Transdermal therapeutic system for transdermal administration of selexipag

Abstract

The present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of selexipag.

Description

[Technical field]

[0001] The present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of selexipag, its manufacturing process and use. [Background technology]

[0002] The active ingredient selexipag (also known as 2-[4-[(5,6-diphenylpyrazin-2-yl)-propan-2-ylamino]butoxy]-N-methylsulfonylacetamide or CAS number 475086-01-2) is a drug used, for example, to treat pulmonary arterial hypertension (PAH). Selexipag and its active metabolite ACT-333679 (also known as MRE-269) bind to prostacyclin receptors, which leads to vasodilation in the pulmonary circulation. Selexipag (left) and its active metabolite ACT-333679 in its free base form (free carboxylic acid) (right) have the following chemical formula: [ka]

[0003] Selexipag can be used to treat pulmonary arterial hypertension (PAH).

[0004] So far, selexipag can be administered via the oral route or via the intravenous route. However, there is currently no commercially available TTS for transdermal administration of selexipag.

[0005] One challenge in developing a TTS for transdermal administration of selexipag is the permeation of selexipag through the skin. This challenge was addressed in US2019 / 0099383A1 by developing a patch containing ACT-333679 in its free base form. Skin permeability was achieved with a composition containing ACT-333679. However, this composition does not contain selexipag. In addition, the provision of an ACT-333679-containing patch is not exemplified.

[0006] Against this background, there is a need in the art for a TTS for the transdermal administration of selexipag. Summary of the Invention

[0007] It is an object of certain embodiments of the present invention to provide a TTS for the transdermal administration of selexipag.

[0008] It is a further object of certain embodiments of the present invention to provide a TTS for transdermal delivery of selexipag, the TTS having a simple structure, e.g., comprising less than 15, less than 10, or less than 6 components for said transdermal delivery.

[0009] It is a further object of certain embodiments of the present invention to provide a TTS for transdermal delivery of selexipag, which can be produced with consistent quality.

[0010] It is a further object of certain embodiments of the present invention to provide a TTS for transdermal administration of selexipag that provides a permeation rate sufficient to achieve a therapeutically effective dose over an extended administration period, such as over 48 hours, or over 72 hours, or over 84 hours, or over 168 hours, preferably over 168 hours.

[0011] It is a further object of certain embodiments of the present invention to provide a TTS for transdermal administration of selexipag that provides improved permeation rates over an extended administration period, such as, for example, over 48 hours, or over 72 hours, or over 84 hours, or over 168 hours, preferably over 168 hours.

[0012] It is a further object of the present invention to provide a TTS for transdermal administration of selexipag having high active agent utilization, i.e., a TTS, which does not require a high excess amount of active agent to provide sufficient release performance during the administration period.

[0013] It is a further object of certain embodiments of the present invention to provide a TTS for transdermal administration of selexipag, which is suitable for use in methods of treating human patients.

[0014] It is an object of certain embodiments of the present invention to provide a TTS for transdermal administration of selexipag, which TTS is easy to manufacture.

[0015] At least one of these and other objects is achieved by the present invention, which, according to a first aspect, is directed to a transdermal therapeutic system for the transdermal administration of selexipag comprising a self-adhesive selexipag-containing layer structure, said self-adhesive selexipag-containing layer structure comprising: A) a lining layer; B) a selexipag-containing layer, 1. Selexipag, 2. At least one polarity, and 3. A selexipag-containing layer comprising at least one non-polar polymer.

[0016] According to a second aspect, the present invention is directed to a transdermal therapeutic system according to the first aspect for use in a method of treating a human patient.

[0017] definition Within the meaning of the present invention, the term "transdermal therapeutic system" (TTS) refers to a system in which an active agent (e.g., selexipag) is administered to the systemic circulation via transdermal delivery, and refers to the entire individual dosage unit that is applied to the patient's skin after removing an optional release liner, and contains a therapeutically effective amount of active agent in an active agent-containing layer structure and optionally an additional adhesive overlay that overlays the active agent-containing layer structure. The active agent-containing layer structure may be disposed on a release liner (a removable protective layer), and thus the TTS may further include a release liner. Within the meaning of the present invention, the term "TTS" refers in particular to a system that provides transdermal delivery, excluding, for example, active agent delivery via iontophoresis or microporation. A transdermal therapeutic system may also be referred to as a transdermal drug delivery system (TDDS) or a transdermal delivery system (TDS).

[0018] Within the meaning of the present invention, the term "selexipag-containing layer structure" refers to a layer structure containing a therapeutically effective amount of selexipag, which includes a backing layer and at least one active agent-containing layer. Preferably, the selexipag-containing layer structure is a selexipag-containing self-adhesive layer structure.

[0019] Within the meaning of the present invention, the term "therapeutically effective amount" refers to the amount of active agent in the TTS that is sufficient to provide symptomatic treatment of, for example, pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) when administered to a patient by the TTS. The TTS usually contains more active agent in the system than is actually provided to the skin and systemic circulation. This excess amount of active agent is usually necessary to provide sufficient driving force for delivery from the TTS to the systemic circulation. It should be understood that the selexipag-containing layer according to the present invention contains a therapeutically effective amount of selexipag.

[0020] Within the meaning of the present invention, terms such as "active substance" and "active agent", as well as the term "selexipag", refer to selexipag in any pharma- ceutically acceptable chemical and morphological form and physical state. These forms include, but are not limited to, cocrystals, solvates, hydrates, clathrates, and the like, as well as selexipag in the form of particles that may be micronized, crystalline, and / or amorphous, and any mixture of the aforementioned forms. When selexipag is contained in a medium such as a solvent, it may be dissolved or dispersed, or may be partially dissolved and partially dispersed.

[0021] Within the meaning of the present invention, the term "selexipag" refers to selexipag in any pharma- ceutically acceptable chemical and morphological form and physical state.

[0022] Unless otherwise indicated, the amount of selexipag in the layer structure is calculated based on selexipag with respect to the amount of selexipag included in the TTS during manufacture of the TTS. For example, if 0.1 mmol (equivalent to 49.7 mg) of selexipag is included in the TTS during manufacture, the amount of selexipag in the layer structure is 0.1 mmol or 49.7 mg within the meaning of the present invention.

[0023] The selexipag starting material included in the TTS during manufacture of the TTS may be in particulate form. Selexipag may be present, for example, in particulate form and / or dissolved in the active agent-containing layer structure.

[0024] Within the meaning of the present invention, the term "particle" refers to a solid particulate material comprising individual particles, the dimensions of which are negligible compared to the material. In particular, particles are solids and include plastic / deformable solids, including amorphous and crystalline materials.

[0025] Within the meaning of the present invention, the term "dispersing" refers to a step or combination of steps in which the starting material (e.g., selexipag) is not completely dissolved. Dispersion within the meaning of the present invention includes dissolution of a portion of the starting material (e.g., selexipag particles), depending on the solubility of the starting material (e.g., the solubility of selexipag in the coating composition).

[0026] There are two main types of TTS for active agent delivery: matrix-type TTS and reservoir-type TTS. The release of the active agent in matrix-type TTS is mainly controlled by the matrix containing the active agent itself. In contrast, reservoir-type TTS typically requires a rate-controlling membrane to control the release of the active agent. In principle, matrix-type TTS may also contain a rate-controlling membrane. However, compared to reservoir-type TTS, matrix-type TTS has the advantage that a rate-determining membrane is usually not required and dose dumping due to membrane rupture cannot occur. In summary, matrix-type transdermal therapeutic systems (TTS) are less complicated and easier to manufacture and more convenient for patients to use.

[0027] Within the meaning of the present invention, a "matrix-type TTS" refers to a system or structure in which the active agent is homogeneously dissolved and / or dispersed in a polymer carrier, i.e., a matrix, forming a matrix layer together with the active agent and optionally remaining ingredients. In such a system, the matrix layer controls the release of the active agent from the TTS. Preferably, the matrix layer has sufficient cohesion to be self-supporting so that sealing between other layers is not required. Thus, the active agent-containing layer may in one embodiment of the present invention be an active agent-containing matrix layer in which the active agent is homogeneously distributed in the polymer matrix. In certain embodiments, the active agent-containing matrix layer may comprise two active agent-containing matrix layers that may be laminated together. A matrix-type TTS may in particular be in the form of a "drug-in-adhesive" type TTS, which refers to a system in which the active agent is homogeneously dissolved and / or dispersed in a pressure-sensitive adhesive matrix. In this context, the active agent-containing matrix layer may also be referred to as an active agent-containing pressure-sensitive adhesive layer or an active agent-containing pressure-sensitive adhesive matrix layer. A TTS comprising an active agent dissolved and / or dispersed in a polymer gel, e.g., a hydrogel, is also considered to be of matrix type according to the present invention.

[0028] A TTS having a liquid active agent-containing reservoir is referred to by the term "reservoir-type TTS". In such a system, the release of the active agent is preferably controlled by a rate-controlling membrane. In particular, the reservoir is sealed between a backing layer and a rate-controlling membrane. Thus, the active agent-containing layer may in one embodiment be an active agent-containing reservoir layer, which preferably contains a liquid or semi-liquid reservoir containing the active agent. Furthermore, a reservoir-type TTS typically additionally contains a skin contact layer, and the reservoir layer and the skin contact layer may be separated by a rate-controlling membrane. In the reservoir layer, the active agent is preferably dissolved in a solvent such as ethanol or water or silicone oil. The skin contact layer typically has adhesive properties.

[0029] Reservoir-type TTS is not to be understood as matrix-type within the meaning of the present invention. However, microreservoir TTS (two-phase systems with deposits (e.g., spheres, droplets) of an active substance-containing internal phase dispersed in a polymeric external phase) that are considered in the art to be mixed forms of matrix-type TTS and reservoir-type TTS, which differ in the concept of drug transport and drug delivery from homogeneous single-phase matrix-type TTS and reservoir-type TTS, are considered to be matrix-type within the meaning of the present invention. The size of the microreservoir droplets can be determined by optical microscopy measurements (e.g., by Leica MZ16 with camera, e.g., Leica DSC320) by taking pictures of the microreservoir at different positions with an enhancement factor of 10 to 400 times, depending on the required detection limit. By using image analysis software, the size of the microreservoir can be determined.

