing layer of 106 (example 3a) and 103 (example 3b) g/m ² . The dried film was laminated with a substrate (eg, siliconized MN 19) to obtain a guanfacine-containing self-adhesive layer structure.

Receiving TTS

[0282] See example 1.

Skin permeability measurement

[0283] the Penetrated amount of TTS obtained according to examples 3a-b was determined as described for examples 1a-d above. Sections with a release area of 1.188 cm ² were obtained by stamping from TTS.

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

EXAMPLE 4A

[0286] The compositions of the guanfacine-containing coating compositions according to Examples 4a are summarized in Table 4.1 below. Values in % refer to amounts in % by weight.

Preparation of the coating composition

[0288] The active pharmaceutical ingredient was dispersed in the solvent n-heptane and sonicated for approximately 45 minutes. Added adhesive. These two steps can also be carried out in reverse order. Using a dissolution stirrer, the mixture was homogenized at 1000 rpm for 15 minutes.

Application of the coating composition

[0289] See Example 1a-d for the coating process. The coating thickness gave the area weight of the guanfacine-containing layer of 100 (example 4a) g/m ² . The dried film was laminated with a substrate (hostaphan, 15 µm) to obtain a guanfacine-containing self-adhesive layered structure.

Receiving TTS

[0290] See example 1.

Skin permeability measurement

[0291] the Penetrated amount of TTS obtained according to examples 4a was determined as described for examples 1a-d above. Sections with a release area of 1.188 cm ² were obtained by stamping from TTS.

[0292] The results are shown in Table 4.2 and in FIG. 10.

COMPARATIVE EXAMPLE 1

[0294] Comparative Example 1 is a 15/85 mixture of Oppanol B10 and Oppanol B100 and guanfacine base. The composition of the guanfacine-containing coating composition according to Comparative Example 1 is summarized in Table 4.1 below. Values in % refer to quantities in % by mass

Preparation of the coating composition

[0296] The active pharmaceutical ingredient was dispersed in the solvent n-heptane and sonicated for 10 minutes. Then the adhesive mixture was added. These two steps can also be carried out in reverse order. Using a dissolution stirrer, the mixture was homogenized at 100-500 rpm for 30 minutes.

Application of the coating composition

[0297] See Example 1a-d for the coating process. The thickness of the coating gave the area weight of the guanfacine-containing layer of 91 g/m ² . The dried film was laminated with a substrate (siliconized MN 19) to obtain a guanfacine-containing self-adhesive layer structure.

Receiving TTS

[0298] See example 1.

Skin permeability measurement

[0299] the Penetrated amount of TTS obtained according to comparative example 1 was determined as described for examples 1a-d above. Sections with a release area of 1.188 cm ² were obtained by stamping from TTS.

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

COMPARATIVE EXAMPLE 2A-B

Coating composition

[0302] The compositions of the guanfacine-containing coating compositions according to Comparative Examples 2a-b are summarized in Table 5.1 below. Values in % refer to amounts in % by weight.

Preparation of the coating composition

[0304] The active pharmaceutical ingredient was dispersed in the solvent ethyl acetate and sonicated for about 5 minutes. Then the adhesives were added. These two steps can also be carried out in reverse order. Using a dissolution stirrer, the mixture was homogenized at 500-800 rpm for about 10 minutes.

In the case of comparative example 2a, the active pharmaceutical ingredient was dispersed directly in the adhesive. The mixture was stirred at 500 rpm for approximately 10 minutes.

Application of the coating composition

[0305] See Example 1a-d for the coating process. For Comparative Example 2b, the coating composition was applied to a 100 µm PET film. The coating thickness gave the area weight of the guanfacine-containing layer of 49 (comparative example 2a) and 50 (comparative example 2b) g/m ² . The dried film was laminated with a substrate (PET, 15 µm, transparent) to obtain a guanfacine-containing self-adhesive layer structure.

Receiving TTS

[0306] See example 1.

