Transdermal therapeutic system for transdermal administration of fingolimod

Abstract

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

Description

[Technical field]

[0001] The present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of fingolimod, processes for its manufacture and use, and methods of treatment therewith. [Background technology]

[0002] The active ingredient, fingolimod (2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol), is a sphingosine-1-phosphate receptor modulator. Immunomodulators sequester lymphocytes in lymph nodes, preventing them from contributing to autoimmune responses.

[0003] Fingolimod-containing products are commercially available for treating patients with relapsing-remitting multiple sclerosis. The commercially available product GILENYA® contains 0.5 mg of fingolimod hydrochloride in a hard capsule for oral administration.

[0004] Several side effects have been associated with products for oral administration. For transdermal therapeutic systems (TTS) for transdermal administration of active agents, lower side effects are expected compared to oral dosage forms. Furthermore, due to the simple mode of application of the TTS, higher convenience is achieved for the patient. In particular, a longer administration period (e.g., 1 week) on the skin of human patients is beneficial for compliance. However, providing a TTS with sufficient permeation rate of the active agent and the desired physical properties for the required period is technically challenging. In particular, in the case of fingolimod, which requires enzymatic activation (phosphorylation) in cells to cause internalization of sphingosine-1-phosphate receptors, which internalization sequesters lymphocytes in lymph nodes, the question is whether the TTS can deliver fingolimod to the enzyme for phosphorylation in sufficient amounts and fast enough to achieve a systemic effect.

[0005] Although there are known reports of substances that enhance the transdermal permeability of active agents, such skin permeation enhancers may delay the release of active agents due to physical or chemical transformation of the active agents in some cases, cause additional skin irritation, and negatively affect the physical properties of the TTS (e.g., adhesion and low-temperature flow properties). Since fingolimod, which has an amino-diol structure, is prone to react with functional groups, providing a TTS with sufficient permeation rate over an extended period of time for transdermal administration of fingolimod is particularly challenging.

[0006] There is a need in the art for a fingolimod TTS that does not have the problems mentioned above. In particular, there is a need for a TTS for transdermal administration of fingolimod that provides an early onset of therapeutic effect and continuous delivery of fingolimod over an extended period of time, thereby improving patient compliance. Summary of the Invention

[0007] It is an object of certain embodiments of the present invention to provide a TTS for transdermal administration of fingolimod (eg, fingolimod base).

[0008] It is a further object of certain embodiments of the present invention to provide a TTS for transdermal administration of fingolimod (eg, fingolimod base) that provides a sufficient permeation rate for achievement of a therapeutically effective dose.

[0009] It is a further object of the present invention to provide a TTS for transdermal administration of fingolimod (e.g. fingolimod base) with high active agent utilization (i.e. a TTS that does not require a high excess amount of active agent to provide sufficient release performance during the administration period).

[0010] It is an object of certain embodiments of the present invention to provide a TTS for transdermal administration of fingolimod (eg, fingolimod base) that provides an early onset of permeation of fingolimod.

[0011] An object of certain embodiments of the present invention is to provide a TTS for transdermal administration of fingolimod (e.g., fingolimod base) that provides a sufficient permeation rate of fingolimod over the desired administration period (e.g., over 84 hours or 168 hours).

[0012] It is an object of certain embodiments of the present invention to provide a TTS for transdermal administration of fingolimod (e.g., fingolimod base) that requires a relatively small amount of fingolimod to be contained therein, provides an early onset of fingolimod permeation, and provides a sufficient permeation rate of fingolimod over the administration period (e.g., over 84 hours or 168 hours).

[0013] It is an object of certain embodiments of the present invention to provide a TTS for transdermal administration of fingolimod that is easy to manufacture.

[0014] These objects and others are achieved by the present invention which relates to a transdermal therapeutic system for transdermal administration of fingolimod, comprising a fingolimod-containing layer structure according to one embodiment, the fingolimod-containing layer structure comprising a backing layer and a fingolimod-containing layer comprising a therapeutically effective amount of fingolimod (e.g., fingolimod base), at least one polymer and dodecan-1-ol, wherein the weight ratio of dodecan-1-ol:fingolimod is in the range of 1.5:1 to 5:1.

[0015] It has been found that a fingolimod (eg, fingolimod base) containing TTS according to the present invention provides advantageous fingolimod delivery over an extended period of time with a short lag time for permeation of fingolimod following application of the TTS.

[0016] According to a further aspect, the TTS according to the invention is for use in a method for treating an immune disorder, preferably multiple sclerosis. Thus, according to one aspect, the invention relates to the use of the TTS according to the invention for the manufacture of a medicament, preferably for the manufacture of a medicament for the treatment of multiple sclerosis, and to a method for treating an immune disorder, preferably a method for treating multiple sclerosis.

[0017] According to yet another aspect, the present invention provides a method for producing a method for manufacturing a pharmaceutical composition comprising: 1) A fingolimod-containing coating composition, a) fingolimod (e.g. fingolimod base), b) at least one polymer; c) dodecan-1-ol, d) optionally a solvent; providing the composition comprising: 2) coating a fingolimod-containing coating composition onto a release liner in an amount that provides a desired areal weight; 3) drying the coated fingolimod-containing coating composition to provide a fingolimod-containing layer; 4) laminating the fingolimod-containing layer to a backing layer to provide a fingolimod-containing layer structure; 5) optionally providing an additional skin contact layer by coating and drying an active agent-free or active agent-containing coating composition according to steps 2 and 3, removing the release liner of the fingolimod-containing layer, and laminating the adhesive side of the skin contact layer onto the adhesive side of the fingolimod-containing layer to provide a fingolimod-containing layer structure; 6) punching out individual systems from the fingolimod-containing layered structure; 7) optionally adhering the active agent-free self-adhesive layer structure, which also includes a backing layer and an active agent-free pressure-sensitive adhesive layer, to a separate system, which is larger than the separate system of the fingolimod-containing layer structure; The present invention also relates to a method for producing a TTS according to the present invention, comprising:

[0018] According to yet another aspect, the present invention relates to the use of dodecan-1-ol for reducing the permeation lag time of fingolimod (e.g., fingolimod base) in a transdermal therapeutic system for the transdermal administration of fingolimod.

[0019] According to a particular aspect, the present invention relates to a transdermal therapeutic system for transdermal administration of fingolimod comprising a fingolimod-containing layer structure, the fingolimod-containing layer structure comprising A) a backing layer and B) a fingolimod-containing layer, the fingolimod-containing layer comprising a) a therapeutically effective amount of fingolimod (e.g., fingolimod base), b) at least one silicone acrylic hybrid pressure sensitive adhesive, and c) dodecan-1-ol, wherein the weight ratio of dodecan-1-ol:fingolimod is in the range of 1.5:1 to 5:1.

[0020] According to another specific aspect, the present invention relates to a transdermal therapeutic system for transdermal administration of fingolimod comprising a fingolimod-containing layer structure, the fingolimod-containing layer structure comprising A) a backing layer and B) a fingolimod-containing layer, the fingolimod-containing layer comprising a) a therapeutically effective amount of fingolimod (e.g., fingolimod base), b) at least one polymer-based pressure-sensitive adhesive, c) dodecan-1-ol, and d) at least one cellulose derivative (e.g., ethyl cellulose), wherein the weight ratio of dodecan-1-ol:fingolimod is in the range of 1.5:1 to 5:1.

[0021] According to yet another specific aspect, the present invention relates to a transdermal therapeutic system for transdermal administration of fingolimod, comprising a fingolimod-containing layer structure, the fingolimod-containing layer structure comprising A) a backing layer and B) a fingolimod-containing layer; the fingolimod-containing layer comprises a) a therapeutically effective amount of fingolimod (e.g., fingolimod base), b) at least one acrylate-based pressure-sensitive adhesive, and c) dodecan-1-ol, wherein the weight ratio of dodecan-1-ol:fingolimod is in the range of 1.5:1 to 5:1, the fingolimod-containing layer does not comprise a polymer selected from the group consisting of alkyl methacrylate copolymers, aminoalkyl methacrylate copolymers, methacrylic acid copolymers, methacrylic acid ester copolymers, ammonioalkyl methacrylate copolymers, and polyvinylpyrrolidone, and the fingolimod-containing layer does not comprise organosulfur compounds.

[0022] According to yet another specific aspect, the present invention relates to a transdermal therapeutic system for transdermal administration of fingolimod, comprising a fingolimod-containing layer structure, the fingolimod-containing layer structure comprising A) a backing layer and B) a fingolimod-containing layer, the fingolimod-containing layer comprising a) a therapeutically effective amount of fingolimod (e.g., fingolimod base), b) at least one pressure-sensitive adhesive based on polyisobutylene or polysiloxane, and c) dodecan-1-ol, the weight ratio of dodecan-1-ol:fingolimod being in the range of 1.5:1 to 5:1, the fingolimod-containing layer being free of a polymer selected from the group consisting of alkyl methacrylate copolymers, aminoalkyl methacrylate copolymers, methacrylic acid copolymers, methacrylic acid ester copolymers, ammonioalkyl methacrylate copolymers, and polyvinylpyrrolidone, and the fingolimod-containing layer being free of organosulfur compounds.

[0023] 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., fingolimod) is administered to the systemic circulation via transdermal delivery, and refers to the entire individual dosage unit that is applied to the skin of a patient 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 on top of the active agent-containing layer structure. The active agent-containing layer structure may be placed 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" particularly refers to a system that provides transdermal delivery, excluding active delivery, for example, 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).

[0024] Within the meaning of the present invention, the term "fingolimod-containing layer structure" refers to a layer structure containing a therapeutically effective amount of fingolimod and comprising a backing layer and at least one active agent-containing layer. Preferably, the fingolimod-containing layer structure is a fingolimod-containing self-adhesive layer structure.

[0025] Within the meaning of the present invention, the term "therapeutically effective amount" refers to an amount of active agent in the TTS that is sufficient to provide treatment for immune disorders (e.g., multiple sclerosis) if 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 the 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.

[0026] Within the meaning of the present invention, the terms "active substance", "active agent" and the like, and the term "fingolimod" refer to fingolimod in any pharma- ceutically acceptable chemical and morphological forms and physical states, including, but not limited to, fingolimod in its free base form, protonated or partially protonated fingolimod, fingolimod salts, and acid addition salts formed in particular by the addition of inorganic or organic acids (such as fingolimod hydrochloride or sulfate, fingolimod phosphate, fingolimod tartrate, fingolimod maleate, fingolimod oxalate, fingolimod acetate, fingolimod lactate, etc.), solvates, hydrates, clathrates, complexes, etc., and fingolimod in the form of particles, which may be micronized, crystalline, and / or amorphous, as well as any mixture of the aforementioned forms. When contained in a medium such as a solvent, fingolimod may be dissolved or dispersed, or may be partially dissolved and partially dispersed. In the present invention, the fingolimod base is preferably dissolved or dispersed in a solvent of a polymer to form a fingolimod-containing coating composition, and is contained in the dried matrix layer in a dissolved or dispersed form, or in a partially dissolved and partially dispersed form.

[0027] When it is mentioned that fingolimod is used in a specific form in the manufacture of the TTS, this does not exclude interactions (e.g. salt formation or complex formation) between this form of fingolimod and other components of the fingolimod-containing layer structure in the final TTS. This means that even if fingolimod is included in its free base form, it may be present in the final TTS in a protonated or partially protonated form, or in the form of an acid addition salt, or if it is included in the form of a salt, a part of it may be present as a free base in the final TTS. Unless otherwise indicated, the amount of fingolimod in a particular layer structure relates to the amount of fingolimod included in the TTS during the manufacture of the TTS and is calculated based on the free base form fingolimod. For example, if a) 0.1 mmol (equal to 30.75 mg) fingolimod base or b) 0.1 mmol (equal to 34.39 mg) fingolimod hydrochloride is included in the TTS during manufacture, the amount of fingolimod in the layer structure, within the meaning of the present invention, is in both cases 30.75 mg (i.e. 0.1 mmol).

[0028] The fingolimod starting material included in the TTS during the manufacture of the TTS may be in the form of particles. Fingolimod may be present in the active agent-containing layer structure, for example in the form of particles that are preferably uniformly dispersed within the active agent-containing layer structure.

[0029] Within the meaning of the present invention, the term "particle" refers to a solid particulate material comprising individual particles, the size of which is negligible compared to the material. In particular, the particles are solids, including plastic / deformable solids, including amorphous and crystalline materials.

[0030] 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. fingolimod) is not dissolved or is not completely dissolved. Dispersing in the meaning of the present invention includes the dissolution of a portion of the starting material (e.g. fingolimod particles) depending on the solubility of the starting material (e.g. solubility of fingolimod in the coating composition).

[0031] There are two main types of TTS for active agent delivery, namely matrix-type TTS and reservoir-type TTS. The release of the active agent in matrix-type TTS is mainly controlled by the matrix containing the active agent itself. In contrast, reservoir-type TTS typically requires a rate-controlling membrane to control the release of the active agent. In principle, matrix-type TTS may also contain a rate-controlling membrane. However, matrix-type TTS usually has the advantage over reservoir-type TTS in that a rate-determining membrane is not required and dose dumping due to membrane rupture cannot occur. In summary, matrix-type transdermal therapeutic systems (TTS) are less complicated to manufacture and easier and more convenient to use by patients.

[0032] Within the meaning of the present invention, a "matrix-type TTS" refers to a system or structure in which the active agent is homogeneously dissolved and / or dispersed in a polymeric carrier (i.e., matrix), with the active agent and optionally remaining ingredients forming a matrix layer. In such a system, the matrix layer controls the release of the active agent from the TTS. Preferably, the matrix layer has sufficient adhesion to be self-supporting, so that sealing between other layers is not required. Thus, the active agent-containing layer, in one embodiment of the present invention, may be an active agent-containing matrix layer in which the active agent is homogeneously distributed in the polymeric matrix. In certain embodiments, the active agent-containing matrix layer may comprise two active agent-containing matrix layers that may be laminated together. The matrix-type TTS may be in the form of a "drug-in-adhesive" type TTS, which refers in particular to a system in which the active agent is homogeneously dissolved and / or dispersed in a pressure-sensitive adhesive matrix. In this context, the active agent-containing matrix layer may also be referred to as an active agent-containing pressure-sensitive adhesive layer or an active agent-containing pressure-sensitive adhesive matrix layer. A TTS that includes an active agent dissolved and / or dispersed within a polymer gel (eg, a hydrogel) is also considered to be a matrix type in accordance with the present invention.

[0033] A TTS with a liquid active agent-containing reservoir is referred to by the term "reservoir-type TTS". In such a system, the release of the active agent is preferably controlled by a rate-controlling membrane. In particular, the reservoir is sealed between a backing layer and a rate-controlling membrane. Thus, the active agent-containing layer may in one embodiment be an active agent-containing reservoir layer, which preferably comprises a liquid reservoir containing an active agent. Furthermore, a reservoir-type TTS typically additionally comprises a skin contact layer, which 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 in silicone oil. The skin contact layer typically has adhesive properties.

[0034] Reservoir-type TTS should not be understood as being matrix-type within the meaning of the present invention. However, microreservoir TTS (biphasic systems with deposits (e.g. spheres, droplets) of an inner active substance-containing phase dispersed in an outer polymer phase), which are considered in the art to be a mixed form of matrix-type TTS and reservoir-type TTS, different from homogeneous single-phase matrix-type TTS and reservoir-type TTS in the concept of drug transport and drug delivery, are judged to be matrix-type within the meaning of the present invention. The size of the microreservoir droplets can be determined by optical microscopy (e.g. Leica MZ16 with a camera (e.g. Leica DSC320)) by taking pictures of the microreservoir at different positions with an enhancement factor between 10 and 400 times, depending on the required detection limit. By using image analysis software, the size of the microreservoir can be determined.