[0030] Within the meaning of the present invention, the term "selexipag-containing layer" refers to a layer that contains selexipag and provides a release area. This term encompasses a selexipag-containing matrix layer and a selexipag-containing reservoir layer. When the selexipag-containing layer is a selexipag-containing matrix layer, the layer is present in a matrix-type TTS. When the polymer is a pressure-sensitive adhesive, the matrix layer can also represent the adhesive layer of the TTS, such that there is no additional skin contact layer. Alternatively, the additional skin contact layer can be present as an adhesive layer and / or an adhesive overlay is provided. The additional skin contact layer is typically manufactured to be free of selexipag. However, due to a concentration gradient, selexipag will migrate from the matrix layer to the additional skin contact layer over time until equilibrium is reached. The additional skin contact layer may be present on the selexipag-containing matrix layer or may be separated from the selexipag-containing matrix layer by a membrane, preferably a rate-controlling membrane. Preferably, the selexipag-containing matrix layer has sufficient adhesive properties so that there is no additional skin contact layer. When the selexipag-containing layer is a selexipag-containing reservoir layer, it is present in a reservoir-type TTS, and this layer contains selexipag in a liquid reservoir. In addition, there is preferably an additional skin contact layer to provide adhesive properties. Preferably, a rate-controlling membrane separates the reservoir layer from the additional skin contact layer. The additional skin contact layer can be manufactured to be selexipag-free or to contain selexipag. If the additional skin contact layer does not contain an active agent, the active agent will migrate from the reservoir layer to the skin contact layer over time due to concentration gradient until equilibrium is reached. In addition, an adhesive overlay may be provided.

[0031] As used herein, the selexipag-containing layer is preferably a selexipag-containing matrix layer, which is referred to as the final solidified layer. Preferably, the selexipag-containing matrix layer is obtained after coating and drying a solvent-containing coating composition as described herein. Alternatively, the selexipag-containing matrix layer is obtained after melt-coating and cooling. The selexipag-containing matrix layer can also be produced by laminating two or more such solidified layers (e.g., dried or cooled layers) of the same composition to provide the desired areal weight. The matrix layer can be self-adhesive (in the form of a pressure-sensitive adhesive matrix layer) or the TTS can include an additional skin-contact layer of pressure-sensitive adhesive to provide sufficient tack. Preferably, the matrix layer is a pressure-sensitive adhesive matrix layer. Optionally, an adhesive overlay may be present.

[0032] Within the meaning of the present invention, the term "pressure-sensitive adhesive" (also abbreviated as "PSA") refers to a material that should adhere, especially with finger pressure, be permanently tacky, exert a strong holding force, and be removable from a smooth surface without leaving a residue. When in contact with the skin, the pressure-sensitive adhesive layer is "self-adhesive", in other words it provides adhesion to the skin so that no further assistance is usually required for fixing to the skin. The "self-adhesive" layer structure comprises a pressure-sensitive adhesive layer for skin contact, i.e. a pressure-sensitive adhesive skin contact layer, which may be provided in the form of a pressure-sensitive adhesive matrix layer or in the form of an additional layer. An adhesive overlay may still be employed to improve the adhesive force. The pressure-sensitive adhesive properties of the pressure-sensitive adhesive depend on the polymer or polymer composition used (for example a mixture of silicone and acrylic polymers, or a combination of a polyisobutylene mixture and polyvinylpyrrolidone). In particular, the pressure-sensitive adhesive according to the present invention may comprise at least one polyvinylpyrrolidone and at least one non-polar polymer.

[0033] Within the meaning of the present invention, the term "polymer" refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, including homopolymers consisting of one type of monomer, and copolymers consisting of two or more types of monomers. Polymers can be of any structure, such as linear polymers, star polymers, comb polymers, brush polymers, and in the case of copolymers, of any monomer sequence, for example, alternating, statistical, block copolymers, or graft polymers. The minimum molecular weight varies depending on the type of polymer and is known to those skilled in the art. Polymers can have, for example, a molecular weight of more than 2000 Daltons, preferably more than 5000 Daltons, and more preferably more than 10,000 Daltons. Correspondingly, compounds with a molecular weight of less than 2000 Daltons, preferably less than 5000 Daltons, or more preferably less than 10,000 Daltons are usually referred to as oligomers.

[0034] Within the meaning of the present invention, the term "polar polymers" is preferably used for those polymers that are soluble in water or swollen by water. Polar polymers are preferably essentially composed of monomer units that contain polar functional groups, such as hydroxyl, carbonyl, carboxyl, amino, quaternary ammonium, sulfhydryl, phosphate, sulfate and certain carboxylates, which are polar. The term polar polymers encompasses polar acrylic polymers and polyvinylpyrrolidones.

[0035] Within the meaning of the present invention, the term "non-polar polymers" is used for those polymers that are neither soluble in water nor swollen by water. Non-polar polymers are essentially composed of monomers that are non-polar. Non-polar polymers include materials such as polyethylene, polyisobutylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene or polysiloxane.

[0036] Within the meaning of the present invention, the term "skin contact layer" refers to a layer included in the active agent-containing layer structure that is in direct contact with the patient's skin during administration. This may be the active agent-containing layer. If the TTS includes an additional skin contact layer, the other layer of the active agent-containing layer structure does not contact the skin and does not necessarily have self-adhesive properties. As outlined above, the additional skin contact layer bonded to the active agent-containing layer may absorb part of the active agent over time. The additional skin contact layer may be used to enhance adhesion. The size of the additional skin contact layer and the active agent-containing layer are usually coextensive and correspond to the release area. However, the area of ​​the additional skin contact layer may also be larger than the area of ​​the active agent-containing layer. In such cases, the release area still refers to the area of ​​the active agent-containing layer.

[0037] Within the meaning of the present invention, the term "area weight" refers to the dry weight of a particular layer, e.g., the matrix layer, and is expressed in g / m 2 Due to manufacturing variations, area weight values ​​require a tolerance of ±10%, preferably ±7.5%.

[0038] Unless otherwise indicated, "%" refers to % by weight.

[0039] Within the meaning of the present invention, the term "crosslinker" refers to a substance capable of crosslinking functional groups contained within a polymer.

[0040] Within the meaning of the present invention, the term "adhesive overlay" refers to a self-adhesive layer structure that does not contain an active agent, has a larger area than the active agent-containing structure, and provides an additional area for adhesion to the skin, but does not provide an area for release of the active agent, thereby improving the overall adhesive properties of the TTS. The adhesive overlay comprises a backing layer, which may provide occlusive or non-occlusive properties, and an adhesive layer. Preferably, the backing layer of the adhesive overlay provides non-occlusive properties.

[0041] Within the meaning of the present invention, the term "backing layer" refers to a layer that supports an active agent-containing layer or forms the backing of an adhesive overlay. At least one backing layer in a TTS, and usually the backing layer of an active agent-containing layer, is substantially impermeable to the active agent contained therein during storage and administration, thus preventing activity loss or cross-contamination in accordance with regulatory requirements. Preferably, the backing layer is also occlusive, meaning that it is substantially impermeable to water and water vapor. Suitable materials for the backing layer include polyethylene terephthalate (PET), polyethylene (PE), ethylene vinyl acetate-copolymer (EVA), polyurethane, and mixtures thereof. Thus, suitable backing layers are, for example, PET laminates, EVA-PET laminates and PE-PET laminates. Woven or nonwoven backing layers are also suitable.

[0042] The TTS according to the present invention may be characterized by certain parameters measured in an in vitro skin permeation test.

[0043] Unless otherwise indicated, in vitro permeation studies are performed in Franz diffusion cells with explanted split-thickness human skin with a thickness of 500 μm and intact epidermis, using an aqueous buffer solution (32° C.) containing 0.9% aqueous sodium chloride, 3% vanillin, 0.5% methyl-β-cyclodextrin, 30% acetonitrile as the receiving medium.

[0044] The amount of active substance permeated into the receiving medium is determined at regular intervals using a validated HPLC method with a UV photometric detector by taking a sample volume, which is completely or partially replaced with fresh medium when taking the sample volume, and the measured amount of active substance permeated relates to the amount permeated between the last two sampling times and not to the total amount permeated up to that point.

[0045] Therefore, within the meaning of the present invention, the parameter "permeation amount" is defined as μg / cm 2and relates to the amount of active substance permeated at a particular time interval. For example, in the in vitro permeation test described above, the amount of active substance permeated into the receiving medium is measured at, for example, 0, 8, 24, 36, 48, 72, 104, 144 and 168 hours, and the "permeation amount" of active substance can be obtained for, for example, a sample interval of 36 to 48 hours, corresponding to the measurement result at 48 hours, and the receiving medium is completely replaced at 36 hours.

[0046] The permeation amount can also be given as a "cumulative permeation amount" corresponding to the cumulative amount of active substance permeated at a certain time point. For example, in the above in vitro permeation test, the amount of active substance permeated into the receiving medium is measured at, for example, 0, 3, 6, 8, 24 and 32 hours, and the "cumulative permeation amount" of the active substance at 32 hours corresponds to the sum of the permeation amounts from 0 to 3 hours, 3 to 6 hours, 6 to 8 hours, 8 to 24 hours and 24 to 32 hours.

[0047] Within the meaning of the present invention, the parameter "skin permeation rate" at a specific sample interval at a specific time is expressed as μg / cm 2 - μg / cm at the sample interval provided at time and measured by the in vitro permeation test described above 2 The "skin permeation rate" is calculated by dividing the amount of permeation at the sample interval by the time of the sample interval. For example, in the above in vitro permeation test, the amount of active substance permeated into the receiving medium is measured at, for example, 0, 8, 24, 36, 48, 72, 104, 144 and 168 hours, and the "skin permeation rate" at 48 hours is calculated as the amount of permeation at the sample interval from 36 hours to 48 hours divided by 12 hours.

[0048] The "cumulative skin permeation rate" can be calculated from each cumulative permeation amount by dividing the cumulative permeation amount by the elapsed time. For example, in the above in vitro permeation test, the amount of active substance permeated into the receiving medium is measured at, for example, 0, 8, 24, 32, 48, 72, 104, 144 and 168 hours, and the "cumulative skin permeation rate" at 48 hours is calculated as the cumulative permeation amount at 48 hours (see above) divided by 48 hours, unless otherwise indicated.

