Transdermal therapeutic system containing agomelatine

Abstract

The present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, to such an agomelatine TTS for use in a method of treatment, to a method of treatment comprising applying such an agomelatine TTS, and to a process for the manufacture of such a TTS.

Description

Technical Field

[0001] The present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of agomelatine into the systemic circulation, as well as its manufacturing process, treatment method, and use.

Background Art

[0002] The active agent agomelatine (N-(2-(7-methoxy-1-naphthyl)ethyl)acetamide) is a melatoninergic antidepressant developed by Les Laboratoires Servier. Its chemical structure is very similar to that of melatonin.

Chemical Formula

[0003] As a melatonin agonist that stimulates MT1 and MT2 receptors, agomelatine can mediate the synchronization of the circadian rhythm like melatonin. However, in addition to melatonin, in contrast to melatonin, agomelatine is also a 5-HT2B / 5-HT2C antagonist, and blocking the serotonergic 5HT2C receptor promotes the release of dopamine and norepinephrine in the prefrontal cortex. In MT1 / MT2 agomelatine and 5HT2C antagonism, an unexpected synergistic effect has been observed, and this synergistic effect is considered to explain the antidepressant effect and the unique clinical profile of agomelatine.

[0004] Agomelatine is approved in Europe under the trade names Valdoxan (registered trademark), Melitor (registered trademark), and Thymanax (registered trademark), and is indicated for the treatment of major depressive disorder (MDD). The currently available form is a film-coated tablet containing a dose of 25 mg, which is prescribed as an initial dose of 1 tablet taken at bedtime, with the option to double the dose if no improvement is seen. Agomelatine is the only antidepressant on the market with the above-described mechanism of action.

[0005] Oral agomelatine undergoes extensive first-pass and systemic metabolism, mainly via cytochrome CYP1A2. Agomelatine is well absorbed orally (more than 80%), but its overall bioavailability is very low (less than 5%), with significant inter-individual variability. The time to reach maximum plasma concentration and the elimination half-life t 1 / 2 are both approximately 1 to 2 hours. At steady state, the volume of distribution is 35 liters and plasma protein binding is 95%.

[0006] Compared with other antidepressants, agomelatine seems to exert its effects more rapidly (usually within 1 week), and major side effects commonly known with other antidepressants, such as weight gain, sexual dysfunction, anticholinergic symptoms, and cardiotoxicity, seem to be reduced. However, agomelatine has a risk of hepatotoxicity, the mechanism of which remains unknown and manifests as an increase in alanine aminotransferase (ALAT) and / or aspartate aminotransferase values. In some exceptional cases, the outcome was fatal or required liver transplantation. Furthermore, it has also been reported that liver dysfunction is associated with a substantial increase in agomelatine exposure. In patients with moderate liver dysfunction compared with healthy subjects, up to 140-fold increases in AUC and c max values were observed.

[0007] In an effort to establish a sublingual dosage form of agomelatine, Servier and Novartis likely to avoid first-pass metabolism and the above-mentioned drawbacks associated therewith (low oral bioavailability and hepatotoxicity), placebo-controlled randomized trials were conducted using 1 and 2 mg (Servier) or 0.5 and 1 mg of sublingual tablets of agomelatine (Novartis). The results of the 2008 / 2009 Servier trial have not been published. In the Novartis study initiated in 2011 / 2011, the efficacy of sublingual tablets of agomelatine was not superior to placebo and there was no clear dose-response relationship, but at least hepatotoxicity was shown to be rare. One of the reasons for such results seems to be the marked irritation caused by agomelatine when administered to the oral mucosa. As a result, the FDA decided not to approve this drug in the United States, despite being superior to other active ingredients in the treatment of MDD.

[0008] Transdermal administration of agomelatine not only avoids first-pass metabolism and the associated disadvantages of oral administration, but also avoids the irritating sensations induced by sublingual tablets. Furthermore, the bioavailability of the agomelatine transdermal therapeutic system should be higher, and thus it may be possible to reduce the dose depending on whether it can actually demonstrate an increase in systemic delivery of the active agent compared to oral dosage forms. This not only enhances cost-effectiveness but also addresses dose-related issues such as hepatotoxicity. Although transdermal delivery of agomelatine has been investigated, it seems difficult to formulate a suitable dosage form for passive transdermal delivery of agomelatine.

[0009] Passive transport of an active agent through the skin from a transdermal therapeutic system (TTS) utilizes the driving force based on the concentration gradient between the concentration of the active agent in the transdermal system and on the outer surface of the skin and the concentration in the bloodstream. Such passive transport is advantageous from the viewpoints of the complexity of the TTS and the convenience of administration as compared with TTSs that utilize active transport such as iontophoresis or micro-poration. However, in order to generate such a driving force, it is necessary to balance a sufficiently high drug concentration in the TTS and an excessive solubility of the drug in the active-containing layer. The latter is because it counteracts the high skin penetration rate. Agomelatine is a poorly soluble drug, and several different polymorphic forms of agomelatine are known. Recrystallization of the drug during storage is not desirable because it may affect the performance of the TTS by crystallization of the drug in an unpredictable form and thus may lead to a decrease in the shelf life. Therefore, in order to prevent recrystallization of the drug during storage and to achieve a sufficiently high drug concentration, the formulation must be such that the solubility of agomelatine is sufficiently high. This requirement needs to be balanced with sufficient skin penetration of the drug.

[0010] Furthermore, since agomelatine is mainly used for resynchronization of the circadian rhythm, in contrast to the continuous and stable drug exposure required for 24-hour treatment of chronic diseases (and often achieved by TTS formulations), the desired drug release profile is a rapid initial increase followed by release only overnight.

[0011] Agomelatine TTS formulations containing isopropanol have been proposed, but since isopropanol is a volatile solvent, the composition of formulations containing isopropanol is expected to change over time due to evaporation of the solvent. The overall supply amount also seems to be small in such formulations. It seems that some other formulations depending on fatty acid-based ionic liquids have been investigated, but the drug concentration in these formulations is very low, and as a result, the layer thickness had to be increased to dimensions such that TTS production is not practical on a large-scale / industrial scale.

[0012] Currently, commercially available agomelatine TTSs are not available.

[0013] In summary, there is a great need for alternative dosage forms of agomelatine to overcome the disadvantages of the oral and sublingual administration routes. As outlined above, TTS can address these drawbacks.

[0014] Therefore, in the art, there is a need for an agomelatine TTS with a sufficiently high skin permeability of the drug. SUMMARY OF THE INVENTION

[0015] An object of the present invention is to provide an agomelatine TTS that overcomes the above-mentioned drawbacks of current agomelatine administration.

[0016] Therefore, an object of the present invention is to provide a TTS for transdermal administration of agomelatine that provides a permeation rate sufficient to achieve a therapeutically effective dose.

[0017] A further object of the present invention is to provide a TTS for transdermal administration of agomelatine that provides a drug release profile with a rapid initial increase, enabling overnight application suitable for administration just before bedtime, and removal of the TTS in the morning.

[0018] An object of the present invention is also to provide a TTS for transdermal administration of agomelatine that has sufficient storage stability with respect to the stability of the active agent and the stability of the composition and / or drug release profile, particularly preventing (re)crystallization of the active substance.

[0019] Another object of the present invention is to provide a TTS for transdermal administration of agomelatine, where hepatotoxicity and inter-individual variability are reduced and bioavailability is increased compared to oral administration.

[0020] A further object of the present invention is to provide a TTS for transdermal administration of asenapine that provides good patient compliance, meets the requirements of convenient use considering size and thickness, and / or is easy to manufacture and cost-effective in manufacturing.

[0021] According to one aspect, these and other objects are achieved by the present invention relating to a transdermal therapeutic system for the transdermal administration of agomelatine comprising a self - adhesive layer structure containing a therapeutically effective amount of agomelatine, said self - adhesive layer structure comprising: A) a backing layer; and B) i) agomelatine; ii) a hydrophobic polymer; and iii) an agomelatine - containing layer comprising at least 1% by weight of a crystallization inhibitor selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone - polyvinyl acetate copolymers wherein: Here, the hydrophobic polymer is selected from the group consisting of polyisobutylene, styrene - isoprene - styrene block copolymer, silicone - acrylic hybrid polymer, silicone - based pressure - sensitive adhesives, and any mixtures thereof.

[0022] According to another aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of agomelatine comprising a self - adhesive layer structure containing a therapeutically effective amount of agomelatine, said self - adhesive layer structure comprising: A) a backing layer; and B) i) agomelatine; and ii) an agomelatine - containing layer comprising a hydrophobic polymer wherein: Here, the hydrophobic polymer is selected from the group consisting of polyisobutylene, styrene - isoprene - styrene block copolymer, silicone - acrylic hybrid polymer, silicone - based pressure - sensitive adhesives, and any mixtures thereof, and the agomelatine - containing layer is of the micro - reservoir type.

[0023] According to a particular embodiment of the present invention, the transdermal therapeutic system according to the present invention is for use in a method of treatment, preferably for use in a method of treating major depressive disorder.

[0024] According to another embodiment, the present invention relates to a method of treatment, in particular to a method of treating major depressive disorder, which comprises applying a transdermal therapeutic system according to the present invention to the skin of a human patient.

[0025] According to yet another embodiment, the present invention relates to the use of the transdermal therapeutic system of the present invention in the manufacture of a medicament for treatment, preferably for the treatment of major depressive disorder.

[0026] According to yet another aspect, the present invention comprises the following steps: i) combining at least agomelatine, a hydrophobic polymer, and a crystallization inhibitor selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone - polyvinyl acetate copolymer in a solvent to obtain a coating composition; ii) coating the coating composition on a backing layer or a release liner or any intermediate layer; iii) drying the coated coating composition to form an agomelatine - containing layer and relates to a process for manufacturing an agomelatine - containing layer, wherein, the hydrophobic polymer is selected from the group consisting of polyisobutylene, styrene - isoprene - styrene block copolymer, silicone - acrylic hybrid polymer, and a pressure - sensitive adhesive based on polysiloxane.

[0027] According to a particular embodiment, the present invention also relates to a transdermal therapeutic system for the transdermal administration of agomelatine obtained by such a manufacturing process.

[0028] According to a specific embodiment, the present invention also relates to a transdermal therapeutic system for the transdermal administration of agomelatine, comprising a self - adhesive layer structure containing a therapeutically effective amount of agomelatine, the self - adhesive layer structure comprising: A) a backing layer, and B) i) 2 - 6% by weight of agomelatine; ii) a hydrophobic polymer; iii) 2 to 7% by weight of polyvinylpyrrolidone; and iv) an agomelatine-containing layer containing 2 to 7% by weight of a permeation enhancer selected from levulinic acid and polyethylene glycol ether and where the hydrophobic polymer is selected from polysiloxane-based pressure-sensitive adhesives the areal weight of the agomelatine-containing layer ranges from 35 to 70 g / m 2 ².

[0029] According to another embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of agomelatine, comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, said self-adhesive layer structure comprising A) a backing layer and B) i) 2 to 6% by weight of agomelatine; ii) a hydrophobic polymer; and iii) an agomelatine-containing layer containing 7 to 15% by weight of polyvinylpyrrolidone and where the hydrophobic polymer is selected from polysiloxane-based pressure-sensitive adhesives the areal weight of the agomelatine-containing layer ranges from 35 to 70 g / m 2 ².

[0030] Within the scope of the meaning of the present invention, the term "transdermal therapeutic system" (TTS) refers to a system in which an active agent (agomelatine) is administered into the systemic circulation by transdermal delivery, which is applied to the skin of a patient and contains a therapeutically effective amount of agomelatine in a self-adhesive layer structure, and optionally includes an additional adhesive overlay on top of the asenapine-containing self-adhesive layer structure, referring to the entire individual dosage unit. The self-adhesive layer structure can be disposed on a release liner (removable protective layer), and thus, the TTS can further include the release liner. Within the scope of the meaning of the present invention, the term "TTS" specifically refers to a system that provides passive transdermal delivery excluding active transport similar to methods including, for example, iontophoresis or micro-poration.

[0031] Within the scope of the meaning of the present invention, the term "agomelatine-containing self-adhesive layer structure" or "self-adhesive layer structure containing a therapeutically effective amount of agomelatine" refers to an active agent-containing structure that provides a release area of agomelatine during administration. The adhesive overlay increases the overall size of the TTS but does not increase the release area. The agomelatine-containing self-adhesive layer structure includes a backing layer and at least one agomelatine-containing layer.

[0032] Within the scope of the meaning of the present invention, the term "therapeutically effective amount" refers to the amount of the active agent in the TTS that is sufficient to provide agomelatine blood levels in a similar range (e.g., about 10% to about 1000% as measured by AUC) compared to the blood levels obtained with a single oral administration of 25 mg of oral agomelatine when administered to a patient by the TTS. The TTS usually contains more active substance in the system than the active substance actually provided to the skin and the systemic circulation. This excess amount of the active agent is usually necessary to provide a sufficient driving force for passive transport from the TTS to the systemic circulation.

[0033] Within the scope of the meaning of the present invention, terms such as "active substance" and "active agent", as well as the term "agomelatine", refer to agomelatine in any pharmaceutically acceptable chemical and morphological forms and physical states. These forms include the free, dissociated, or any related forms of agomelatine such as hydrates, solvates, etc., as well as the particulate form that can be in micronized form, crystalline form, especially one of its polymorphic forms, and / or amorphous form, and any hybrid type form of any of the aforementioned forms or a mixed form of them of agomelatine, but are not limited thereto. When agomelatine is contained in a medium such as a solvent, it can be dissolved or dispersed, or can be partially dissolved and partially dispersed.

[0034] When it is stated that agomelatine is used in a specific form during the manufacture of a TTS, this does not exclude the interaction between this form of agomelatine and the other components of the agomelatine-containing self-adhesive layer structure, so the active substance will ultimately be present in another form in the TTS. This means that even if agomelatine is contained in its free dissociated form, it can be present in the final TTS in the form of a hydrate or solvate, or if it is contained in one of its polymorphic forms, it can be present in the final TTS in amorphous form. Unless otherwise specified, in particular, the amount of agomelatine in the self-adhesive layer structure is related to the amount of agomelatine contained in the TTS during the manufacture of the TTS and is calculated based on the free form of agomelatine. That is, when agomelatine is contained in an amount of 0.1 mmol, the amount of agomelatine in the self-adhesive layer structure is considered to be 24.3 mg within the scope of the meaning of the present invention regardless of whether agomelatine was contained in the TTS during manufacture in its free form or any related form (the molecular weight of agomelatine is 243 g / mol).

[0035] The agomelatine starting material contained in the TTS during the manufacture of the TTS can be in particulate form. Agomelatine can, for example, be present in the self-adhesive layer structure in particulate form and / or can be dissolved.

[0036] Within the scope of the meaning of the present invention, the term "particle" refers to particulate matter of a solid that includes individual particles and whose dimensions are very small compared to that of the matter. Specifically, the particles are solids including plastics / deformable solids, including amorphous and crystalline substances.

[0037] Within the scope of the meaning of the present invention, the term "disperse" refers to a step or combination of steps in which the starting material (e.g., agomelatine) is not completely dissolved. Dispersion in the meaning of the present invention includes partial dissolution of the starting material (e.g., agomelatine particles), depending on the solubility of the starting material (e.g., the solubility of agomelatine in the coating composition).

[0038] There are two main types of TTSs that use passive agent delivery, namely, matrix-type TTSs and reservoir-type TTSs. In matrix-type TTSs, the active agent is contained in the matrix, and in reservoir-type TTSs, the active agent is contained in a liquid or semi-liquid reservoir. So-called microreservoir-type TTSs are considered in the art to be a mixture of matrix-type TTSs and reservoir-type TTSs. The release of the active agent in matrix-type TTSs is mainly controlled by the matrix containing the active agent itself. In contrast, reservoir-type TTSs require a rate-controlling membrane to control the release of the active agent. Matrix-type TTSs are usually advantageous in that they do not require a rate-determining membrane and dose dumping due to membrane breakage cannot occur compared to reservoir-type TTSs. In summary, matrix-type transdermal therapeutic systems (TTSs) are simpler to manufacture, can be easily used by patients, and are convenient for patients. Microreservoir-type TTSs also do not require a rate-determining membrane, but, in contrast to "classical" matrix-type TTSs, the drug release profile is often characterized by a faster onset and higher activity utilization, which is often advantageous.