[0035] Within the meaning of the present invention, the term "active agent-containing layer" refers to a layer that contains an active agent and provides a release area. The term includes active agent-containing matrix layers and active agent-containing reservoir layers. If the active agent-containing layer is an active agent-containing matrix layer, said layer is present in a matrix-type TTS. If the polymer is a pressure-sensitive adhesive, the matrix layer may also present the adhesive layer of the TTS, such that there is no additional skin contact layer. Alternatively, the additional skin contact layer may be present as an adhesive layer and / or an adhesive overlay is provided. The additional skin contact layer is typically manufactured to be active agent-free. However, due to the concentration gradient, the active agent 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 active agent-containing matrix layer or may be separated from the active agent-containing matrix layer by a membrane, preferably a rate-controlling membrane. Preferably, the active agent-containing matrix layer has sufficient adhesive properties, such that there is no additional skin contact layer. If the active agent-containing layer is an active agent-containing reservoir layer, the layer is present in a reservoir-type TTS, and the layer contains an active agent in a liquid reservoir. In addition, an additional skin contact layer is preferably present to provide adhesive properties. Preferably, a rate-controlling membrane separates the reservoir layer from the additional skin contact layer. The additional skin contact layer can be made to be active agent-free or active agent-containing. If the additional skin contact layer is active agent-free, the active agent will migrate from the reservoir layer to the skin contact layer over time due to a concentration gradient until equilibrium is reached. In addition, an adhesive overlay can be provided.

[0036] As used herein, the active agent-containing layer is preferably an active agent-containing matrix layer, which is referred to as the final solidified layer. Preferably, the active agent-containing matrix layer is obtained after coating and drying a solvent-containing coating composition as described herein. Alternatively, the active agent-containing matrix layer is obtained after melt coating and cooling. The active agent-containing matrix layer can also be produced by laminating two or more such solidified layers (e.g., dried or cooled layers) of the same composition to provide the desired areal weight. The matrix layer can be self-adhesive (in the form of a pressure-sensitive adhesive matrix layer) or the TTS can include an additional skin-contact layer of pressure-sensitive adhesive to provide sufficient adhesion. Preferably, the matrix layer is a pressure-sensitive adhesive matrix layer. Optionally, an adhesive overlay can be present. The matrix layer according to the present invention does not contain non-volatile solvent in an amount of more than 40% by weight based on the matrix layer. In certain embodiments of the present invention, the active agent-containing matrix layer contains non-volatile solvent in an amount of about 5% to about 20% by weight based on the active agent-containing matrix layer. Preferably, the active agent-containing matrix layer does not contain a non-volatile solvent.

[0037] Within the meaning of the present invention, the term "pressure-sensitive adhesive" (also abbreviated as "PSA") refers to a material that should adhere, especially by finger pressure, be permanently tacky, exert strong holding power, and be removable from a smooth surface without leaving a residue. The pressure-sensitive adhesive layer is "self-adhesive" when in contact with the skin, i.e. typically provides adhesion to the skin such that no further assistance is required for fixation on the skin. The "self-adhesive" layer structure comprises a pressure-sensitive adhesive layer for skin contact (i.e. a pressure-sensitive adhesive skin contact layer), which 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 utilized to promote adhesion. The pressure-sensitive adhesive properties of the pressure-sensitive adhesive depend on the polymer or polymer composition used.

[0038] Within the meaning of the present invention, the term "silicone acrylic hybrid polymer" refers to a polymerization product that contains repeat units of silicone subtype and acrylate subtype. Silicone acrylic hybrid polymer thus contains a silicone phase and an acrylic phase. The term "silicone acrylic hybrid" is intended to represent more than a simple blend of silicone-based subtype and acrylate-based subtype. Instead, the term represents a polymerized hybrid species that includes silicone-based subtype and acrylate-based subtype polymerized together. In the context of hybrid polymers used in the present invention, the terms acrylate and acrylic are generally used interchangeably, so silicone acrylic hybrid polymers can also be referred to as "silicone acrylate hybrid polymers".

[0039] Within the meaning of the present invention, the term "silicone acrylic hybrid pressure sensitive adhesive" refers to a silicone acrylic hybrid polymer in the form of a pressure sensitive adhesive. Silicone acrylic hybrid pressure sensitive adhesives are described, for example, in EP2599 847 and WO2016 / 130408. Examples of silicone acrylic hybrid pressure sensitive adhesives include PSA series 7-6100 and 7-6300 (7-610X and 7-630X; X=1, n-heptane based / X=2, ethyl acetate based), which are manufactured and supplied by Dow Corning in n-heptane or ethyl acetate. Depending on the solvent in which the silicone acrylic hybrid PSA is supplied, it has been found that the arrangement of the silicone phase and the acrylic phase is different, providing a continuous silicone or acrylic external phase and a corresponding discontinuous internal phase. If the silicone acrylic hybrid PSA is supplied in n-heptane, the composition contains a continuous silicone external phase and a discontinuous acrylic internal phase. If the silicone acrylic hybrid PSA composition is supplied in ethyl acetate, the composition contains a continuous acrylic external phase and a discontinuous silicone internal phase.

[0040] Within the meaning of the present invention, the term "silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality" includes the condensation reaction product of a silicone resin, a silicone polymer, and a silicon-containing capping agent that provides said acrylate or methacrylate functionality. It should be understood that the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality can contain only acrylate functionality, only methacrylate functionality, or both acrylate and methacrylate functionality.

[0041] As used herein, active agent-containing matrix layer is a layer that contains active agent dissolved or dispersed in at least one polymer, or a layer that contains active agent dissolved in a solvent to form an active agent-solvent mixture that is dispersed in the form of deposits (particularly droplets) in at least one polymer.Preferably, at least one polymer is a polymer-based pressure-sensitive adhesive (such as a silicone pressure-sensitive adhesive or a silicone acrylic hybrid pressure-sensitive adhesive).Within the meaning of the present invention, the term "pressure-sensitive adhesive layer" refers to the pressure-sensitive adhesive layer obtained from a solvent-containing adhesive coating composition after coating on a film and evaporating the solvent.

[0042] Within the meaning of the present invention, the term "skin contact layer" refers to a layer contained 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 contains an additional skin contact layer, the other layer of the active agent-containing layer structure is not in contact with the skin and does not necessarily have self-adhesive properties. As outlined above, the additional skin contact layer attached to the active agent-containing layer may absorb a portion of the active agent over time. The additional skin contact layer may be used to promote adhesion. The size of the additional skin contact layer and the active agent-containing layer is usually coextensive and corresponds to the release area. However, the area of ​​the additional skin contact layer may 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.

[0043] Within the meaning of the present invention, the term "areal weight" means g / m 2 Area weight refers to the dry weight of a particular layer (e.g., of a matrix layer) provided in. Area weight values ​​are subject to a tolerance of ±10% (preferably ±7.5%) due to manufacturing variations.

[0044] Unless otherwise indicated, "%" refers to % by weight.

[0045] Within the meaning of the present invention, the term "polymer" refers to any substance consisting of so-called repeating units obtained by polymerization of 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, etc., and in the case of copolymers, can be of any monomer arrangement, such as alternating copolymers, statistical copolymers, block copolymers, or graft polymers. The minimum molecular weight varies depending on the polymer type and is known to those skilled in the art. Polymers can have a molecular weight of, for example, more than 2000 Daltons, preferably more than 5000 Daltons, and more preferably more than 10,000 Daltons. Correspondingly, compounds with a molecular weight of less than 2000 Daltons, preferably less than 5000 Daltons, and more preferably less than 10,000 Daltons are usually referred to as oligomers.

[0046] Within the meaning of the present invention, the term "crosslinker" refers to a substance capable of crosslinking functional groups contained within a polymer.

[0047] Within the meaning of the present invention, the term "adhesive overlay" refers to a self-adhesive layer structure that is free of active agents and is larger in area than the active agent-containing structure, providing additional areas for adhesion to the skin, but not providing areas for release of the active agent, thereby promoting 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.

[0048] 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 periods, thus preventing active substance loss or cross-contamination in accordance with regulatory requirements. Preferably, the backing layer is also occlusive (meaning substantially impermeable to water and water vapor). Suitable materials for the backing layer include polyethylene terephthalate (PET), polyethylene (PE), ethylene vinyl acetate-copolymer (EVA), polyurethane, and mixtures thereof. Suitable backing layers are thus, for example, PET laminates, EVA-PET laminates, and PE-PET laminates. Woven or nonwoven backing materials are also suitable.

[0049] The TTS according to the invention may be characterized by certain parameters as measured in an in vitro skin permeation test.

[0050] Unless otherwise indicated, in vitro permeation tests are performed on dermatome-harvested split-thickness human skin with an intact epidermis at a thickness of 500 μm, with phosphate buffer at pH 5.5 (0.1% methyl-β-cyclodextrin and 0.1% saline azide at 32° C.) as receptor medium. The amount of active substance permeated into the receptor medium is determined at regular intervals using a validated HPLC method with a UV photometric detector by taking sample volumes. The receptor medium is completely or partially replaced by fresh medium when taking sample volumes, and the measured amount of active substance permeated relates to the amount permeated between the two previous sampling points, and not to the total amount permeated so far.

[0051] 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 in a sample interval at a particular time elapsed. For example, in the in vitro permeation test described above, where the amount of active substance permeated into the receptor medium is measured, for example, at 0, 8, 24, 36, 48, 72, 104, 144, and 168 hours, the amount of "active substance" permeation can be given, for example, for the sample interval from 36 to 48 hours, corresponding to the measurement at 48 hours, where the receptor medium has been completely replaced at 36 hours.

[0052] The permeation amount can also be given as "cumulative permeation amount", which corresponds to the cumulative amount of active agent permeated at a particular time point. For example, in the in vitro permeation test described above, where the amount of active agent permeated into the receptor medium is measured at, for example, 0, 8, 24, 36, 48, 72, 104, 144, and 168 hours, the cumulative permeation amount of "active agent" in 48 hours corresponds to the sum of the permeation amounts from 0 to 8 hours, from 8 to 24 hours, from 24 to 36 hours, and from 36 to 48 hours.

[0053] Within the meaning of the present invention, the parameter "skin permeation rate" for a particular sample interval at a particular time elapsed is expressed as μg / cm 2 - the amount of permeation (μg / cm) at said sample intervals provided in hours and measured by the in vitro permeation test described above 2 For example, in the skin permeation rate in the in vitro permeation test described above, where the amount of active substance permeated into the receptor medium is measured at, for example, 0, 8, 24, 36, 48, 72, 104, 144, and 168 hours, the "skin permeation rate" at 48 hours is calculated as the amount permeated in the sample interval from 36 hours to 48 hours divided by 12 hours.

[0054] 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 in vitro permeation test described above, in which the amount of active substance permeated into the receptor medium is measured at, for example, 0, 8, 24, 32, 48, 72, 104, 144, and 168 hours, 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.

[0055] Within the meaning of the present invention, the term "active agent utilization" refers to the cumulative permeation amount after a certain time period (eg, after 72 hours) divided by the initial loading amount of active agent.

[0056] Within the meaning of the present invention, the above parameters "permeation amount" and "skin permeation rate" (and "cumulative permeation amount" and "cumulative skin permeation rate") refer to the 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

number

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

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

[0059] Within the meaning of the present invention, the term "extended period of time" relates to a period of at least or about 72 hours (3 days), about 84 hours (3.5 days), at least or about 96 hours (4 days), or about 168 hours (7 days).

[0060] Within the meaning of the present invention, the term "room temperature" refers to the unmodified temperature found indoors in the laboratory where the experiments are performed, which usually falls within 15-35°C, preferably about 18-25°C.

[0061] Within the meaning of the present invention, the term "patient" refers to a subject presenting with clinical symptoms of a particular condition(s) indicating the need for treatment, a subject being treated preventatively or prophylactically for a condition, or a subject who has been diagnosed with a condition to be treated.

[0062] Within the meaning of the present invention, the term "pharmacokinetic parameters" refers to blood curves (e.g., C ) obtained by administering, e.g., single doses, multiple doses, or constant doses of an active agent-containing TTS (e.g., fingolimod-containing TTS) to healthy human subjects in clinical trials. max , C t , and AUC t1-t2 ) Pharmacokinetic parameters for individual subjects are expressed as arithmetic and geometric means (e.g., mean C max , mean AUCt, and mean AUCINF), as well as additional statistics such as the respective standard deviations and standard errors, minimum, maximum, and median if the list of values ​​is ranked. In the context of the present invention, pharmacokinetic parameters (e.g., C max , C t , and AUC t1-t2) refers to the geometric mean value unless otherwise indicated. It cannot be excluded that the absolute mean value obtained for a particular TTS in clinical trials varies to a certain degree between studies. To allow for the comparison of absolute mean values ​​between studies, a reference formulation (e.g. any future product based on the present invention) can be used as an internal standard. A comparison of the AUC per release area of ​​each reference product in previous and subsequent studies can be used to obtain a correction factor that takes into account the differences between studies.

[0063] A clinical trial according to the present invention refers to a trial conducted in full compliance with the International Conference for Harmonization of Clinical Trials (ICH) and all local applicable Good Clinical Practices (GCP) and regulations.

[0064] Within the meaning of the present invention, the term "subject population" refers to at least 5, preferably at least 10, individual subjects.

[0065] Within the meaning of the present invention, the term "geometric mean" refers to the mean of log-transformed data that has been transformed back to the original scale.

[0066] Within the meaning of the present invention, the term "arithmetic mean" refers to the sum of all observed values ​​divided by the total number of observations.

[0067] Within the meaning of the present invention, the parameter "AUC" corresponds to the area under the concentration-time curve. The AUC value is proportional to the total amount of active agent absorbed into the blood circulation and is therefore a measure for bioavailability.

[0068] Within the meaning of the present invention, "AUC t1-t2 The parameter " is given in (ng / ml) time and is calculated by the linear trapezoidal method for the area under the concentration-time curve from time t1 to time t2, unless otherwise indicated. Other calculation methods are, for example, the log-trapezoidal method and the linear-log-trapezoidal method.

[0069] Within the meaning of the present invention, "C max The parameter " is provided in (ng / ml) and relates to the maximum observed blood concentration of the active agent.

[0070] Within the meaning of the present invention, "C t The parameter " is provided in (ng / ml) and relates to the observed blood concentration of active agent at time t.

[0071] Within the meaning of the present invention, max The parameter is provided in time and C max It relates to the time point at which a value is reached. In other words, t max is the time point of the highest concentration observed.

[0072] Within the meaning of the present invention, the term "coating composition" refers to a composition containing all the components of a matrix layer in a solvent that can be coated onto a backing layer or release liner to form a matrix layer upon drying.

[0073] Within the meaning of the present invention, the term "pressure-sensitive adhesive composition" refers to a pressure-sensitive adhesive in a mixture with at least a solvent, such as n-heptane or ethyl acetate.

[0074] 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.