Skin permeability measurement

[0307] The permeate amount of TTS obtained according to Comparative Example 2a-b was determined by experiments in accordance with the OECD guidelines (adopted April 13, 2004) was performed using a 10.0 ml Franz diffusion cell. The thickness-divided skin of a Göttingen pygmy pig (female) was used. The dermatome was used to obtain 800 µm thick skin with intact epidermis for all TTSs. Sections with a release area of 1.165 cm ² were obtained by stamping from TTS. The permeated amount of guanfacine in the receptor medium of the Franz diffusion cell (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacterial agent) was measured at a temperature of 32±1° C. and the corresponding cumulative permeated amount was calculated.

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

The present invention relates in particular to the following additional items:

1. A transdermal therapeutic system for transdermal administration of guanfacine, comprising a guanfacine-containing layered structure, said guanfacine-containing layered structure comprising the following:

A) substrate; And

B) guanfacine-containing layer;

wherein the transdermal therapeutic system comprises at least one silicone polymer.

2. Transdermal therapeutic system according to claim 1,

where the guanfacine-containing layer is a guanfacine-containing matrix layer containing the following:

i) guanfacine; And

ii) at least one silicone polymer.

3. Transdermal therapeutic system according to any one of paragraphs. 1 or 2, where the guanfacine-containing layer structure is self-adhesive and preferably does not contain an additional skin contact layer.

4. Transdermal therapeutic system according to any one of paragraphs. 1-3, wherein at least one silicone polymer is a silicone pressure sensitive adhesive.

5. Transdermal therapeutic system according to any one of paragraphs. 1-4, where the guanfacine-containing layered structure contains a therapeutically effective amount of guanfacine.

6. Transdermal therapeutic system according to any one of paragraphs. 1-5, where the guanfacine in the guanfacine-containing layer structure is present in the form of a free base, which is preferably dispersed in the guanfacine-containing layer.

7. Transdermal therapeutic system according to any one of paragraphs. 1-6, where the guanfacine-containing layered structure contains guanfacine in an amount of 1-100 mg/TTS, preferably 8-72 mg/TTS.

8. Transdermal therapeutic system according to any one of paragraphs. 1-7, where the guanfacine-containing layer contains guanfacine in an amount of 1-20%, more preferably 3-16% by weight, based on the total weight of the guanfacine-containing layer.

9. Transdermal therapeutic system according to any one of paragraphs. 1-8, where the guanfacine-containing layer contains at least one silicone polymer in an amount of 20-99%, preferably 30-97%, most preferably 35-90% by weight, based on the total weight of the guanfacine-containing layer.

10. Transdermal therapeutic system according to any one of paragraphs. 1-9, wherein at least one silicone polymer can be obtained by polycondensation of a silanol-terminated polydimethylsiloxane and a silicate resin.

11. The transdermal therapeutic system of claim 10 wherein the residual silanol functionality of at least one silicone polymer is blocked with trimethylsiloxy groups.

12. Transdermal therapeutic system according to any one of paragraphs. 1-11, where the guanfacine-containing layer contains at least one additional polymer selected from the group consisting of the following: acrylate polymers, silicone-acrylic hybrid polymers, polyisobutylenes and styrene-isoprene-styrene block copolymers, preferably selected from the group, consisting of acrylate polymers and silicone-acrylic hybrid polymers.

13. Transdermal therapeutic system according to any one of paragraphs. 1-12, where the guanfacine-containing layer contains a first polymer, which is a silicone polymer, in an amount of 35-70% by weight, and a second polymer, which is selected from the group consisting of the following: silicone polymers, acrylate polymers and silicone-acrylic hybrid polymers, in an amount of 15-45% by weight, in each case based on the total weight of the guanfacine-containing layer.

14. Transdermal therapeutic system according to any one of paragraphs. 12 or 13, where the acrylate polymer can be obtained from one or more monomers selected from the following: acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, t-octylacrylamide and vinyl acetate, preferably from one or more monomers selected from ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate and vinyl acetate.