[0039] Within the scope of the meaning of the present invention, "matrix-type TTS" refers to a system or structure in which the active substance is homogeneously dissolved and / or dispersed in a polymer carrier, i.e., a matrix, and forms a matrix layer together with the active agent and optionally remaining components. In such a system, the matrix layer controls the release of the active agent from the TTS. The matrix-type TTS may also include a rate-controlling membrane. Specifically, the matrix-type TTS can be in the form of an "adhesive drug" type of TTS, which refers to a system in which the active substance is homogeneously dissolved and / or dispersed in a pressure-sensitive adhesive matrix.

[0040] A TTS having a rate-controlling membrane and a liquid or semi-liquid active agent-containing reservoir, in which the release of the active agent from the TTS is controlled by the rate-controlling membrane, is referred to by the term "reservoir-type TTS". The reservoir-type TTS should not be understood as a matrix-type TTS within the scope of the meaning of the present invention.

[0041] Within the scope of the meaning of the present invention, "microreservoir-type TTS" refers to a system or structure in which the active agent-containing layer is a two-phase layer having an internal active-containing phase in an external matrix phase. As used herein, the term "biphasic" refers to a system of two distinguishable, e.g., visually distinguishable, regions, an outer phase and an inner phase, and the inner phase is in the form of dispersed deposits within the outer phase. Such deposits are, for example, solid solution droplets. Visually distinguishable deposits can be identified using a microscope.

[0042] Within the scope of the meaning of the present invention, the terms "matrix layer" or "matrix-type layer" refer to any layer containing an active substance uniformly dissolved and / or dispersed in a polymer carrier. Typically, the matrix layer is present in a matrix-type TTS as an active agent-containing layer. A reservoir-type TTS may include, in addition to the reservoir layer and the rate-controlling membrane, an additional adhesive layer that functions as a skin contact layer. In such a reservoir-type TTS, the additional adhesive layer is often manufactured as a layer that does not contain an active agent. However, due to the concentration gradient, the active agent migrates over time from the reservoir to the additional adhesive layer until equilibrium is reached. Therefore, in such a reservoir-type TTS, after equilibrium has been achieved for some time, the additional adhesive layer contains the active agent and should be regarded as an active agent-containing layer in the meaning of the present invention.

[0043] The active agent-containing layer is, for example, the final solidified layer obtained after coating and drying a solvent-containing coating composition. The active agent-containing layer can also be manufactured by laminating two or more such solidified layers (for example, dried layers) of the same composition in order to provide a desired areal weight. The active agent-containing layer can be self-adhesive (in the form of a pressure-sensitive adhesive layer), or the TTS can include an additional skin contact layer of a pressure-sensitive adhesive in order to provide sufficient adhesion. In particular, the active agent-containing layer is a pressure-sensitive adhesive layer.

[0044] Within the scope of the meaning of the present invention, the term "two-phase layer" refers to the final two-phase layer of a micro-reservoir type TTS solidified after coating a coating mixture, for example, by drying a solvent-containing coating mixture or cooling a hot-melt coating mixture. According to the present invention, a solvent-containing coating mixture is preferred. The two-phase layer can also be manufactured by laminating two or more layers (for example, dried layers) of the same composition in order to provide a desired areal weight.

[0045] Within the scope of the meaning of the present invention, the term "dry two-phase layer" refers to a two-phase layer (solvent-based layer) obtained from a solvent-containing coating mixture after coating on a film and evaporating the solvent, and should be distinguished from a two-phase layer (hot-melt-based layer) obtained from a hot-melt coating mixture.

[0046] Within the scope of the meaning of the present invention, the term "pressure-sensitive adhesive" refers to a material that adheres particularly by finger pressure, is permanently sticky, exhibits strong holding power, and can be removed from a smooth surface without leaving residues. The pressure-sensitive adhesive layer is "self-adhesive" when in contact with the skin, i.e., it provides an adhesive force to the skin such that typically no further assistance is required for fixation to the skin. The "self-adhesive" layer structure includes a pressure-sensitive adhesive layer for skin contact, which can be provided in the form of a pressure-sensitive adhesive activator-containing layer or in the form of an additional layer, i.e., a pressure-sensitive adhesive skin contact layer. An adhesive overlay can still be used to improve the adhesive force.

[0047] Within the scope of the meaning of the present invention, the term "skin contact layer" refers to a layer contained in a TTS that directly contacts the patient's skin during administration. If the TTS includes an additional skin contact layer, the other layers do not contact the skin and do not necessarily have self-adhesive properties. As outlined above, the skin contact layer can absorb a portion of the active agent over time and as a result can be regarded as an active agent-containing layer. The release area is provided by the area of the active agent-containing layer. The skin contact layer can be used to enhance adhesion. The sizes of the additional skin contact layer and the active agent-containing layer are usually coextensive and correspond to the release region.

[0048] Within the scope of the meaning of the present invention, the term "areal weight" refers to the dry weight of a specific layer, e.g., an active agent-containing layer, provided in g / m 2 and is subject to a tolerance of ±10%, preferably ±7.5%, due to variations during manufacturing.

[0049] Unless otherwise indicated, "%" refers to weight percent.

[0050] Within the scope of the meaning of the present invention, the term "polymer" refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, and includes homopolymers consisting of one type of monomer and copolymers consisting of two or more types of monomers. The polymer can have any structure such as a linear polymer, a star polymer, a comb polymer, a brush polymer, etc., and in the case of a copolymer, can have any monomer arrangement, for example, an alternating, statistical, block copolymer, or a graft polymer. The minimum molecular weight varies depending on the type of polymer and is known to those skilled in the art. The polymer can have a molecular weight of, for example, more than 2,000 Daltons, preferably more than 5,000 Daltons, more preferably more than 10,000 Daltons. Correspondingly, a compound having a molecular weight of less than 2,000 Daltons, preferably less than 5,000 Daltons, or more preferably less than 10,000 Daltons is usually referred to as an oligomer.

[0051] Within the scope of the meaning of the present invention, the term "crosslinking agent" refers to a substance that can crosslink functional groups contained in a polymer.

[0052] Within the scope of the meaning of the present invention, the term "adhesive overlay" refers to a self-adhesive layer structure that does not contain an activator, has a larger area than the activator-containing structure, and provides an additional area that adheres to the skin but does not provide an area for releasing the activator. Thereby, the overall adhesion characteristics of the TTS are enhanced. The adhesive overlay includes a backing layer and an adhesive layer.

[0053] Within the scope of the meaning of the present invention, the term "backing layer" refers to a layer that supports, for example, a layer containing agomelatine or forms the backing of an adhesive overlay. At least one backing layer in the TTS, and usually the backing layer of the layer containing agomelatine, is occlusive with respect to the activator contained in the layer during the storage and administration periods, that is, substantially impermeable, and therefore prevents loss of the active substance or cross-contamination in accordance with regulatory requirements.

[0054] The TTS according to the present invention can be characterized by certain parameters measured in an in vitro skin permeation test.

[0055] The in vitro penetration test is carried out in a Franz diffusion cell using human or animal skin, preferably excised stratified human skin having a thickness of 800 μm and an intact epidermis, and a receptor medium (the receptor medium may contain, for example, 60% by volume of phosphate buffer (pH 5.5), 30% by volume of dipropylene glycol, and 10% by volume of acetonitrile, and up to 40% by volume of an organic solvent such as ethanol, acetonitrile, isopropanol, dipropylene glycol, PEG400, with or without addition) and a phosphate buffer (having 0.1% saline azide at 32 °C) at pH 5.5 or 7.4.

[0056] Unless otherwise indicated, the in vitro permeation test is carried out using excised stratified human skin having a thickness of 800 μm and an intact epidermis and a phosphate buffer at pH 5.5 (having 0.1% saline azide at 32 °C) as the receptor medium. The amount of the active substance permeated into the receptor medium is determined at regular intervals using an effective HPLC method with a UV photometric detector by taking sample volumes. The receptor medium is completely or partially replaced with fresh medium when taking sample volumes, and the measured amount of the permeated active substance is related to the amount permeated between the last two sample collection time points and not related to the total amount permeated up to that point.

[0057] Therefore, within the scope of the meaning of the present invention, the parameter of "permeation amount" is provided in μg / cm 2 and is related to the amount of the active substance permeated at sample intervals at a certain elapsed time. For example, in the above-described in vitro permeation test in which the amount of the active substance permeated into the receptor medium is measured at time points of, for example, 0, 2, 4, 8, 12, and 24 hours, the "permeation amount" of the active substance can be provided over a sample interval from 8 hours to 12 hours and corresponds to the measurement result at the 12-hour time point.

[0058] The permeation amount can also be provided as the "cumulative permeation amount" corresponding to the cumulative amount of the active substance permeated at a specific point in time. For example, in the above in vitro permeation test where the amount of the active substance permeated into the receptor medium was measured at, for example, the 0, 2, 4, 8, 12, and 24-hour time points, the "cumulative permeation amount" of the active substance at the 12-hour time point corresponds to the sum of the permeation amounts from 0 to 2 hours, 2 to 4 hours, 4 to 8 hours, and 8 to 12 hours.

[0059] Within the scope of the present invention, a parameter called "skin permeation rate" over a specific sample interval at a specific elapsed time is provided in μg / (cm 2 time), and is calculated by dividing the permeation amount at the said sample interval measured by the above in vitro permeation test in μg / cm 2 by the time of the said sample interval. For example, in the skin permeation rate in the above in vitro permeation test where the amount of the active substance permeated into the receptor medium was measured at, for example, the 0, 2, 4, 8, 12, and 24-hour time points, the "skin permeation rate" at the 12-hour time point is calculated as the permeation amount at the sample interval from 8 to 12 hours divided by 4 hours.

[0060] The "cumulative skin permeation rate" can be calculated from each cumulative permeation amount by dividing the cumulative permeation amount by the elapsed time. For example, in the above in vitro permeation test where the amount of the active substance permeated into the receptor medium was measured at, for example, the 0, 2, 4, 8, 12, and 24-hour time points, the "cumulative skin permeation rate" at the 12-hour time point is calculated as the cumulative permeation amount over 12 hours (see above) divided by 12 hours.

[0061] Within the scope of the present invention, the above parameters of permeation amount and skin permeation rate (as well as cumulative permeation amount and cumulative skin permeation rate) refer to the average value calculated from at least three in vitro permeation test experiments.

[0062] The TTS according to the present invention can be characterized by certain parameters measured in in vitro clinical studies.

[0063] Within the scope of the meaning of the present invention, the term "administration" refers to the application of the dosage form, i.e., the TTS, to the skin of the patient, after which it is maintained on the skin for a certain period of time.

[0064] In typical continuous treatment of MDD, the frequency of drug administration is kept high enough to maintain a therapeutically effective plasma concentration. The interval between two administrations of the dosage form, also called the dosing interval, needs to be adjusted appropriately. Within the scope of the meaning of the present invention, the term "dosing interval" refers to the period between two consecutive TTS administrations, i.e., the interval between two consecutive times when the TTS is applied to the skin of the patient. To maintain the plasma concentration at the therapeutic level, the TTS is usually maintained on the skin of the patient throughout the entire dosing interval and removed only at the end of the dosing interval, at which time a new TTS is applied to the skin. For example, if the dosing interval is 168 hours or 7 days, the TTS is applied to the skin of the patient and maintained on the skin of the patient for 168 hours or 7 days. After 168 hours or 7 days, the TTS is removed from the skin and a new TTS is applied. Thus, a dosing interval of 168 hours or 7 days enables a once-weekly TTS replacement mode for 24-hour treatment.

[0065] In the case of continuous treatment with agomelatine, the TTS is usually administered once a day (24-hour dosing interval), preferably at bedtime. The TTS can be applied to the skin of the patient shortly before bedtime (e.g., 1 - 2 hours) in particular to take into account the delay in the onset of the drug and can be maintained on the skin until 24 hours. When the TTS is maintained on the skin for 24 hours, the TTS can be removed and a new TTS can be applied simultaneously. In the case of agomelatine, it may be possible to remove the TTS during the day because maintaining the plasma concentration at the therapeutic level for 24 hours is not necessary or may be contraindicated for resynchronization of the circadian rhythm. As a result, the patient does not have a TTS during the day. With application only overnight, the TTS is maintained on the skin only at night, e.g., for 4 - 12 hours, 6 - 10 hours, or during sleep, depending on the length of the patient's sleep, and then removed in the morning.

[0066] Within the scope of the meaning of the present invention, the term "room temperature" refers to the unmodified temperature found in the laboratory where the experiment is conducted, and is usually within the range of 15 to 35 °C, preferably about 18 to 25 °C.

[0067] Within the scope of the meaning of the present invention, the term "patient" refers to a subject presenting clinical signs of a particular symptom(s) suggesting a need for treatment, a subject being prophylactically or preventively treated against a medical condition, or a subject having received a diagnosis of a medical condition to be treated.

[0068] The clinical study according to the present invention refers to a study conducted in full compliance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) as well as the Good Clinical Practice (GCP) and regulatory agencies of all applicable regions.

[0069] Within the scope of the meaning of the present invention, the term "coating composition" refers to a composition containing all components of a drug-containing layer in a solvent that can be coated on a backing layer or release liner to form a drug-containing layer upon drying.

[0070] Within the scope of the meaning of the present invention, the term "dissolve" refers to the process of obtaining a solution that is transparent and contains no visible particles.

[0071] Within the scope of the meaning of the present invention, the term "solvent" refers to any liquid substance that is preferably a volatile organic liquid such as methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, hexane, n-heptane, toluene, and mixtures thereof.

[0072] Within the scope of the meaning of the present invention, unless otherwise specified, the term "about" refers to an amount that is ±10% of the disclosed amount. In some embodiments, the term "about" refers to an amount that is ±5% of the disclosed amount. In some embodiments, the term "about" refers to an amount that is ±2% of the disclosed amount.

Brief Description of the Drawings

[0073]

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Mode for Carrying Out the Invention

[0074] TTS Structure The present invention relates to a transdermal therapeutic system for the transdermal administration of agomelatine, comprising a self-adhesive layer structure containing agomelatine.

[0075] The self-adhesive layer structure contains a therapeutically effective amount of agomelatine and comprises A) a backing layer and B) an agomelatine-containing layer containing i) agomelatine and ii) a hydrophobic polymer.

[0076] Accordingly, a transdermal therapeutic system for the transdermal administration of agomelatine comprises a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, said self-adhesive layer structure A) a backing layer; and B) i) agomelatine; and ii) an agomelatine-containing layer containing a hydrophobic polymer. and comprises.

[0077] In certain embodiments, the agomelatine-containing layer further comprises a crystallization inhibitor or comprises at least 1% by weight of a crystallization inhibitor.

[0078] Accordingly, in certain embodiments, a transdermal therapeutic system for the transdermal administration of agomelatine comprises a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, said self-adhesive layer structure A) a backing layer; and B) i) agomelatine; ii) a hydrophobic polymer; and iii) an agomelatine-containing layer containing at least 1% by weight of a crystallization inhibitor. and comprises.

[0079] The backing layer is in particular substantially impermeable to agomelatine.

[0080] The TTS according to the invention can in particular be a matrix-type TTS or a microreservoir-type TTS, more preferably a microreservoir-type TTS.

[0081] In such matrix-type or micro-reservoir-type TTSs, a therapeutically effective amount of agomelatine is contained in the agomelatine-containing layer. The self-adhesive layer structure in such matrix-type or micro-reservoir-type TTSs may include one or more additional layers such as a skin contact layer. Such additional layers may or may not contain an active agent. As outlined above, even if the skin contact layer is manufactured as a layer that does not contain an active agent, after equilibration, it contains agomelatine and as a result, may also be regarded as an additional agomelatine-containing matrix-type or micro-reservoir-type layer. The additional layer and the agomelatine-containing layer may contain the same hydrophobic polymer or different polymers. Any of the agomelatine-containing layer and the additional layer(s) may be in direct contact with each other or may be separated by a membrane such as a rate-controlling membrane. When the agomelatine-containing layer is prepared by laminating two layers of substantially the same composition, the resulting bilayer should be regarded as one layer.