[0049] Within the meaning of the present invention, the above parameters "permeation amount" and "skin permeation rate" (as well as "cumulative permeation amount" and "cumulative skin permeation rate") refer to average values ​​calculated from at least three in vitro permeation test experiments. Unless otherwise indicated, the standard deviation (SD) of these average values ​​is calculated according to the formula:

number

number

[0050] Within the meaning of the present invention, the term "room temperature" refers to the unaltered temperature found in the laboratory where the experiments are carried out, usually within 15-35°C, preferably about 18-25°C.

[0051] Within the meaning of the present invention, the term "dissolving" refers to the process of obtaining a solution that is clear and does not contain any particles, visible to the naked eye.

[0052] Within the meaning of the present invention, the term "extended period" relates to a period of at least or about 24 hours, at least or about 48 hours, at least or about 84 hours, at least or about 168 hours, at least or about 1 day, at least or about 2 days, at least or about 3.5 days, or at least or about 7 days, or a period of from about 24 hours to about 168 hours or from about 1 to 7 days(s), or from about 48 hours to about 168 hours or from about 2 to about 7 days.

[0053] Within the meaning of the present invention, the term "solvent" refers to any liquid substance, preferably a volatile organic liquid such as methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, hexane, n-heptane, toluene, and mixtures thereof.

[0054] Within the meaning of the present invention, the term "additive" refers to any component of the selexipag-containing layer in the TTS according to the present invention other than selexipag, at least one polar polymer and at least one non-polar polymer.

[0055] Within the meaning of the present invention, the term "patient" refers to a subject who exhibits clinical signs of one or more particular symptoms indicating the need for treatment, a subject being treated preventatively or prophylactically against a condition, or a subject who has been diagnosed with a condition to be treated. [Brief description of the drawings]

[0056] [Figure 1] FIG. 1 depicts the skin permeation rate (also known as Δ flux) of selexipag for TTS prepared according to Example 1 (Formulations 1-3) over a time interval of 168 hours. [Diagram 2] FIG. 1 depicts the skin permeation rate of selexipag for TTS prepared according to Example 2 (Formulations 4-7) over a time interval of 168 hours. [Diagram 3] FIG. 1 depicts the skin permeation rate of selexipag for TTS prepared according to Example 3 (Formulations 8-12) over a time interval of 168 hours. [Figure 4] FIG. 1 depicts the skin permeation rate of selexipag for TTS prepared according to Example 4 (Formulations 13-15) over a time interval of 168 hours. [Diagram 5] FIG. 1 depicts the skin permeation rate of selexipag for TTS prepared according to Example 5 (Formulations 16-19) over a time interval of 168 hours. [Figure 6]FIG. 1 depicts the skin permeation rate of selexipag for TTS prepared according to Example 6 (Formulations 20-25) over a time interval of 168 hours. [Figure 7] 1 depicts the cumulative permeation of MRE-269 (also known as ACT-333679) for compositions prepared according to Example 9 (Compositions 1 and 2) over a 168 hour time interval. [Figure 8] FIG. 1 depicts the cumulative permeation of selexipag for compositions prepared according to Example 9 (Compositions 1 and 2) over a 168 hour time interval. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] TTS structure The present invention relates to a transdermal therapeutic system for transdermal administration of selexipag, comprising a selexipag-containing layer structure.

[0058] The selexipag-containing layer structure according to the present invention comprises A) a backing layer and B) a selexipag-containing layer comprising a therapeutically effective amount of selexipag, at least one polar polymer and at least one non-polar polymer. The selexipag-containing layer structure is preferably a selexipag-containing self-adhesive layer structure.

[0059] The backing layer is preferably substantially impermeable to selexipag. Additionally, the backing layer is preferably occlusive, as outlined above.

[0060] The selexipag-containing layer can be attached directly to the backing layer such that there are no additional layers between the backing layer and the selexipag-containing layer.

[0061] The TTS according to the present invention may be a matrix-type TTS or a reservoir-type TTS, preferably a matrix-type TTS.

[0062] The selexipag-containing layer structure according to the present invention is usually placed on a removable protective layer (release liner), which is removed immediately before application therefrom to the surface of the patient's skin.Thus, the TTS may further comprise a release liner.The thus protected TTS is usually stored in a blister pack or a seam-sealed pouch.The packaging may be child-resistant and / or elderly-friendly.

[0063] In a preferred embodiment of the present invention, the selexipag-containing layer is a selexipag-containing pressure-sensitive adhesive layer and represents a skin contact layer. That is, the selexipag-containing layer structure does not include an additional skin contact layer attached to the selexipag-containing layer. In this context, the selexipag-containing layer is preferably a selexipag-containing matrix layer that is self-adhesive. The self-adhesive properties of the selexipag-containing layer structure are preferably provided by at least one polar polymer and / or at least one non-polar polymer. Thus, in a preferred embodiment of the present invention, the at least one polar polymer and / or at least one non-polar polymer is a pressure-sensitive adhesive. Further details regarding the selexipag-containing layer and the at least one polar and non-polar polymer according to the present invention are provided further below.

[0064] In another embodiment of the present invention, the selexipag-containing layer structure further comprises an additional skin contact layer. The skin contact layer is preferably self-adhesive and provides adhesive properties. Thus, in one embodiment of the present invention, the selexipag-containing layer structure further comprises C) a skin contact layer on the selexipag-containing layer. In this regard, the additional skin contact layer may also contain at least one polar polymer and / or at least one non-polar polymer. For example, when the additional skin contact layer comprises a pressure-sensitive adhesive based on polysiloxane and acrylic polymer, the selexipag-containing layer may comprise the same pressure-sensitive adhesive based on polysiloxane and acrylic polymer or a different pressure-sensitive adhesive based on polysiloxane and acrylic polymer, or a different polymer. The additional skin contact layer may preferably be obtained by coating and drying an adhesive coating composition.

[0065] In certain embodiments of the present invention, when the selexipag-containing layer structure includes an additional skin-contacting layer, the additional skin-contacting layer has a mass of about 10 to about 160 g / m 2 , about 10~100g / m 2 Or about 10 to about 60 g / m 2 The skin contact layer has an areal weight of about 40% by weight to about 100% by weight, preferably about 50% by weight to about 100% by weight, more preferably about 60% by weight to about 100% by weight, based on the skin contact layer. The skin contact layer may contain an active agent. The active agent may be selexipag as well. The active agent in the skin contact layer may also be an additional active agent suitable for administration together with selexipag. In a preferred embodiment, the skin contact layer does not contain an active agent, i.e., is prepared without the addition of an active agent.

[0066] According to certain embodiments of the present invention, the TTS may further include an adhesive overlay. This adhesive overlay is particularly larger in area than the selexipag-containing structure and is attached thereto to improve the adhesive properties of the entire transdermal therapeutic system. The adhesive overlay includes a backing layer and an adhesive layer. The adhesive overlay provides additional area to adhere to the skin, but does not add to the release area of ​​selexipag. The adhesive overlay includes a self-adhesive polymer or a self-adhesive polymer mixture selected from the group consisting of silicone acrylic hybrid polymers, acrylic polymers, polysiloxanes, polyisobutylenes, and mixtures thereof, which may be the same or different from any polymer or polymer mixture included in the selexipag-containing layer structure. In one embodiment, the TTS does not include an adhesive overlay on top of the selexipag-containing layer structure.

[0067] Depending on the dose, the release area of ​​TTS is approximately 1 cm 2 ~Approx. 150cm 2 , preferably about 5 cm 2 ~Approx. 130cm 2 , more preferably about 10 cm 2~120cm 2 The range is less than.

[0068] The TTS according to the present invention may further comprise one or more antioxidants. The antioxidants may be contained in the selexipag-containing layer or in the additional skin contact layer, or in both the selexipag-containing layer and the additional skin contact layer. Suitable antioxidants are sodium metabisulfite, ascorbyl palmitate, tocopherol and its esters, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole or propyl gallate, preferably butylhydroxytoluene, ascorbyl palmitate and tocopherol. The antioxidants may conveniently be present in the selexipag-containing layer, preferably in an amount of about 0.001 to about 1.0% of the selexipag-containing layer, more preferably in an amount of about 0.02 to about 0.5% of the selexipag-containing layer.

[0069] The TTS according to the invention may further comprise, in addition to the above-mentioned components, at least one excipient or further component from the group of, for example, crosslinkers, solubilizers, fillers, tackifiers, film formers, plasticizers, stabilizers, emollients, skin care substances, permeation enhancers, pH regulators and preservatives. In one preferred embodiment of the invention, no additional excipients or additives are required.

[0070] Selexipag-containing layer As outlined in more detail above, the TTS according to the present invention comprises a selexipag-containing layer structure comprising a selexipag-containing layer. The selexipag-containing layer according to the present invention comprises a therapeutically effective amount of selexipag, at least one polar polymer and at least one non-polar polymer. Such a composition of the selexipag-containing layer contributes to a TTS with low complexity in structure, since the selexipag-containing layer contains only a small amount of components and at the same time provides sufficient release characteristics. Further details regarding sufficient "release characteristics" can be found in the respective sections and in the Examples section below.

[0071] According to a specific embodiment, the content of selexipag in the selexipag-containing layer is in the range of about 0.1 to about 10% by weight, preferably about 0.1 to about 8.0% by weight, more preferably about 0.3 to about 6.5% by weight, particularly about 0.5 to about 5.5% by weight, based on the total weight of the selexipag-containing layer. The content of selexipag is preferably in the range of about 0.5 to about 3.0% by weight, based on the total weight of the selexipag-containing layer. Alternatively, the content of selexipag is preferably in the range of more than about 3.0 to about 6% by weight, based on the total weight of the selexipag-containing layer.