15. Transdermal therapeutic system according to any one of paragraphs. 12-14, where the silicone-acrylic hybrid polymer contains a silicone phase and an acrylate phase in a weight ratio of 60:40 to 40:60

16. Transdermal therapeutic system according to any one of paragraphs. 12-15, wherein 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 crosslinked to itself and covalently bonded to the silicone polymer and/or silicone resin.

17. Transdermal therapeutic system according to any one of paragraphs. 12-15, where the silicone-acrylic hybrid polymer is a silicone-acrylic hybrid pressure-sensitive adhesive obtained from the following:

(a) a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group.

18. Transdermal therapeutic system according to any one of paragraphs. 12-15 or 17, wherein the silicone-acrylic hybrid polymer is a silicone-acrylic hybrid pressure-sensitive adhesive containing the reaction product of the following:

(a) a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group;

(b) an ethylenically unsaturated monomer; And

(c) initiator.

19. Transdermal therapeutic system according to any one of paragraphs. 17 or 18, wherein the silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group contains a condensation reaction product of the following:

(a1) silicone resin, and

(a2) silicone polymer, and

(a3) a silicon-containing blocking agent containing an acrylate or methacrylate functional group.

20. Transdermal therapeutic system according to any one of paragraphs. 17-19, wherein the silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group contains a condensation reaction product of the following:

(a1) silicone resin, and

(a2) silicone polymer, and

(a3) a silicon-containing blocking agent containing an acrylate or methacrylate functional group, where the specified silicon-containing blocking agent is characterized by the General formula XYR' _b SiZ _3-b where X represents a monovalent radical according to the General formula AE, where E represents - O- or -NH-, and A is an acrylic group or a methacrylic group, Y is a divalent alkylene radical characterized by 1-6 carbon atoms, R' is a methyl or phenyl radical, Z is a monovalent hydrolyzable organic radical or halogen, and b is 0 or 1;

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

and where the silicon-containing blocking agent reacts with the pressure-sensitive adhesive after the silicone resin and the silicone polymer undergo a condensation reaction to form the pressure-sensitive adhesive, or the silicon-containing blocking agent reacts in situ with the silicone resin and the silicone polymer.

21. Transdermal therapeutic system according to any one of paragraphs. 18-20, where the ethylenically unsaturated monomer is selected from the group consisting of the following: aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates, cycloaliphatic methacrylates, and combinations thereof, each of these compounds containing up to 20 carbon atoms in the alkyl radical, and where the ethylenically unsaturated monomer represents is preferably a combination of 2-ethylhexyl acrylate and methyl acrylate, particularly preferably in a ratio of 40:60 to 70:30.

22. Transdermal therapeutic system according to any one of paragraphs. 18-21, where the reaction product of the following:

(a) a silicon-containing pressure-sensitive adhesive composition containing an acrylate or methacrylate functional group;

(b) an ethylenically unsaturated monomer; And

(c) initiator,

contains a continuous acrylic outer phase and a discrete silicone inner phase.

23. Transdermal therapeutic system according to any one of paragraphs. 1-22, where the guanfacine-containing layer further comprises at least one auxiliary substance selected from the group consisting of dispersing agents, penetration enhancers and solubilizers, or at least two auxiliary substances selected from the group consisting of dispersing agents, enhancers solubilizers, preferably so that a combination of a dispersing agent and a penetration enhancer, or a combination of a dispersing agent and a solubilizer, or a combination of a penetration enhancer and a solubilizer, or at least three adjuvants selected from the group consisting of dispersing agents, penetration enhancers and solubilizers, preferably such that a combination of a dispersing agent, a penetration enhancer and a solubilizer is present.

24. The transdermal therapeutic system of claim 23, wherein the dispersing agent is selected from the group consisting of the following: fatty acid esters of polyhydric alcohols, fatty alcohols, polyethylene glycols having a number average molecular weight of 300-400, polyethylene glycol alkyl ethers, and wherein the dispersing agent the agent is preferably a C ₈ -C ₂₀ alkyl ether of polyethylene glycol, characterized by 2-10 EO units.