[0082] In reservoir-type TTSs, the active agent is contained in a liquid or semi-liquid reservoir. The self-adhesive layer structure in such reservoir-type TTSs may include one or more additional layers such as a skin contact layer. Such additional layers may or may not contain an active agent. As outlined above, even if the skin contact layer is manufactured as a layer that does not contain an active agent, after equilibration, it contains agomelatine and as a result, may also be regarded as an agomelatine-containing layer in the meaning of the present invention. The reservoir-type TTS further includes a rate-controlling membrane that separates the reservoir from the skin contact layer.

[0083] Thus, in certain embodiments, the self-adhesive layer structure includes an additional reservoir layer located between the backing layer and the agomelatine-containing layer, and a further rate-controlling membrane located between the additional reservoir layer and the agomelatine-containing layer.

[0084] In certain embodiments, the self-adhesive layer structure according to the present invention includes an additional skin contact layer. The additional skin contact layer is self-adhesive and provides an adhesive force between the self-adhesive layer structure and the patient's skin during administration.

[0085] In such an embodiment, the self - adhesive layer structure may or may not include a film located between the agomelatine - containing layer and the additional skin - contact layer, and this film is preferably a rate - controlling film.

[0086] In another embodiment, the self - adhesive layer structure according to the invention does not include an additional skin - contact layer. Then, sufficient adhesion between the self - adhesive layer structure during administration and the patient's skin is provided by other means, for example, by the agomelatine - containing layer and / or the adhesive layer. In particular, the self - adhesive layer structure can consist of a backing layer and an agomelatine - containing layer.

[0087] Thus, according to certain embodiments of the invention, the TTS may further include an adhesive overlay or may not include an adhesive overlay, preferably does not include an adhesive overlay. This adhesive overlay is in particular larger than the agomelatine - containing self - adhesive layer structure and can be attached thereto to enhance the adhesion properties of the entire transdermal therapeutic system. The adhesive overlay also includes a backing layer. The area of the adhesive overlay increases the overall size of the TTS but does not increase the release area. The adhesive overlay includes a self - adhesive polymer or a mixture of self - adhesive polymers selected from the group consisting of acrylic polymers, polyisobutylene, styrene - isoprene - styrene copolymers, polysiloxanes, and mixtures thereof, which may be the same as or different from any (e.g., hydrophobic) polymer or polymer mixture included in the active - agent - containing self - adhesive layer structure.

[0088] The self - adhesive layer structure according to the invention is usually located 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 include a release liner. The TTS thus protected is usually stored in a hermetically sealed pouch. This packaging can be safe for children and / or user - friendly for the elderly.

[0089] Agomelatine-containing layer As outlined in more detail above, the TTS according to certain embodiments of the invention comprises a self-adhesive layer structure comprising an agomelatine-containing layer.

[0090] In these embodiments, the agomelatine-containing layer i) agomelatine, and ii) a hydrophobic polymer and.

[0091] As outlined above, the agomelatine-containing layer may further comprise a crystallization inhibitor, or at least 1% by weight of a crystallization inhibitor.

[0092] In some particular embodiments, the agomelatine-containing layer is of the microreservoir type or the matrix type, preferably of the microreservoir type. In such embodiments, the agomelatine may be in a completely dissolved or dispersed form.

[0093] As already shown, the active agent-containing layer in a microreservoir-type TTS is a two-phase layer having an inner active substance-containing phase in an outer matrix phase, and the inner phase is in the form of deposits dispersed in the outer phase.

[0094] When the agomelatine-containing layer contains a crystallization inhibitor, it is presumed that the agomelatine is present in a uniform form with the crystallization inhibitor in the inner phase, and the hydrophobic polymer is present as a separate phase, forming the outer phase of the two-phase layer.

[0095] Thus, in certain embodiments of the invention, the agomelatine-containing layer a) an outer phase having a pressure-sensitive adhesive composition containing a hydrophobic polymer, and b) a dry two-phase layer having an inner phase having a composition containing agomelatine, wherein the inner phase forms deposits dispersed in the outer phase.

[0096] As already outlined, when the crystallization inhibitor is included in the agomelatine-containing layer, it is assumed to be present together with agomelatine within the droplets of the internal phase and to form a homogeneous phase, which can be, for example, a viscous liquid or an amorphous phase, or a so-called solid solution of agomelatine dissolved in the crystallization inhibitor, and optional further excipients such as solubilizers. Thus, in such embodiments, the composition of the internal phase comprises a crystallization inhibitor, preferably the pressure-sensitive adhesive composition of the external phase is substantially free of crystallization inhibitor, specifically, the pressure-sensitive adhesive composition of the external phase may comprise 5% by weight or less, preferably 3% by weight or less, or more preferably 1% by weight or less of the crystallization inhibitor.

[0097] On the other hand, the hydrophobic polymer should be present in the external phase. Thus, in these embodiments, the composition of the internal phase is substantially free of hydrophobic polymer, specifically, the composition of the internal phase may comprise 5% by weight or less, preferably 3% by weight or less, or more preferably 1% by weight or less of the hydrophobic polymer.

[0098] As the term "microreservoir" indicates, the dispersed deposits are of micrometer size, i.e., in certain embodiments, the dispersed deposits have an average particle size of from 0.1 to 100 μm, or from 0.5 to 50 μm.

[0099] The microreservoir system has the advantage that there is no need to increase the drug solubility of the actual adhesive layer, i.e., the external phase (which may lead to insufficient drug release), and a sufficient amount of the active substance can be dissolved in the internal phase. Without wishing to be bound by theory, it is assumed that the balance between a sufficient amount of the active substance in the internal phase and low drug solubility in the external phase leads to a good permeation profile of the TTS of the present invention. Such a system also has the advantage that it can prevent (re)crystallization of the activity and related limitations with respect to storage stability.

[0100] Also, generally, regardless of whether the agomelatine-containing layer is of the microreservoir type or not, in certain embodiments of the present invention, the agomelatine-containing layer does not contain agomelatine crystals.

[0101] Furthermore, the areal weight of the agomelatine-containing layer is one of the factors determining the amount of the active substance. A certain thickness is required to obtain a sufficient amount of the active substance, and in particular, it is also difficult to coat a very thin layer with sufficient precision. On the other hand, a very thick layer is not only uncomfortable to wear and prone to peeling off from the skin, but also difficult to manufacture and tends to lead to continuous release of the active substance for more than 24 hours, which is not a desirable release profile in the case of agomelatine. Eventually, the areal weight of the agomelatine-containing layer is preferably at least 25 g / m 2 , more preferably at least 35 g / m 2 , most preferably at least 40 g / m 2 , or the areal weight is preferably 150 g / m 2 or less, more preferably 120 g / m 2 or less, most preferably 90 g / m 2 or less, or the areal weight is preferably 25 - 150 g / m 2 , more preferably 35 - 120 g / m 2 , most preferably 40 - 90 g / m 2 .

[0102] Since the release area controls the effective dose, a specific minimum size is required for the release area. However, if the release area is too large, the size of the TTS becomes large, wearing becomes uncomfortable, and patient compliance decreases. Considering this, in a specific embodiment of the present invention, the transdermal therapeutic system has a release area of at least 1 cm 2 , preferably at least 5 cm 2 , more preferably at least 10 cm 2 , or the release area is 100 cm 2 or less, preferably 60 cm 2 or less, more preferably 50 cm 2 or less, or the release area is 1 - 100 cm 2 , preferably 5 - 60 cm 2 , more preferably 10 - 50 cm 2 .

[0103] As outlined above, although not wishing to be bound by theory, it is considered that a sufficient amount of the active agent contained in the TTS is necessary to achieve certain advantageous features of the TTS according to the present invention, such as good in vitro skin permeation. On the other hand, if the amount of the active substance is too large, it may lead to problems of undesirable storage stability such as recrystallization of the active substance, and it may also cause skin irritation due to too high a drug concentration. The amount of agomelatine contained in the TTS can be controlled bidirectionally by adjusting the concentration and / or the area weight of the agomelatine-containing layer. Details regarding the area weight are as described above. Regarding the concentration, the agomelatine-containing layer contains at least 0.5% by weight of agomelatine, preferably at least 1% by weight of agomelatine, more preferably at least 1.5% by weight of agomelatine, or the agomelatine-containing layer contains 8% by weight or less of agomelatine, preferably 6% by weight or less of agomelatine, more preferably 5% by weight or less of agomelatine, or the agomelatine-containing layer contains 0.5 to 8% by weight of agomelatine, preferably 1 to 6% by weight of agomelatine, more preferably 1.5 to 5% by weight of agomelatine.

[0104] Thus, in a particular embodiment of the present invention, the agomelatine-containing layer contains at least 0.04 mg / cm per release area 2 , preferably at least 0.06 mg / cm 2 , more preferably at least 0.08 mg / cm 2 , most preferably at least 0.1 mg / cm 2 of agomelatine, or the agomelatine-containing layer contains 0.4 mg / cm or less 2 , preferably 0.3 mg / cm or less 2 , more preferably 0.25 mg / cm or less 2 , most preferably 0.2 mg / cm or less 2 of agomelatine.

[0105] Regarding the amount of the active substance per TTS, the amount of agomelatine contained in the transdermal therapeutic system is at least 0.5 mg, preferably at least 1 mg, more preferably at least 2 mg, or the amount of agomelatine contained in the transdermal therapeutic system is 15 mg or less, preferably 10 mg or less, more preferably 8 mg or less, or the amount of agomelatine contained in the transdermal therapeutic system is 0.5 to 15 mg, preferably 1 to 10 mg, more preferably 2 to 8 mg.

[0106] In a certain specific embodiment of the present invention, the agomelatine-containing layer is a pressure-sensitive adhesive composition.

[0107] As will be understood in more detail below, in a specific embodiment, it is preferable to use ethanol as a solvent and not to use water for the coating composition for preparing the agomelatine-containing layer. Therefore, the transdermal therapeutic system according to the present invention can preferably be obtained (and / or obtained) by drying a coated coating composition containing agomelatine, a hydrophobic polymer, optionally a crystallization inhibitor, polyvinylpyrrolidone, and ethanol. Further, the transdermal therapeutic system according to the present invention can preferably be obtained (and / or obtained) by drying a coated coating composition that is substantially free of water, for example, contains less than 1% by weight, preferably less than 0.5% by weight, more preferably less than 0.1% by weight of water.

[0108] Considering the stability of the composition of the agomelatine-containing layer, the agomelatine-containing layer preferably does not contain volatile components that evaporate during storage and change the composition. Therefore, in certain embodiments, the agomelatine-containing layer is substantially free of volatile solvents. Volatile solvents in this sense can be selected from the group consisting of C1 to C3 straight-chain and branched alcohols, ethyl acetate, hexane, n-heptane, and any mixtures thereof. In particular, the agomelatine-containing layer contains 5% by weight or less, preferably 3% by weight or less, more preferably 1% by weight or less of volatile solvents. In particular, the agomelatine-containing layer may be substantially free of isopropanol, for example, contains 5% by weight or less, preferably 3% by weight or less, more preferably 1% by weight or less of isopropanol.

[0109] There is a possibility that the solubility of agomelatine is too high, and also regarding the reduction in the tendency to form a microreservoir type layer, the agomelatine-containing layer preferably contains only a limited amount of acrylic polymer. Therefore, in certain embodiments, the agomelatine-containing layer does not contain an amount of acrylic polymer exceeding 70% by weight, preferably exceeding 50% by weight, more preferably exceeding 30% by weight of the agomelatine-containing layer.

[0110] Agomelatine According to the present invention, the self-adhesive layer structure contains a therapeutically effective amount of agomelatine, and the self-adhesive layer structure includes an agomelatine-containing layer.

[0111] According to the present invention, the active agent agomelatine can be in any form in the TTS, particularly in the agomelatine-containing layer, that is, in its free, dissociated, or any related forms such as hydrates, solvates, etc., as well as in the form of particles in micronized form, crystalline form, particularly one of its polymorphic forms, and / or amorphous form, and can exist in any hybrid type form or mixed form of any of the aforementioned forms. Preferably, agomelatine exists in the free dissociated form.

[0112] Furthermore, in certain embodiments, agomelatine is included in the agomelatine-containing layer in a dissolved form, a dispersed form, a crystalline form, in particular one of its polymorphic forms, an amorphous form, a hydrate, a solvate, a hybrid type form of any of the foregoing forms, or a mixed form thereof.

[0113] In certain embodiments, the agomelatine-containing layer composition can be obtained (and / or is obtained) by incorporating the agomelatine in a dissolved form, a dispersed form, a crystalline form, in particular one of its polymorphic forms, an amorphous form, a hydrate, a solvate, a hybrid type form of any of the foregoing forms, or a mixed form thereof.

[0114] The agomelatine in the agomelatine-containing layer can be (completely) dissolved, or the agomelatine-containing layer can preferably contain agomelatine particles composed of the agomelatine in its free dissociated form, such that the agomelatine is present in a dispersed form. Needless to say, when the agomelatine is present in a dispersed form, nevertheless, the agomelatine-containing layer can also contain the agomelatine in a dissolved form, depending on the solubility of the active substance in the agomelatine-containing layer (e.g., saturated or supersaturated).

[0115] In a preferred embodiment, the agomelatine is completely dissolved, for example, at least 90 mol%, preferably at least 95 mol%, more preferably at least 98 mol%, and most preferably at least 99 mol% of the agomelatine in the agomelatine-containing layer is present in a dissolved form.

[0116] As outlined above, the amount of agomelatine in the TTS is considered important for good release of the active substance and can be adjusted, for example, by the agomelatine concentration. Thus, in certain embodiments, the concentration of agomelatine in the agomelatine-containing layer is 0.5 to 8% by weight, preferably 1 to 6% by weight, more preferably 1.5 to 5% by weight of the agomelatine-containing layer.

[0117] In certain embodiments, agomelatine has a purity of at least 95%, preferably at least 98%, more preferably at least 99%, as determined by quantitative HPLC. Quantitative HPLC can be performed by reverse-phase HPLC with UV detection. Specifically, when HPLC is performed at a uniform concentration, the following conditions can be used. Column: RP octadecyl phase XTerra RP18 100mmx3.9mm; 3.5μm or equivalent Mobile phase: 0.06 mol KH 2 PO 4 Buffer / acetonitrile (60:40; v:v); pH 2.5 Gradient: Uniform concentration Flow rate: 1.0 mL Injection volume: 20 μL Column temperature: 23 °C Wavelength: 229 nm and 275 nm Run time: 5 minutes

[0118] The TTS according to the present invention advantageously exhibits improved stability with respect to the agomelatine content and agomelatine degradation.

[0119] Thus, in certain embodiments, the agomelatine-containing layer initially (i.e., immediately after manufacture, e.g., within 1 week) contains at least 95%, preferably at least 97%, more preferably at least 98%, even more preferably at least 99% of the theoretical amount of agomelatine contained in the agomelatine-containing layer. The theoretical amount of agomelatine is calculated from the amount of agomelatine used in the coating composition and the (actual) areal weight of the coated and dried agomelatine-containing layer of the TTS being tested.

[0120] The agomelatine-containing layer may initially also contain less than 0.5%, preferably less than 0.3%, more preferably less than 0.2%, even more preferably less than 0.1% of the total amount of agomelatine-related degradation products.

[0121] In certain other embodiments, the TTS according to the present invention is stable during storage, i.e., they may maintain the initial agomelatine content value or present a small amount of degradation products as follows.

[0122] In one embodiment of such embodiments, after being stored at 25 °C and 60% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months, the agomelatine-containing layer contains at least 95%, preferably at least 97%, more preferably at least 98%, and even more preferably at least 99% of the theoretical amount of agomelatine contained in the agomelatine-containing layer.

[0123] The agomelatine-containing layer may also contain less than 1.0%, preferably less than 0.5%, more preferably less than 0.2%, and even more preferably less than 0.1% of the total amount of agomelatine-related degradation substances after being stored at 25 °C and 60% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months.