[0072] According to certain embodiments, the selexipag-containing layer further comprises an enhancer, which is preferably selected from the group consisting of tetrahydrofurfuryl alcohol polyethylene glycol ether, levulinic acid, transcutol, lauryl lactate, methyl laurate, dihydrolevoglucosenone, dimethylpropylene urea, and mixtures thereof.Preferably, the enhancer is methyl laurate.Surprisingly, it has been found that the use of such additional enhancers can increase the release characteristics, for example, by providing a permeation enhancing effect, and at the same time, only one of these enhancers is required, which helps to reduce the complexity of TTS.

[0073] According to a particular embodiment, the selexipag-containing layer further comprises an enhancer in the range of about 2.0 to about 15.0 wt%, more preferably about 3.0 to about 8.0 wt%, particularly about 4.0 to about 6.0 wt%, based on the total weight of the selexipag-containing layer. Alternatively or in addition, the mass ratio of the mass of selexipag to the mass of the enhancer in the selexipag-containing layer is in the range of about 0.01 to about 3.0, preferably about 0.1 to about 2.0, more preferably about 0.1 to about 1.5, or about 0.1 to about 0.9, or about 0.5 to about 1.5.

[0074] The selexipag-containing layer may be a selexipag-containing matrix layer or a selexipag-containing reservoir layer. The selexipag-containing layer is preferably a selexipag-containing matrix layer containing selexipag homogeneously dispersed or dissolved in a polymer matrix. In another preferred embodiment, the selexipag-containing layer is a selexipag-containing two-phase matrix layer comprising an internal phase containing a therapeutically effective amount of selexipag and an external phase containing at least one polar polymer and at least one non-polar polymer, the internal phase forming a deposit dispersed in the external phase. The content of the internal phase in the two-phase matrix layer may be about 5% to 40% by volume based on the volume of the two-phase matrix layer.

[0075] According to certain preferred embodiments, the selexipag-containing layer is a self-adhesive selexipag-containing matrix layer.

[0076] In certain embodiments, the selexipag-containing layer can be obtained by coating and drying a selexipag-containing coating composition comprising selexipag, preferably by coating and drying a selexipag-containing coating composition comprising at least one polar polymer and at least one non-polar polymer, and a therapeutically effective amount of selexipag.

[0077] In certain embodiments, the area weight of the selexipag-containing layer is from about 50 to about 250 g / m 2 , preferably about 70 to about 220 g / m 2 , more preferably about 80 to about 180 g / m 2 and specific 95 to 160 g / m 2 The range is.

[0078] According to certain embodiments, the content of the at least one polar polymer in the selexipag-containing layer ranges from about 5 to about 80% by weight, preferably from about 10 to about 50% by weight, or from about 5 to about 30% by weight, more preferably from about 15 to about 40% by weight, even more preferably from about 15 to about 30% by weight, still more preferably from about 15 to about 27% by weight, especially from about 15 to about 25% by weight, based on the total weight of the selexipag-containing layer. Preferably, the at least one polar polymer is selected from the group consisting of acrylic polymers, polyvinylpyrrolidone, and combinations thereof. Further details regarding the at least one polar polymer according to the present invention are further provided below.

[0079] According to a particular embodiment, the content of the at least one non-polar polymer in the selexipag-containing layer is in the range of about 50 to about 90% by weight, preferably about 60 to about 85% by weight, in particular about 70 to about 80% by weight, based on the total weight of the selexipag-containing layer. According to a particular alternative embodiment, the content of the at least one non-polar polymer in the selexipag-containing layer is in the range of about 5 to about 40% by weight, preferably about 10 to about 30% by weight, in particular about 12 to about 25% by weight, based on the total weight of the selexipag-containing layer. Preferably, the at least one non-polar polymer is a styrene polymer or polyisobutylene. Further details regarding the at least one non-polar polymer according to the present invention are provided further below.

[0080] According to certain embodiments, the mass ratio of selexipag to the combined mass of the at least one polar polymer and the at least one non-polar polymer in the selexipag-containing layer is about 1×10 -3 ~ about 0.1, preferably about 5 × 10 -3 ~Approx. 9×10 -2 or about 9 x 10 -3 ~Approx. 7×10 -2 It should be understood that in this connection the dry weight, i.e. the weight without solvent, of the respective polymer is taken into account.

[0081] According to certain embodiments, the mass ratio of the at least one polar polymer to the non-polar polymer in the selexipag-containing layer ranges from about 0.01 to about 10.0, preferably from about 0.1 to 5.0, or from about 0.2 to about 2.0, preferably from about 0.2 to about 0.8, it being understood that in this context the dry mass, i.e. the mass without solvent, of each polymer is taken into account.

[0082] When an additional skin contact layer is used, components of the selexipag-containing layer, such as selexipag and optional additional active agents, optional auxiliary polymers, optional antioxidants, and optional additional excipients or additives such as enhancers, may migrate to the additional skin contact layer over time, however, this depends on the components and materials of the skin contact layer.

[0083] In one embodiment of the invention, the selexipag-containing layer comprises a therapeutically active amount of selexipag, a polar polymer, and a non-polar polymer. Alternatively, the selexipag-containing layer comprises a therapeutically active amount of selexipag, a polar polymer, a non-polar polymer, and an enhancer as described herein.

[0084] In one embodiment of the present invention, in the selexipag-containing layer, at least one non-polar polymer is a polyisobutylene polymer and / or a styrene polymer, and at least one polar polymer is an acrylic polymer and / or a polyvinylpyrrolidone.In a preferred embodiment, at least one non-polar polymer is a polyisobutylene polymer, and at least one polar polymer is an acrylic polymer and / or a polyvinylpyrrolidone.In a further preferred embodiment, at least one non-polar polymer is a styrene polymer, and at least one polar polymer is a polyvinylpyrrolidone.

[0085] Polar Polymers The selexipag-containing layer according to the present invention comprises at least one polar polymer, which may be selected from the group consisting of acrylic polymers, polyvinylpyrrolidone, and mixtures thereof.

[0086] Preferably, the content of the at least one polar polymer in the selexipag-containing layer is in the range of 5.0-30.0% by weight, preferably 15.0-27.0% by weight, based on the total weight of the selexipag-containing layer.

[0087] In a preferred embodiment, the at least one polar polymer is a polymer-based pressure sensitive adhesive.

[0088] According to one embodiment of the present invention, the at least one polar polymer is an acrylate-based polymer, i.e. an acrylic polymer, preferably an acrylate-based pressure-sensitive adhesive. The acrylate-based pressure-sensitive adhesive may also be referred to as an acrylate-based pressure-sensitive adhesive, or an acrylate pressure-sensitive adhesive. The acrylate-based pressure-sensitive adhesive may preferably have a solids content of 30% to 60%. Such acrylate-based pressure-sensitive adhesives may or may not contain functional groups such as hydroxy groups, carboxylic acid groups, neutralized carboxylic acid groups, and mixtures thereof. Thus, the term "functional groups" refers in particular to hydroxy groups and carboxylic acid groups, as well as deprotonated carboxylic acid groups.

[0089] Corresponding commercial products are available, for example, from Henkel under the trade name Duro-Tak®. Such acrylate-based pressure-sensitive adhesives are based on monomers selected from one or more of acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, t-octyl acrylamide and vinyl acetate, and are provided in ethyl acetate, heptane, n-heptane, hexane, methanol, ethanol, isopropanol, 2,4-pentanedione, toluene or xylene, or mixtures thereof. Suitable acrylate-based pressure-sensitive adhesives are based on monomers selected from two or more of acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, t-octyl acrylamide and vinyl acetate.

[0090] In one embodiment of the present invention, the at least one polar polymer may be an acrylic polymer, which is a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and optionally glycidyl-methacrylate.

[0091] Specifically, the following acrylate-based pressure sensitive adhesives are available: Duro-Tak® 387-2510 or Duro-Tak® 87-2510 (copolymers based on 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and methyl acrylate, provided as a solution in ethyl acetate and hexane), Duro-Tak™ 87-4287 (a hydroxyl-containing acrylic copolymer based on vinyl acetate, 2-ethylhexyl-acrylate and 2-hydroxyethyl-acrylate, the copolymer being provided as a solution in ethyl acetate without the use of a crosslinker); Duro-Tak® 387-2287 or Duro-Tak® 87-2287 (copolymers based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate, and glycidyl-methacrylate provided as a solution in ethyl acetate without a crosslinker), Duro-Tak™ 387-2516 or Duro-Tak™ 87-2516 (copolymers based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate provided as solutions in ethyl acetate, ethanol, n-heptane and methanol with a titanium crosslinker), Duro-Tak® 387-2051 or Duro-Tak® 87-2051 (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 (acrylic copolymer containing carboxylic acid groups, the copolymer being based on acrylic acid, 2-ethylhexyl acrylate, glycidyl methacrylate and methyl acrylate and provided as a solution in ethyl acetate and hexane), Duro-Tak™ 87-4098 (a non-functional acrylic copolymer, the copolymer being based on 2-ethylhexyl-acrylate and vinyl acetate and provided as a solution in ethyl acetate); Duro-Tak™ 87-9301 (a non-functional acrylic copolymer obtained without the use of a crosslinker and provided in ethyl acetate); - Duro-Tak™ 87-2052 (a copolymer based on acrylic acid and vinyl acetate, containing free carboxylic acid groups, obtained using a crosslinking agent and provided in ethyl acetate, heptane, ethanol and isopropanol).

[0092] In a preferred embodiment, the at least one polar polymer is Duro-Tak™ 87-9301 (a functional group-free acrylic copolymer obtained without the use of a crosslinker and provided in ethyl acetate) or Duro-Tak™ 87-2052 (a copolymer based on acrylic acid and vinyl acetate containing free carboxylic acid groups, obtained using a crosslinker and provided in ethyl acetate, heptane, ethanol and isopropanol), in particular Duro-Tak™ 87-2052.

[0093] In certain embodiments, the selexipag-containing layer according to the present invention comprises an acrylic polymer in an amount of about 10.0 to about 35.0% by weight, preferably about 20.0 to about 30.0% by weight, based on the total weight of the selexipag-containing layer.