25. The transdermal therapeutic system of claim 23 or 24 wherein the penetration enhancer is selected from the group consisting of the following: diethylene glycol monoethyl ether (transcutol), oleic acid, levulinic acid, caprylic/capric acid triglycerides, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, triacetin, dimethylpropylene urea and oleyl alcohol, and is preferably oleyl alcohol.

26. Transdermal therapeutic system according to any one of paragraphs. 23-25, where the solubilizer is selected from the group consisting of the following: copolymers derived from esters of acrylic and methacrylic acid, polyvinylpyrrolidone, copolymers of vinylpyrrolidone-vinyl acetate and graft copolymers of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol, and is preferably a graft copolymer of polyvinylcaprolactam-polyvinyl acetate- polyethylene glycol.

27. Transdermal therapeutic system according to any one of paragraphs. 23-26, where at least one auxiliary substance is present in an amount of 0.5-10% by weight or 1-10% by weight, based on the total weight of the guanfacine-containing layer.

28. Transdermal therapeutic system according to any one of paragraphs. 1-27, where the release area is in the range from 1 to 100 cm ² , preferably from 2.5 to 50 cm ² ; and/or where the area weight of the guanfacine-containing layer is in the range from 40 to 250 g/m ² , preferably from 50 to 150 g/m ² .

29. Transdermal therapeutic system according to any one of paragraphs. 1-28, wherein the guanfacine loading of the transdermal therapeutic system is in the range of 0.2 to 2.4 mg/cm ² , preferably 0.2 to 1.5 mg/cm ² .

30. Transdermal therapeutic system according to any one of paragraphs. 1-29, wherein the transdermal therapeutic system provides, via steady state transdermal delivery, an average plasma concentration of guanfacine of 1-20 ng/mL, preferably 1-15 ng/mL.

31. Transdermal therapeutic system according to any one of paragraphs. 1-30, providing a percutaneous penetration rate of guanfacine, as measured in a Franz diffusion cell using dermatotomized human skin, of:

0.01 mcg / (cm ² * h) - 8 mcg / (cm ² * h) in the first 24 hours,

0.05 mcg / (cm ² * h) - 10 mcg / (cm ² * h) from 24 to 72 hours.

32. Transdermal therapeutic system according to any one of paragraphs. 1-31 providing a cumulative penetrating amount of guanfacine, as measured in a Franz diffusion cell using dermatotomized human skin, of 0.05 mg/cm ² - 0.7 mg/cm ² , preferably 0.1-0.6 mg/cm ² over a period of 72 hours.

33. Transdermal therapeutic system according to any one of paragraphs. 1-32 for use in a method of treating a human patient, preferably a human patient aged 6-17 years.

34. Transdermal therapeutic system according to any one of paragraphs. 1-32 for use in a method of treating hypertension or attention deficit hyperactivity disorder (ADHD) and/or as adjunctive therapy to stimulant drugs in a human patient, preferably a human patient aged 6-17 years.

35. Transdermal therapeutic system for use according to any one of paragraphs. 33 or 34, wherein the transdermal therapeutic system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, more preferably about 84 hours.

36. A method of treating a human patient, preferably a human patient aged 6-17 years, by applying a transdermal therapeutic system, as defined in one of paragraphs. 1-32, on the patient's skin.

37. A method of treating hypertension or attention deficit hyperactivity disorder (ADHD) in a human patient, preferably a human patient aged 6-17 years, by applying a transdermal therapeutic system, as defined in one of paragraphs. 1-32, on the patient's skin.

38. A method of treating a human patient according to any one of paragraphs. 36 or 37, wherein the transdermal therapeutic system is applied to the patient's skin for at least 24 hours, preferably at least 72 hours, more preferably about 84 hours.