[0124] In one embodiment of such embodiments, after being stored at 30 °C and 75% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months, the agomelatine-containing layer contains at least 95%, preferably at least 97%, more preferably at least 98%, and even more preferably at least 99% of the theoretical amount of agomelatine contained in the agomelatine-containing layer.

[0125] The agomelatine-containing layer may also contain less than 1.0%, preferably less than 0.5%, more preferably less than 0.2%, and even more preferably less than 0.1% of the total amount of agomelatine-related degradation substances after being stored at 30 °C and 75% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months.

[0126] In one embodiment of such an embodiment, after being stored at 40° C. and 75% relative humidity for at least 3 months, preferably at least 6 months, the agomelatine-containing layer contains at least 95%, preferably at least 96%, more preferably at least 97%, still more preferably at least 98% of the theoretical amount of agomelatine contained in the agomelatine-containing layer.

[0127] The agomelatine-containing layer may also contain a total amount of agomelatine-related decomposition products of less than 1.0%, preferably less than 0.7%, more preferably less than 0.5%, still more preferably less than 0.4% after being stored at 40° C. and 75% relative humidity for at least 3 months, preferably at least 6 months.

[0128] The TTS according to the present invention is also advantageously stable during storage with respect to the adhesion and removability of the agomelatine-containing layer from the release liner, i.e., they can maintain the adhesive force and the peel force over time.

[0129] Thus, in certain embodiments, the adhesive force of the agomelatine-containing layer decreases by less than 25%, preferably less than 10%, more preferably less than 5% after being stored at 25° C. and 60% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, most preferably at least 12 months.

[0130] In certain embodiments, the adhesive force of the agomelatine-containing layer decreases by less than 25%, preferably less than 10%, more preferably less than 5% after being stored at 30° C. and 75% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, most preferably at least 12 months.

[0131] The adhesive force of the agomelatine-containing layer also decreases by less than 20%, preferably less than 10%, more preferably less than 3% after being stored at 40° C. / 75% relative humidity for at least 3 months, preferably at least 6 months.

[0132] In certain embodiments, the peel strength of the agomelatine-containing layer increases by less than 150%, preferably less than 100%, more preferably less than 30%, and most preferably less than 12 months after storage at 25 °C and 60% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months.

[0133] In certain embodiments, the peel strength of the agomelatine-containing layer increases by less than 250%, preferably less than 150%, more preferably less than 100% after storage at 30 °C and 75% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months.

[0134] The peel strength of the agomelatine-containing layer also increases by less than 250%, preferably less than 100%, more preferably less than 60% after storage at 40 °C / 75% relative humidity for at least 3 months, preferably at least 6 months.

[0135] The method for determining the agomelatine content, the total amount of agomelatine-related decomposition products, as well as the adhesive strength and peel strength is preferably carried out as described in Examples 8b and 8d.

[0136] Hydrophobic polymer As outlined above, the TTS according to the invention comprises a self-adhesive layer structure comprising an agomelatine-containing layer comprising a hydrophobic polymer.

[0137] This hydrophobic polymer provides sufficient adhesion of the agomelatine-containing layer. According to certain embodiments, the hydrophobic polymer may also provide sufficient adhesive strength. In such embodiments, and generally, the hydrophobic polymer may be selected from pressure-sensitive adhesive polymers.

[0138] In a preferred embodiment, the amount of the hydrophobic polymer is at least 75% by weight, preferably at least 80% by weight, more preferably at least 75% by weight, and / or the amount of the hydrophobic polymer is 98% by weight or less, preferably 94% by weight or less, more preferably 90% by weight or less. In particular, the amount of the hydrophobic polymer is 75 to 98% by weight, preferably 80 to 94% by weight, more preferably 85 to 90% by weight of the agomelatine-containing layer.

[0139] Polymers suitable as the hydrophobic polymer according to the present invention are selected from the group consisting of polyisobutylene, styrene-isoprene-styrene block copolymer, silicone acrylic hybrid polymer, silicone-based pressure-sensitive adhesive, and any mixture thereof.

[0140] The hydrophobic polymer is present in the agomelatine-containing layer, but may also be included in an optional adhesive overlay.

[0141] The hydrophobic polymer is usually supplied and used in a solvent such as n-heptane or ethyl acetate. The solid content of the pressure-sensitive adhesive is usually 30% to 80%.

[0142] Suitable hydrophobic polymers according to the present invention are commercially available under the brand names of, for example, Oppanol™ (polyisobutylene), JSR-SIS (styrene-isoprene-styrene copolymer), SilAc Hybrid PSA (silicone acrylic hybrid polymer), or BIO-PSA (silicone-based pressure-sensitive adhesive).

[0143] In a preferred embodiment, the hydrophobic polymer is a silicone-based pressure-sensitive adhesive polymer.

[0144] The silicone-based pressure-sensitive adhesive may also be referred to as a silicone-based pressure-sensitive adhesive or a silicone pressure-sensitive adhesive. They are advantageous in terms of the utilization of the active substance and the overall release profile.

[0145] These siloxane-based pressure-sensitive adhesives provide suitable tack and rapid bonding, suitable adhesion and cohesion qualities, long-term adhesion to the skin, high flexibility, permeability to moisture, as well as compatibility with many active substances and film substrates for various skin types, including wet skin. They can provide sufficient amine resistance and thus improved stability in the presence of amines. Such pressure-sensitive adhesives are based on the resin-in-polymer concept in which a polysiloxane-based pressure-sensitive adhesive is prepared by a condensation reaction of a polydimethylsiloxane endblocked with silanol and a silica resin (also called a silicate resin), with the remaining silanol functional groups additionally sealed with trimethylsiloxy groups for amine stability. The content of the polydimethylsiloxane endblocked with silanol contributes to the viscous component of the viscoelastic behavior and affects the wetting and diffusivity characteristics of the adhesive. The resin acts as an adhesive and a reinforcing agent and is involved in the elastic component. The precise balance between the polydimethylsiloxane endblocked with silanol and the resin provides precise adhesion properties.

[0146] In view of the above, silicone-based pressure-sensitive adhesives are generally obtained by polycondensation of silanol-terminated polydimethylsiloxane and a silicate resin. In other words, in a preferred embodiment, the pressure-sensitive adhesive based on polysiloxane is a soluble silicate resin polycondensed with silanol-terminated polydimethylsiloxane. Amine-compatible silicone-based polymers, especially amine-compatible silicone-based pressure-sensitive adhesives, can be obtained by reacting a silicone-based polymer, especially a silicone-based pressure-sensitive adhesive, with trimethylsilyl (e.g., hexamethyldisilazane) so as to reduce the silanol content of the polymer. As a result, the residual silanol functional groups are at least partially, preferably mostly or completely, blocked with trimethylsiloxy groups. Thus, in certain embodiments, the pressure-sensitive adhesive based on polysiloxane is a soluble silicate resin polycondensed with silanol-terminated polydimethylsiloxane, and the silanol groups of the polydimethylsiloxane not bonded to the soluble silicate resin are either free silanol groups or are trimethylsilylated.

[0147] As shown above, the tackiness of the silicone-based polymer can be altered by the resin-to-polymer ratio, i.e., the ratio of silanol-terminated polydimethylsiloxane to silicate resin, preferably from 70:30 to 50:50, preferably from 65:35 to 55:45. Increasing the amount of polydimethylsiloxane relative to the resin increases the tackiness. A highly tacky silicone-based polymer preferably has a resin-to-polymer ratio of 55:45, a medium-tack silicone-based polymer preferably has a resin-to-polymer ratio of 60:40, and a low-tack silicone-based polymer preferably has a resin-to-polymer ratio of 65:35. In a preferred embodiment, the pressure-sensitive adhesive based on polysiloxane is a soluble silicate resin polycondensed with silanol-terminated polydimethylsiloxane having a resin-to-polymer ratio of 65:35, 60:40, or 55:45. A highly tacky silicone-based polymer preferably has a complex viscosity of about 5x10 6poises, and a silicone-based polymer of medium tackiness preferably has a complex viscosity of about 5x10 at 0.01 rad / s and 30 °C 7 poises, and a low-tack silicone-based polymer preferably has a complex viscosity of about 5x10 at 0.01 rad / s and 30 °C 8 poises. A high-tack amine-compatible silicone-based polymer preferably has a complex viscosity of about 5x10 at 0.01 rad / s and 30 °C 6 poises, and a medium-tack amine-compatible silicone-based polymer preferably has a complex viscosity of about 5x10 at 0.01 rad / s and 30 °C 8 poises, and a low-tack amine-compatible silicone-based polymer preferably has a complex viscosity of about 5x10 at 0.01 rad / s and 30 °C 9 poises.

[0148] Examples of commercially available silicone-based PSA compositions typically include the standard BIO-PSA series (7-4400, 7-4500, and 7-4600 series), which are manufactured by Dow Corning and supplied in n-heptane or ethyl acetate, the amine-compatible (end-capped) BIO-PSA series (7-4100, 7-4200, and 7-4300 series), and the Soft Skin Adhesives series (7-9800). For example, BIO-PSA 7-4201 has a solution viscosity of 450 mPas at 25 °C and a solids content of about 60% in heptane, as well as a complex viscosity of 1×10 at 0.01 rad / s at 30 °C 8 characterized by a complex viscosity of poises. BIO-PSA 7-4301 has a solution viscosity of 500 mPas at 25 °C and a solids content of about 60% in heptane, as well as a complex viscosity of 5×10 at 0.01 rad / s at 30 °C 6 having a complex viscosity of poises.

[0149] Pressure-sensitive adhesives based on polysiloxane are supplied and used in a solvent such as n-heptane, ethyl acetate or other volatile silicone fluids. The solids content of the polysiloxane-based pressure-sensitive adhesive in the solvent is usually 60 to 85%, preferably 70 to 80%, or 60 to 75%. Those skilled in the art recognize that the solids content can be changed by adding a suitable amount of solvent.

[0150] For example, a polysiloxane-based pressure-sensitive adhesive available from Dow Corning can be obtained according to the following scheme.

Chemical formula

[0151] For example, a polysiloxane-based amine-compatible pressure-sensitive adhesive available from Dow Corning can be obtained according to the following scheme.

Chemical formula

[0152] In certain embodiments, the polysiloxane-based pressure-sensitive adhesive according to the present invention is characterized by a solution viscosity in 60% solids in n-heptane at 25°C of greater than about 150 mPa s, or from about 200 mPa s to about 700 mPa s, when measured using a Brookfield RVT viscometer with a spindle number 5 at 50 rpm. These can also be characterized by a complex viscosity at 0.01 rad / s and 30°C of less than about 1x10 9 poise, or from about 1x10 5 to about 9x10 8 poise. Also, in certain embodiments, the polysiloxane-based pressure-sensitive adhesive is characterized by a solution viscosity in 60% solids in ethyl acetate at 25°C of greater than about 350 mPa s, or from about 400 mPa s to about 1500 mPa s, when measured using a Brookfield RVT viscometer with a spindle number 5 at 50 rpm, or by a complex viscosity at 30°C and 0.01 rad / s of from about 1x10 5 to about 1x10 7 poise or from about 5x10 6 poise.

[0153] In another embodiment, the hydrophobic polymer is polyisobutylene.

[0154] Suitable polyisobutylene according to the present invention is available under the trade name Oppanol®. Combinations of high molecular weight polyisobutylene (B100 / B80) and low molecular weight polyisobutylene (B10, B11, B12, B13) can be used. Suitable ratios of low molecular weight polyisobutylene and high molecular weight polyisobutylene are in the range of 100:1 to 1:100, particularly 95:5 to 40:60, preferably 90:10 to 80:20 or 60:40 to 20:80, preferably 50:50 to 30:70. Preferred examples of combinations of polyisobutylene are B10 / B100 in a ratio of 85 / 15 or 40 / 60. Oppanol® B100 has a viscosity average molecular weight M v , and a weight average molecular weight M w of 1,550,000, and an average molecular weight distribution M w / M n of 2.9. Oppanol® B10 has a viscosity average molecular weight M v of 40,000, and a weight average molecular weight M w of 53,000, and an average molecular weight distribution M w / M n of 3.2. In certain embodiments, polybutene can be added to the polyisobutylene. The solids content of polyisobutylene in the solvent is typically 30 to 50%, preferably 35 to 40%. Those skilled in the art will recognize that the solids content can be varied by adding a suitable amount of solvent.

[0155] In yet another embodiment, the hydrophobic polymer is a styrene-isoprene-styrene block copolymer.

[0156] The hydrophobic polymer can also be a silicone acrylic hybrid polymer.

[0157] Silicone acrylate pressure-sensitive adhesives are typically supplied and used in solvents such as n-heptane and ethyl acetate. The solid content of the pressure-sensitive adhesive is usually 30% to 80%. Those skilled in the art recognize that the solid content can be changed by adding a suitable amount of solvent.

[0158] Preferably, the weight ratio of silicone to acrylate in the silicone acrylate 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.

[0159] Suitable commercially available silicone acrylate pressure-sensitive adhesives include the 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, the 7-6102 silicone acrylate hybrid PSA with a 50 / 50 silicone / acrylate ratio has a solution viscosity of 2,500 cP at 25 °C and a solid content of about 50% in ethyl acetate and a complex viscosity of 1.0e7 poise at 0.1 rad / s at 30 °C. The 7-6302 silicone acrylate hybrid PSA with a 50 / 50 silicone / acrylate ratio has a solution viscosity of 1,500 cP at 25 °C and a solid content of about 50% in ethyl acetate and a complex viscosity of 4.0e6 poise at 0.1 rad / s at 30 °C.

[0160] Depending on the solvent in which the silicone acrylic hybrid pressure - sensitive adhesive is supplied, the arrangement of the silicone phase and the acrylic phase, which provide a continuous external phase of silicone or acrylic and the corresponding discontinuous internal phase, is different. When 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. When 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 substances that can induce an 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 using a pressure - sensitive adhesive film or layer prepared from a silicone acrylic hybrid PSA composition adhered to a silicone - coated release liner. The pressure - sensitive adhesive film contains a continuous silicone external phase when the silicone - coated release liner cannot be removed, or can hardly be removed, from the pressure - sensitive adhesive film (laminated to the backing film) due to the blocking of two silicone surfaces. Blocking results from the adhesion of two silicone layers with similar surface energies. The silicone adhesive shows good spreading on the silicone - coated liner and can thus produce good adhesion to the liner. When the silicone - coated 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 thus has low or almost no adhesion to the silicone - coated liner.

[0161] According to a preferred embodiment of the present invention, the silicone acrylate hybrid polymer is a silicone acrylate hybrid pressure-sensitive adhesive that can be obtained from a silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups. It should be understood that the silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups may contain only acrylate functional groups, only methacrylate functional groups, or both acrylate functional groups and methacrylate functional groups.

[0162] According to a certain embodiment of the present invention, the silicone acrylate hybrid pressure-sensitive adhesive comprises a reaction product of (a) a silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups, (b) an ethylenically unsaturated monomer, and (c) an initiator. That is, the silicone acrylate hybrid pressure-sensitive adhesive is a product of a chemical reaction between these reactants ((a), (b), and (c)). In particular, the silicone acrylate hybrid pressure-sensitive adhesive comprises a reaction product of (a) a silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups, (b) a (meth)acrylate monomer, and (c) an initiator (i.e., in the presence of an initiator). That is, the silicone acrylate hybrid pressure-sensitive adhesive comprises a product of a chemical reaction between these reactants ((a), (b), and (c)).

[0163] The reaction product of (a) a silicone-containing pressure-sensitive adhesive composition containing acrylate or methacrylate functional groups, (b) an ethylenically unsaturated monomer, and (c) an initiator may contain a continuous silicone outer phase and a discontinuous acrylic inner phase, or the reaction product of (a), (b), and (c) may contain a continuous acrylic outer phase and a discontinuous silicone inner phase.

[0164] According to a certain embodiment of the present invention, the silicone acrylate hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin, and an acrylic polymer, and the acrylic polymer is self-crosslinked by covalent bonds and covalently bonded to the silicone polymer and / or the silicone resin.