[0094] In certain embodiments, at least one polar polymer can be polyvinylpyrrolidone, such as crospovidone.Preferably, polyvinylpyrrolidone can be soluble polyvinylpyrrolidone, but alternatively, it can be insoluble / crosslinked polyvinylpyrrolidone, also known as crospovidone, such as Kollidon® CL, Kollidon® CL-M and Kollidon® CL-SF, and polyvinylpyrrolidone-polyvinyl acetate copolymer, also known as crospovidone, such as Kollidon® VA64. Further suitable polyvinylpyrrolidones are Plasdone® K-12 (having a weight average molecular weight of about 3,700 to 4,300 g / mol), Plasdone® K-17 (having a weight average molecular weight of about 9,500 to 10,500 g / mol), Plasdone® K-25 (having a weight average molecular weight of about 33,500 to 34,500 g / mol), Plasdone® K-29 / 32 (having a weight average molecular weight of about 57,500 to 58,500 g / mol). , Plasdone® K-90 (having a weight average molecular weight of about 1,299,500 to 1,300,500 g / mol), Plasdone® C-12 (having a weight average molecular weight of about 3,700 to 4,300 g / mol), Plasdone® C-17 (having a weight average molecular weight of about 9,500 to 10,500 g / mol) and Plasdone® C-30 (having a weight average molecular weight of about 57,500 to 58,500 g / mol). In this context, the average molecular weight is preferably determined via SEC-MALS.

[0095] In certain embodiments, the selexipag-containing layer according to the present invention comprises polyvinylpyrrolidone, preferably crospovidone, in an amount of about 5.0 to about 30.0% by weight, preferably about 15.0 to about 27.0% by weight or about 15.0 to about 25.0% by weight, based on the total weight of the selexipag-containing layer.

[0096] In certain embodiments, the selexipag-containing layer according to the present invention comprises at least two polar polymers, in which it is preferred that one polar polymer is an acrylic polymer and one polar polymer is polyvinylpyrrolidone, preferably crospovidone.

[0097] Non-polar polymers The selexipag-containing layer according to the present invention comprises at least one non-polar polymer.This also means that the selexipag-containing layer can comprise a mixture of non-polar polymers.Preferably, at least one non-polar polymer is selected from the group consisting of silicone polymer, polyisobutylene, styrene polymer, and mixtures thereof, in particular, from the group consisting of polyisobutylene, styrene polymer, and mixtures thereof.In a particular embodiment, at least one non-polar polymer is a pressure-sensitive adhesive.

[0098] In one embodiment, the at least one non-polar polymer is silicone polymer.Silicone polymer is polysiloxane-based polymer.These polysiloxane-based polymers are preferably polysiloxane-based pressure-sensitive adhesives.Polysiloxane-based pressure-sensitive adhesives can also be referred to as silicone-based pressure-sensitive adhesives or silicone pressure-sensitive adhesives.

[0099] According to a particular embodiment, the at least one non-polar polymer is polyisobutylene or the at least one non-polar polymer comprises a polyisobutylene mixture. In this regard, the content of the at least one non-polar polymer in the selexipag-containing layer is preferably in the range of 50.0-90.0 wt.%, preferably 60.0-85.0 wt.%, in particular 70.0-80.0 wt.%, based on the total weight of the selexipag-containing layer.

[0100] In a particular embodiment, polyisobutylene can be obtained by blending 50-95% by weight, preferably 60-90% by weight, in particular 75-90% by weight, based on the total weight of polyisobutylene, with 5-50% by weight, preferably 10-40% by weight, in particular 10-25% by weight, based on the total weight of polybutene. In this connection, the weight ratio of the mass of polyisobutylene to the mass of polybutene is preferably 20:1 to 1:1, in particular 8:1 to 3:1 by weight, and Duro-Tak® 87-6908 provided by Henkel (having about 85% by weight polyisobutylene and 15% by weight polybutene provided in n-heptane) can be specified as a suitable polyisobutylene. The solid content of polyisobutylene in the solvent is usually 30-50%, preferably 35-40%.

[0101] The at least non-polar polymer may comprise a polyisobutylene mixture that is a combination of low molecular weight polyisobutylene and high molecular weight polyisobutylene, with a mass ratio of the low molecular weight polyisobutylene to the high molecular weight polyisobutylene ranging from 99:1 to 50:50, preferably the low molecular weight polyisobutylene having a viscosity average molecular weight of 38,000 to 42,000 g / mol and / or a weight average molecular weight of 34,000 to 40,000 g / mol, and the high molecular weight polyisobutylene having a viscosity average molecular weight of 1,100,000 to 1,120,000 g / mol and / or a weight average molecular weight of 1,540,000 to 1,560,000 g / mol.

[0102] Suitable polyisobutylenes according to the present invention are available under the trade name Oppanol®. Combinations of high molecular weight polyisobutylene (N100 / N80) and low molecular weight polyisobutylene (B10, B11, B12, B13) may be used. Suitable ratios of low molecular weight polyisobutylene and high molecular weight polyisobutylene range from 100:1 to 1:100, preferably from 95:5 to 40:60, more preferably from 90:10 to 80:20. A preferred example of a polyisobutylene combination is B10 / N100 in a ratio of 85 / 15. Oppanol® N100 has a viscosity average molecular weight M of 1,110,000.v , and a weight average molecular weight M of 1,550,000 w , and an average molecular weight distribution M of 2.9 w / M n Oppanol® B10 has a viscosity average molecular weight M of 40,000. v , and a weight average molecular weight M of 53,000 w , and the average molecular weight distribution M w / M n In a particular embodiment, polybutene can be added to the polyisobutylene. The solid content of the polyisobutylene in the solvent is usually 30-50%, preferably 35-40%. Those skilled in the art know that the solid content may be changed by adding a suitable amount of solvent.

[0103] According to another embodiment, the at least one non-polar polymer is a styrene polymer, preferably a styrene thermoplastic elastomer. In this connection, the content of the at least one non-polar polymer in the selexipag-containing layer is preferably in the range of 5.0-40.0 wt.%, preferably 10.0-30.0 wt.%, in particular 12.0-25.0 wt.%, based on the total weight of the selexipag-containing layer.

[0104] Suitable styrene thermoplastic elastomers are styrene-isoprene block copolymers, preferably styrene-isoprene-styrene block copolymers. In this context, it is preferred if the mass ratio of styrene to the mass of isoprene is between 1:20 and 1:2, preferably between 1:15 and 1:3. JSR SIS5002, JSR SIS5229, JSR SIS5250, JSR SIS5403 and JSR SIS5505 (manufactured by JSR Life Science) are designated as suitable styrene-isoprene-styrene block copolymers.

[0105] Preferably, the styrene-isoprene block copolymer comprises 5 to 30% by weight, preferably 10 to 20% by weight, of styrene units, based on the total amount of the styrene-isoprene block copolymer.

[0106] Preferably, the styrene-isoprene block copolymer has a melt flow rate (determined according to JIS K7210, 200° C., 49.0 N) of 1 to 30 g / 10 min, preferably 5 to 20 g / 10 min, in particular 6 to 15 g / 10 min.

[0107] Further suitable styrene thermoplastic elastomers are styrene-butadiene block copolymers. In this connection, it is preferred if the mass ratio of styrene to the mass of butadiene is 1:5 to 2:1, preferably 1:3 to 1.1:1. JSR TR2000, JSR TR2001, JSR TR2250, JSR TR2500, JSR TR2630, JSR TR2787, JSR TR1084 and JSR TR1600 (from JSR Life Science) are designated as suitable styrene-isoprene block copolymers.

[0108] Preferably, the styrene-isoprene block copolymer comprises 30 to 60% by weight, preferably 35 to 55% by weight, of styrene units, based on the total amount of the styrene-isoprene block copolymer.

[0109] Preferably, the styrene-isoprene block copolymer has a melt flow rate (determined according to JIS K7210, 200° C., 49.0 N) of 1 to 25 g / 10 min, preferably 5 to 20 g / 10 min, in particular 6 to 15 g / 10 min.

[0110] In a particular embodiment, the selexipag-containing layer according to the present invention comprises a tackifier. Preferably, the tackifier is a thermoplastic ester resin, in particular a thermoplastic ester resin derived from glycerol and highly stabilized rosin. Preferably, the tackifier has an acid number (mg KOH / g, determined according to ASTM D465) of 3 to 12, preferably 4 to 10, in particular 5 to 9.

[0111] According to the present invention, the term "rosin" refers to a natural product obtained from the exudation of trees of the pine family. Rosin consists of about 90% or more by weight of mixed unsaturated acids, based on the total weight of the rosin. Rosin acids are mainly monobasic carboxylic acids, all contain a phenanthrene skeleton, all have 20 carbon atoms in the molecule, and the main difference between the acids is the number and position of the double bonds. The acids can have conjugated double bonds, such as abietic acid, or non-conjugated double bonds, such as pimaric acid. Natural rosins can be classified into several types depending on their origin. There are gum rosins, wood rosins, and tall oil rosins (for further information, see, for example, "Modern Surface Coatings" Paul Nylen et al, Interscience Publishers 1965, p 133-137). Due to its structure, rosin is generally not suitable for use in adhesive formulations. The double bonds of rosin acids result in oxidative instability, and the isomeric composition causes rosin to crystallize. Therefore, rosin must be subjected to chemical reactions that modify the double bond positions and change the rosin acid isomer composition. Processes for stabilizing rosin are well known (stabilization by hydrogenation, dehydrogenation or disproportionation).

[0112] In certain embodiments, the selexipag-containing layer comprises a styrene polymer and further comprises a tackifier, and preferably the weight ratio of the mass of the styrene polymer to the mass of the tackifier is 1:5 to 1:1, preferably 1:4 to 1:2, and / or the content of the tackifier in the selexipag-containing layer is in the range of 30.0 to 80.0 wt.%, preferably 40.0 to 70.0 wt.%, in particular 45.0 to 60.0 wt.%, based on the total weight of the selexipag-containing layer.

[0113] Emission Characteristics The TTS according to the present invention is designed to administer selexipag transdermally into the systemic circulation for a predefined extended period of time (such as about 48 hours, or about 84 hours, or about 168 hours).

[0114] According to one particular embodiment, the TTS according to the invention has a concentration of 10-120 μg / cm over a 48 hour period, as measured in a Franz diffusion cell using explanted human skin. 2 , preferably 20 to 115 μg / cm 2 , especially 25 to 55 μm / cm 2 or 70~115μm / cm 2 The cumulative permeation amount of selexipag is provided.