39. A method of obtaining a guanfacine-containing layer for use in a transdermal therapeutic system according to any one of paragraphs. 1-32, which includes the following steps:

1) combining at least the following components:

i) guanfacine;

ii) at least one silicone polymer; and to obtain a coating composition;

2) applying the coating composition to a substrate or protective coating to obtain an applied coating composition; And

3) drying the applied coating composition to form a guanfacine-containing layer.

40. A method for producing a guanfacine-containing layer according to claim 39, wherein the silicone polymer is provided as a solution, wherein the solvent is ethyl acetate or n-heptane.

41. Transdermal therapeutic system obtained using the method according to one of paragraphs. 40 or 41.

42. A transdermal therapeutic system for transdermal administration of guanfacine, comprising a guanfacine-containing layered structure, said guanfacine-containing layered structure comprising the following:

A) substrate; And

B) a guanfacine-containing layer, preferably a guanfacine-containing matrix layer, containing the following:

i) guanfacine in an amount of 3-13% by weight, based on the total weight of the guanfacine-containing layer;

ii) at least one silicone polymer in an amount of 35-90% by weight, based on the total weight of the guanfacine-containing layer;

iii) at least one dispersing agent in an amount of 2-6% by weight, based on the total weight of the guanfacine-containing layer;

iv) at least one penetration enhancer in an amount of 2-10% by weight, based on the total weight of the guanfacine-containing layer; And

v) optionally at least one solubilizer in an amount of 0.5-4% by weight, based on the total weight of the guanfacine-containing layer.

43. The transdermal therapeutic system of claim 42, wherein the guanfacine-containing layer is a guanfacine-containing matrix layer that contains the following:

i) guanfacine in an amount of 3-13% by weight, based on the total weight of the guanfacine-containing layer;

ii) at least one silicone polymer in an amount of 35-90% by weight, based on the total weight of the guanfacine-containing layer;

iii) C ₈ -C ₂₀ polyethylene glycol alkyl ether having 2-10 EO units, in an amount of 2-6% by weight based on the total weight of the guanfacine-containing layer;

iv) oleyl alcohol in an amount of 2-10% by weight, based on the total weight of the guanfacine-containing layer; And

v) optionally a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in an amount of 0.5-4% by weight, based on the total weight of the guanfacine-containing layer.

44. The transdermal therapeutic system according to claim 42 or 43, wherein the guanfacine-containing layer is a guanfacine-containing matrix layer that contains the following:

i) guanfacine in an amount of 3-13% by weight, based on the total weight of the guanfacine-containing layer;

ii) a first silicone polymer in an amount of 50-70% by weight, based on the total weight of the guanfacine-containing layer, and a second silicone polymer in an amount of 15-25% by weight, based on the total weight of the guanfacine-containing layer;

iii) C ₈ -C ₂₀ polyethylene glycol alkyl ether having 2-10 EO units, preferably polyoxyethylene lauryl ether (4), in an amount of 3-5% by weight based on the total weight of the guanfacine-containing layer;

iv) oleyl alcohol in an amount of 5-9% by weight, based on the total weight of the guanfacine-containing layer; And

v) optionally a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in an amount of 0.5-3% by weight, based on the total weight of the guanfacine-containing layer.

45. Transdermal therapeutic system according to any one of paragraphs. 42-44, where the area weight of the guanfacine-containing layer is in the range from 80 to 120 g/m ² , preferably from 90 to 120 g/m ² .