[0075] 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. [Brief description of the drawings]

[0076] [Figure 1a]1 illustrates the cumulative permeation of fingolimod over a 168 hour time interval for TTS prepared according to Example 1, Comparative Example A, Example 2, and Comparative Example B. [Figure 1b] 1 illustrates the skin permeation rate of fingolimod over a time interval of 168 hours for TTS prepared according to Example 1, Comparative Example A, Example 2, and Comparative Example B. [Figure 2a] 1 illustrates the cumulative permeation of fingolimod over a 168 hour time interval for TTS prepared according to Example 3, Comparative Example C, Example 4, and Comparative Example D. [Figure 2b] 1 illustrates the skin permeation rate of fingolimod over a time interval of 168 hours for TTS prepared according to Example 3, Comparative Example C, Example 4, and Comparative Example D. [Figure 3a] 1 illustrates the cumulative permeation of fingolimod over a 168 hour time interval for TTS prepared according to Example 4, Comparative Example D, Example 5, and Comparative Example E. [Figure 3b] 1 illustrates the skin permeation rate of fingolimod over a time interval of 168 hours for TTS prepared according to Example 4, Comparative Example D, Example 5, and Comparative Example E. [Figure 4a] 1 illustrates the cumulative permeation of fingolimod over a 168 hour time interval for TTS prepared according to Example 1, Comparative Example A, and Comparative Example F. [Figure 4b] 1 illustrates the skin permeation rate of fingolimod over a time interval of 168 hours for TTS prepared according to Example 1, Comparative Example A, and Comparative Example F. [Figure 5a] 1 illustrates the cumulative permeation of fingolimod over a time interval of 168 hours for TTS prepared according to Example 7-1 and Example 7-2. [Figure 5b] 1 illustrates the skin permeation rate of fingolimod over a time interval of 168 hours for TTS prepared according to Example 7-1 and Example 7-2. [Figure 6]1 illustrates concentrations of fingolimod and fingolimod phosphate in whole blood of minipigs over a time interval of 168 hours following daily oral administration of 0.5 mg fingolimod Gilenya™ capsules. [Figure 7] 1 illustrates the concentration of fingolimod in miniature pig whole blood over a time interval of 168 hours after application of a TTS prepared according to Examples 9-1 to 9-4. [Figure 8] 1 illustrates the concentration of fingolimod phosphate in miniature pig whole blood over a time interval of 168 hours after application of TTS prepared according to Examples 9-1 to 9-4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0077] TTS structure The present invention relates to a transdermal therapeutic system for transdermal administration of fingolimod, comprising a fingolimod-containing layer structure.

[0078] The fingolimod-containing layer structure according to the present invention comprises A) a backing layer, and B) a fingolimod-containing layer comprising a therapeutically effective amount of fingolimod, at least one polymer, and dodecan-1-ol. The fingolimod-containing layer structure is preferably a fingolimod-containing self-adhesive layer structure.

[0079] The backing layer is preferably substantially impermeable to fingolimod. Furthermore, as outlined above, it is preferred that the backing layer is occlusive.

[0080] The fingolimod-containing layer may be attached directly to the backing layer such that there are no additional layers between the backing layer and the fingolimod-containing layer.

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

[0082] The fingolimod-containing layer structure according to the present invention is usually placed on a removable protective layer (release liner), which is removed immediately before application 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.

[0083] In a preferred embodiment of the present invention, the fingolimod-containing layer is a fingolimod-containing pressure-sensitive adhesive layer and presents a skin contact layer. That is, the fingolimod-containing layer structure does not include an additional skin contact layer attached to the fingolimod-containing layer. In this context, the fingolimod-containing layer is preferably a self-adhesive fingolimod-containing matrix layer. The self-adhesive properties of the fingolimod-containing layer structure are preferably provided by a polymer. Thus, in a preferred embodiment of the present invention, the at least one polymer is a pressure-sensitive adhesive. Further details regarding the fingolimod-containing layer and the at least one polymer according to the present invention are provided further below.

[0084] In another embodiment of the present invention, the fingolimod-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 fingolimod-containing layer structure further comprises C) a skin contact layer on the fingolimod-containing layer. In this connection, the additional skin contact layer may also contain at least one polymer, which may be the same polymer or a different polymer as the at least one polymer contained in the fingolimod-containing layer. For example, when the additional skin contact layer comprises a polysiloxane-based pressure-sensitive adhesive, the fingolimod-containing layer may comprise the same polysiloxane-based pressure-sensitive adhesive, or a different polysiloxane-based pressure-sensitive adhesive, or a different non-hybrid or hybrid polymer. The additional skin contact layer is preferably obtainable by coating and drying an adhesive coating composition.

[0085] In certain embodiments of the invention where the fingolimod-containing layer structure includes an additional skin contact layer, the additional skin contact layer has a thickness 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% to about 100% by weight, preferably about 50% to about 100% by weight, more preferably about 60% to about 100% by weight, based on the skin contact layer. The skin contact layer may include an active agent. The active agent may also be fingolimod. The active agent in the skin contact layer may also be an additional active agent that is reasonable to administer together with fingolimod. In a preferred embodiment, the skin contact layer is active agent free, i.e., prepared without the addition of an active agent.

[0086] According to certain embodiments of the present invention, the TTS may further comprise an adhesive overlay, which is particularly larger in area than the fingolimod-containing structure and is attached thereto to promote the adhesive properties of the entire transdermal therapeutic system. The adhesive overlay comprises a backing layer and an adhesive layer. The adhesive overlay provides additional area for adhesion to the skin but does not add an area for release of fingolimod. The adhesive overlay comprises 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 contained in the fingolimod-containing layer structure. In one embodiment, the TTS does not contain an adhesive overlay on top of the fingolimod-containing layer structure.

[0087] Depending on the dosage, the release area of ​​the TTS is approximately 1 cm 2 ~about 50cm 2 , preferably about 1 cm 2 ~50cm 2 The range is less than.

[0088] The TTS according to the invention may further comprise one or more antioxidants. The antioxidants may be contained in the fingolimod-containing layer or in the additional skin contact layer, or in both the fingolimod-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 be conveniently present in the fingolimod-containing layer, preferably in an amount of about 0.001 to about 1.0% of the fingolimod-containing layer, more preferably in an amount of about 0.02 to about 0.5% of the fingolimod-containing layer.

[0089] In addition to the above-mentioned components, the TTS according to the present invention may further comprise at least one excipient or additive from the group of, for example, crosslinking agent, solubilizing agent, filling agent, tackifying agent, film-forming agent, plasticizing agent, stabilizing agent, softening agent, skin care agent, permeation enhancer, pH adjuster, and preservative.Generally, according to the present invention, it is preferred that no additional excipient or additive is required.Therefore, the TTS has a low complexity composition.In certain embodiments, no additional additive (such as skin permeation enhancer) is present in the TTS.

[0090] Fingolimod-containing layer As outlined in more detail above, the TTS according to the present invention comprises a fingolimod-containing layer structure comprising a fingolimod-containing layer. The fingolimod-containing layer according to the present invention comprises a therapeutically effective amount of fingolimod, at least one polymer and dodecan-1-ol. The weight ratio of dodecan-1-ol to fingolimod in the fingolimod-containing layer ranges from 1.5:1 to 5:1.

[0091] According to certain embodiments, the fingolimod-containing layer contains dodecan-1-ol and fingolimod in a weight ratio of dodecan-1-ol to fingolimod of 1.5:1 to 4:1, 1.5:1 to 2.5:1, 3:1 to 4:1, about 2.0:1, or about 3.3:1.

[0092] The fingolimod-containing layer may be a fingolimod-containing matrix layer or a fingolimod-containing reservoir layer. It is preferred that the fingolimod-containing layer is a fingolimod-containing matrix layer that contains fingolimod uniformly dispersed or dissolved in a polymer matrix. In another preferred embodiment, the fingolimod-containing layer is a fingolimod-containing biphasic matrix layer that includes an inner phase that contains a therapeutically effective amount of fingolimod and an outer phase that contains at least one polymer, and the inner phase forms a deposit dispersed in the outer phase. The content of the inner phase in the biphasic matrix layer may be about 5% to 40% by volume based on the volume of the biphasic matrix layer.

[0093] According to certain preferred embodiments, the fingolimod-containing layer is a self-adhesive fingolimod-containing matrix layer.

[0094] In certain embodiments, the fingolimod-containing layer can be obtained by coating and drying a fingolimod-containing coating composition comprising fingolimod in the form of a free base (preferably by coating and drying a fingolimod-containing coating composition comprising at least one polymer and dodecan-1-ol and a therapeutically effective amount of fingolimod in a weight ratio of dodecan-1-ol:fingolimod of 1.5:1 to 5:1).

[0095] According to a particular embodiment, the fingolimod-containing layer has a density of about 50 to about 200 g / m 2 , preferably about 60 to about 180 g / m 2 , more preferably about 80 to about 160 g / m 2 , about 100g / m 2 , or about 150 g / m 2It has an areal weight of

[0096] According to certain embodiments, the fingolimod-containing layer contains dodecan-1-ol in an amount of 2% to 40%, preferably 2% to 30%, more preferably 4% to 20%, about 10%, or about 15%, by weight based on the fingolimod-containing layer.

[0097] According to certain embodiments, the fingolimod-containing layer contains fingolimod in an amount of 1% to 20%, preferably 1% to 15%, more preferably 2% to 10%, about 3%, or about 7.5%, by weight based on the fingolimod-containing layer.

[0098] In certain embodiments, fingolimod in the fingolimod-containing layer may include pharma- ceutically acceptable chemical and morphological forms and physical states, such as pharma- ceutically acceptable salts thereof. In one embodiment, the fingolimod-containing layer includes a pharma- ceutically acceptable salt of fingolimod, such as fingolimod hydrochloride. However, according to the present invention, fingolimod in the fingolimod-containing layer is preferably included in the form of a free base.

[0099] According to certain embodiments, the fingolimod-containing layer contains at least one polymer in an amount of about 40% to about 99% by weight, preferably about 50% to about 99% by weight, more preferably about 60% to about 99% by weight, based on the fingolimod-containing layer. The at least one polymer is preferably selected from the group consisting of silicone-acrylic hybrid polymers, polysiloxane-based polymers, polyisobutylene-based polymers, and acrylate polymers. Further details regarding the at least one polymer according to the present invention are provided further below.

[0100] In one embodiment, the fingolimod-containing layer comprises a further polymer selected from the group consisting of silicone-acrylic hybrid polymers, polysiloxane-based polymers, polyisobutylene-based polymers, and acrylate polymers. The fingolimod-containing layer may thus comprise a blend of at least two polymers characterized by different chemical or physical properties. In a particular embodiment, the fingolimod-containing layer comprises a blend of at least two polyisobutylenes characterized by different physical properties.

[0101] In certain embodiments, the fingolimod-containing layer further comprises an auxiliary polymer. The auxiliary polymer may be contained in an amount of about 0.5% to about 20%, about 0.5% to about 10%, or about 1% to about 5% by weight based on the fingolimod-containing layer. The auxiliary polymer is preferably selected from the group consisting of alkyl methacrylate copolymers, amino alkyl methacrylate copolymers, methacrylic acid copolymers, methacrylic acid ester copolymers, ammonio alkyl methacrylate copolymers, polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymers, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymers, cellulose derivatives, and mixtures thereof. In one embodiment, the auxiliary polymer is a cellulose derivative (preferably ethyl cellulose).

[0102] In certain other embodiments, the fingolimod-containing layer does not comprise polyvinylpyrrolidone, and preferably the fingolimod-containing layer does not comprise a polymer selected from the group consisting of alkyl methacrylate copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, methacrylic acid ester copolymer, ammonioalkyl methacrylate copolymer, and polyvinylpyrrolidone.

[0103] According to certain embodiments, the total amount of polymer contained in the fingolimod-containing layer is in the range of about 50% to about 99% by weight, preferably about 60% to about 99% by weight, and more preferably about 70% to about 99% by weight, based on the fingolimod-containing layer.

[0104] When an additional skin contact layer is used, the components of the fingolimod-containing layer (such as fingolimod and optional additional active agents, optional auxiliary polymers, optional antioxidants, and optional additional excipients or additives) may migrate into the additional skin contact layer over time, however this depends on the components and the material of the skin contact layer.

[0105] According to certain embodiments, the fingolimod-containing layer does not include fatty acid esters.

[0106] According to certain embodiments, the fingolimod-containing layer does not include an ester of dodecanol (eg, lauryl lactate).

[0107] According to certain embodiments, the fingolimod-containing layer does not include organosulfur compounds (eg, DMSO).

[0108] According to certain embodiments, the fingolimod-containing layer is free of esters of dodecanol, organosulfur compounds, and fatty acid esters.

[0109] In one embodiment of the invention, the fingolimod-containing layer consists of fingolimod, dodecan-1-ol, and a polymer (eg, a polymer-based pressure sensitive adhesive).

[0110] polymer The fingolimod-containing layer according to the present invention comprises at least one polymer, which may be selected from the group consisting of silicone acrylic hybrid polymers, polysiloxane-based polymers, polyisobutylene-based polymers, and acrylate polymers.

[0111] In a preferred embodiment, the at least one polymer is a polymer-based pressure sensitive adhesive.

[0112] According to one embodiment of the present invention, at least one polymer is a silicone acrylic hybrid polymer.The silicone acrylic hybrid polymer comprises a polymerized hybrid species, which comprises a silicone-based subspecies and an acrylate-based subspecies polymerized together.The silicone acrylic hybrid polymer thus comprises a silicone phase and an acrylic phase.Preferably, the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive.

[0113] Silicone acrylic hybrid pressure sensitive adhesives are usually supplied and used in solvents such as n-heptane and ethyl acetate. The solids content of pressure sensitive adhesives is usually between 30% and 80%. Those skilled in the art know that the solids content can be modified by adding a suitable amount of solvent.

[0114] Preferably, the weight ratio of silicone to acrylate in the silicone acrylic hybrid pressure sensitive adhesive is 5:95 to 95:5, or 20:80 to 80:20, more preferably 40:60 to 60:40, and most preferably the ratio of silicone to acrylate is about 50:50. Suitable silicone acrylic hybrid pressure sensitive adhesives having a weight ratio of silicone to acrylate of 50:50 are, for example, commercially available silicone acrylic hybrid pressure sensitive adhesives 7-6102, silicone / acrylate ratio 50 / 50, and 7-6302, silicone / acrylate ratio 50 / 50, supplied in ethyl acetate by Dow Corning.

[0115] Suitable commercially available silicone acrylic hybrid pressure sensitive adhesives include PSA series 7-6100 and 7-6300 (7-610X and 7-630X; X=1, n-heptane based / X=2, ethyl acetate based) manufactured and supplied by Dow Corning in n-heptane or ethyl acetate. For example, 7-6102 silicone acrylic hybrid PSA with a 50 / 50 silicone / acrylate ratio is characterized by a solution viscosity of 2,500 cP at about 50% solids content in ethyl acetate at 25° C. and a complex viscosity of 1.0e7 poise at 0.1 rad / s at 30° C. 7-6302 silicone acrylic hybrid PSA with a 50 / 50 silicone / acrylate ratio has a solution viscosity of 1,500 cP at about 50% solids content in ethyl acetate at 25° C. and a complex viscosity of 4.0e6 poise at 0.1 rad / s at 30° C.