[0115] According to a particular embodiment, the TTS according to the invention has a concentration of 20-130 μg / cm over an 84 hour period, as measured in a Franz diffusion cell using explanted human skin. 2 , preferably 35 to 100 μg / cm 2 , especially 45 to 80 μm / cm 2 The cumulative permeation amount of selexipag is provided.

[0116] In certain embodiments, the TTS according to the present invention is a concentration of 30-250 μg / cm over a 168 hour period as measured in a Franz diffusion cell using explanted human skin. 2 , preferably 65 to 230 μg / cm 2 , especially 65-130μg / cm 2 or 170-230μg / cm 2 The cumulative permeation amount of selexipag is provided.

[0117] In certain embodiments, the TTS according to the present invention is between 40 and 200 μg / cm over a 168 hour period as measured in a Franz diffusion cell using explanted human skin. 2 , preferably 60 to 150 μg / cm 2 , especially 65 to 120 μm / cm 2 The cumulative permeation amount of selexipag is provided.

[0118] According to one particular embodiment, the TTS according to the invention has a concentration of 80-260 μg / cm over a 168 hour period as measured in a Franz diffusion cell using explanted human skin. 2 , preferably 150 to 240 μg / cm 2 , especially 170~230μm / cm2 The cumulative permeation amount of selexipag is provided.

[0119] In a further particular embodiment, the TTS according to the invention provides selexipag in an amount of 0.2 to 10 mg, preferably 0.3 to 5 mg, in particular 0.4 to 2.0 mg, over a period of 168 hours, as measured in a Franz diffusion cell using explanted human skin.

[0120] Medical Use / Treatment Method According to a second aspect of the present invention, the TTS according to the present invention is for use in a method of treating a human patient. Such a method of treating a human patient may comprise administering the TTS to the skin of the patient. Preferably, the TTS according to the present invention is for use in a method of treating pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). In particular, such treatment comprises administering the TTS to the skin of a human patient.

[0121] According to one aspect, the present invention relates to the use of a TTS according to the invention for the manufacture of a medicament for the treatment of a human patient.

[0122] According to another aspect, the invention relates to a method of treating a human patient.

[0123] Manufacturing method The selexipag-containing layer may be manufactured according to any suitable method.

[0124] In certain embodiments, the method of making the selexipag-containing layer comprises: 1) combining at least the components selexipag, at least one polar polymer and at least one non-polar polymer in a solvent to obtain a coating composition; 2) coating the coating composition onto a backing layer or release liner or an optional intermediate liner; and 3) drying the coated coating composition to form a selexipag-containing layer.

[0125] In this method, preferably in step 1) at least one promoter is added.

[0126] In the above mentioned process, preferably the solvent is selected from alcoholic solvents, in particular methanol, ethanol, isopropanol and mixtures thereof, and non-alcoholic solvents, in particular ethyl acetate, hexane, n-heptane, petroleum ether, toluene and mixtures thereof, more preferably selected from methanol, n-heptane and ethyl acetate.

[0127] In certain embodiments, the at least one polar polymer and the at least one non-polar polymer are provided in a solvent selected from the group consisting of ethyl acetate, n-heptane, methanol or ethanol, preferably having a solids content of 30-60% by weight.

[0128] In step 3), the drying is preferably carried out at a temperature of 40 to 90°C, more preferably 50 to 80°C. EXAMPLES

[0129] The present invention will now be described more fully with reference to the accompanying examples, although it should be understood that the following descriptions are illustrative only and should not be construed as limiting the invention in any way.

[0130] Example 1 Coating Composition Formulations 1 to 3 of the selexipag-containing coating composition are summarized below. [Table 1-1] [Table 1-2]

[0131] Preparation of the Coating Composition Formulation 1: Selexipag was placed in a container and the enhancer tetrahydrofurfuryl alcohol polyethylene glycol ether was added. Successively, the solvents ethyl acetate and a pre-solution of Povidone K90F (in ethyl alcohol) were mixed into the slurry. DURO-TAK87-4287 was added to the mass, which was then stirred for a minimum of 1 hour.

[0132] Formulation 2: Selexipag was placed in a container and the enhancers tetrahydrofurfuryl alcohol polyethylene glycol and DURO-TAK adhesive were added. The mass was stirred for a minimum of 1 hour.

[0133] Formulation 3: Selexipag was placed in a container and the enhancers tetrahydrofurfuryl alcohol polyethylene glycol ether and a pre-solution of Povidone K90F (in ethyl alcohol) were mixed into a slurry. DURO-TAK adhesive was added to the mass, which was then stirred for a minimum of 1 hour.

[0134] Coating of the coating composition The resulting coating composition containing selexipag was coated onto a silicone-treated PET foil. The coated material was dried at room temperature for 15 minutes and at 60°C for 15 minutes, and then laminated onto a beige PET backing. The areal weight was determined.

[0135] Preparation of TTS (all examples) Individual systems (TTS) were then die cut from the selexipag-containing self-adhesive layer structure.

[0136] In certain embodiments, the TTS described above may comprise a larger surface area adhesive overlay, preferably with rounded corners, i.e., an additional self-adhesive layer structure, including a pressure-sensitive adhesive matrix layer free of active ingredients and a backing layer, preferably skin-colored. The TTS is then die-cut and sealed into a pouch of the primary packaging material.

[0137] Example 2 Coating Composition Formulations 4-7 of the selexipag-containing coating composition are summarized below. [Table 2] [Table 3]

[0138] Preparation of the Coating Composition Selexipag was placed in a container and the rsp. enhancer was added. The solvent was continuously mixed into the slurry. DURO-TAK87-6908 was added to the mass and then stirred for 1 hour. Finally, Crospovidone was added to the mass with stirring. The mass was stirred for an additional 2 hours.

[0139] Coating of the coating composition See Example 1.

[0140] Preparation of TTS (all examples) See Example 1.

[0141] Example 3 Coating Composition Formulations 8 and 9 of the selexipag-containing coating composition are summarized below. [Table 4]

[0142] Preparation of the Coating Composition Formulation 8: Selexipag was placed in a container and the enhancer methyl laurate was added. The solvent was continuously mixed into the slurry. DURO-TAK87-6908 was added to the mass and then stirred for 1 hour. Finally, Crospovidone was added to the mass with stirring. The mass was stirred for an additional 2 hours.

[0143] Formulation 9: Selexipag was placed in a container and the solvent was added successively. DURO-TAK87-6908 was added to the mass and then stirred for a minimum of 1 hour. Finally, Crospovidone was added to the mass with stirring. The mass was stirred for an additional 2 hours.

[0144] Coating of the coating composition See Example 1.

[0145] Preparation of TTS (all examples) See Example 1.

[0146] Example 4 Coating Composition Formulations 10-12 of the selexipag-containing coating composition are summarized below. [Table 5]

[0147] Preparation of the Coating Composition Formulation 10 / 12: Selexipag was placed in a container and the enhancer methyl laurate was added. The solvent was continuously mixed into the slurry. DURO-TAK87-6908 was added to the mass and then stirred for 1 hour. Finally, Crospovidone was added to the mass with stirring. The mass was stirred for an additional 2 hours.

[0148] Formulation 11: Selexipag was placed in a container and the solvent was added successively. DURO-TAK87-6908 was added to the mass and then stirred for a minimum of 1 hour. Finally, Crospovidone was added to the mass with stirring. The mass was stirred for an additional 2 hours.

[0149] Coating of the coating composition See Example 1.

[0150] Preparation of TTS (all examples) See Example 1.

[0151] Example 5 Coating Composition Formulations 13-15 of the selexipag-containing coating composition are summarized below. [Table 6]

[0152] Preparation of the Coating Composition Formulation 13 / 15: Selexipag was placed in a container and the enhancer methyl laurate was added. The solvent was continuously mixed into the slurry. Styrene-isoprene-styrene block copolymer was added to the mass and then stirred for 1 hour. Finally, Crospovidone was added to the mass with stirring. The mass was stirred for another 2 hours.

[0153] Formulation 14: Selexipag was placed in a vessel and the solvent was added successively. Styrene-isoprene-styrene block copolymer was added to the mass and then stirred for a minimum of 1 hour. Finally, Crospovidone was added to the mass with stirring. The mass was stirred for an additional 2 hours.

[0154] Coating of the coating composition See Example 1.

[0155] Preparation of TTS (all examples) See Example 1.

[0156] Example 6 Coating Composition Formulations 16-19 of the selexipag-containing coating composition are summarized below. [Table 7] [Table 8]

[0157] Preparation of the Coating Composition Formulation 16: Selexipag was placed in a container and the solvent was added successively. DURO-TAK87-6908 was added to the mass and then stirred for a minimum of 1 hour. Finally, Crospovidone was added to the mass with stirring. The mass was stirred for an additional 2 hours.

[0158] Formulations 17-19: Selexipag was placed in a container and the enhancer methyl laurate was added. Successively, the solvent was mixed into the slurry. DURO-TAK87-6908 was added to the mass, which was then stirred for 1 hour. Finally, Crospovidone was added to the mass with stirring. The mass was stirred for an additional 2 hours.

[0159] Coating of the coating composition See Example 1.

[0160] Preparation of TTS (all examples) See Example 1.

[0161] Example 7 Coating Composition Formulations 20-25 of the selexipag-containing coating composition are summarized below. [Table 9] [Table 10]

[0162] Preparation of the Coating Composition Formulation 20 / 23: Selexipag was placed in a container and the solvent n-heptane was added. DURO-TAK adhesive was added to the mass and then stirred for a minimum of 1 hour.

[0163] Formulation 21 / 24: Selexipag was placed in a container and the enhancer methyl laurate and solvent n-heptane were added. DURO-TAK adhesive was added to the mass and then mixed for a minimum of 1 hour.

[0164] Formulation 22 / 25: Selexipag was placed in a container and the enhancer methyl laurate and the solvent n-heptane were added. DURO-TAK adhesive was added to the mass and then mixed for a minimum of 1 hour. Finally, Crospovidone was added to the mass with stirring. The mass was stirred for an additional 2 hours.

[0165] Coating of the coating composition See Example 1.