[0165] According to certain other embodiments of the present invention, the silicone acrylic hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin, and an acrylic polymer, and the silicone resin comprises triorganosiloxy units R 3 SiO 1 / 2 (where R is an organic group), and tetrafunctional siloxy units SiO 4 / 2 , and contains them in a molar ratio of 0.1 to 0.9 of R 4 / 2 units per SiO 3 SiO 1 / 2 unit.

[0166] 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)acrylate, dialkoxyalkylsilyl (meth)acrylate, and mixtures thereof, or contains a terminal-capped alkoxysilyl functional group. The alkoxysilyl functional group may preferably be selected from the group consisting of trimethoxysilyl group, dimethoxymethylsilyl group, triethoxysilyl, diethoxymethylsilyl group, and mixtures thereof.

[0167] The acrylic polymer may also be prepared from a mixture containing a polysiloxane-containing monomer, preferably a mixture containing polydimethylsiloxane mono(meth)acrylate.

[0168] According to certain embodiments of the present invention, the silicone acrylic hybrid polymer can be prepared by a) reacting a silicone polymer with a silicone resin to form a resulting product, and b) reacting the resulting product of a) with an acrylic polymer containing reactive functional groups, where these components are reacted in an organic solvent.

[0169] According to a predetermined embodiment of the present invention, a silicone acrylic hybrid polymer can be prepared by a) reacting a silicone resin with an acrylic polymer containing reactive functional groups to form a resulting product, and b) reacting the resulting product of a) with a silicone polymer, where these components are reacted in an organic solvent.

[0170] According to a predetermined embodiment of the present invention, a silicone acrylic hybrid polymer can be prepared by a) reacting a silicone polymer with an acrylic polymer containing reactive functional groups to form a resulting product, and b) reacting the resulting product of a) with a silicone resin, where these components are reacted in an organic solvent.

[0171] Further suitable acrylic polymers, silicone resins, and silicone polymers that can be used to chemically react the silicone polymer, silicone resin, and acrylic polymer together to provide the silicone acrylic hybrid polymer according to the previous paragraphs are detailed in WO2010 / 124187.

[0172] Crystallization inhibitors and solubilizers As outlined above, according to certain aspects and embodiments of the present invention, the agomelatine-containing layer comprises a crystallization inhibitor.

[0173] Within the meaning of the present invention, a "crystallization inhibitor" is any substance that can prevent the recrystallization of TTS, in particular the active agent agomelatine in the agomelatine-containing layer of the present invention. Those skilled in the art know suitable crystallization inhibitors.

[0174] Not only for the above-mentioned anti-recrystallization effect, but also for the advantageous effect on the permeation profile (see below), a certain amount of crystallization inhibitor is required. On the other hand, if a large amount is blended, the solubility of the drug is too high, which may have an adverse effect on the permeation rate. Therefore, the agomelatine-containing layer preferably contains at least 1% by weight of the crystallization inhibitor. In a preferred embodiment, the agomelatine-containing layer contains at least 1.5% by weight, preferably at least 2.5% by weight, more preferably at least 4% by weight, and most preferably at least 5% by weight of such a crystallization inhibitor, while on the other hand, it contains 30% by weight or less, preferably 25% by weight or less, more preferably 20% by weight or less, and most preferably 15% by weight or less of the crystallization inhibitor. For example, the agomelatine-containing layer may contain 1.5 to 30% by weight, preferably 2.5 to 25% by weight, more preferably 4 to 20% by weight, and most preferably 5 to 15% by weight of the crystallization inhibitor.

[0175] Particularly interesting as a crystallization inhibitor is a polymer with enhanced water absorption ability. This is because higher water absorption and / or moisture absorption helps to maintain / improve the adhesion properties of the agomelatine-containing layer, and such substances are thought to contribute to the good skin permeation behavior of the microreservoir system. That is, without wishing to be bound by any theory, in the microreservoir system, the crystallization inhibitor present in the internal phase together with the active agent has a higher affinity for water than the active agent. As a result, the water in the skin absorbed during the application of the TTS to the patient's skin replaces the dissolved active agent. The molecules of the replaced active agent are affected by the high driving force for diffusion from the TTS into the skin and within the skin.

[0176] Thus, in certain embodiments, the agomelatine-containing layer comprises a crystallization inhibitor selected from polymers that provide improved water absorption and / or moisture absorption of the agomelatine-containing layer. Such polymers are well known in the art. Among them, polyvinylpyrrolidone and polyvinylpyrrolidone-vinyl acetate copolymers are particularly suitable and preferred. Polyvinylpyrrolidone-vinyl acetate copolymers are commercially available, for example, under the brand name Kollidon® VA64 supplied by BASF.

[0177] In certain embodiments, the crystallization inhibitor is selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone-vinyl acetate copolymers. Preferably, the crystallization inhibitor is polyvinylpyrrolidone, and in particular, the crystallization inhibitor is selected from soluble polyvinylpyrrolidone.

[0178] Within the scope of the meaning of the present invention, the term "soluble polyvinylpyrrolidone" refers to polyvinylpyrrolidone, also known as povidone, which is soluble in at least ethanol, preferably in water, diethylene glycol, methanol, n-propanol, 2-propanol, n-butanol, chloroform, methylene chloride, 2-pyrrolidone, macrogol 400, 1,2 propylene glycol, 1,4 butanediol, glycerol, triethanolamine, propionic acid, and acetic acid, at more than 10%. Examples of commercially available polyvinylpyrrolidone include Kollidon® 12PF, Kollidon® 17PF, Kollidon® 25, Kollidon® 30, and Kollidon® 90F, or povidone K90F, supplied by BASF. Different grades of Kollidon® are defined in terms of the K value, which reflects the average molecular weight of the polyvinylpyrrolidone grade. Kollidon® 12PF is characterized by a K value range of 10.2 to 13.8 corresponding to a nominal K value of 12. Kollidon® 17PF is characterized by a K value range of 15.3 to 18.4 corresponding to a nominal K value of 17. Kollidon® 25 is characterized by a K value range of 22.5 to 27.0 corresponding to a nominal K value of 25, and Kollidon® 30 is characterized by a K value range of 27.0 to 32.4 corresponding to a nominal K value of 30. Kollidon® 90F is characterized by a K value range of 81.0 to 97.2 corresponding to a nominal K value of 90. Preferred Kollidon® grades are Kollidon® 12PF, Kollidon® 30, and Kollidon® 90F. For all grades and types of polyvinylpyrrolidone, it is preferred that the amount of peroxide is within a certain restricted range. Specifically, the amount of peroxide is 500 ppm or less, more preferably 150 ppm or less, and most preferably 100 ppm or less.

[0179] Within the scope of the meaning of the present invention, the term "K value" refers to a value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the European Pharmacopoeia (Ph.Eur.) and USP monograph for "povidone".

[0180] Thus, in certain embodiments, the crystallization inhibitor is 9 to 15, preferably 10.2 to 13.8, 15 to 20, preferably 15.3 to 18.4, 20 to 27, preferably 22.5 to 27.0, 27 to 35, preferably 27.0 to 32.4, and 75 to 110, preferably 81.0 to 97.2 a polyvinylpyrrolidone having a K value within a range selected from the group of ranges consisting of, or any mixture thereof, more preferably a polyvinylpyrrolidone having a K value within the range of 27.0 to 32.4 or 81.0 to 97.2 and any mixture thereof, and most preferably a polyvinylpyrrolidone having a K value within the range of 81.0 to 97.2.

[0181] In certain embodiments of the present invention, the agomelatine-containing layer contains a solubilizer.

[0182] Within the meaning of the present invention, the term "solubilizer" refers to any substance that can substantially increase the solubility of agomelatine in the agomelatine-containing layer, for example, by at least 1 percentage point (by weight relative to the amount of agomelatine in the agomelatine-containing layer) per 10% by weight, preferably per 5% by weight, more preferably per 1% by weight, and most preferably per 0.5% by weight of the solubilizer added to the agomelatine-containing layer.

[0183] In certain preferred embodiments, the solubilizer is selected from the group consisting of dipropylene glycol, lauryl lactate, and a mixture of a propylene glycol monoester and a diester of a fatty acid, such as a mixture of propylene glycol monocaprylate (type II), a propylene glycol monoester and a diester of a fatty acid in a ratio of more than 90% monoester and less than 10% diester, which is commercially available under the brand name Capryol. Here, the fatty acid is mainly caprylic acid (commercially available as Capryol (trademark) 90 supplied by Gattefosse), levulinic acid, polyethylene glycol ethers, especially polyethylene glycol fatty alcohol ethers (such as those commercially available under the name Brij (registered trademark)), for example, polyethylene glycol dodecyl ether with an average molecular weight Mn of about 362 commercially available as Brij (registered trademark) L4, and diethylene glycol monoethyl ether (commercially available under the name transcutol (registered trademark)).

[0184] A certain minimum amount of the solubilizer is advantageous in that it contributes to preventing the recrystallization of the active agent in the agomelatine-containing layer. On the other hand, if the amount of the solubilizer is too large, the cohesiveness of the agomelatine-containing layer may be impaired, so a balance needs to be taken. Considering these factors, in certain preferred embodiments, the agomelatine-containing layer contains at least 1.5% by weight, preferably at least 2.5% by weight, more preferably at least 4% by weight, and most preferably at least 5% by weight of the solubilizer, while on the other hand, it contains 30% by weight or less, preferably 25% by weight or less, more preferably 20% by weight or less, and most preferably 15% by weight or less of the solubilizer. For example, the agomelatine-containing layer may contain 1.5 to 30% by weight, preferably 2.5 to 25% by weight, more preferably 4 to 20% by weight, and most preferably 5 to 15% by weight of the solubilizer. In another embodiment, the agomelatine-containing layer does not contain a solubilizer selected from the group consisting of dipropylene glycol, lauryl lactate, a mixture of a propylene glycol monoester and a diester of a fatty acid, levulinic acid, polyethylene glycol ethers, and diethylene glycol monoethyl ether.

[0185] In addition, regarding the advantageous effect of preventing the recrystallization of agomelatine, the crystallization inhibitor and the solubilizer may complement each other. Therefore, in certain embodiments, especially when the crystallization inhibitor is present in a sufficient amount, the agomelatine-containing layer does not contain a solubilizer selected from the group consisting of dipropylene glycol, lauryl lactate, a mixture of propylene glycol monoester and diester of fatty acid, levulinic acid, and polyethylene glycol ether. Also, preferably, the total amount of the crystallization inhibitor and the solubilizer present in the agomelatine-containing layer is at least 2.5% by weight, preferably at least 3.5% by weight, more preferably at least 4% by weight, most preferably at least 5% by weight, and / or 30% by weight or less, preferably 25% by weight or less, more preferably 20% by weight or less, most preferably 15% by weight or less, for example, 1.5 to 30% by weight, preferably 2.5 to 25% by weight, more preferably 4 to 20% by weight, most preferably 5 to 15% by weight.

[0186] Finally, the amount of the crystallization inhibitor and / or the solubilizer necessary to effectively prevent the recrystallization of agomelatine also depends on the amount of agomelatine present in the agomelatine-containing layer. Therefore, the ratio of the total amount of the crystallization inhibitor and the solubilizer present in the agomelatine-containing layer to the amount of agomelatine present in the agomelatine-containing layer is preferably at least 1:2, more preferably at least 1:1, most preferably at least 2:1. This total amount refers to the amount of the crystallization inhibitor when no solubilizer is present.

[0187] Further additives The agomelatine-containing layer of the TTS according to the present invention may contain further excipients or additives selected from the group consisting of cross-linking agents, further solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners, skin care substances, penetration enhancers, i.e., substances that affect the barrier properties of the stratum corneum in the sense of increasing the permeability of the active agent, pH adjusters, and preservatives.

[0188] Particularly preferred additives are stabilizers. Such additives may be present in the agomelatine-containing layer in an amount of from 0.001 to 15% by weight of the agomelatine-containing layer per additive. In certain embodiments, the total amount of all additives is from 0.001 to 25% by weight of the agomelatine-containing layer. Hereinafter, when ranges of amounts of specific additives are provided, such ranges refer to the amounts per individual additive.

[0189] It should be noted that in pharmaceutical formulations, formulation ingredients are categorized according to their physicochemical and physiological properties and according to their functions. This means in particular that a substance or compound classified in a certain category is not excluded from classification in another category of formulation ingredients. For example, a particular polymer can be not only a crystallization inhibitor but also a tackifier. Some substances can, for example, be typical plasticizers and at the same time act as penetration enhancers. A person skilled in the art can, based on their general knowledge, determine to which category (or categories) of formulation ingredients a particular substance or compound belongs. Details of excipients and additives are provided below, but these should not be understood as being exclusive. Other substances not specifically listed herein may also be used according to the invention, and substances and / or compounds specifically listed in one category of formulation ingredients are not excluded from use as another formulation ingredient in the context of the present invention.

[0190] The crosslinking agent can be selected from the group consisting of aluminum and titanium crosslinking agents such as aluminum acetylacetonate, titanium acetylacetonate, or polybutyl titanate. The amount of the crosslinking agent can range from 0.005 to 1% by weight, preferably from 0.01 to 0.1% by weight, of the agomelatine-containing layer. The agomelatine-containing layer can also include a self-crosslinkable polymer, i.e., a polymer containing crosslinkable functional groups such as glycidyl groups that react upon heating. According to a further specific embodiment, the agomelatine-containing layer includes the above crosslinking agent and the self-crosslinkable polymer.

[0191] In addition to the aforementioned solubilizers, the agomelatine-containing layer may further contain additional solubilizers. Preferred additional solubilizers include, for example, glycerols, polyglycerols, propylene glycol, and polyoxyethylene esters of medium-chain and / or long-chain fatty acids, such as glyceryl monolaurate, medium-chain glycerides, and medium-chain triglycerides, non-ionic solubilizers prepared by reacting castor oil with ethylene oxide, and any mixtures thereof that may further contain fatty acids or fatty alcohols; cellulose, methylcellulose, and their derivatives, such as hydroxypropylcellulose and hypromellose acetate succinate; various cyclodextrins and their derivatives; non-ionic triblock copolymers having a central hydrophobic polyoxypropylene chain flanked by two hydrophilic polyoxyethylene chains known as poloxamers; graft copolymers based on polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam abbreviated as PVAc-PVCap-PEG and also known as Soluplus®; natural-derived castor oil, polyethylene glycol 400, polyoxyethylene sorbitan monooleate (such as polysorbate 80), or a purified grade of propylene glycol; diethylene glycol monoethyl ether; and any of the soluble polyvinylpyrrolidones described below, as well as insoluble / crosslinked polyvinylpyrrolidones also known as crospovidones such as Kollidon® CL, Kollidon® CL-M, and Kollidon® CL-SF.

[0192] However, the permeation enhancers described below can also act as additional solubilizers.

[0193] Fillers such as silica gel, titanium dioxide, and zinc oxide can be used in combination with the polymer to affect certain physical parameters such as adhesion and bond strength in a desirable manner.

[0194] The agomelatine-containing layer needs to have self-adhesive properties. If a hydrophobic polymer that does not provide sufficient self-adhesive properties is selected, a tackifier is added. The tackifier can be selected from triglycerides, polyethylene glycol, dipropylene glycol, resins, resin esters, terpenes and their derivatives, ethylene vinyl acetate adhesives, dimethyl polysiloxane, and polybutene, and mixtures thereof. In certain embodiments, the agomelatine-containing layer contains a tackifier in an amount of 5 to 15% of the agomelatine-containing layer.

[0195] In certain embodiments, the agomelatine-containing layer contains a stabilizer selected from sodium metabisulfite, ascorbic acid and its ester derivatives, butylated hydroxytoluene, tocopherol and its ester derivatives, such as tocopheryl acetate and tocopheryl linoleate, preferably tocopherol and its ester derivatives, and ascorbic acid and its ester derivatives, especially ascorbyl esters of fatty acids such as ascorbyl palmitate, and α-tocopherol. When the agomelatine-containing layer contains a stabilizer, the amount of the stabilizer is 0.001 to 2% by weight of the agomelatine-containing layer.

[0196] In one embodiment, the agomelatine-containing layer further contains a softening agent / plasticizer. Exemplary softening agents / plasticizers include linear or branched saturated or unsaturated alcohols having 6 to 20 carbon atoms, triglycerides, and polyethylene glycol.