[0116] Depending on the solvent in which the silicone acrylic hybrid pressure sensitive adhesive is provided, the arrangement of the silicone phase and the acrylic phase is different, providing a silicone or acrylic continuous external phase and a corresponding discontinuous internal phase. If the silicone acrylic hybrid pressure sensitive adhesive is provided in n-heptane, the composition contains a continuous silicone external phase and a discontinuous acrylic internal phase. If the silicone acrylic hybrid pressure sensitive adhesive is provided in ethyl acetate, the composition contains a continuous acrylic external phase and a discontinuous silicone internal phase. After evaporating the solvent in which the silicone acrylic hybrid pressure sensitive adhesive is provided, the phase arrangement of the resulting pressure sensitive adhesive film or layer corresponds to the phase arrangement of the solvent-containing adhesive coating composition. For example, in the absence of any substance that can induce the inversion of the phase arrangement in the silicone acrylic hybrid pressure sensitive adhesive composition, the pressure sensitive adhesive layer prepared from the silicone acrylic hybrid pressure sensitive adhesive in n-heptane provides a continuous silicone external phase and a discontinuous acrylic internal phase, and the pressure sensitive adhesive layer prepared from the silicone acrylic hybrid pressure sensitive adhesive in ethyl acetate provides a continuous acrylic external phase and a discontinuous silicone internal phase. The phase arrangement of the composition can be determined, for example, in a peel force test by a pressure-sensitive adhesive film or layer prepared from the composition of silicone-acrylic hybrid PSA attached to a siliconized release liner. A pressure-sensitive adhesive film contains a continuous silicone external phase if the siliconized release liner cannot be removed from the pressure-sensitive adhesive film (laminated to a backing film) or can be hardly removed due to blocking of the two silicone surfaces. Blocking results from the adhesion of two silicone layers that contain similar surface energies. The adhesive shows good spreading on the siliconized liner and can therefore generate good adhesion to the liner. If the siliconized release liner can be easily removed, the pressure-sensitive adhesive film contains a continuous acrylic external phase. The acrylic adhesive does not have good spreading due to different surface energies and therefore has low or little adhesion to the siliconized liner.

[0117] According to a preferred embodiment of the present invention, the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive that can be obtained from a silicon-containing pressure-sensitive adhesive composition that contains acrylate or methacrylate functional groups. It should be understood that the silicon-containing pressure-sensitive adhesive composition that contains acrylate or methacrylate functional groups can contain only acrylate functional groups, only methacrylate functional groups, or both acrylate and methacrylate functional groups.

[0118] According to a particular embodiment of the present invention, the silicone acrylic hybrid pressure sensitive adhesive comprises the reaction product of (a) a silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups, (b) an ethylenically unsaturated monomer, and (c) an initiator. That is, the silicone acrylic hybrid pressure sensitive adhesive is the product of the chemical reaction between these reactants ((a), (b), and (c)). In particular, the silicone acrylic hybrid pressure sensitive adhesive comprises the reaction product of (a) a silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functional groups, (b) a (meth)acrylate monomer, and (c) an initiator (i.e., in the presence of the initiator). That is, the silicone acrylic hybrid pressure sensitive adhesive comprises the product of the chemical reaction between these reactants ((a), (b), and (c)).

[0119] The reaction product of (a) a silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups, (b) an ethylenically unsaturated monomer, and (c) an initiator may contain a continuous silicone external phase and a discontinuous acrylic internal phase, or the reaction product of (a), (b) and (c) may contain a continuous acrylic external phase and a discontinuous silicone internal phase.

[0120] The silicon-containing pressure sensitive adhesive composition (a) containing acrylate or methacrylate functional groups is typically present in the silicone acrylic hybrid pressure sensitive adhesive in an amount of from 5 to 95 (more typically from 25 to 75) parts by weight, based on 100 parts by weight of the hybrid pressure sensitive adhesive.

[0121] The ethylenically unsaturated monomer (b) is typically present in the silicone acrylic hybrid pressure sensitive adhesive in an amount of from 5 to 95 (more typically from 25 to 75) parts by weight, based on 100 parts by weight of the hybrid pressure sensitive adhesive.

[0122] The starting material (c) is typically present in the silicone acrylic hybrid pressure sensitive adhesive in an amount of from 0.005 to 3 (more typically from 0.01 to 2) parts by weight, based on 100 parts by weight of the hybrid pressure sensitive adhesive.

[0123] According to a particular embodiment of the present invention, the silicon-containing pressure-sensitive adhesive composition (a) containing acrylate or methacrylate functional groups comprises the condensation reaction product of (a1) silicone resin, (a2) silicone polymer, and (a3) ​​silicon-containing capping agent that provides said acrylate or methacrylate functional groups. Silicone resin (a1) can also be referred to as silicate resin or silica resin. Preferably, silicone polymer (a2) is a polysiloxane, preferably polydimethylsiloxane. It should be understood that (a1) and (a2) form a silicone-based pressure-sensitive adhesive by polycondensation, and acrylate or methacrylate functional groups are introduced by reaction with (a3).

[0124] According to one particular embodiment of the present invention, the silicon-containing pressure-sensitive adhesive composition (a) containing acrylate or methacrylate functional groups is (a1) a silicone resin; (a2) a silicone polymer; (a3) a silicon-containing capping agent providing said acrylate or methacrylate functionality, said capping agent having the general formula XYR′ b SiZ 3-b (In the formula, X is a monovalent radical of the general formula AE-, E is -O- or -NH-; A is an acrylic or methacrylic group; Y is a divalent alkylene radical having 1 to 6 carbon atoms; R' is a methyl group or a phenyl group; Z is a monovalent hydrolyzable organic radical or a halogen; b is 0 or 1) The silicon-containing capping agent, The condensation reaction product of a silicone resin and a silicone polymer are reacted to form a pressure sensitive adhesive, and a silicon-containing capping agent is introduced before, during, or after reacting the silicone resin and the silicone polymer; After the silicone resin and silicone polymer have been condensed to form the pressure sensitive adhesive, the silicon-containing capping agent reacts with the pressure sensitive adhesive; or The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer.

[0125] According to certain embodiments of the present invention, the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality comprises a condensation reaction product of a pressure-sensitive adhesive and a silicon-containing capping agent that provides said acrylate or methacrylate functionality. That is, the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functionality is essentially a pressure-sensitive adhesive capped or endblocked with a silicon-containing capping agent that provides said acrylate or methacrylate functionality, and the pressure-sensitive adhesive comprises a condensation reaction product of a silicone resin and a silicone polymer. Preferably, the silicone resin is reacted in an amount of 30 to 80 parts by weight to form the pressure-sensitive adhesive, and the silicone polymer is reacted in an amount of 20 to 70 parts by weight to form the pressure-sensitive adhesive. These parts by weight are both based on 100 parts by weight of the pressure-sensitive adhesive. Although not required, the pressure-sensitive adhesive may include a catalytic amount of a condensation catalyst. A variety of silicone resins and silicone polymers are suitable for forming the pressure-sensitive adhesive.

[0126] According to certain embodiments of the present invention, the silicone acrylic hybrid pressure sensitive adhesive comprises: (a) a silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups, (a1) a silicone resin; (a2) a silicone polymer; (a3) a silicon-containing capping agent providing said acrylate or methacrylate functionality, said capping agent having the general formula XYR′ b SiZ 3-b (In the formula, X is a monovalent radical of the general formula AE-, E is -O- or -NH-; A is an acrylic or methacrylic group; Y is a divalent alkylene radical having 1 to 6 carbon atoms; R' is a methyl group or a phenyl group; Z is a monovalent hydrolyzable organic radical or a halogen; b is 0 or 1) The silicon-containing capping agent, The condensation reaction product of a silicone resin and a silicone polymer are reacted to form a pressure sensitive adhesive, and a silicon-containing capping agent is introduced before, during, or after reacting the silicone resin and the silicone polymer; After the silicone resin and silicone polymer are condensed to form the pressure sensitive adhesive, a silicon-containing capping agent is reacted with the pressure sensitive adhesive; or The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer; the composition; (b) ethylenically unsaturated monomers; and (c) Starting material It is the reaction product of:

[0127] The silicone acrylic hybrid composition used in the present invention comprises: (i) a silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups, A silicone resin, A silicone polymer; The silicon-containing capping agent providing the acrylate or methacrylate functionality is of the general formula XYR' b SiZ 3-b (In the formula, X is a monovalent radical of the general formula AE-, E is -O- or -NH-; A is an acrylic or methacrylic group; Y is a divalent alkylene radical having 1 to 6 carbon atoms; R' is a methyl group or a phenyl group; Z is a monovalent hydrolyzable organic radical or a halogen; b is 0 or 1) The silicon-containing capping agent, The condensation reaction product of a silicone resin and a silicone polymer are reacted to form a pressure sensitive adhesive, and a silicon-containing capping agent is introduced before, during, or after reacting the silicone resin and the silicone polymer; After the silicone resin and silicone polymer are condensed to form the pressure sensitive adhesive, a silicon-containing capping agent is reacted with the pressure sensitive adhesive; or The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer; providing said composition; (ii) polymerizing the ethylenically unsaturated monomer and the silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups of step (i) in the presence of an initiator, optionally at a temperature of from 50° C. to 100° C. or from 65° C. to 90° C., to form a silicone acrylic hybrid composition; It can be described by being prepared by a method comprising:

[0128] During polymerization of the ethylenically unsaturated monomer containing acrylate or methacrylate functional groups and the silicon-containing pressure-sensitive adhesive composition, the ratio of silicone to acrylic can be controlled and optimized as desired. The ratio of silicone to acrylic can be controlled by various mechanisms in and during the method. An illustrative example of one such mechanism is the rate-controlled addition of the ethylenically unsaturated monomer(s) to the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups. In certain applications, it may be desirable to have a silicone-based sub-species or overall silicone content that exceeds the acrylate-based sub-species or overall acrylic content. In other applications, it may be desirable for the opposite to be true. Regardless of the end use application, as already described above, it is generally preferred that the silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups is present in the silicone acrylic hybrid composition in an amount of preferably from about 5 to about 95, more preferably from about 25 to about 75, and even more preferably from about 40 to about 60 parts by weight, based on 100 parts by weight of the silicone acrylic hybrid composition.

[0129] According to one particular embodiment of the present invention, the silicone acrylic hybrid composition used in the present invention comprises (i) a silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups, A silicone resin, A silicone polymer; The silicon-containing capping agent providing the acrylate or methacrylate functionality is of the general formula XYR' b SiZ 3-b (In the formula, X is a monovalent radical of the general formula AE-, E is -O- or -NH-; A is an acrylic or methacrylic group; Y is a divalent alkylene radical having 1 to 6 carbon atoms; R' is a methyl group or a phenyl group; Z is a monovalent hydrolyzable organic radical or a halogen; b is 0 or 1) The silicon-containing capping agent, The condensation reaction product of a silicone resin and a silicone polymer are reacted to form a pressure sensitive adhesive, and a silicon-containing capping agent is introduced before, during, or after reacting the silicone resin and the silicone polymer; After the silicone resin and silicone polymer are condensed to form the pressure sensitive adhesive, a silicon-containing capping agent is reacted with the pressure sensitive adhesive; or The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer; Providing the composition: (ii) polymerizing the ethylenically unsaturated monomer and the silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups of step (i) in a first solvent in the presence of an initiator at a temperature between 50° C. and 100° C. to form a silicone acrylic hybrid composition; (iii) removing the first solvent; and (iv) adding a second solvent to form a silicone acrylic hybrid composition, the phase distribution of the silicone acrylic hybrid composition being selectively controlled by the selection of the second solvent; It can be described by being prepared by a method comprising:

[0130] The silicone acrylic hybrid PSA composition used in the present invention comprises (i) a silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups, A silicone resin, A silicone polymer; The silicon-containing capping agent providing the acrylate or methacrylate functionality is of the general formula XYR' b SiZ 3-b (In the formula, X is a monovalent radical of the general formula AE-, E is -O- or -NH-; A is an acrylic or methacrylic group; Y is a divalent alkylene radical having 1 to 6 carbon atoms; R' is a methyl group or a phenyl group; Z is a monovalent hydrolyzable organic radical or a halogen; b is 0 or 1) The silicon-containing capping agent, The condensation reaction product of a silicone resin and a silicone polymer are reacted to form a pressure sensitive adhesive, and a silicon-containing capping agent is introduced before, during, or after reacting the silicone resin and the silicone polymer; After the silicone resin and silicone polymer are condensed to form the pressure sensitive adhesive, a silicon-containing capping agent is reacted with the pressure sensitive adhesive; or The silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer; Providing the composition: (ii) polymerizing the ethylenically unsaturated monomer and the silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups of step (i) in a first solvent in the presence of an initiator at a temperature between 50° C. and 100° C. to form a silicone acrylic hybrid composition; (iii) adding a processing solvent, the processing solvent having a higher boiling point than the first solvent; and (iv) applying heat at a temperature between 70° C. and 150° C. such that a majority of the first solvent is selectively removed; (v) removing the treatment solution; and (vi) adding a second solvent to form a silicone acrylic hybrid composition, the phase distribution of the silicone acrylic hybrid composition being selectively controlled by the selection of the second solvent; It may also be described by being prepared by a method comprising the steps of:

[0131] The silicone resin according to the preceding paragraph has the formula R X 3 SiO 1 / 2 and triorganosiloxy units of the formula SiO 4 / 2 In the present invention, the copolymer may include a copolymer containing tetrafunctional siloxy units of from 0.1 to 0.9 (preferably about 0.6 to 0.9) triorganosiloxy units for each tetrafunctional siloxy unit. Preferably, each R X independently represent a monovalent hydrocarbon radical having 1 to 6 carbon atoms, a vinyl group, a hydroxyl group, or a phenyl group.

[0132] The silicone polymer according to the preceding paragraph may comprise at least one polydiorganosiloxane, preferably end-capped (end-blocked) with a functional group selected from the group consisting of hydroxyl, alkoxy, hydride, vinyl, or mixtures thereof. The diorgano substituents may be selected from the group consisting of dimethyl, methylvinyl, methylphenyl, diphenyl, methylethyl, (3,3,3-trifluoropropyl)methyl, and mixtures thereof. Preferably, the diorgano substituents contain only methyl groups. The molecular weight of the polydiorganosiloxane will typically range from about 50,000 to about 1,000,000 (preferably from about 80,000 to about 300,000). Preferably, the polydiorganosiloxane is end-blocked TR. X ASiO 1 / 2 AR terminated by unit X The polydiorganosiloxane comprises SiO units and has a viscosity of about 100 centipoise to about 30,000,000 centipoise at 25° C., and each A radical is R X or a halohydrocarbon radical having 1 to 6 carbon atoms, each T radical being independently selected from R X , OH, H, or OR Y Each R is independently selected from the group consisting of Y is independently an alkyl radical having 1 to 4 carbon atoms.