[0166] Preparation of TTS (all examples) See Example 1.

[0167] Example 8 Measurement of skin permeability The permeation amount of selexipag prepared according to Examples 1-7 and the corresponding skin permeation rate of TTS were determined by in vitro experiments according to OECD guidelines (adopted on April 13, 2004) performed using 7.0 ml Franz diffusion cells. Split-thickness human skin (female chest or abdomen, born 1964, 1984, 1992, 1993) from cosmetic surgery was used (Example 1: [female chest, date of birth unknown]; Example 2: [female abdomen, born 1984]; Example 3: [female abdomen, born 1992]; Example 4: [female abdomen, born 1992]; Example 5: [female abdomen, born 1992]; Example 6: [female abdomen, born 1964]; and Example 7: [female abdomen, born 1993]). A dermatome was used to prepare skin with intact epidermis for all TTS at a thickness of 500 μm. 2 Die cuts with an area of ​​were punched out from the TTS. The permeation amount of selexipag in the receiving medium (aqueous buffer containing 0.9% aqueous sodium chloride, 3% vanillin, 0.5% methyl-β-cyclodextrin, 30% acetonitrile) in Franz diffusion cells at a temperature of 32±1° C. was measured, and the corresponding cumulative permeation amount and skin permeation rate were calculated.

[0168] The results are shown in Table 11 below and in Figures 1 to 6. [Table 11]

[0169] Example 9 Formulation of the Composition To determine the permeation of selexipag and its active metabolite MRE-269 through fresh human skin tissue, the following experiment was performed.

[0170] A modified Keshary-Chien diffusion cell using fresh human skin as a barrier between the donor and acceptor compartments was used in this experiment. The acceptor compartment contained acceptor medium (0.9% NaCl + 3% vanillin + 0.5% methyl-β-cyclodextrin + 30% acetonitrile in purified water) and the donor chamber contained a liquid solution of selexipag in oleic acid, dipropylene glycol, ethanol and purified water. Liquid solution composition 1 was applied as a suspension with undissolved selexipag, whereas composition 2 was centrifuged before application and only the clear centrate was applied. The compositions of selexipag-containing coating compositions 1 and 2 are summarized below. [Table 12]

[0171] Fresh human skin from a plastic surgery operation was used (upper arm, female, 31 years old). Immediately after surgery, the skin was prepared to remove adipose tissue, then placed in tissue wetted with perfusion solution and wrapped in sterile gauze. Transport on ice (same day) was performed to keep the skin tissue cool, but not frozen to maintain physiological activity. Upon arrival, the skin was gently pressed dry and harvested at 500 μm without prior freezing. Finally, the skin tissue was harvested at 3.843 cm 2 The sample was punched out to a size of 100 mm.

[0172] A ring of adhesive foam (27 mm outer diameter, 18 mm inner diameter) was applied on top of the skin. This complex was placed in the acceptor compartment of the diffusion cell. The donor compartment was placed on top and fixed with clamps to the acceptor chamber. The donor compartment was filled with approximately 94 mg of liquid solution and the acceptor compartment was filled with 10 mL of acceptor medium. The diffusion cell was incubated in a water bath (32 °C ± 0.5 °C) with continuous stirring at 700 rpm (including a magnetic stirrer in the acceptor compartment) to allow homogenous temperature and API concentration distribution. After 24–48–120–144–168 h, the acceptor solution was completely removed and the cell was refilled with fresh acceptor.

[0173] The acceptor solution sample was filtered through a syringe filter and analyzed by HPLC. Quantification of selexipag was performed using an external standard. The concentration of the active metabolite MRE-269 was recalculated with the response factor between selexipag and the active metabolite MRE-269.

[0174] After 168 hours of permeation, the diffusion cells were removed and the skin was washed with purified water to remove any residual liquid solution. Extraction of selexipag and MRE-269 from the skin was performed by shaking overnight in methanol. The extracts were then diluted with acceptor medium, filtered, and analyzed by HPLC analogue to the permeation samples.

[0175] The active metabolite MRE-269 was detected at each sampling time point in all permeation and skin extract samples. Figure 7 shows the cumulative data of the active metabolite MRE-269 in the acceptor medium. Continuous release of the active metabolite occurred over 7 days, proving the general presence of the active enzyme responsible for the metabolism of selexipag in the skin and its continuous activity over 7 days under in vitro conditions. Compared to the cumulative data of selexipag in the acceptor medium (Figure 8), the release of MRE-269 started later, which is compatible with the metabolism that occurred earlier.

[0176] The present invention specifically relates to the following further clauses: Clause 1. A transdermal therapeutic system for transdermal administration of selexipag comprising a self-adhesive selexipag-containing layer structure, the self-adhesive selexipag-containing layer structure comprising: A) a lining layer; B) a selexipag-containing layer, 1. A therapeutically effective amount of selexipag, 2. at least one polar polymer, and 3. The transdermal therapeutic system comprising: a selexipag-containing layer comprising at least one non-polar polymer. Clause 2. The transdermal therapeutic system described in Clause 1, wherein the content of selexipag in the selexipag-containing layer is in the range of about 0.1 to about 8.0% by weight, preferably about 0.5 to about 5.5% by weight, based on the total weight of the selexipag-containing layer. Clause 3. The mass ratio of selexipag to the total mass of at least one polar polymer and at least one non-polar polymer in the selexipag-containing layer is about 1×10 -3 ~ about 0.1, preferably about 5 × 10 -3 ~Approx. 9×10 -2 , or about 9 × 10 -3 ~Approx. 7×10 -2 The transdermal therapeutic system according to clause 1 or 2, wherein the range is Clause 4. The transdermal therapeutic system of any one of clauses 1 to 3, wherein the selexipag-containing layer further comprises an enhancer. Clause 5. The transdermal therapeutic system according to any one of clauses 1 to 4, wherein the selexipag-containing layer further comprises an enhancer selected from the group consisting of tetrahydrofurfuryl alcohol polyethylene glycol ether, levulinic acid, transcutol, lauryl lactate, methyl laurate, dihydrolevoglucosenone, dimethylpropylene urea, and mixtures thereof, in particular methyl laurate. Clause 6. The transdermal therapeutic system according to any one of clauses 1 to 5, wherein the selexipag-containing layer further comprises an enhancer in the range of about 2.0 to about 15.0% by weight, more preferably about 3.0 to about 8.0% by weight, based on the total weight of the selexipag-containing layer. Clause 7. The transdermal therapeutic system according to any one of clauses 4 to 6, wherein the mass ratio of the selexipag to the enhancer in the selexipag-containing layer is in the range of about 0.01 to about 3.0, preferably about 0.1 to about 2.0, more preferably about 0.1 to about 1.5, or about 0.1 to about 0.9, or about 0.5 to about 1.5. Clause 8. The at least one non-polar polymer is a pressure sensitive adhesive; and / or The transdermal therapeutic system according to any one of clauses 1 to 7, wherein the at least one non-polar polymer is selected from the group consisting of silicone polymers, polyisobutylene polymers, styrene polymers, and mixtures thereof, preferably selected from polyisobutylene polymers, styrene polymers, and mixtures thereof. Clause 9. The transdermal therapeutic system according to any one of clauses 1 to 8, wherein the at least one non-polar polymer is a polyisobutylene blend, which is a combination of polyisobutylene and polybutene, preferably in a weight ratio of the mass of the polyisobutylene to the mass of the polybutene of about 20:1 to about 1:1, in particular about 8:1 to about 3:1. Clause 10. The transdermal therapeutic system according to any one of clauses 1 to 9, wherein the at least one non-polar polymer is a styrene polymer, preferably a styrene-isoprene-styrene block copolymer, more preferably, the weight ratio of the mass of the styrene to the mass of the isoprene is from about 1:20 to about 1:2, preferably from about 1:15 to about 1:3. Clause 11. The transdermal therapeutic system according to clause 10, wherein the selexipag-containing layer further comprises a tackifier, preferably a thermoplastic ester resin, in particular a thermoplastic ester resin derived from glycerol and highly stabilized rosin. Clause 12. The selexipag-containing layer further comprises a tackifier; 12. The transdermal therapeutic system according to clause 10 or 11, wherein the weight ratio of the mass of the styrene polymer to the mass of the tackifier is from about 1:5 to about 1:1, preferably from about 1:4 to about 1:2, and / or the content of the tackifier in the selexipag-containing layer is in the range of from about 30.0 to about 80.0% by weight, preferably from about 40.0 to about 70.0% by weight, in particular from about 45.0 to about 60.0% by weight, based on the total weight of the selexipag-containing layer. Clause 13. The transdermal therapeutic system according to any one of clauses 10 to 12, wherein the tackifier has an acid number (mg KOH / g, determined according to ASTM D465) of from about 3 to about 12, preferably from about 4 to about 10, in particular from about 5 to about 9. Clause 14. The transdermal therapeutic system described in any one of clauses 1 to 13, wherein the at least one polar polymer is selected from the group consisting of acrylic polymers, polyvinylpyrrolidone, and mixtures thereof. Clause 15. The transdermal therapeutic system according to any one of clauses 1 to 14, wherein said at least one polar polymer is polyvinylpyrrolidone, preferably crospovidone. Clause 16. The transdermal therapeutic system according to any one of clauses 1 to 15, wherein the at least one polar polymer is an acrylic polymer, preferably a copolymer based on acrylic acid and vinyl acetate containing free carboxylic acid groups. Clause 17. The content of the at least one non-polar polymer in the selexipag-containing layer is in the range of about 50.0 to about 90.0% by weight, preferably about 60.0 to about 85.0% by weight, particularly about 70.0 to about 80.0% by weight, based on the total weight of the selexipag-containing layer; or 17. The transdermal therapeutic system according to any one of clauses 1 to 16, wherein the content of the at least one non-polar polymer in the selexipag-containing layer is in the range of about 5.0 to about 40.0% by weight, preferably about 10.0 to about 30.0% by weight, in particular about 12.0 to about 25.0% by weight, based on the total weight of the selexipag-containing layer. Clause 18. The transdermal therapeutic system according to any one of clauses 1 to 17, wherein the content of the at least one polar polymer, preferably an acrylic polymer, in the selexipag-containing layer is in the range of about 10.0 to about 35.0% by weight, preferably about 20.0 to about 30.0% by weight, based on the total weight of the selexipag-containing layer. Clause 19. The transdermal therapeutic system described in any one of clauses 1 to 17, wherein the content of the at least one polar polymer, preferably polyvinylpyrrolidone, in the selexipag-containing layer is in the range of about 5.0 to about 30.0% by weight, preferably about 15.0 to about 27.0% by weight, or about 15.0 to about 25.0% by weight, based on the total weight of the selexipag-containing layer. Clause 20. The transdermal therapeutic system according to any one of clauses 1 to 19, wherein the mass ratio of the polar polymer to the non-polar polymer in the selexipag-containing layer is in the range of about 0.01 to about 10.0, preferably about 0.1 to 5.0, or about 0.2 to about 2.0, preferably about 0.2 to about 0.8. Clause 21. The transdermal therapeutic system described in any one of clauses 1 to 20, wherein the at least one non-polar polymer is a polyisobutylene polymer and / or a styrene polymer, and the at least one polar polymer is an acrylic polymer and / or a polyvinylpyrrolidone. Clause 22. The transdermal therapeutic system described in any one of clauses 1 to 21, wherein the at least one non-polar polymer is a polyisobutylene polymer and the at least one polar polymer is an acrylic polymer and / or polyvinylpyrrolidone. Clause 23. The transdermal therapeutic system described in any one of clauses 1 to 21, wherein the at least one non-polar polymer is a styrene polymer and the at least one polar polymer is polyvinylpyrrolidone. Clause 24. The selexipag-containing layer is a selexipag-containing matrix layer, and / or the area weight of the selexipag-containing layer is about 70 to about 220 g / m 2 , preferably about 95 to about 160 g / m 2 The transdermal therapeutic system according to any one of clauses 1 to 23, wherein the range is Article 25. 10 μg / cm over a 48 hour period, measured in Franz diffusion cells using excised human skin 2 ~120μg / cm 2 , preferably 20 μg / cm 2 ~115μg / cm 2 , especially 25-55μg / cm 2 , or 70-115 μg / cm 2 and / or 30 μg / cm over a 168 hour period, measured in Franz diffusion cells using excised human skin 2 ~250μg / cm 2 , preferably 65 μg / cm 2 ~230μg / cm 2 , especially 65-130μg / cm 2 , or 170-230 μg / cm 2 25. The transdermal therapeutic system according to any one of clauses 1 to 24, providing a cumulative permeation amount of selexipag of. Clause 26. The selexipag-containing layer structure comprises: A) a lining layer; B) a selexipag-containing layer, 1. A therapeutically effective amount of selexipag, 2. at least one polar polymer, and 3. The transdermal therapeutic system according to any one of clauses 1 to 25, comprising: a selexipag-containing layer comprising at least one non-polar polymer. Clause 27. The selexipag-containing layer structure comprises: A) a lining layer; B) a selexipag-containing layer, 1. A therapeutically effective amount of selexipag, 2. At least one polar polymer which is polyvinylpyrrolidone; and 3. The transdermal therapeutic system according to any one of clauses 1 to 25, comprising: a selexipag-containing layer comprising at least one non-polar polymer, the at least one non-polar polymer comprising polyisobutylene. Clause 28. The selexipag-containing layer structure comprises: A) a lining layer; B) a selexipag-containing layer, 1. A therapeutically effective amount of selexipag, 2. at least one polar polymer; 3. at least one non-polar polymer, and 4. The transdermal therapeutic system of any one of clauses 1 to 25, comprising: a selexipag-containing layer, the selexipag-containing layer comprising at least one enhancer. Clause 29. The selexipag-containing layer structure comprises: A) a lining layer; B) a selexipag-containing layer, 1. A therapeutically effective amount of selexipag, 2. at least one polar polymer; 3. at least one non-polar polymer, and 4. The transdermal therapeutic system of any one of clauses 1 to 25, comprising: the selexipag-containing layer comprising at least one enhancer which is methyl laurate. Clause 30. The selexipag-containing layer structure comprises: A) a lining layer; B) a selexipag-containing layer, 1. A therapeutically effective amount of selexipag, 2. at least one polar polymer which is an acrylic polymer; and 3. The transdermal therapeutic system according to any one of clauses 1 to 25, comprising: a selexipag-containing layer comprising at least one non-polar polymer, the at least one non-polar polymer comprising polyisobutylene. Clause 31. The selexipag-containing layer structure comprises: A) a lining layer; B) a selexipag-containing layer, 1. A therapeutically effective amount of selexipag, 2. at least one polar polymer which is an acrylic polymer; 3. at least one non-polar polymer, the at least one non-polar polymer comprising polyisobutylene; 4. The transdermal therapeutic system of any one of clauses 1 to 25, comprising: the selexipag-containing layer comprising at least one enhancer which is methyl laurate. Clause 32. A transdermal therapeutic system according to any one of clauses 1 to 31 for use in a method for treating a human patient. Clause 33. A transdermal therapeutic system according to any one of clauses 1 to 31 for use in a method for treating pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) in a human patient.