[0197] In certain embodiments, the agomelatine-containing layer contains a permeation enhancer selected from caprylic acid, glycerol, 2,5-dimethylisosorbide, dimethyl ethylene urea, N,N-diethyl-meta-toluamide, polyethylene glycol, propylene glycol monocaprylate, 2-methoxy-4-(prop-2-en-1-yl)phenol, lactic acid, and laurocapram.

[0198] In certain embodiments, the agomelatine-containing layer does not contain a penetration enhancer selected from diethylene glycol monoethyl ether, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lactic acid, dimethyl ethylene urea and dimethyl propylene urea.

[0199] The agomelatine-containing layer according to the present invention may contain a pH adjuster. Preferably, the pH adjuster is selected from amine derivatives, inorganic alkali derivatives, and polymers having basic functionality and acidic functionality, respectively.

[0200] Release characteristics The TTS according to the present invention is designed to transdermally administer a certain amount of agomelatine into the systemic circulation, particularly at night.

[0201] Administration of the TTS of the present invention generally preferably comprises applying the transdermal therapeutic system to the skin of a human patient and maintaining it on the skin for at least 2 hours, preferably at least 4 hours, more preferably at least 6 hours, and / or 24 hours or less, preferably 18 hours or less, more preferably 14 hours or less, and / or 2 to 24 hours, preferably 4 to 18 hours, more preferably 6 to 14 hours.

[0202] In certain embodiments of the present invention, the above-mentioned TTS according to the present invention is measured with a Franz diffusion cell using excised human skin, 0.5 μg / cm 2 -hr to 15 μg / cm 2 -hr, 1 μg / cm 2 -hr to 20 μg / cm 2 -hr, 2 μg / cm 2 -hr to 25 μg / cm 2 -hr, and 1 μg / cm 2 -hr to 15 μg / cm 2 -hr of the skin permeation rate of agomelatine.

[0203] In certain embodiments, the transdermal therapeutic system according to the present invention has a cumulative permeation amount of agomelatine of at least 0.01 mg / cm 2 , preferably at least 0.015 mg / cm 2 , more preferably at least 0.02 mg / cm 2 , and / or 0.2 mg / cm 2 or less, preferably 0.15 mg / cm 2 or less, more preferably 0.1 mg / cm 2 or less, and / or 0.01 mg / cm 2 to 0.2 mg / cm 2 , preferably 0.015 mg / cm 2 to 0.15 mg / cm 2 , more preferably 0.02 mg / cm 2 to 0.1 mg / cm 2 as measured by a Franz diffusion cell using excised human skin at 8 hours.

[0204] In certain embodiments, the transdermal therapeutic system according to the present invention provides an agomelatine utilization rate of at least 10%, preferably at least 15%, more preferably at least 20% after 8 hours as measured by a Franz diffusion cell using excised human skin.

[0205] Therapeutic method / Medical use According to certain aspects of the present invention, the TTS according to the present invention is for use in a method of treatment, specifically a method of treating a human patient. According to another aspect, the present invention relates to a method of treatment comprising applying a transdermal therapeutic system according to the present invention to the skin, particularly the skin of a human patient. In yet another aspect, the present invention relates to the use of a transdermal therapeutic system according to the present invention in the manufacture of a medicament for treatment, preferably for treating a human patient.

[0206] The majority of more than 80% of patients suffering from classical mood disorders (major depressive disorder, the depressive phase of bipolar disorder, or generalized anxiety disorder) show disruptions in the sleep-wake cycle and sleep architecture. Characteristically, difficulty falling asleep (increased sleep latency) followed by inadequate sleep leads to significant daytime sleepiness, further impairing the ability to function properly in daily life and establishing a vicious cycle. Regarding depression, there are no specific treatment guidelines, but the available options generally are based on the premise that depression and sleep disorders share a bidirectional relationship, so that successful treatment of one condition mutually benefits the other.

[0207] In recent years, it has become increasingly clear that circadian rhythm disruption, i.e., the maladjustment and dysfunction of the "body clock" that regulates not only major physiological functions such as body temperature and blood pressure but also the responses of very complex neurotransmitters to the time of day, is a major factor in major depressive disorders that requires therapeutic attention. Dysfunction of the link between the suprachiasmatic nucleus, the pineal gland, and the neurohormone (melatonin) it produces has been suggested as the main cause of these phenomena. Melatonin is strongly supported (and sold) as a "non-photic circadian resynchronizer" for treating jet lag and insomnia associated with shift work, and there have been many publications on the antidepressant and anxiolytic effects of melatonin. Due to the low oral bioavailability of melatonin, synthetic melatonin receptor agonists have been investigated. The most prominent among them is agomelatine.

[0208] Agomelatine is approved for the treatment of depression, but its use has been proposed for the treatment of other indications such as bipolar disorder, generalized anxiety disorder, Smith-Magenis syndrome, periventricular leukomalacia, OCD, etc.

[0209] Thus, in certain embodiments, the TTS according to the present invention is preferably for use in a method of treating major depressive disorder. Similarly, in certain other embodiments, the present invention relates to a method of treating major depressive disorder, and the transdermal therapeutic system according to the present invention is applied to the skin, particularly the skin of a human patient. In yet other embodiments, the present invention relates to the use of the transdermal therapeutic system of the present invention in the manufacture of a medicament for treating major depressive disorder.

[0210] Treatment of major depressive disorder, also known as depression or major depressive disorder, includes treatment of conditions such as major depressive episodes, anxiety symptoms, sleep-wake cycle disorders, daytime sleepiness, and insomnia (the majority of MDD patients, i.e., more than 80%, suffer from depression combined with insomnia) in patients with depression / MDD. In other embodiments, general treatment may also refer to the treatment of bipolar disorder, generalized anxiety disorder, Smith-Magenis syndrome, periventricular leukomalacia, or OCD.

[0211] As outlined above, transdermal delivery avoids the first-pass effect and thus the TTS according to the present invention has a lower risk of hepatotoxicity than oral agomelatine formulations. Thus, there are no restrictions regarding the patient group to be treated. Thus, the treatment includes the treatment of human patients with or without liver dysfunction, including patients with at least mild or at least moderate liver dysfunction.

[0212] Also, in certain embodiments, treatment with the transdermal therapeutic system of the present invention provides a reduction in at least one agomelatine-related side effect as compared to an equivalent oral dose of agomelatine. As outlined above, in certain embodiments, such agomelatine-related side effects are hepatotoxicity. The comparison with an equivalent oral dose of agomelatine should be understood as a comparison of the incidence and intensity of side effects in clinical studies when using doses of transdermal and oral agomelatine that result in substantially the same agomelatine plasma exposure. The incidence of at least one agomelatine-related side effect compared to an equivalent oral dose of agomelatine can be reduced by at least about 30%, preferably at least about 40%, more preferably at least about 70%, most preferably at least about 80%, and / or the intensity of at least one agomelatine-related side effect compared to an equivalent oral dose of agomelatine can be reduced. The intensity of the side effect can be determined, for example, by classifying the side effect on a scale indicating intensity such as "mild", "moderate", or "severe", and the reduction in intensity can be quantified by comparing the median intensity.

[0213] In any of the treatments outlined for the above aspects and embodiments, the transdermal therapeutic system is preferably applied to the skin of a human patient and maintained on the skin for at least 2 hours, preferably at least 4 hours, more preferably at least 6 hours, and / or 24 hours or less, preferably 18 hours or less, more preferably 14 hours or less, and / or 2 to 24 hours, preferably 4 to 18 hours, more preferably 6 to 14 hours.

[0214] In another embodiment, the TTS according to the present invention can also be for use in a method of reducing at least one agomelatine-related side effect in a patient as compared to an equivalent oral dose of agomelatine.

[0215] The present invention also relates to a method of reducing at least one agomelatine-related side effect in a patient being treated with oral agomelatine therapy, the method comprising a) discontinuing the oral agomelatine therapy and b) Administering a transdermal therapeutic system according to the present invention to the skin of a patient, wherein the transdermal therapeutic system provides a reduction in at least one agomelatine-related side effect as compared to an equivalent oral dose of agomelatine.

[0216] In such a method, the transdermal therapeutic system can deliver an amount of agomelatine equivalent to the amount of agomelatine originally provided by oral agomelatine therapy.

[0217] Manufacturing process The present invention further relates to a process for manufacturing an agomelatine-containing layer for use in a transdermal therapeutic system, as well as to a corresponding self-adhesive layer structure comprising the agomelatine-containing layer and the corresponding TTS.

[0218] According to one aspect of the present invention, a process for manufacturing an agomelatine-containing layer for use in a transdermal therapeutic system comprises i) combining at least agomelatine, a hydrophobic polymer, and a crystallization inhibitor selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone-polyvinyl acetate copolymer in a solvent to obtain a coating composition; ii) coating the coating composition onto a backing layer or a release liner or any intermediate layer; iii) drying the coated coating composition to form an agomelatine-containing layer. and comprises.

[0219] According to another aspect of the present invention, a process for manufacturing an agomelatine-containing layer for use in a transdermal therapeutic system comprises i) combining at least agomelatine and a hydrophobic polymer in a solvent to obtain a coating composition; ii) coating the coating composition onto a backing layer or a release liner or any intermediate layer; iii) drying the coated coating composition to form a microreservoir-type agomelatine-containing layer; and includes.

[0220] In such a process, the hydrophobic polymer is selected from the group consisting of polyisobutylene, styrene-isoprene-styrene block copolymer, silicone acrylic hybrid polymer, and pressure-sensitive adhesives based on polysiloxane.

[0221] In this manufacturing process, preferably, in step i), agomelatine dissolves or disperses, more preferably dissolves, to obtain a coating composition.

[0222] Since agomelatine is poorly soluble in water and there is a risk of recrystallization, it is preferable not to use water.

[0223] Therefore, in the above process, the solvent can be selected from alcohol solvents, specifically methanol, ethanol, isopropanol, and mixtures thereof, and non-alcohol solvents, specifically ethyl acetate, hexane, n-heptane, heptane, petroleum ether, toluene, and mixtures thereof. Preferably, the solvent includes an alcohol solvent selected from methanol, ethanol, isopropanol, and mixtures thereof, and more preferably, the solvent contains or consists of ethanol.

[0224] Furthermore, the solvent substantially does not contain water. For example, the solvent contains less than 1% by weight, preferably less than 0.5% by weight, more preferably less than 0.1% by weight of water.

[0225] The priorities of the hydrophobic polymer, crystallization inhibitor, and other components in the agomelatine-containing layer are as described above. Thus, in some embodiments, step i) consists of combining at least agomelatine, a hydrophobic polymer, polyvinylpyrrolidone, and a solubilizer selected from the group consisting of dipropylene glycol, lauryl lactate, a mixture of a propylene glycol monoester and a diester of a fatty acid, levulinic acid, a polyethylene glycol ether, and diethylene glycol monoethyl ether in a solvent to obtain a coating composition. Also, in step i), agomelatine is combined in a dissolved form, a dispersed form, a crystalline form, particularly one of its polymorphic forms, an amorphous form, a hydrate, a solvate, a hybrid type form of any of the foregoing forms, or a mixed form thereof.

[0226] In step iii), drying is preferably carried out at room temperature and / or at a temperature of 40 to 90 °C, more preferably 50 to 70 °C, in one or more cycles.

[0227] The self-adhesive layer structure comprising the agomelatine-containing layer and the corresponding TTS can be produced using further manufacturing steps such as laminating with a backing layer to obtain the self-adhesive layer structure, punching out individual TTSs, packaging them, and sealing them, for example, in a pouch of a primary packaging material, as known to a person skilled in the art. Such further steps preferably result in a self-adhesive layer structure or a TTS as described in the previous chapter.

[0228] The present invention relates in particular to an agomelatine-containing layer and to self-adhesive layer structures and transdermal therapeutic systems obtainable (and / or obtained) by the above process.

Examples

[0229] Hereinafter, the present invention will be more fully described with reference to the accompanying examples. However, it should be understood that the following description is merely illustrative and should in no way be construed as limiting the present invention. The numerical values provided in the examples regarding the amounts of components or areal weights in the composition may vary slightly due to fluctuations during production.

[0230] Examples 1A to 1C Coating composition The formulations of the agomelatine-containing coating compositions of Examples 1a to 1c are summarized in Table 1.1 below. As also shown in Table 1.1, the formulations are based on weight percentages.

[0231] [Table 1]

[0232] Preparation of the coating composition In the case of Example 1a, a beaker was charged with agomelatine. Acrylic adhesive Duro-Tak (trademark) (3) 87-4098 was added, and then the mixture was stirred until a clear solution was obtained (for about 30 minutes).

[0233] In the case of Example 1b, a beaker was charged with agomelatine. Acrylic adhesive Duro-Tak (trademark) (3) 87-2353 was added, and then the mixture was stirred until a viscous mixture was obtained (for about 14 minutes). Next, ethyl acetate was added while stirring, and the homogeneous and clear mixture was stirred for about 2.5 hours.

[0234] In the case of Example 1c, a beaker was charged with agomelatine. Silicone pressure-sensitive adhesive Q7-4302 was added, and the mixture was stirred (for about 10 minutes). First, 0.6 g of ethanol was added while stirring, and after about 10 minutes, an additional 0.2 g of ethanol was added. Next, Povidone K90 was added while stirring, thereby increasing the viscosity. A slightly opaque and homogeneous mixture was obtained.

[0235] Coating of the coating composition The obtained agomelatine-containing coating composition was coated onto a polyester film (a polyethylene terephthalate film, single-sided silicon-treated, 100 μm thick, which can function as the release liner in Examples 1a and 1b, 74 μm thick, which can function as the fluoropolymer-coated release liner in Example 1c), and dried at room temperature for about 10 minutes and at 60 °C (Example 1a) and 70 °C (Examples 1b and 1c) for about 10 minutes respectively. The thickness of the coating gave a basis weight of 46.6 g / m 2 (Example 1a), 49.5 g / m 2 (Example 1b), and 50.7 g / m 2 (Example 1c) respectively. A polyethylene terephthalate backing layer (23 μm thick) was laminated onto the dried film to obtain an agomelatine-containing self-adhesive layer structure.

[0236] Preparation of TTS (for all examples) Subsequently, individual systems (TTS) were punched out from the agomelatine-containing self-adhesive layer structure. In certain embodiments, the TTS described above may preferably have rounded corners and may comprise a further self-adhesive layer having a larger surface area, which contains a pressure-sensitive adhesive matrix layer without the active ingredient. This is advantageous when the TTS does not adhere sufficiently to the skin based only on its physical properties and / or when the agomelatine-containing matrix layer has prominent corners (square or rectangular shape) for the purpose of avoiding waste. The TTS was then punched out and sealed into a pouch of the primary packaging material under a protective atmosphere, i.e., by flowing nitrogen gas, as is customary in the art.

[0237] All TTS described herein as examples did not contain crystals as observed by the naked eye immediately after preparation, unless explicitly indicated otherwise.

[0238] Measurement of skin permeation rate The permeation amount of TTS prepared according to Examples 1a to 1c and the corresponding skin permeation rate were determined by in vitro experiments according to the OECD guidelines (adopted on April 13, 2004) using a 7.0 mL Franz diffusion cell. Split human skin (abdomen) from cosmetic surgery was used. Using a dermatome, skin with intact epidermis for all TTSs was prepared to a thickness of 800 μm. A die cut having an area of 1.156 cm 2 was punched out from the TTS. The permeation amount of agomelatine in the receptor medium of the Franz cell (phosphate buffer pH 5.5 with 0.1% sodium azide saline as antibacterial agent) at a temperature of 32 ± 1 °C was measured and the corresponding skin permeation rate was calculated. The results are shown in Table 1.2 and Figure 1a.

[0239]

Table 2

[0240] Utilization rate of agomelatine The utilization rate of agomelatine at the 8-hour time point was calculated based on the cumulative permeation amounts at the 8- and 24-hour time points and the initial agomelatine content. The results are shown in Tables 1.3 and 1.4, and Figures 1b and 1c.