[0133] As an example of the use of preferred silicone resins and preferred silicone polymer forms, one type of pressure sensitive adhesive is (i) Each present SiO 4 / 2 R of 0.6~0.9 for units X 3 SiO 1 / 2 R in mole ratio units X 3 SiO 1 / 2 Units and SiO 4 / 2 (ii) 30 to 80 parts by weight (inclusive) of at least one resin copolymer consisting essentially of endblock TR X ASiO 1 / 2 AR terminated by unit X at least one polydiorganosiloxane comprising SiO units, the polydiorganosiloxane having a viscosity of from about 100 centipoise to about 30,000,000 centipoise at 25° C., each R X is a monovalent organic radical selected from the group consisting of hydrocarbon radicals of 1 to 6 carbon atoms (inclusive), and each A radical is R X or a halohydrocarbon radical having 1 to 6 carbon atoms (inclusive), each T radical being independently selected from R X , OH, H, or OR Y Each R is independently selected from the group consisting of Yare independently an alkyl radical of 1 to 4 carbon atoms (inclusive), in about 20 to about 70 parts by weight of said polydiorganosiloxane, (iii) at least one of the silicon-containing capping agents (also referred to throughout as endblocking agents) described below in a sufficient amount to provide a silanol content or concentration in the range of 5,000 to 15,000 (more typically 8,000 to 13,000) ppm, and, if desired, (iv) an additional catalytic amount ( (ii)), and, if necessary, (v) an organic solvent inert to (i), (ii), (iii), and (iv) to reduce the viscosity of the mixture of (i), (ii), (iii), and (iv), in an effective amount, and condensing the mixture of (i), (ii), (iii), and (iv) until at least a substantial amount of the silicon-containing capping agent(s) has reacted with the silicon-bonded hydroxyl radicals and T radicals of (i) and (ii). Additional organosilicon endblocking agents may be used in conjunction with the silicon-containing capping agent(s) (iii) of the present invention.

[0134] Silicon-containing capping agents according to the preceding paragraphs may be selected from the group consisting of acrylate-functional silanes, acrylate-functional silazanes, acrylate-functional disilazanes, acrylate-functional disiloxanes, methacrylate-functional silanes, methacrylate-functional silazanes, methacrylate-functional disilazanes, meth-acrylate-functional disiloxanes, and combinations thereof, and may be represented by the general formula XYR′ b SiZ 3-bwherein X is a monovalent radical of the general formula AE-, E is -O- or -NH-, A is an acrylic or methacrylic group, Y is a divalent alkylene radical having 1 to 6 carbon atoms, R' is a methyl or phenyl group, Z is a monovalent hydrolyzable organic radical or a halogen, and b is 0, 1 or 2. Preferably, the monovalent hydrolyzable organic radical is of the general formula R''0-, wherein R'' is an alkylene radical. Most preferably, this particular endblocking agent is 3-methacryloxypropyldimethylchlorosilane, 3-methacryloxypropyldichlorosilane, 3-methacryloxypropyltrichlorosilane, 3-methacryloxypropyldimethylmethoxysilane, 3-methacryloxypropylmethyldimethoxysilane, 3-methacryloxypropyltrimethoxysilane, 3-methacryloxypropyldimethylethoxysilane, 3-methacryloxypropylmethyldiethoxysilane, 3-methacryloxypropyltriethoxysilane, (methacryloxymethyl)dimethylmethoxysilane, (methacryloxymethyl)methyldimethoxysilane, (methacryloxymethyl)trimethoxy ...

[0033] The compound is selected from the group consisting of silane, (methacryloxymethyl)dimethylethoxysilane, (methacryloxymethyl)methyldiethoxysilane, methacryloxymethyltriethoxysilane, methacryloxy-propyltriisopropoxysilane, 3-methacryloxypropyldimethylsilazane, 3-acryloxy-propyldimethylchlorosilane, 3-acryloxypropyldichlorosilane, 3-acryloxypropyl-trichlorosilane, 3-acryloxypropyldimethylmethoxysilane, 3-acryloxy-propylmethyldimethoxysilane, 3-acryloxypropyltrimethoxysilane, 3-acryloxypropyl-dimethylsilazane, and combinations thereof.

[0135] The ethylenically unsaturated monomer according to the previous paragraph can be any monomer having at least one carbon-carbon double bond.Preferably, the ethylenically unsaturated monomer according to the previous paragraph can be a compound selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates, cycloaliphatic methacrylates, and combinations thereof.It should be understood that each of the compounds (aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates, and cycloaliphatic methacrylates) contains an alkyl radical.The alkyl radical of these compounds can contain up to 20 carbon atoms. The aliphatic acrylate that may be selected as one of the ethylenically unsaturated monomers is selected from the group consisting of methyl acrylate, ethyl acrylate, propyl acrylate, n-butyl acrylate, iso-butyl acrylate, tert-butyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, iso-octyl acrylate, iso-nonyl acrylate, iso-pentyl acrylate, tridecyl acrylate, stearyl acrylate, lauryl acrylate, and mixtures thereof. The aliphatic methacrylate that may be selected as one of the ethylenically unsaturated monomers is selected from the group consisting of methyl methacrylate, ethyl methacrylate, propyl methacrylate, n-butyl methacrylate, iso-butyl methacrylate, tert-butyl methacrylate, hexyl methacrylate, 2-ethylhexyl methacrylate, iso-octyl methacrylate, iso-nonyl methacrylate, iso-pentyl methacrylate, tridecyl methacrylate, stearyl methacrylate, lauryl methacrylate, and mixtures thereof. The alicyclic acrylate that may be selected as one of the ethylenically unsaturated monomers is cyclohexyl acrylate, and the alicyclic methacrylate that may be selected as one of the ethylenically unsaturated monomers is cyclohexyl methacrylate.

[0136] It should be understood that the ethylenically unsaturated monomer used to prepare the silicone acrylic hybrid pressure sensitive adhesive can be two or more ethylenically unsaturated monomers. That is, a combination of ethylenically unsaturated monomers can be polymerized (more specifically copolymerized) with the silicon-containing pressure sensitive adhesive composition containing acrylate or methacrylate functional groups and the initiator. According to a certain embodiment of the present invention, the silicone acrylic hybrid pressure sensitive adhesive is prepared by using at least two different ethylenically unsaturated monomers (preferably selected from the group of 2-ethylhexyl acrylate and methyl acrylate), preferably in a ratio of 40:60 to 70:30, more preferably in a ratio of 65:35 to 55:45 or 55:45 to 45:50, particularly preferably in a ratio of 50% 2-ethylhexyl acrylate and 50% methyl acrylate, or in a ratio of 60% 2-ethylhexyl acrylate and 40% methyl acrylate, as the acrylic monomer.

[0137] The initiator according to the previous paragraph can be any suitable material for initiating the polymerization of the silicon-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups and ethylenically unsaturated monomers to form silicone acrylic hybrids.For example, free radical initiators selected from the group of peroxides, azo compounds, redox initiators, and photoinitiators can be used.

[0138] Further suitable silicone resins, silicone polymers, silicon-containing capping agents, ethylenically unsaturated monomers, and initiators that can be used in accordance with the preceding paragraphs are detailed in WO2007 / 145996, EP2599847A1, and WO2016 / 130408.

[0139] According to certain embodiments of the present invention, the silicone acrylic hybrid polymer comprises the reaction product of a silicone polymer, a silicone resin, and an acrylic polymer, where the acrylic polymer is covalently self-crosslinked and covalently bonded to the silicone polymer and / or the silicone resin.

[0140] According to certain other embodiments of the present invention, the silicone acrylic hybrid polymer comprises the reaction product of a silicone polymer, a silicone resin, and an acrylic polymer, the silicone resin comprising triorganosiloxy units R 3 SiO 1 / 2 where R is an organic group, and tetrafunctional siloxy units SiO 4 / 2 Each of the SiO 4 / 2 R of 0.1 to 0.9 3 SiO 1 / 2 The molar ratio of each component is expressed as:

[0141] The acrylic polymer may include at least an alkoxysilyl-functional monomer, a polysiloxane-containing monomer, a halosilyl-functional monomer, or an alkoxyhalosilyl-functional monomer. Preferably, the acrylic polymer is prepared from an alkoxysilyl-functional monomer selected from the group consisting of trialkoxysilyl (meth)acrylates, dialkoxyalkylsilyl (meth)acrylates, and mixtures thereof, or includes end-capped alkoxysilyl functional groups. The alkoxysilyl functional groups may preferably be selected from the group consisting of trimethoxylsilyl groups, dimethoxymethylsilyl groups, triethoxylsilyl groups, diethoxymethylsilyl groups, and mixtures thereof.

[0142] Acrylic polymers can also be prepared from mixtures that include polysiloxane-containing monomers, preferably mixtures that include polydimethylsiloxane mono(meth)acrylate.

[0143] The silyl-functional monomer is typically used in an amount of from 0.2 to 20% by weight of the acrylic polymer, and more preferably the amount of silyl-functional monomer will range from about 1.5 to about 5% by weight of the acrylic polymer.

[0144] The amount of polysiloxane-containing monomer is typically used in an amount of from 1.5 to 50% by weight of the acrylic polymer, and more preferably the amount of polysiloxane-containing monomer will range from about 5 to about 15% by weight of the acrylic polymer.

[0145] Alternatively, the acrylic polymer includes a block or graft copolymer of acrylic and polysiloxane. An example of a polysiloxane block copolymer is a polydimethylsiloxane-acrylic block copolymer. The preferred amount of siloxane block is 10-50% by weight of the total block polymer.

[0146] The acrylic polymer includes an alkyl (meth)acrylate monomer. Preferred alkyl (meth)acrylates that can be used have up to about 18 carbon atoms in the alkyl group, preferably 1 to about 12 carbon atoms in the alkyl group. Preferred low glass transition temperature (Tg) alkyl acrylates with homopolymer Tg less than about 0° C. have about 4 to about 10 carbon atoms in the alkyl group and include butyl acrylate, amyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, octyl acrylate, isooctyl acrylate, decyl acrylate, isomers thereof, and combinations thereof. Butyl acrylate, 2-ethylhexyl acrylate, and isooctyl acrylate are particularly preferred. The acrylic polymer component can further include (meth)acrylate monomers with high Tg, such as methyl acrylate, ethyl acrylate, methyl methacrylate, and isobutyl methacrylate.

[0147] The acrylic polymer component may further include polyisobutylene groups to improve the low temperature flow properties of the resulting adhesive.

[0148] The acrylic polymer component may include nitrogen-containing polar monomers, examples of which include N-vinylpyrrolidone, N-vinylcaprolactam, N-tertiary octyl acrylamide, dimethylacrylamide, diacetone acrylamide, N-tertiary butyl acrylamide, N-isopropyl acrylamide, cyanoethyl acrylate, N-vinyl acetamide, and N-vinyl formamide.

[0149] The acrylic polymer component may include one or more hydroxyl-containing monomers, such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, hydroxypropyl acrylate, and / or hydroxypropyl methacrylate.

[0150] The acrylic polymer component may include carboxylic acid-containing monomers, if desired. Useful carboxylic acids preferably contain from about 3 to about 6 carbon atoms and include, among others, acrylic acid, methacrylic acid, itaconic acid, β-carboxyethyl acrylate, and the like. Acrylic acid is particularly preferred.

[0151] Other useful and well known comonomers include vinyl acetate, styrene, cyclohexyl acrylate, alkyl di(meth)acrylates, glycidyl methacrylate, and allyl glycidyl ether, as well as macromers such as poly(styryl) methacrylate.

[0152] One acrylic polymer component that can be used in the practice of the present invention is an acrylic polymer containing from about 90 to about 99.5% by weight butyl acrylate and from about 0.5 to about 10% by weight dimethoxymethylsilyl methacrylate.

[0153] According to certain embodiments of the present invention, a silicone acrylic hybrid polymer may be prepared by a) reacting a silicone polymer with a silicone resin to form a resultant product, and b) reacting the resultant product of a) with an acrylic polymer containing reactive functional groups, where the components are reacted in an organic solvent.

[0154] According to certain embodiments of the present invention, a silicone acrylic hybrid polymer may be prepared by a) reacting a silicone resin with an acrylic polymer containing reactive functional groups to form a resultant product, and b) reacting the resultant product of a) with a silicone polymer, where the components are reacted in an organic solvent.

[0155] According to certain embodiments of the present invention, a silicone acrylic hybrid polymer may be prepared by a) reacting a silicone polymer with an acrylic polymer containing reactive functional groups to form a resultant product, and b) reacting the resultant product of a) with a silicone resin, where the components are reacted in an organic solvent.

[0156] Further suitable acrylic polymers, silicone resins, and silicone polymers that can be used to chemically react together to provide a silicone acrylic hybrid polymer according to the previous paragraph are detailed in WO2010 / 124187.

[0157] According to certain embodiments of the present invention, at least one polymer is a non-hybrid polymer. A non-hybrid polymer (e.g., a non-hybrid pressure sensitive adhesive) is a polymer (e.g., a polymer-based pressure sensitive adhesive) that does not contain a hybrid species. Non-hybrid polymers (e.g., non-hybrid pressure sensitive adhesives) based on polysiloxane, polyisobutylene, and acrylate are preferred.

[0158] Non-hybrid polymers (eg, non-hybrid pressure sensitive adhesives) can be included in the active agent-containing layer structure and / or in the adhesive overlay.

[0159] Non-hybrid pressure sensitive adhesives are typically supplied and used in solvents such as n-heptane and ethyl acetate. The solids content of pressure sensitive adhesives is typically between 30% and 80%.

[0160] Suitable non-hybrid polymers according to the invention are commercially available, for example under the trade names BIO-PSA (polysiloxane-based pressure sensitive adhesive), Oppanol™ (polyisobutylene), or Duro-Tak™ (acrylic polymer).

[0161] According to one embodiment of the present invention, at least one polymer is a polysiloxane-based polymer. The polysiloxane-based polymer may also be referred to as a silicone-based polymer or a polysiloxane-based polymer. The suitable polysiloxane-based polymer is preferably a polysiloxane-based pressure-sensitive adhesive. The polysiloxane-based pressure-sensitive adhesive may also be referred to as a silicone-based adhesive, a silicone-based pressure-sensitive adhesive, a polysiloxane-based adhesive, or a polysiloxane-based pressure-sensitive adhesive. These polysiloxane-based pressure-sensitive adhesives provide suitable adhesion and rapid bonding to various skin types (including wet skin), suitable adhesive and cohesive qualities, sustained adhesion to skin, high flexibility, permeability to moisture, and compatibility with many active substances and film substrates. It is possible to provide the adhesive with sufficient amine resistance and thus promoting stability in the presence of amines. Such pressure sensitive adhesives are based on the resin-in-polymer concept, where polysiloxane-based pressure sensitive adhesives are prepared by condensation reaction of silanol endblocked polydimethylsiloxane with silica resin (also called silicate resin) and the remaining silanol functional groups are additionally capped with trimethylsiloxy groups for amine stability. The content of silanol endblocked polydimethylsiloxane contributes to the viscoelastic behavior of the viscous component and influences the wetting and spreading properties of the adhesive. The resin acts as a tackifier and reinforcing agent and participates in the elastic component. The right balance between silanol endblocked polydimethylsiloxane and resin provides the right adhesive properties.

[0162] Examples of commercially available silicone-based PSA compositions include the standard BIO-PSA series (7-4400, 7-4500, and 7-4600 series) and the amine-compatible (end-capped) BIO-PSA series (7-4100, 7-4200, and 7-4300 series), typically manufactured and distributed by Dow Corning in n-heptane or ethyl acetate. For example, BIO-PSA 7 (4201) has a solution viscosity of 450 mPas at 25° C. and about 60% solids content in heptane and a viscosity of 1×10 at 0.01 rad / s at 30° C. 8 It is characterized by a complex viscosity in poise. BIO-PSA 7-4301 has a solution viscosity of 500 mPas at 25° C. and approximately 60% solids content in heptane, and a complex viscosity of 1×10 at 0.01 rad / s at 30° C. 6 It has a complex viscosity in poise.

[0163] Polysiloxane-based pressure-sensitive adhesives are supplied and used in a solvent such as n-heptane, ethyl acetate, or other volatile silicone fluids. The solids content of polysiloxane-based pressure-sensitive adhesives in the solvent is usually between 60 and 85% (preferably between 70 and 80% or between 60 and 75%). Those skilled in the art know that the solids content can be modified by adding a suitable amount of solvent.