Claims

1. A transdermal therapeutic system for transdermal administration of selexipag comprising a self-adhesive selexipag-containing layer structure, the self-adhesive selexipag-containing layer structure comprising: A) a backing layer; B) a selexipag-containing layer, 1. Selexipag, 2. at least one polar polymer, and 3. The transdermal therapeutic system comprising: the self-adhesive selexipag-containing layer comprising at least one non-polar polymer.

2. 2. The transdermal therapeutic system according to claim 1, wherein the content of selexipag in the selexipag-containing layer is in the range of 0.1 to 8.0% by weight, preferably 0.5 to 5.5% by weight, based on the total weight of the selexipag-containing layer.

3. the selexipag-containing layer further comprises an enhancer, preferably selected from the group consisting of tetrahydrofurfuryl alcohol polyethylene glycol ether, levulinic acid, transcutol, lauryl lactate, methyl laurate, dihydrolevoglucosenone, dimethylpropylene urea, and mixtures thereof, in particular methyl laurate; and / or 3. The transdermal therapeutic system of claim 1 or 2, wherein the selexipag-containing layer further comprises an enhancer in the range of 2.0 to 15.0 wt %, more preferably 3.0 to 8.0 wt %, based on the total weight of the selexipag-containing layer.

4. the at least one non-polar polymer is a pressure sensitive adhesive; and / or The transdermal therapeutic system according to any one of claims 1 to 3, wherein the at least one non-polar polymer is selected from the group consisting of silicone polymers, polyisobutylene polymers, styrene polymers, and mixtures thereof, preferably selected from polyisobutylene polymers, styrene polymers, and mixtures thereof.

5. The transdermal therapeutic system according to any one of claims 1 to 4, wherein the at least one non-polar polymer is a polyisobutylene blend, which is a combination of polyisobutylene and polybutene, preferably in a weight ratio of the mass of the polyisobutylene to the mass of the polybutene of 20:1 to 1:1, in particular 8:1 to 3:

1.

6. The transdermal therapeutic system according to any one of claims 1 to 5, wherein the at least one non-polar polymer is a styrene polymer, preferably a styrene-isoprene-styrene block copolymer, more preferably the weight ratio between the mass of the styrene and the mass of the isoprene is from 1:20 to 1:2, preferably from 1:15 to 1:

3.

7. The transdermal therapeutic system of claim 6, wherein the selexipag-containing layer further comprises a tackifier, preferably a thermoplastic ester resin, in particular a thermoplastic ester resin derived from glycerol and highly stabilized rosin.

8. the selexipag-containing layer further comprises a tackifier; 8. The transdermal therapeutic system according to claim 6 or 7, wherein the weight ratio of the mass of the styrene polymer to the mass of the tackifier is from 1:5 to 1:1, preferably from 1:4 to 1:2, and / or the content of the tackifier in the selexipag-containing layer is in the range of 30.0 to 80.0 wt.%, preferably 40.0 to 70.0 wt.%, in particular 45.0 to 60.0 wt.%, based on the total weight of the selexipag-containing layer.

9. The transdermal therapeutic system according to any one of claims 1 to 8, wherein the at least one polar polymer is selected from the group consisting of acrylic polymers, polyvinylpyrrolidone, and mixtures thereof.

10. The transdermal therapeutic system according to any one of claims 1 to 9, wherein said at least one polar polymer is polyvinylpyrrolidone, preferably crospovidone.

11. the content of the at least one non-polar polymer in the selexipag-containing layer is in the range of 50.0 to 90.0 wt. %, preferably 60.0 to 85.0 wt. %, in particular 70.0 to 80.0 wt. %, based on the total weight of the selexipag-containing layer; or The transdermal therapeutic system according to any one of claims 1 to 10, wherein the content of the at least one non-polar polymer in the selexipag-containing layer is in the range of 5.0 to 40.0 wt.%, preferably 10.0 to 30.0 wt.%, in particular 12.0 to 25.0 wt.%, based on the total weight of the selexipag-containing layer.

12. The transdermal therapeutic system according to any one of claims 1 to 11, wherein the content of the at least one polar polymer, preferably polyvinylpyrrolidone, in the selexipag-containing layer is in the range of 5.0 to 30.0 wt%, preferably 15.0 to 27.0 wt%, based on the total weight of the selexipag-containing layer.

13. The selexipag-containing layer is a selexipag-containing matrix layer, and / or the area weight of the selexipag-containing layer is 70 to 220 g / m ２ , preferably 95 to 160 g / m ２ The transdermal therapeutic system according to any one of claims 1 to 12, wherein the range is

14. 10 μg / cm over a 48 hour period as measured in Franz diffusion cells using excised human skin ２ ~120μg / cm ２ , preferably 20 μg / cm ２ ~115μg / cm ２ and / or 30 μg / cm over a 168 hour period as measured in Franz diffusion cells using excised human skin ２ ~250μg / cm ２ , preferably 65 μg / cm ２ ~230μg / cm ２ Provide the cumulative permeation amount of selexipag of The transdermal therapeutic system according to any one of claims 1 to 13.

15. A transdermal therapeutic system according to any one of claims 1 to 14 for use in a method for treating a human patient.

Images