Claims (33)

1. A transdermal therapeutic system (TTS) for transdermal administration of guanfacine, comprising a guanfacine-containing layered structure, said guanfacine-containing layered structure comprising: A) substrate; And B) guanfacine-containing layer; moreover, the transdermal therapeutic system contains at least one silicone polymer; where guanfacine-containing layer contains at least one silicone polymer in the amount of 30 to 97%; and where the guanfacine-containing layer additionally contains at least two auxiliary substances selected from the group consisting of dispersing agents, penetration enhancers and solubilizers, where each of at least two auxiliary substances is present in an amount of 0.5 - 10% by weight in calculated on the total weight of the guanfacine-containing layer. 2. Transdermal therapeutic system according to claim 1, where the guanfacine-containing layer is a guanfacine-containing matrix layer containing: i) guanfacine; And ii) at least one silicone polymer. 3. Transdermal therapeutic system according to any one of paragraphs. 1 or 2, wherein the guanfacine-containing layer structure is self-adhesive and preferably does not contain an additional skin contact layer. 4. Transdermal therapeutic system according to any one of paragraphs. 13, where the guanfacine in the guanfacine-containing layer structure is in the form of a free base, which is preferably dispersed in the guanfacine-containing layer, and/or where guanfacine-containing layered structure contains guanfacine in the amount of 1-75 mg/TTS, preferably 3-30 mg/TTS. 5. Transdermal therapeutic system according to any one of paragraphs. 14, where the guanfacine-containing layer contains guanfacine in an amount of 1-20%, more preferably 3-16% by weight, based on the total weight of the guanfacine-containing layer. 6. Transdermal therapeutic system according to any one of paragraphs. 15, where the guanfacine-containing layer contains at least one silicone polymer in an amount of 35 to 90% by weight, based on the total weight of the guanfacine-containing layer. 7. Transdermal therapeutic system according to any one of paragraphs. 16, where at least one silicone polymer can be obtained by polycondensation polydimethylsiloxane with a blocked terminal silanol group and a silicate resin. 8. Transdermal therapeutic system according to any one of paragraphs. 1 - 7, where the guanfacine-containing layer contains a first polymer, which is a silicone polymer in an amount of 35 - 70% by weight, and a second polymer, which is selected from the group consisting of: silicone polymers, acrylate polymers and silicone-acrylic hybrid polymers in an amount of 15 - 45% by weight, in each case based on the total weight of the guanfacine-containing layer. 9. Transdermal therapeutic system according to any one of paragraphs. 1-8, wherein the dispersing agent is selected from the group consisting of: fatty acid esters with polyhydric alcohols, fatty alcohols, polyethylene glycols having a number average molecular weight of 300-400, polyethylene glycol alkyl ethers, and wherein the dispersing agent is preferably a C8-C20 alkyl ether polyethylene glycol, characterized by 2 to 10 EO units. 10. Transdermal therapeutic system according to any one of paragraphs. 1-9, wherein the penetration enhancer is selected from the group consisting of: diethylene glycol monoethyl ether (transcutol), oleic acid, levulinic acid, caprylic/capric acid triglycerides, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, triacetin, dimethylpropylene urea and oleyl alcohol, and preferably is oleyl alcohol. 11. Transdermal therapeutic system according to any one of paragraphs. 1 to 10 wherein the solubilizer is selected from the group consisting of: copolymers derived from esters of acrylic and methacrylic acid, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, and is preferably a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer . 12. Transdermal therapeutic system according to any one of paragraphs. 1 - 11, where each of at least two auxiliary substances is present in an amount of 1 - 10% by weight, based on the total weight of the guanfacine-containing layer. 13. Transdermal therapeutic system according to any one of paragraphs. 1 - 12, where the area weight of the guanfacine-containing layer is in the range from 40 to 250 g/m ² , preferably from 50 to 150 g/m ² ; and/or where the release area is in the range from 1 to 100 cm ² , preferably from 2.5 to 50 cm ² . 14. The use of a transdermal therapeutic system according to any one of paragraphs. 1-13 in a method of treating a human patient aged 6-17 years. 15. The use of a transdermal therapeutic system according to any one of paragraphs. 1-13 in a method for the treatment of hypertension or attention deficit hyperactivity disorder (ADHD) and/or as adjunctive therapy to stimulant drugs in a human patient aged 6 to 17 years. 16. Application according to any one of paragraphs. 14 or 15, wherein the transdermal therapeutic system is applied to the patient's skin for at least 24 hours, or at least 72 hours, or about 84 hours.

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