[0164] According to one embodiment of the invention, the at least one polymer is a polyisobutylene-based polymer (preferably a polyisobutylene-based pressure-sensitive adhesive). A suitable polyisobutylene according to the invention is available under the trade name Oppanol®. A combination of high molecular weight polyisobutylene (e.g. N100, N80) and medium molecular weight polyisobutylene (e.g. B10, B12) may be used. A suitable ratio of medium molecular weight polyisobutylene to high molecular weight polyisobutylene ranges from 100:1 to 1:100, preferably from 95:5 to 40:60, more preferably from 90:10 to 80:20. A preferred example for a polyisobutylene combination is B10: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 Mv of 40,000, a weight average molecular weight Mw of 53,000 and an average molecular weight distribution M of 3.2. w / M n In certain embodiments, polybutene can be added to polyisobutylene. The solid content of polyisobutylene in the solvent is usually between 30-50% (preferably between 35-40%). Those skilled in the art know that the solid content can be modified by adding a suitable amount of solvent.

[0165] According to one embodiment of the invention, the at least one polymer is an acrylate-based 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 between 30% and 60%. Such acrylate-based pressure sensitive adhesives may or may not contain functional groups, such as hydroxy groups, carboxylic acid groups, neutralized carboxylic acid groups, and mixtures thereof. Thus, the term "functional groups" refers in particular to hydroxy groups and carboxylic acid groups, as well as deprotonated carboxylic acid groups.

[0166] 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, and 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, t-octyl acrylamide, and vinyl acetate.

[0167] In a preferred embodiment, the acrylate-based pressure sensitive adhesive does not contain vinyl acetate.

[0168] In one embodiment of the present invention, the at least one polymer is an acrylate-based pressure sensitive adhesive that is a copolymer based on 2-ethylhexyl acrylate, 2-hydroxyethyl-acrylate, and methyl acrylate.

[0169] Specific acrylate-based pressure sensitive adhesives include: Duro-Tak™ 387-2510 or Duro-Tak™ 87-2510 (copolymer 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 copolymer based on vinyl acetate, 2-ethylhexyl acrylate, and 2-hydroxyethyl-acrylate, provided as a solution in ethyl acetate without 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 crosslinker), Duro-Tak™ 387-2516 or Duro-Tak™ 87-2516 (a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl-acrylate, and glycidyl-methacrylate provided as a solution in ethyl acetate, ethanol, n-heptane, and methanol with a titanium crosslinker); Duro Tak™ 387-2051 or Duro Tak™ 87-2051 (a copolymer based on acrylic acid, butyl acrylate, 2-ethylhexyl acrylate and vinyl acetate provided as a solution in ethyl acetate and heptane); Duro-Tak™ 387-2353 or Duro-Tak™ 87-2353 (a copolymer based on acrylic acid, 2-ethylhexyl acrylate, glycidyl methacrylate, and methyl acrylate provided as a solution in ethyl acetate and hexane); Duro-Tak™ 87-4098 (a copolymer based on 2-ethylhexyl acrylate and vinyl acetate, provided as a solution in ethyl acetate) It is available as.

[0170] In a preferred embodiment, the acrylate-based pressure sensitive adhesive does not contain a crosslinker.

[0171] In a preferred embodiment of the present invention, the acrylate-based pressure sensitive adhesive does not contain a carboxyl group as a functional group.

[0172] In one embodiment, the acrylate-based pressure sensitive adhesive is free of functional groups.

[0173] Auxiliary polymers may be added, for example, to promote cohesion and / or adhesion, or to reduce the low temperature fluidity of the polymer layer, as solubilizers, or as crystallization inhibitors.

[0174] The auxiliary polymer may be selected from the group consisting of alkyl methacrylate copolymers, amino alkyl methacrylate copolymers, methacrylic acid copolymers, methacrylic acid ester copolymers, ammonio alkyl methacrylate copolymers, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymers, cellulose derivatives, and mixtures thereof. In one embodiment, the auxiliary polymer is a cellulose derivative, preferably ethyl cellulose.

[0175] Emission Characteristics The TTS according to the present invention is designed to administer fingolimod transdermally into the systemic circulation for a predetermined extended period of time (e.g., at least or about 72 hours, about 84 hours, or about 96 hours, preferably about 168 hours).

[0176] In one embodiment, the TTS according to the invention described above provides an average release rate of 0.1-1.0 mg / day, preferably 0.3-0.7 mg / day, more preferably 0.4-0.6 mg / day of fingolimod over an extended period of time (e.g., at least or about 72 hours, about 84 hours, about 96 hours, or about 168 hours). For example, the TTS according to the invention described above provides an average release rate of 0.1-1.0 mg / day of fingolimod over at least 72 hours.

[0177] In certain embodiments, the TTS according to the invention described above provides a therapeutic effect of 1.5 μg / cm2 within the first 24 hours of administration as measured in a Franz diffusion cell on dermatome-harvested human skin. 2 > 1.5 μg / cm 2 Super~15.0μg / cm 2 , about 2.0μg / cm 2 ~15.0μg / cm 2 , 2.5-15.0μg / cm 2 , 3.0-15.0μg / cm 2 , or 5.0 to 15.0 μg / cm 2 The cumulative permeation amount of fingolimod is preferably determined by measuring the amount of fingolimod permeated through a Franz diffusion cell in 500 μm thick dermatome-excised human skin using a phosphate buffer solution of pH 5.5 containing 0.1% methyl-β-cyclodextrin and 0.1% saline azide as an antibacterial agent at a temperature of 32±1° C.

[0178] In certain embodiments, the TTS according to the invention described above provides a therapeutic effect of 6.0 μg / cm2 within the first 36 hours of administration as measured in a Franz diffusion cell on dermatome-harvested human skin. 2 >6.0 μg / cm2 Super~40.0μg / cm 2 , about 7.0μg / cm 2 ~40.0μg / cm 2 , 9.0-40.0μg / cm 2 , 10.0-40.0μg / cm 2 , or 15.0 to 40 μg / cm 2 The cumulative permeation amount of fingolimod is preferably determined by measuring the amount of fingolimod permeated through a Franz diffusion cell in 500 μm thick dermatome-excised human skin using a phosphate buffer solution of pH 5.5 containing 0.1% methyl-β-cyclodextrin and 0.1% saline azide as an antibacterial agent at a temperature of 32±1° C.

[0179] In certain embodiments, the TTS according to the invention described above has a therapeutic efficacy of 0.1 μg / cm 16 hours after administration as measured in a Franz diffusion cell on dermatome-harvested human skin. 2 - More than 0.1 μg / cm 2 -Over time ~1.0μg / cm 2 -time, approximately 0.15μg / cm 2 -Time~1.0μg / cm 2 -time, 0.2~1.0μg / cm 2 -hours or 0.2μg / cm 2 -Time~1.0μg / cm 2 The present invention provides a skin permeation rate of fingolimod in -h, which is preferably determined by measuring the amount of fingolimod permeated in a Franz diffusion cell in 500 μm thick dermatome-excised human skin using a phosphate buffer solution of pH 5.5 containing 0.1% methyl-β-cyclodextrin and 0.1% saline azide as an antibacterial agent at a temperature of 32±1°C.

[0180] According to certain embodiments of the invention, the TTS has a C ratio of 0.2:1 to 0.8:1, 0.3:1 to 0.7:1, or about 0.5:1 over a period of about 168 hours following administration of a single dose to a subject population. max Fingolimod phosphate: C maxThe ratio of fingolimod is provided.

[0181] Methods of Treatment / Medical Use According to a particular embodiment of the invention, the TTS according to the invention is for use in a method of treating an immune disorder, such as multiple sclerosis.

[0182] According to certain embodiments of the present invention, the TTS is for use in a method for treating an immune disorder, wherein the transdermal therapeutic system is applied onto the skin of a patient for at least or about 72 hours (3 days), about 84 hours (3.5 days), or about 168 hours (7 days). Preferably, the TTS is applied for about 168 hours (7 days).

[0183] According to certain embodiments of the invention, the TTS has a C ratio of 0.2:1 to 0.8:1, 0.3:1 to 0.7:1, or about 0.5:1 over a period of about 168 hours following administration of a single dose to a subject population. max Fingolimod phosphate: C max The ratio of fingolimod is provided.

[0184] According to one aspect, the present invention relates to fingolimod base for use in a method for treating an immune disorder, preferably multiple sclerosis, wherein the fingolimod base is administered to the skin of a patient in a transdermal therapeutic system according to the present invention.

[0185] According to one aspect, the present invention relates to the use of the TTS according to the present invention for the manufacture of a medicament for treating an immune disorder. In particular, the present invention relates to the use of the TTS according to the present invention for the manufacture of a medicament for treating multiple sclerosis, preferably the TTS is applied to the skin of a patient for at least about 72 hours (3 days), about 84 hours (3.5 days), or about 168 hours (7 days).

[0186] According to another aspect, the present invention relates to a method of treating an immune disorder, preferably multiple sclerosis, by applying a transdermal therapeutic system according to the present invention to the skin of a patient. In this regard, the TTS described above is preferably applied to the skin of a patient for at least about 72 hours (3 days), about 84 hours (3.5 days), or about 168 hours (7 days).

[0187] Manufacturing method The present invention relates to 1) A fingolimod-containing coating composition, a) fingolimod (e.g. fingolimod base), b) at least one polymer (e.g., a polymer-based pressure sensitive adhesive); c) dodecan-1-ol, d) optionally a solvent; providing said composition comprising: 2) coating a fingolimod-containing coating composition onto a release liner in an amount that provides a desired areal weight; 3) drying the coated fingolimod-containing coating composition to provide a fingolimod-containing layer; 4) laminating the fingolimod-containing layer to a backing layer to provide a fingolimod-containing layer structure; 5) optionally providing an additional skin contact layer by coating and drying an active agent-free or active agent-containing coating composition according to steps 2 and 3, removing the release liner of the fingolimod-containing layer, and laminating the adhesive side of the skin contact layer onto the adhesive side of the fingolimod-containing layer to provide a fingolimod-containing layer structure; 6) punching out individual systems from the fingolimod-containing layered structure; 7) optionally adhering the active substance-free self-adhesive layer structure, which also comprises a backing layer and an active agent-free pressure-sensitive adhesive layer, to a separate system, which is larger than the separate system of the fingolimod-containing self-adhesive layer structure; The present invention further relates to a method for producing a transdermal therapeutic system according to the present invention, comprising:

[0188] In a preferred embodiment, at least one polymer is a pressure sensitive adhesive polymer, preferably provided as a solution in ethyl acetate, n-heptane, or hexane.

[0189] In one embodiment, in step 1), fingolimod is present in the form of fingolimod base and is combined with dodecanol and at least one polymer in ethyl acetate, n-heptane, or hexane to provide a fingolimod-containing coating composition.

[0190] In step 3) and optionally step 5) of the above preparation process, drying is preferably carried out at a temperature of 20-90°C. EXAMPLES

[0191] The present invention will now be more fully described with reference to the accompanying examples. However, it should be understood that the following description is illustrative only and should not be construed as limiting the invention in any way.

[0192] Example 1 Coating Composition The formulation of the fingolimod base-containing coating composition is summarized below. [Table 1]

[0193] Preparation of the Coating Composition Fingolimod base was placed in a suitable mixing vessel (beaker) and n-heptane was added. Subsequently, a pressure sensitive adhesive (DURO-TAK 87-6908, based on polyisobutylene in the form of a mixture in n-heptane, with a solids content of 38% by weight, purchased from Henkel) was added to the slurry. Ethyl cellulose (purchased from IMCD) was added to the mixture with stirring and the mass was stirred for approximately 3 hours.

[0194] For Comparative Example F, octyldodecanol (Eutanol™ G, purchased from Sigma Aldrich) was added followed by n-heptane.

[0195] For Example 1, 1-dodecanol (purchased from Alfa Aesar) was added followed by n-heptane.

[0196] Coating of the coating composition The fingolimod base-containing coating composition was coated onto a slippery polyethylene terephthalate (PET) foil (which can serve as a release liner) within 24 hours and dried at room temperature and at 60° C. for 15 minutes each.

[0197] The coating thickness, after removal of the solvent, is approximately 100 g / m 2 The dried film was then laminated with a backing layer (polyethylene terephthalate (PET) foil 19 μm) to provide a fingolimod-containing self-adhesive layer structure.

[0198] Preparation of TTS (all examples) Individual systems (TTS) were then die cut from the fingolimod-containing self-adhesive layer structure.

[0199] In certain embodiments, the TTS described above may be provided with an adhesive overlay (i.e., a larger surface area additional self-adhesive layer structure) preferably with rounded corners, including a pressure-sensitive adhesive matrix layer free of active ingredients and a preferably skin-colored backing layer, and then the TTS is die-cut and enclosed into a pouch of the primary packaging material.

[0200] Example 2 Coating Composition The formulation of the fingolimod base-containing coating composition is summarized below. [Table 2]

[0201] Preparation of the Coating Composition Fingolimod base was placed in a suitable mixing vessel (beaker) and n-heptane was added. Pressure sensitive adhesive (DURO-TAK 87-6908, purchased from Henkel, based on polyisobutylene in the form of a mixture in n-heptane, with a solids content of 38% by weight) was added to the slurry. Polyvinylpyrrolidone (Kollidon™, purchased from BASF) was added to the mixture with stirring and the mass was stirred for approximately 3 hours.

[0202] For Example 2, 1-dodecanol (purchased from Alfa Aesar) was added followed by n-heptane.

[0203] Coating of the coating composition See Example 1.

[0204] Preparation of TTS See Example 1.

[0205] Example 3 Coating Composition The formulation of the fingolimod base-containing coating composition is summarized below. [Table 3]

[0206] Preparation of the Coating Composition Fingolimod base was placed in a suitable mixing vessel (beaker) and n-heptane was added. Pressure sensitive adhesive (DURO-TAK 87-6908, based on polyisobutylene in the form of a mixture in n-heptane, with a solids content of 38% by weight, purchased from Henkel) was added to the slurry. Crospovidone was added to the mixture with stirring, and the mass was stirred for approximately 3 hours.

[0207] For Example 3, 1-dodecanol (purchased from Alfa Aesar) was added followed by n-heptane.

[0208] Coating of the coating composition See Example 1.

[0209] Preparation of TTS See Example 1.

[0210] Example 4 Coating Composition The formulation of the fingolimod base-containing coating composition is summarized below. [Table 4]

[0211] Preparation of the Coating Composition Fingolimod base was placed in a suitable mixing vessel (beaker) and n-heptane was added. Pressure sensitive adhesive (an acrylic adhesive in ethyl acetate and hexane, with a solids content of 41.2% by weight, purchased from Henkel, DURO-TAK 387-2510) was added to the slurry. The mass was stirred for approximately 3 hours.

[0212] For Example 4, 1-dodecanol (purchased from Alfa Aesar) was added followed by the solvent n-heptane.

[0213] Coating of the coating composition See Example 1.

[0214] Preparation of TTS See Example 1.

[0215] Example 5 Coating Composition The formulation of the fingolimod-containing coating composition is summarized below. [Table 5]

[0216] Preparation of the Coating Composition Fingolimod base was placed in a suitable mixing vessel (beaker) and n-heptane was added. Pressure sensitive adhesive (acrylic adhesive in ethyl acetate and hexane, DURO-TAK 387-2510, purchased from Henkel, with a solids content of 41.2% by weight) was added to the slurry. Polyvinylpyrrolidone (Kollidon™, purchased from BASF) was added to the mixture with stirring and the mass was stirred for approximately 3 hours.