[0241]

Table 3

[0242]

Table 4

[0243] The in vitro experiments show that Example 1c according to specific aspects and embodiments of the present invention, wherein the agomelatine-containing layer comprises a silicone-based PSA as a hydrophobic polymer and PVP as a crystallization inhibitor, provides an excellent skin permeation rate when compared to Examples 1a and 1b based on an acrylic polymer as an adhesive.

[0244] Examples 2A to 2E Coating composition The formulations of the agomelatine-containing coating compositions of Examples 2a to 2e are summarized in Table 2.1 below. As also shown in Table 2.1, the formulations are based on weight percentages.

[0245]

Table 5

[0246] Preparation of the coating composition For Examples 2a to 2d, the beaker was charged with agomelatine. A solvent (ethanol for Examples 2a and 2b, ethyl acetate for Examples 2c and 2d), a pressure-sensitive adhesive (SilAc Hybrid PSA 7-6301 for Examples 2a and 2b, Duro-Tak (trademark) (3) 87-2516 for Examples 2c and 2d), and lauryl lactate (Examples 2a and 2c) or Capryol 90 (Examples 2b and 2d) were added respectively. The mixture was then stirred. When used, polyvinylpyrrolidone was added with stirring (Examples 2a and 2b), and after stirring for about 2 hours, a white homogeneous mixture was obtained.

[0247] For Example 2e, the beaker was charged with agomelatine. A pressure-sensitive silicone adhesive Q7-4302, lauryl lactate, and ethanol were added and stirred. Polyvinylpyrrolidone was added with stirring, and after stirring for about 2 hours, an opaque homogeneous mixture was obtained.

[0248] Coating of the coating composition For the coating processes of Examples 2a, 2b, and 2e, refer to Example 1c. The coating thickness gave an area weight of 47.9 g / m 2 (Example 2a), 45.7 g / m 2 (Example 2b), and 55.9 g / m 2 (Example 2e) respectively. A polyethylene terephthalate backing layer (thickness 23 μm) was laminated onto the dried film to obtain an agomelatine-containing self-adhesive layer structure.

[0249] The resulting agomelatine-containing coating compositions of Examples 2c and 2d were coated onto a polyethylene terephthalate film (one-sided silicon-treated, 75 μm thick, which can function as a release liner) and dried at room temperature for about 10 minutes and at 70 °C for 10 minutes. The thickness of the coating gave an area weight of 49.1 g / m 2 (Example 2c) and 47.8 g / m 2 (Example 2b), respectively. A polyethylene terephthalate backing layer (23 μm thick) was laminated onto the dried film to obtain an agomelatine-containing self-adhesive layer structure.

[0250] Preparation of TTS See Example 1.

[0251] Measurement of skin permeation rate The permeation amount and the corresponding skin permeation rate of the TTSs prepared according to Examples 2a to 2e were determined as in Example 1 above. Split human skin (abdomen) from cosmetic surgery was used. A die cut having an area of 1.154 cm 2 was punched out from the TTS. The results are shown in Table 2.2 and Figure 2a.

[0252]

Table 6

[0253] Utilization rate of agomelatine The utilization rate of agomelatine at the 8-hour time point was calculated based on the cumulative permeation amounts at the 8- and 24-hour time points and the initial agomelatine content. The results are shown in Tables 2.3 and 2.4, and Figures 2b and 2c.

[0254]

Table 7

[0255]

Table 8

[0256] In vitro experiments have shown that Examples 2a and 2b according to certain aspects and embodiments of the present invention, where the agomelatine-containing layer contains a silicone acrylic hybrid polymer as a hydrophobic polymer, PVP as a crystallization inhibitor, and Capryol 90 or lauryl lactate as a solubilizer, provide an excellent skin permeation rate when compared to Examples 2c and 2d based on an acrylic polymer as an adhesive. Example 2e is based on a silicone-based PSA as a hydrophobic polymer, PVP as a crystallization inhibitor, and lauryl lactate as a solubilizer, and provides an even better skin permeation rate.

[0257] All of Examples 2a - 2e are based on an active concentration of 4 wt% instead of 8 wt% as in Examples 1a - 1c, and the areal weight is maintained at the same level. This is the reason why the total active content per release area is lower in Examples 2a - 2e (about half of the total active content of Examples 1a - 1c), which may be the reason why the advantageous release profiles of Examples 2a - 2e show a decrease in the permeation rate from the 8th hour to the 24th hour, in contrast to Examples 1a - 1c.

[0258] Examples 3A - 3D Coating composition The formulations of the agomelatine-containing coating compositions of Examples 3a - 3d are summarized in Table 3.1 below. As also shown in Table 3.1, the formulations are based on weight percentages.

[0259]

Table 9

[0260] Preparation of coating composition In the case of Examples 3a to 3d, the beaker was charged with agomelatine. Ethanol, transcutol (Example 3b) or dipropylene glycol (Example 3c) or levulinic acid (Example 3d), and a pressure-sensitive adhesive (Q7-4302) were added. Then, the mixture was stirred. Polyvinylpyrrolidone was added while stirring, and after stirring for about 3 hours, an opaque and homogeneous mixture was obtained.

[0261] Coating of the coating composition The resulting agomelatine-containing coating compositions of Examples 3a to 3d were coated onto a polyester film (74 μm thick, which can function as a release liner coated with a fluoropolymer), and dried at room temperature for about 10 minutes and at 70 °C for 10 minutes. The thickness of the coating was 63.4 g / m 2 (Example 3a), 63.5 g / m 2 (Example 3b), 63.3 g / m 2 (Example 3c), and 76.8 g / m 2 (Example 3d) gave the basis weights. A polyethylene terephthalate backing layer (23 μm thick) was laminated onto the dried film to obtain an agomelatine-containing self-adhesive layer structure.

[0262] Microscopic observation The agomelatine-containing layers of Examples 3a to 3d were observed using a microscope (Leica DM6000M microscope equipped with a digital camera DFC450 and Leica Application Suite version 4.5) immediately after production and after 4 weeks of storage. The layers in all the examples observed showed droplets (approximate maximum droplet size of about 5 μm), and were thus determined to be of the microreservoir type. Figure 3d shows a micrograph of the agomelatine-containing layer of Example 3d after 4 weeks of storage. Example 3d was also observed after 2 years of storage, and still presented a microreservoir without crystals having slightly larger droplets (approximate maximum droplet size of about 10 μm).

[0263] Preparation of TTS See Example 1.

[0264] Measurement of Skin Permeation Rate The permeation amount and the corresponding skin permeation rate of the TTSs prepared according to Examples 2e and 3a to 3d were determined by in vitro experiments according to the OECD guideline (adopted on April 13, 2004) using a 7.0 mL Franz diffusion cell. Stratified minipig skin (ventral abdomen) was used. Using a skinning knife, skin with intact epidermis for all TTSs was prepared to a thickness of 800 μm. A die cut having an area of 1.154 cm 2 was punched out from the TTS. The agomelatine permeation amount in the receptor medium of the Franz cell (phosphate buffer pH 5.5 with 0.1% sodium azide physiological saline as an antibacterial agent) at a temperature of 32 ± 1 °C was measured, and the corresponding skin permeation rate was calculated. The results are shown in Table 3.2 and Figure 3a.

[0265] [Table 10]

[0266] Utilization Rate of Agomelatine The utilization rate of agomelatine at the 8-hour time point was calculated based on the cumulative permeation amounts at the 8- and 24-hour time points and the initial agomelatine content. The results are shown in Tables 3.3 and 3.4, and Figures 3b and 3c.

[0267] [Table 11]

[0268] [Table 12]

[0269] The in vitro experiments showed a good skin permeation rate, an advantageous release profile showing a decrease in the permeation rate from the 8th to the 24th hour, and the utilization rates of all test examples exemplifying formulations containing PVP as a crystallization inhibitor and various substances as solubilizers were satisfactory.

[0270] Examples 4A to 4E Coating composition The formulations of the agomelatine-containing coating compositions of Examples 4a to 4e are summarized in Table 4.1 below. As also shown in Table 4.1, the formulations are based on weight percentages.

[0271] [Table 13]

[0272] Preparation of coating composition In the case of Example 4a, a beaker was charged with agomelatine. Ethyl acetate and a pressure-sensitive adhesive (Q7-4302) were added. The mixture was then stirred and a clear mixture was obtained after about 2 hours.

[0273] In the case of Examples 4b to 4e, a beaker was charged with agomelatine. A solvent (ethyl acetate in Example 4b, ethanol in Examples 4c to 4e), dipropylene glycol (in Examples 4b and 4d) or levulinic acid (in Example 4e), and a pressure-sensitive adhesive (Q7-4302) were added. The mixture was then stirred. When used, polyvinylpyrrolidone was added with stirring (Examples 4c to 4e) and the mixture was stirred for about 1 to 2 hours to obtain an opaque and homogeneous mixture.

[0274] Coating of coating composition The resulting agomelatine-containing coating compositions of Examples 4a to 4e were coated onto a polyester film (74 μm thick, which can function as a release liner coated with a fluoropolymer) and dried at room temperature for about 10 minutes, at 60 °C for 10 minutes (Examples 4a and 4b), and at 70 °C for 10 minutes (Examples 4c to 4e). If necessary, coating and drying were repeated to achieve the desired coating thickness. The coating thickness was 41.9 g / m 2 (Example 4a), 41.9 g / m 2 (Example 4b), 45.3 g / m 2 (Example 4c), 52.2 g / m 2 (Example 4d), and 46.7 g / m2 The areal weight of (Example 4e) was given. A polyethylene terephthalate backing layer (thickness 23 μm) was laminated on the dried film to obtain an agomelatine-containing self-adhesive layer structure.

[0275] Microscopic observation The agomelatine-containing layers of Examples 4b and 4c were observed immediately after production using a microscope (Leica DM6000M microscope equipped with a digital camera DFC450 and Leica Application Suite version 4.5). Since these layers showed droplets (approximate maximum droplet sizes of about 10 and 15 μm), they were judged to be of the microreservoir type. Figure 4d shows a micrograph of the agomelatine-containing layer of Example 4c one day after production.

[0276] Preparation of TTS Refer to Example 1.

[0277] Measurement of skin permeation rate The permeation amounts and the corresponding skin permeation rates of the TTSs prepared according to Examples 4a to 4e were determined as in Example 3 above. The results are shown in Table 4.2 and Figure 4a.

[0278] [Table 14]

[0279] Utilization rate of agomelatine The utilization rate of agomelatine at the 8-hour time point was calculated based on the cumulative permeation amounts at the 8- and 24-hour time points and the initial agomelatine content. The results are shown in Tables 4.3 and 4.4, and Figures 4b and 4c.

[0280] [Table 15]

[0281] [Table 16]

[0282] In Examples 4c, 4d, and 4e which contain PVP as a crystallization inhibitor in the agomelatine-containing layer, the agomelatine utilization rate and release profile determined by in vitro experiments are much superior in terms of both a fast start of permeation and a decrease in the absolute permeation rate and from 8 hours to 24 hours of permeation when compared with Examples 4a and 4b.

[0283] Examples 5A - 5D Coating composition The formulations of the agomelatine-containing coating compositions of Examples 5a - 5d are summarized in Table 5.1 below. As also shown in Table 5.1, the formulations are based on weight percentages.

[0284] [Table 17]

[0285] Preparation of coating composition For Examples 5a and 5c, the beaker was charged with agomelatine. Dipropylene glycol, a pressure-sensitive adhesive (SilAc PSA 7 - 6301), and polyvinylpyrrolidone (Example 5c) if used were added. The mixture was then stirred. Ethanol was added while stirring. After about 1 - 2 hours, a white homogeneous mixture (Examples 5a and 5c) was obtained.

[0286] For Example 5b, the beaker was charged with agomelatine. Polyvinylpyrrolidone, dipropylene glycol, and an adhesive (Oppanol B10 / B100 85 / 15) were added and then mixed, and an opaque homogeneous mixture was obtained after about 3 hours.

[0287] For Example 5d, the beaker was charged with agomelatine. A pressure-sensitive adhesive (Q7 - 4302) was added. The mixture was then stirred. Polyvinylpyrrolidone and ethanol were added while stirring, and an opaque homogeneous mixture was obtained after about 1 hour.

[0288] Coating of the coating composition The obtained agomelatine-containing coating compositions of Examples 5a to 5d were coated onto a polyester film (thickness 74 μm, which can function as a fluoropolymer-coated release liner in Examples 5a, 5c and 5d, polyethylene terephthalate film, single-sided silicon-treated, thickness 75 μm, which can function as a release liner in Example 5b), and dried at room temperature for about 10 minutes, at 70 °C (Examples 5a, 5c and 5d) for 10 minutes, and at 90 °C (Example 5b) for 10 minutes, respectively. The thickness of the coating gave an area weight of 37.4 g / m 2 (Example 5a), 64.6 g / m 2 (Example 5b), 52.8 g / m 2 (Example 5c), and 60.6 g / m 2 (Example 5d). A polyethylene terephthalate backing layer (thickness 23 μm) was laminated onto the dried film to obtain an agomelatine-containing self-adhesive layer structure.

[0289] Microscopic observation The agomelatine-containing layers of Examples 5a to 5d were observed using a microscope (Leica DM6000M microscope equipped with a digital camera DFC450 and Leica Application Suite version 4.5) immediately after production (3 - 4 days, Examples 5a and 5d) and after about 32 months (Examples 5b and 5c). The layers of all examples showed droplets and were thus judged to be of the microreservoir type. Example 5d (based on a silicone-based PSA as the hydrophobic polymer) showed a maximum droplet size of about 15 μm, while the droplet size of Example 5b (based on polyisobutylene as the hydrophobic polymer) was relatively large (maximum droplet size of about 60 μm). The droplet sizes of Examples 5a and 5c (based on a silicone acrylate hybrid PSA as the hydrophobic polymer) were very small, so the droplets were difficult to distinguish with the naked eye under the microscope. Figures 5c and 5d show micrographs of the agomelatine-containing layers of Examples 5b and 5d, respectively.

[0290] Preparation of TTS See Example 1.

[0291] Measurement of skin permeation rate The permeation amount and the corresponding skin permeation rate of the TTSs prepared according to Examples 5a to 5d were determined as in Example 3 above. The results are shown in Table 5.2 and Figure 5a.

[0292] [Table 18]

[0293] Utilization rate of agomelatine The utilization rate of agomelatine at the 8-hour time point was calculated based on the cumulative permeation amount and the initial agomelatine content at the 8-hour time point. The results are shown in Table 5.3 and Figure 5b.

[0294] [Table 19]

[0295] These examples show that in Example 5d based on silicone-based PSA as the hydrophobic polymer, when compared with Examples 5a to 5c based on silicone acrylic hybrid polymer or polyisobutylene as the hydrophobic polymer, the agomelatine utilization rate and release profile determined by in vitro experiments are much superior in terms of both a fast start of permeation and the absolute permeation rate.

[0296] Examples 6A to 6D Coating composition The formulations of the agomelatine-containing coating compositions of Examples 6a to 6d are summarized in Table 6.1 below. As also shown in Table 6.1, the formulations are based on weight percentages.

[0297] [Table 20]

[0298] Preparation of coating composition In the case of Example 6a, the beaker was charged with agomelatine and dissolved in ethanol. A pressure-sensitive adhesive (Q7-4202), polyvinylpyrrolidone and dipropylene glycol were added with stirring. An opaque mixture was obtained after about 3 hours.

[0299] In the case of Example 6b, the beaker was charged with agomelatine. Isopropyl alcohol and pressure-sensitive adhesives (Q7-4402 and Duro-Tak™ (3) 87-4287) were added. The mixture was then stirred to obtain an opaque mixture after about 2 hours.

[0300] In the case of Examples 6c and 6d, the beaker was charged with agomelatine. Ethanol and a pressure-sensitive adhesive (SIS-Arkon) were added. The mixture was then stirred. Heptane, polyvinylpyrrolidone (Example 6c), and dipropylene glycol (Example 6d) were added with stirring respectively to obtain an opaque and homogeneous mixture after about 1 hour (Examples 6c and 6d).

[0301] Furthermore, a new batch of Example 3c was prepared with a slight difference in the amount of formulation ingredients used according to the formulation of the agomelatine-containing coating composition as summarized in Table 3.1 above.