[0217] For Example 5, 1-dodecanol (purchased from Alfa Aesar) was added followed by n-heptane.

[0218] Coating of the coating composition See Example 1.

[0219] Preparation of TTS See Example 1.

[0220] Example 6 Skin permeation measurements The permeation amount of fingolimod and the corresponding skin permeation rate of the TTS prepared according to Examples 1 to 5 were determined by in vitro experiments according to OECD guidelines (adopted on April 13, 2004) performed with a 7.0 ml Franz diffusion cell. Split-thickness human skin (female abdomen, born 1996) from a cosmetic surgery procedure was used. A dermatome was used to prepare 500 μm thick skin with intact epidermis for all TTS. 1.16 cm from the TTS was used. 2 A die cut with an area of ​​was punched out. The permeation amount of fingolimod was measured in the receptor medium (phosphate buffer solution at pH 5.5 containing 0.1% methyl-β-cyclodextrin and 0.1% saline azide as antibacterial agent) of Franz diffusion cells at a temperature of 32±1°C, and the corresponding cumulative permeation amount and skin permeation rate were calculated.

[0221] The results are shown in Tables 6-1 to 6-4 below and in Figures 1a to 4b. [Table 6-1] [Table 6-2] [Table 7-1] [Table 7-2] [Table 8] [Table 9]

[0222] Example 7-1 and Example 7-2 Coating Composition The formulation of the fingolimod-containing coating composition is summarized below. [Table 10]

[0223] Preparation of the Coating Composition Fingolimod base was placed in a suitable mixing vessel (beaker) and 1-dodecanol was added. Solvent n-hexane was added to the slurry and ethylcellulose (purchased from IMCD) was added to the mixture with stirring. The mass was stirred for approximately 1.5 hours. Pressure sensitive adhesive (based on polyisobutylene in the form of a mixture in n-heptane, with a solids content of 41.28% by weight, from BASF, Oppanol™ B10 / N100 in a ratio of 85 / 15) was added and the mass was stirred for approximately 1 hour.

[0224] Coating of the coating composition See Example 1.

[0225] Preparation of TTS See Example 1.

[0226] Example 8 Skin permeation measurements The permeation amount of fingolimod and the corresponding skin permeation rate of the TTS prepared according to Examples 7-1 and 7-2 were determined by in vitro experiments according to OECD guidelines (adopted on April 13, 2004) performed with a 7.0 ml Franz diffusion cell. Split-thickness human skin (female abdomen, born in 1991) from a cosmetic surgery was used. A dermatome was used to prepare 500 μm thick skin with intact epidermis for all TTS. 1.16 cm from the TTS was used. 2 A die cut with an area of ​​was punched out. The permeation amount of fingolimod was measured in the receptor medium (phosphate buffer solution at pH 5.5 containing 0.1% methyl-β-cyclodextrin and 0.1% saline azide as antibacterial agent) of Franz diffusion cells at a temperature of 32±1°C, and the corresponding cumulative permeation amount and skin permeation rate were calculated.

[0227] The results are shown in Tables 8-1 and 8-2 below, and in Figures 5a and 5b. [Table 11] [Table 12]

[0228] Example 9 Coating Composition The formulation of the fingolimod-containing coating composition is summarized below. [Table 13-1] [Table 13-2]

[0229] Preparation of the Coating Composition For Example 9-1, fingolimod base is placed in a suitable mixing vessel (beaker) and 1-dodecanol is added. The solvent ethyl acetate is added to the slurry and pressure sensitive adhesive (DURO-TAK™ 387-2516, an acrylic adhesive in ethyl acetate, ethanol, n-heptane, and methanol, with a solids content of 42.8% by weight, purchased from Henkel) is added to the slurry. The mass is stirred for approximately 3 hours.

[0230] For Example 9-2, fingolimod base is placed in a suitable mixing vessel (beaker) and 1-dodecanol is added. The solvent ethyl acetate is added to the slurry and a pressure sensitive adhesive (based on polyisobutylene in the form of a mixture in n-heptane, with a solids content of 41.28% by weight, from BASF, Oppanol™ B10 / N100 in a ratio of 85 / 15) is added. Polyvinylpyrrolidone (Kollidon™ purchased from BASF) is added to the mixture with stirring and the mass is stirred for approximately 4 hours.

[0231] For Example 9-3, fingolimod base is placed in a suitable mixing vessel (beaker) and 1-dodecanol is added. Solvent ethyl acetate is added to the slurry and pressure sensitive adhesive (silicone acrylic hybrid PSA in ethyl acetate, 50% solids content by weight, SilAc-PSA 7-6302 from Dow Corning Healthcare) is added. Polyvinylpyrrolidone (Kollidon™ purchased from BASF) is added to the mixture with stirring and the mass is stirred for approximately 3.5 hours.

[0232] For Example 9-4, fingolimod base is placed in a suitable mixing vessel (beaker) and lauryl lactate is added. 1,2-propanediol and the solvent ethyl acetate are added to the slurry. Polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft (PCL-PVAc-PEG, Soluplus™) is added to the mixture with stirring and the mass is stirred for approximately 1 hour. Pressure sensitive adhesive (silicone acrylic hybrid PSA in ethyl acetate, 50% solids content by weight, SilAc-PSA 7-6302 from Dow Corning Healthcare) is added and the mass is stirred for approximately 3.5 hours.

[0233] Coating of the coating composition The fingolimod base-containing coating composition was coated onto a slippery polyethylene terephthalate (PET) foil (which can serve as a release liner) within 24 hours and dried at room temperature and at 60° C. for 15 minutes each.

[0234] The coating thickness, after removal of the solvent, is approximately 150 g / m 2 The dried film was then laminated with a backing layer (polyethylene terephthalate (PET) foil 19 μm) to provide a fingolimod-containing self-adhesive layer structure.

[0235] Preparation of TTS See Example 1.

[0236] In vivo studies using Goettingen minipigs In the first stage, the metabolism of fingolimod to fingolimod phosphate was investigated in Goettingen minipigs (male, approximately 3-4 months) after oral administration of 0.5 mg fingolimod per day (Gilenya™ capsules) for 7 days to demonstrate the suitability of the study model.

[0237] One Goettingen minipig was used for one daily dose of 0.5 mg fingolimod.

[0238] The study was carried out in an animal room provided with filtered air at a temperature of 21° C.±3° C. The temperature and humidity in the animal room were recorded hourly during the study and records were kept. SDS minipig diet (SMP(E)SQC) from Special Diets Services (Witham Essex and CM8 3AD, UK) was provided twice daily in an amount of approximately 125 g per animal per meal.

[0239] 3 ml blood samples were taken at 0, 0.5, 1, 2, 4, 8, 24, 48, 72, 96, 120, 144, and 168 hours. Analysis was performed by a qualified LC-MS / MS method for the measurement of analytes in minipig K3EDTA whole blood. AUC values ​​were calculated from whole blood concentrations. The results are shown in Tables 9-2 and 9-3 and in Figure 6. [Table 14] [Table 15]

[0240] For comparison purposes, C in humans at steady state after a dose of 0.5 mg / day max Fingolimod phosphate / C max For fingolimod the ratio is approximately 0.5. Steady-state exposure is reached within 1-2 months between once-daily dosing, with an estimated 11-fold accumulation of blood levels from the first dose to steady state.

[0241] In the second stage, the TTS prepared according to Examples 9-1 to 9-4 were tested in an in vivo study (randomized by simple random sampling) using Goettingen minipigs (male, approximately 6-7 months old). 2 Die cuts of area were punched out and one Goettingen minipig was used for one TTS formulation. Seven drug containing TTS and two placebo TTS (each 10 cm2 ) was used per minipig. Total patch wear time for all 9 patches (7 active and 2 placebo) per minipig was 168 hours.

[0242] The study was carried out in an animal room provided with filtered air at a temperature of 21° C.±3° C. The temperature and humidity in the animal room were recorded hourly during the study and records were kept. SDS minipig feed (SMP(E)SQC) from Special Diets Services, Witham Essex and CM8 3AD, UK) was provided twice daily. The amount of feed was approximately 125 g per animal per meal from arrival until the first feeding on day 1, after which animals were fed 150 g feed per meal.

[0243] The above single dose application of TTS (7 active substances and 2 placebos, each 10 cm 2 ), followed by 3 ml blood samples were taken at 0, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168 (patch removal), and 192 hours. Analysis was accomplished by a qualified LC-MS / MS method for the measurement of analytes in minipig K3EDTA whole blood. AUC values ​​were calculated from whole blood concentrations. Results are shown in Tables 9-4 to 9-6 and Figures 7 and 8. [Table 16] [Table 17] [Table 18]

[0244] After removal of the TTS, the skin condition was determined visually and a Draize score was obtained based on the following scoring scheme: Histopathological examination of the epidermis and dermis revealed minimal to mild / moderate local irritation. The remaining amount of fingolimod was determined in the removed TTS by quantitative HPLC, and the amount of fingolimod delivered to the dermis was calculated as the difference relative to the initial amount of fingolimod contained in the TTS. The results are shown in Table 10. [Table 19]

[0245] The invention relates in particular to the following further provisions: 1. A transdermal therapeutic system for transdermal administration of fingolimod, comprising a fingolimod-containing layer structure, The fingolimod-containing layer structure is A) a backing layer, and B) Fingolimod-containing layer Including, The fingolimod-containing layer is a) a therapeutically effective amount of fingolimod; b) at least one polymer; c) dodecan-1-ol, Including, the weight ratio of dodecan-1-ol:fingolimod is in the range of 1.5:1 to 5:1; The system.

[0246] 2. The transdermal therapeutic system described in clause 1, wherein the weight ratio of dodecan-1-ol:fingolimod is in the range of 1.5:1 to 4:1.

[0247] 3. The transdermal therapeutic system described in clause 2, wherein the weight ratio of dodecan-1-ol:fingolimod is in the range of 1.5:1 to 2.5:1.

[0248] 4. The transdermal therapeutic system described in clause 2, wherein the weight ratio of dodecan-1-ol:fingolimod is in the range of 3:1 to 4:1.

[0249] 5. The transdermal therapeutic system of any one of clauses 1 to 4, wherein the at least one polymer is selected from the group consisting of silicone acrylic hybrid polymers, polysiloxane-based polymers, polyisobutylene-based polymers, and acrylate polymers.

[0250] 6. The transdermal therapeutic system of any one of clauses 1 to 4, wherein the at least one polymer is a silicone acrylic hybrid polymer.

[0251] 7. The transdermal therapeutic system described in any one of clauses 1 to 4, wherein the at least one polymer is a polyisobutylene or polysiloxane based polymer.

[0252] 8. The transdermal therapeutic system described in any one of clauses 1 to 4, wherein the at least one polymer is an acrylate polymer.

[0253] 9. The transdermal therapeutic system described in any one of clauses 1 to 8, wherein the at least one polymer is contained in the fingolimod-containing layer in an amount of about 40% to about 99% by weight, preferably about 50% to about 99% by weight, and more preferably about 60% to about 99% by weight, based on the fingolimod-containing layer.

[0254] 10. The transdermal therapeutic system of any one of clauses 1 to 9, wherein the at least one polymer is a polymer-based pressure-sensitive adhesive.

[0255] 11. The transdermal therapeutic system described in clause 6, wherein the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure sensitive adhesive.

[0256] 12. The transdermal therapeutic system described in clause 7, wherein the polyisobutylene-based polymer is a polyisobutylene-based pressure-sensitive adhesive.

[0257] 13. The transdermal therapeutic system described in clause 7, wherein the polysiloxane-based polymer is a polysiloxane-based pressure sensitive adhesive.

[0258] 14. The transdermal therapeutic system described in clause 8, wherein the acrylate polymer is an acrylate-based pressure sensitive adhesive.

[0259] 15. The transdermal therapeutic system described in clause 14, wherein the acrylate-based pressure-sensitive adhesive is based on monomers selected from one or more of acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate, methyl methacrylate, t-octylacrylamide, and vinyl acetate, preferably the acrylate-based pressure-sensitive adhesive is based on 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, and methyl acrylate.

[0260] 16. The transdermal therapeutic system described in any one of clauses 1 to 15, wherein the fingolimod-containing layer comprises an additional polymer selected from the group consisting of silicone-acrylic hybrid polymers, polysiloxane-based polymers, polyisobutylene-based polymers, and acrylate polymers.

[0261] 17. A transdermal therapeutic system described in any one of clauses 1 to 16, wherein the total amount of polymer contained in the fingolimod-containing layer is in the range of about 50% to about 99% by weight, preferably about 60% to about 99% by weight, and more preferably about 70% to about 99% by weight, based on the fingolimod-containing layer.

[0262] 18. The transdermal therapeutic system according to any one of clauses 1 to 17, wherein the fingolimod-containing layer is a fingolimod-containing matrix layer.

[0263] 19. The area weight of the fingolimod-containing layer is about 50 to about 200 g / m 2The transdermal therapeutic system according to any one of clauses 1 to 18, wherein the range is

[0264] 20. The area weight of the fingolimod-containing layer is about 60 to about 180 g / m 2 20. The transdermal therapeutic system according to claim 19, wherein the range is

[0265] 21. The area weight of the fingolimod-containing layer is about 80 to about 160 g / m 2 21. The transdermal therapeutic system according to claim 20, wherein the range is

[0266] 22. The transdermal therapeutic system according to any one of clauses 1 to 21, wherein the fingolimod-containing layer presents a skin contact layer.

[0267] 23. The transdermal therapeutic system according to any one of clauses 1 to 21, wherein the fingolimod-containing layer structure comprises an additional skin contact layer.

[0268] 24. The transdermal therapeutic system described in any one of clauses 1 to 23, wherein the fingolimod-containing layer structure is self-adhesive.

[0269] 25. The transdermal therapeutic system described in any one of clauses 1 to 24, wherein the dodecan-1-ol is contained in an amount of 2% to 40% by weight based on the fingolimod-containing layer.

[0270] 26. The transdermal therapeutic system described in clause 25, wherein the dodecan-1-ol is contained in an amount of 2% to 30% by weight based on the fingolimod-containing layer.

[0271] 27. The transdermal therapeutic system described in clause 26, wherein the dodecan-1-ol is contained in an amount of 4% to 20% by weight based on the fingolimod-containing layer.

[0272] 28. The transdermal therapeutic system described in any one of clauses 1 to 27, wherein the fingolimod is contained in an amount of 1% to 20% by weight based on the fingolimod-containing layer.

[0273] 29. The transdermal therapeutic system described in clause 28, wherein the fingolimod is contained in an amount of 1% to 15% by weight based on the fingolimod-containing layer.

[0274] 30. The transdermal therapeutic system described in clause 29, wherein the fingolimod is contained in an amount of 2% to 10% by weight based on the fingolimod-containing layer.

[0275] 31. The fingolimod-containing layer structure has a density of 0.1 mg / cm based on the fingolimod-containing layer. 2 ~2.0mg / cm 2 31. The transdermal therapeutic system according to any one of clauses 1 to 30, comprising fingolimod.

[0276] 32. The fingolimod-containing layer structure has a density of 0.1 mg / cm based on the fingolimod-containing layer. 2 ~1.5mg / cm 2 32. A transdermal therapeutic system according to claim 31, containing fingolimod of

[0277] 33. The fingolimod-containing layer structure has a density of 0.2 mg / cm based on the fingolimod-containing layer. 2 ~1.2mg / cm 2 33. A transdermal therapeutic system according to clause 32, comprising fingolimod of

[0278] 34. The transdermal therapeutic system according to any one of clauses 1 to 33, wherein said fingolimod is present in the form of a free base.

[0279] 35. A transdermal therapeutic system described in any one of clauses 1 to 34, wherein the fingolimod-containing layer is obtainable by coating and drying a fingolimod-containing coating composition comprising the at least one polymer, as well as the dodecan-1-ol and the therapeutically effective amount of fingolimod in a weight ratio of dodecan-1-ol:fingolimod of 1.5:1 to 5:1.

[0280] 36. The transdermal therapeutic system of any one of clauses 1 to 35, wherein the fingolimod-containing layer further comprises an auxiliary polymer.

[0281] 37. The transdermal therapeutic system described in clause 36, wherein the auxiliary polymer is contained in an amount of about 0.5% to about 20% by weight based on the fingolimod-containing layer.

[0282] 38. The transdermal therapeutic system described in clause 37, wherein the auxiliary polymer is contained in an amount of about 0.5% to about 10% by weight based on the fingolimod-containing layer.

[0283] 39. The transdermal therapeutic system described in clause 38, wherein the auxiliary polymer is contained in an amount of about 1% to about 5% by weight based on the fingolimod-containing layer.

[0284] 40. The transdermal therapeutic system according to any one of clauses 36 to 39, wherein the auxiliary polymer is selected from the group consisting of alkyl methacrylate copolymers, amino alkyl methacrylate copolymers, methacrylic acid copolymers, methacrylic acid ester copolymers, ammonio alkyl methacrylate copolymers, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymers, cellulose derivatives, and mixtures thereof, preferably cellulose derivatives.

[0285] 41. The transdermal therapeutic system described in any one of clauses 1 to 40, wherein the fingolimod-containing layer does not contain polyvinylpyrrolidone.

[0286] 42. The transdermal therapeutic system described in any one of clauses 1 to 41, wherein the fingolimod-containing layer does not contain a polymer selected from the group consisting of alkyl methacrylate copolymers, aminoalkyl methacrylate copolymers, methacrylic acid copolymers, methacrylic acid ester copolymers, ammonioalkyl methacrylate copolymers, and polyvinylpyrrolidone.

[0287] 43. The transdermal therapeutic system according to any one of clauses 1 to 42, wherein the fingolimod-containing layer does not contain an ester of dodecanol.

[0288] 44. A transdermal therapeutic system described in any one of clauses 1 to 43, wherein the fingolimod-containing layer does not contain an organosulfur compound.

[0289] 45. The transdermal therapeutic system according to any one of clauses 1 to 44, wherein the fingolimod-containing layer does not contain a fatty acid ester.

[0290] 46. ​​A transdermal therapeutic system described in any one of clauses 1 to 45, providing an average release rate of 0.1 to 1.0 mg / day of fingolimod, preferably over at least 72 hours, about 84 hours, about 96 hours, or about 168 hours of administration.

[0291] 47. 1.5 μg / cm2 within the first 24 hours of dosing as measured in Franz diffusion cells on dermatome-sampled human skin 2 Cumulative fingolimod permeation of greater than 6.0 μg / cm within the first 36 hours of dosing 2 47. The transdermal therapeutic system according to any one of clauses 1 to 46, providing a cumulative permeation amount of fingolimod of greater than

[0292] 48. 0.1 μg / cm2 16 hours after administration as measured in Franz diffusion cells on dermatome-sampled human skin. 2 - A transdermal therapeutic system according to any one of clauses 1 to 47, providing a skin permeation rate of fingolimod over a period of time.

[0293] 49. A C of 0.2:1 to 0.8:1 over approximately 168 hours of administration following single-dose administration to the study population max Fingolimod phosphate: C max 49. The transdermal therapeutic system according to any one of clauses 1 to 48, providing a ratio of fingolimod.

[0294] 50. A transdermal therapeutic system according to any one of clauses 1 to 49 for use in a method for treating an immune disorder.

[0295] 51. A transdermal therapeutic system according to any one of clauses 1 to 49 for use in a method for treating multiple sclerosis.

[0296] 52. Fingolimod base for use in a method for treating an immune disorder, wherein the fingolimod base is administered to the skin of a patient in a transdermal therapeutic system described in any one of clauses 1 to 49.

[0297] 53. Fingolimod base for use in a method for treating multiple sclerosis, wherein the fingolimod base is administered to the skin of a patient in a transdermal therapeutic system according to any one of clauses 1 to 49.

[0298] 54. Use of a transdermal therapeutic system according to any one of clauses 1 to 49 for the manufacture of a medicine for the treatment of immune disorders.

[0299] 55. Use of a transdermal therapeutic system according to any one of clauses 1 to 49 for the manufacture of a medicinal product for the treatment of multiple sclerosis.

[0300] 56. A method for treating an immune disorder in a patient by applying a transdermal therapeutic system described in any one of clauses 1 to 49 to the patient's skin.

[0301] 57. A method for treating multiple sclerosis by applying a transdermal therapeutic system described in any one of clauses 1 to 49 to the skin of a patient.

[0302] 58. A method for producing a transdermal therapeutic system according to any one of clauses 1 to 51, comprising: 1) A fingolimod-containing coating composition, a) Fingolimod, b) at least one polymer; c) dodecan-1-ol, d) optionally a solvent; providing the composition comprising: 2) coating the fingolimod-containing coating composition onto a release liner in an amount that provides a desired areal weight; 3) drying the coated fingolimod-containing coating composition to provide the fingolimod-containing layer; 4) laminating the fingolimod-containing layer to a backing layer to provide a fingolimod-containing layer structure; 5) optionally providing an additional skin contact layer by coating and drying an active agent-free or active agent-containing coating composition according to steps 2 and 3, removing the release liner of the fingolimod-containing layer, and laminating the adhesive side of the skin contact layer onto the adhesive side of the fingolimod-containing layer to provide a fingolimod-containing layer structure; 6) punching out individual systems from the fingolimod-containing layered structure; 7) optionally adhering an active agent-free self-adhesive layer structure, which also includes a backing layer and an active agent-free pressure-sensitive adhesive layer, to a separate system, which is larger than the separate system of said fingolimod-containing layer structure; The method comprising:

[0303] 59. Use of dodecan-1-ol for reducing the permeation lag time of fingolimod in a transdermal therapeutic system for the transdermal administration of fingolimod.

[0304] 60. A transdermal therapeutic system for transdermal administration of fingolimod, comprising a fingolimod-containing layer structure, The fingolimod-containing layer structure is A) a backing layer, and B) Fingolimod-containing layer Includes; The fingolimod-containing layer is a) a therapeutically effective amount of fingolimod base; b) at least one silicone acrylic hybrid pressure sensitive adhesive; c) dodecan-1-ol, Including, the weight ratio of dodecan-1-ol:fingolimod is in the range of 1.5:1 to 5:1; The system.

[0305] 61. A transdermal therapeutic system for transdermal administration of fingolimod, comprising a fingolimod-containing layer structure, The fingolimod-containing layer structure is A) a backing layer, and B) Fingolimod-containing layer Includes; The fingolimod-containing layer is a) a therapeutically effective amount of fingolimod base; b) at least one polymer-based pressure sensitive adhesive; c) dodecan-1-ol, d) at least one cellulose derivative; Including, the weight ratio of dodecan-1-ol:fingolimod is in the range of 1.5:1 to 5:1; The system.

[0306] 62. A transdermal therapeutic system for transdermal administration of fingolimod, comprising a fingolimod-containing layer structure, The fingolimod-containing layer structure is A) a backing layer, and B) Fingolimod-containing layer Includes; The fingolimod-containing layer is a) a therapeutically effective amount of fingolimod base; b) at least one acrylate-based pressure sensitive adhesive; c) dodecan-1-ol, Including, the weight ratio of dodecan-1-ol:fingolimod is in the range of 1.5:1 to 5:1; the fingolimod-containing layer does not contain a polymer selected from the group consisting of alkyl methacrylate copolymers, aminoalkyl methacrylate copolymers, methacrylic acid copolymers, methacrylic acid ester copolymers, ammonioalkyl methacrylate copolymers, and polyvinylpyrrolidone; the fingolimod-containing layer does not contain an organosulfur compound; The system.

[0307] 63. A transdermal therapeutic system for transdermal administration of fingolimod, comprising a fingolimod-containing layer structure, The fingolimod-containing layer structure is A) a backing layer, and B) Fingolimod-containing layer Includes; The fingolimod-containing layer is a) a therapeutically effective amount of fingolimod base; b) at least one pressure sensitive adhesive based on polyisobutylene or polysiloxane; c) dodecan-1-ol, Including, the weight ratio of dodecan-1-ol:fingolimod is in the range of 1.5:1 to 5:1; the fingolimod-containing layer does not contain a polymer selected from the group consisting of alkyl methacrylate copolymers, aminoalkyl methacrylate copolymers, methacrylic acid copolymers, methacrylic acid ester copolymers, ammonioalkyl methacrylate copolymers, and polyvinylpyrrolidone; the fingolimod-containing layer does not contain an organosulfur compound; The system.

Claims

1. A transdermal therapeutic system for transdermal administration of fingolimod, comprising a fingolimod-containing layer structure, The fingolimod-containing layer structure is A) a backing layer; and B) Fingolimod-containing layer Including, The fingolimod-containing layer is a) a therapeutically effective amount of fingolimod; b) at least one polymer; c) dodecan-1-ol, Including, The system, wherein the weight ratio of dodecan-1-ol:fingolimod is in the range of 1.5:1 to 5:

1.

2. The transdermal therapeutic system of claim 1 , wherein the at least one polymer is selected from the group consisting of silicone acrylic hybrid polymers, polysiloxane-based polymers, polyisobutylene-based polymers, and acrylate polymers.

3. The transdermal therapeutic system according to claim 1 or 2, wherein the at least one polymer is contained in the fingolimod-containing layer in an amount of about 40% to about 99% by weight, and / or about 50% to about 99% by weight, and / or about 60% to about 99% by weight, based on the fingolimod-containing layer.

4. The transdermal therapeutic system according to any one of claims 1 to 3, wherein the at least one polymer is a polymer-based pressure sensitive adhesive.

5. The transdermal therapeutic system according to any one of claims 1 to 4, wherein the fingolimod-containing layer is a fingolimod-containing matrix layer.

6. The transdermal therapeutic system according to any one of claims 1 to 5, wherein the dodecan-1-ol is contained in an amount of 2% to 40% by weight, and / or 2% to 30% by weight, and / or 4% to 20% by weight, based on the fingolimod-containing layer.

7. The transdermal therapeutic system according to any one of claims 1 to 6, wherein the fingolimod is contained in an amount of 1% to 20% by weight, and / or 1% to 15% by weight, and / or 2% to 10% by weight, based on the fingolimod-containing layer.

8. The fingolimod-containing layer structure has a density of 0.1 mg / cm based on the fingolimod-containing layer. 2 ~2.0 mg / cm 2 and / or 0.1 mg / cm 2 ~1.5mg / cm 2 and / or 0.2 mg / cm 2 ~1.2 mg / cm 2 The transdermal therapeutic system according to any one of claims 1 to 7, comprising fingolimod.

9. The transdermal therapeutic system according to any one of claims 1 to 8, wherein the fingolimod-containing layer is obtainable by coating and drying a fingolimod-containing coating composition comprising the at least one polymer, and the dodecan-1-ol and the therapeutically effective amount of fingolimod in a weight ratio of dodecan-1-ol:fingolimod of 1.5:1 to 5:

1.

10. The transdermal therapeutic system according to any one of claims 1 to 9, wherein the fingolimod-containing layer further comprises an auxiliary polymer selected from the group consisting of alkyl methacrylate copolymers, aminoalkyl methacrylate copolymers, methacrylic acid copolymers, methacrylic acid ester copolymers, ammonioalkyl methacrylate copolymers, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymers, cellulose derivatives, and mixtures thereof.

11. The transdermal therapeutic system of claim 10, wherein the auxiliary polymer is contained in an amount of about 0.5% to about 20%, and / or about 0.5% to about 10% by weight, and / or about 1% to about 5% by weight, based on the weight of the fingolimod-containing layer.

12. The transdermal therapeutic system according to any one of claims 1 to 11, wherein the fingolimod-containing layer does not contain polyvinylpyrrolidone.

13. The transdermal therapeutic system according to any one of claims 1 to 12, wherein the fingolimod-containing layer does not contain esters of dodecanol, organosulfur compounds, and / or fatty acid esters.

14. A transdermal therapeutic system described in any one of claims 1 to 13, providing an average release rate of fingolimod of 0.1 to 1.0 mg / day.

15. The transdermal therapeutic system of claim 14, providing an average release rate of 0.1 to 1.0 mg / day of fingolimod for at least 72 hours, about 84 hours, about 96 hours, or about 168 hours of administration.

16. 1.5 μg / cm within the first 24 hours of dosing as measured in Franz diffusion cells with dermatome-sampled human skin. 2 and / or a cumulative fingolimod permeation of greater than 6.0 μg / cm within the first 36 hours of dosing. 2 The transdermal therapeutic system according to any one of claims 1 to 15, which provides a cumulative permeation amount of fingolimod of greater than 1000 mg / kg.

17. 0.1 μg / cm 16 hours after administration as measured in Franz diffusion cells with dermatome-sampled human skin 2 A transdermal therapeutic system according to any one of claims 1 to 16, providing a skin permeation rate of fingolimod exceeding - hours.

18. A C of 0.2:1 to 0.8:1 over a period of approximately 168 hours following administration of a single dose to the subject population. max Fingolimod phosphate: C max A transdermal therapeutic system according to any one of claims 1 to 17, providing a ratio of fingolimod.

19. A transdermal therapeutic system according to any one of claims 1 to 18 for use in a method for treating an immune disorder.

20. A transdermal therapeutic system described in any one of claims 1 to 18 for use in a method for treating multiple sclerosis.

21. A method for producing the transdermal therapeutic system according to any one of claims 1 to 18, comprising the steps of: 1) A fingolimod-containing coating composition, comprising: a) fingolimod, b) at least one polymer; c) dodecan-1-ol, d) optionally a solvent; providing said composition comprising: 2) coating the fingolimod-containing coating composition onto a release liner in an amount that provides a desired areal weight; 3) drying the coated fingolimod-containing coating composition to provide the fingolimod-containing layer; 4) laminating the fingolimod-containing layer to a backing layer to provide a fingolimod-containing layer structure; 5) optionally providing an additional skin contact layer by coating and drying an active agent-free or active agent-containing coating composition according to steps 2 and 3, removing the release liner of the fingolimod-containing layer, and laminating the adhesive side of the skin contact layer onto the adhesive side of the fingolimod-containing layer to provide a fingolimod-containing layer structure; 6) punching out individual systems from the fingolimod-containing layered structure; 7) optionally adhering an active agent-free self-adhesive layer structure, which also includes a backing layer and an active agent-free pressure-sensitive adhesive layer, to a separate system, which is larger than the separate system of said fingolimod-containing layer structure; The method comprising:

22. A transdermal therapeutic system comprising dodecan-1-ol for use in the transdermal administration of fingolimod to reduce the lag time of fingolimod permeation.

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