[0302] Coating of the coating composition The obtained agomelatine-containing coating compositions of Examples 6a to 6d were coated on a polyester film (74 μm thick, which can function as a fluoropolymer-coated release liner for Examples 6a and 6d, a polyethylene terephthalate film, single-sided silicon-treated, 75 μm thick, which can function as a release liner for Examples 6c and 6d), and dried at room temperature for about 10 minutes and at 70 °C for 10 minutes respectively. The thickness of the coating was 61.2 g / m 2 (Example 6a), 57.5 g / m 2 (Example 6b), 58.6 g / m 2 (Example 6c), and 65.6 g / m 2The areal weight of (Example 6d) was given. A polyethylene terephthalate backing layer (thickness 23 μm) was laminated onto the dried film to obtain an agomelatine-containing self-adhesive layer structure.

[0303] For the new batch of the coating of Example 3c, reference may be made to the procedure of the coating of the first batch of Example 3c outlined above. The coating thickness gave an areal weight of 64.5 g / m 2 and a content of agomelatine of 257.5 μg / cm 2 .

[0304] Microscopic observation The agomelatine-containing layers of Examples 6a, 6c and 6d were observed using a microscope (Leica DM6000M microscope equipped with a digital camera DFC450 and Leica Application Suite version 4.5) immediately after production (from a few days up to two weeks). The layers of all examples showed droplets and were thus judged to be of the microreservoir type. Examples 6c and 6d (based on a styrene-isoprene-styrene adhesive as hydrophobic polymer) showed relatively large droplets with maximum droplet sizes of about 30 and 60 μm, respectively, while the droplet size of Example 6a (based on a silicone-based PSA as hydrophobic polymer) was smaller in comparison (maximum droplet size was about 15 μm). Figures 6c and 6d show micrographs of the agomelatine-containing layers of Examples 6a and 6c, respectively.

[0305] Preparation of the TTS Reference may be made to Example 1.

[0306] Measurement of the skin permeation rate The permeation amounts and the corresponding skin permeation rates of the TTSs prepared according to Examples 6a to 6d and the new batch of Example 3c were determined as in Example 3 above. A die-cut having an area of 1.151 cm 2 was punched out from the TTS. The results are shown in Table 6.2 and Figure 6a.

[0307]

Table 21

[0308] Utilization rate of agomelatine The utilization rate of agomelatine at the 8-hour time point was calculated based on the cumulative permeation amounts at the 8- and 12-hour time points and the initial agomelatine content. The results are shown in Tables 6.3, 6.4, and Figure 6b.

[0309] [Table 22]

[0310] [Table 23]

[0311] In Example 6b, the effect of isopropyl alcohol as a permeation enhancer combined with a mixture of an acrylate polymer and a silicone-based PSA was investigated. Surprisingly, Examples 6a and 3c based on a silicone-based PSA as a hydrophobic polymer and containing PVP as a crystallization inhibitor and dipropylene glycol as a solubilizer according to certain embodiments of the present invention showed much better permeation behavior. Also, Examples 6c and 6d based on a styrene-isoprene-styrene adhesive as a hydrophobic polymer showed much better permeation behavior and utilization rate, although not as good as Examples 6a and 3c.

[0312] Examples 7A - 7D Coating composition The formulations of the agomelatine-containing coating compositions of Examples 7a - 7d and 3d' are summarized in Table 7.1 below. As also shown in Table 7.1, the formulations are based on weight percentages.

[0313] [Table 24]

[0314] Preparation of coating composition In the case of Examples 7a and 7b, the beaker was charged with agomelatine. Pressure-sensitive adhesive (Q7-4302), Brij L4 (Example 7a), and levulinic acid (Example 7b) were added respectively. Then, the mixture was stirred. Polyvinylpyrrolidone and ethanol were added while stirring. A transparent mixture was obtained after stirring for about 1 to 2 hours.

[0315] In the case of Example 7c, the beaker was charged with agomelatine. Ethanol, Capryol 90, and pressure-sensitive adhesive (Q7-4302) were added. Then, the mixture was stirred. Polyvinylpyrrolidone was added while stirring. An opaque mixture was obtained after stirring for about 1 hour.

[0316] In the case of Example 7d, the beaker was charged with agomelatine. Pressure-sensitive adhesive and ethanol (Q7-4302) were added. Then, the mixture was stirred. Polyvinylpyrrolidone was added while stirring. An opaque and homogeneous mixture was obtained after stirring for about 1 hour.

[0317] Furthermore, a new batch of Example 3d was prepared with a slight difference in the amounts of the formulation ingredients used, according to the formulation of the agomelatine-containing coating composition as summarized in Table 3.1 above.

[0318] Coating of the coating composition The resulting agomelatine-containing coating compositions of Examples 7a to 7d were coated onto a polyester film (74 μm thick, which can function as a release liner coated with a fluoropolymer in Examples 7a to 7d) and dried at room temperature for about 10 minutes and at 70 °C for 10 minutes (Examples 7a to 7d). The thickness of the coating was 51.4 g / m 2 (Example 7a), 51.6 g / m 2 (Example 7b), 42.7 g / m 2 (Example 7c), and 53.4 g / m 2The areal weight of (Example 7d) was given. A polyethylene terephthalate backing layer (19 μm thick in Examples 7a and 7b, 23 μm thick in Examples 7c and 7d) was laminated onto the dried film to obtain an agomelatine-containing self-adhesive layer structure.

[0319] For the new batch of the coating of Example 3d, refer to the procedure of the coating of the first batch of Example 3d outlined above. The coating thickness gave an areal weight of 65.3 g / m 2 and resulted in an agomelatine content of 260.5 μg / cm 2 .

[0320] Microscopic observation The agomelatine-containing layer of Example 7d and the agomelatine-containing layers prepared in the same way as Examples 7a and 7b (new batch) were observed using a microscope (Leica DM6000M microscope equipped with a digital camera DFC450 and Leica Application Suite version 4.5) after storage for 2 to 4 weeks (new batches of Examples 7a and 7d), and 21 months (new batch of Example 7b). These layers showed droplets and were thus judged to be of the microreservoir type. The droplet sizes were relatively uniform and were in the order of a few micrometers.

[0321] Preparation of TTS Refer to Example 1.

[0322] Measurement of skin permeation rate The permeation amounts and the corresponding skin permeation rates of the TTSs prepared according to Examples 7a to 7d and the new batch of Example 3d were determined as in Example 3 above. Die cuts with an area of 1.188 cm 2 were punched out from the TTSs. The results are shown in Table 7.2 and Figure 7a.

[0323]

Table 25

[0324] Utilization rate of agomelatine The utilization rate of agomelatine at the 8-hour time point was calculated based on the cumulative permeation amounts at the 8- and 24-hour time points and the initial agomelatine content. The results are shown in Tables 7.3 and 7.4, and Figures 7b and 7c.

[0325]

Table 26

[0326]

Table 27

[0327] In vitro experiments have shown good skin permeation rates and release profiles for all examples. However, the skin permeation rate and utilization rate of the new batch of Example 3d, which uses 4 wt% agomelatine in combination with PVP as a crystallization inhibitor and levulinic acid as a solubilizer, are far superior when compared to Example 7b, which uses the same formulation and only 2 wt% agomelatine. The skin permeation rates and release profiles are equivalent between Example 7a, 7c, and 7d, and those of Example 7b and the new batch of Example 3d. However, Example 7d, which does not contain a solubilizer, uses 4 wt% agomelatine, and Examples 7a and 7c contain only 2 wt% agomelatine but contain Brij or Capryol as a solubilizer.

[0328] In vivo study using Göttingen minipigs To evaluate the local tolerance of agomelatine, an in vivo experiment was conducted using Göttingen minipigs (female, approximately 6 - 7 months old, body weight at the start of the study was 13.8 - 14.3 kg). From the TTSs prepared according to the above Examples 3d (new batch), 7a, 7b, and 7c, as well as two additional agomelatine-TTSs and six corresponding placebo TTSs, 10 cm 2 of die cuts with an area were punched out. For each minipig, one die cut (each 10 cm 2) was used. The TTS was fixed with a cover patch of 2 (6.3 * 6.3 cm), and the patch was kept in place. To prevent the animal from interfering with the patch, the application site was further covered with a gauze dressing. Four minipigs were used. The total wearing time of all 12 patches (6 active substances and 6 placebos) for each minipig was 12 hours for animals No. 1 and 2, and 24 hours for animals No. 3 and 4. 2 (6.3*6.3cm) of the cover patch, and to keep the patch in place and prevent the animal from interfering with the patch, the application site was further covered with a gauze dressing. Four minipigs were used. The total wearing time of all 12 patches (6 active substances and 6 placebos) for each minipig was 12 hours for animals No. 1 and 2, and 24 hours for animals No. 3 and 4.

[0329] During the study, the minipigs were kept at 21 ± 3 °C, illuminated from 6:00 am to 6:00 pm, and fed SDS minipig diet (SMP(E)SQC) from a special diet service at about 175 g per animal twice a day, and allowed free access to water.

[0330] After removing the TTS according to the total wearing time as outlined above, the peel-off was quantified as a percentage (0% - 100%), and general adhesion (good adhesion, easy, complete peel-off) was determined qualitatively.

[0331] Furthermore, the skin condition was measured visually, and according to the OECD Chemical Test Guideline No. 404: "Acute Dermal Irritation / Corrosion" adopted on July 28, 2015, the Draize scores were obtained immediately after removing the TTS and 12 hours after removal based on the following scoring scheme.

[0332] Skin was collected from the administration site (the entire site covered by the patch) (sites 1 - 12), and one skin sample per animal was taken from the untreated area for reference in histopathological examination. Samples from all animals were trimmed, and representative specimens were taken for histological processing. The specimens were embedded in paraffin, cut to a nominal thickness of 5 μm, stained with hematoxylin and eosin, and examined under an optical microscope. No findings related to agomelatine or TTS were seen in the histopathological examination of the epidermis and dermis.

[0333] The TTS adhesive strength (adhesive area percentage) after 12 / 24 hours was between 34% and 76% for all formulations (see Table 7.5). The reason for the low patch adhesive area of the TTS according to Example 3d, which was 34%, is thought to be the TTS application site located next to the limbs of the minipig. This is the reason why the adhesive strength appears lower compared to other formulations. The adhesive strengths of Examples 7a to 7c are in the range of 60% - 76%.

[0334] There was no formulation that showed skin irritation 12 hours after TTS removal. Only immediately after TTS removal and cleaning of the application site, the skin at the TTS application sites according to Examples 7a and 7b showed very slight skin irritation with a Draize score of 1 (Table 7.5). The subsequent histopathological evaluation of the tissue including the administration area (12 hours after TTS removal) showed no API / TTS-related findings. The recorded findings were within the range of background changes seen in the skin of Göttingen minipigs of this age and were considered not related to the treatment. These results indicate that the risk of skin irritation with the TTS of the present invention is low.

[0335]

Table 28

[0336] Examples 8A - 8D Coating composition The formulations of the agomelatine-containing coating compositions of Examples 8a to 8d are summarized in Table 8.1 below. As also shown in Table 8.1, the formulations are based on weight percentages.

[0337]

Table 29

[0338] Preparation of coating composition In the case of Example 8a, the beaker was charged with agomelatine. Ethanol, levulinic acid, and a pressure-sensitive adhesive (Q7-4302) were added. Then, the mixture was stirred. Polyvinylpyrrolidone was added while stirring. A transparent mixture was obtained after stirring for about 4 hours (Example 8a).

[0339] In the case of Example 8b, a stainless-steel container was charged with agomelatine. Ethanol, levulinic acid, and a pressure-sensitive adhesive (Q7-4302) were added. Then, the mixture was stirred. Polyvinylpyrrolidone was added while stirring. A transparent mixture was obtained after stirring for about 3 hours (Example 8b).

[0340] In the case of Examples 8c and 8d, the beaker was charged with agomelatine. The pressure-sensitive adhesive (Q7-4302) and ethanol were added. Then, the mixture was stirred. Polyvinylpyrrolidone was added while stirring. Transparent mixtures were obtained after stirring for about 2 hours (Example 8c) and 5 hours (Example 8d), respectively.

[0341] Coating of the coating composition The resulting agomelatine-containing coating compositions of Examples 8a to 8d were coated onto a polyester film (74 μm thick, which can function as a release liner coated with a fluoropolymer) and dried at room temperature for about 10 minutes and at 70 °C for 10 minutes. The thickness of the coating gave areal weights of 50.1 g / m 2 (Example 8a), 50.0 g / m 2 (Example 8b), 49.2 g / m 2 (Example 8c), and 52.0 g / m 2 (Example 8d), respectively. A polyethylene terephthalate backing layer (19 μm thick in Examples 8a to 8d) was laminated onto the dried film to obtain an agomelatine-containing self-adhesive layer structure.

[0342] Microscopic observation The agomelatine-containing layers of Examples 8b and 8d were observed after storage for 4 to 5 months using a microscope (Leica DM6000M microscope equipped with a digital camera DFC450 and Leica Application Suite version 4.5). Since these layers showed droplets, they were judged to be of the microreservoir type. The droplet sizes were relatively uniform, with sizes in the order of several micrometers (the largest droplet size was approximately 10 μm). Figures 8c and 8d show micrographs of the agomelatine-containing layers of Examples 8b and 8d, respectively.

[0343] Preparation of TTS See Example 1.

[0344] Measurement of skin permeation rate The permeation amounts and corresponding skin permeation rates of the TTSs prepared according to Examples 8a to 8d were determined as in Example 1 above. Split human skin from cosmetic surgery (female abdomen, born in 1976) was used. Using a dermatome, skin with intact epidermis was prepared to a thickness of 500 μm for all TTSs. A die cut having an area of 1.157 cm 2 was punched out from the TTS. The results are shown in Table 8.2 and Figure 8a.

[0345]

Table 30

[0346] Utilization rate of agomelatine The utilization rate of agomelatine at the 8-hour time point was calculated based on the cumulative permeation amount and the initial agomelatine content at the 8-hour time point. The results are shown in Table 8.3 and Figure 8b.

[0347]

Table 31

[0348] In vitro experiments have shown good skin permeation rates and utilization rates for both formulations, but the addition of levulinic acid in Examples 8a / 8b appears to be more advantageous when compared to the formulations of Examples 8c / 8d which contain a larger amount of PVP but no solubilizer.

[0349] Measurement of storage stability The long-term storage stability tests of Examples 8b and 8d were carried out under different test conditions, namely storage at 25 °C and 60% relative humidity (RH), 30 °C and 75% RH, and 40 °C and 75% RH. After storage at 25 °C and 60% RH for 3, 6, 9, and 12 months, at 30 °C and 75% RH for 9 and 12 months, and at 40 °C and 75% RH for 3 and 6 months, samples were taken from the TTS, and the amount of agomelatine, as well as various possible degradation substances, were measured by a specific quantitative HPLC method based on the (actual) areal weight of the tested TTS and the agomelatine content calculated therefrom. The adhesive strength of the adhesive layer to the steel plate and the peel strength of the adhesive layer from the release liner were measured using 45.0 mm x 45.0 mm samples at an angle of 90° and a test speed of 300 mm / min for the adhesive strength and 150 mm / min for the peel strength. Furthermore, it was tested whether the removability of the adhesive layer from the release liner was guaranteed, and the compliance was recorded. Also, the possibility of cold flow occurrence was visually inspected, and the compliance to the cold flow tolerance range was recorded. The results are shown in Tables 8.4 - 8.9 and Figures 8e - 8h.

[0350]

Table 32

[0351]

Table 33

[0352]

Table 34

[0353]

Table 35

[0354]

Table 36

[0355]

Table 37

[0356] The stability data show that in Examples 8b and 8d, the initial stability and storage stability are excellent in terms of both the amount of agomelatine (especially with respect to the amount of agomelatine remaining after storage) and the total of possible degradation substances.

[0357] The adhesive strength also remains at a good level over time with a slight decrease.

[0358] The peel strength increases slightly over time, but the increase is within the allowable range, and the removability from the release liner is always guaranteed. Blocking of the release liner or delamination of the adhesive layer is not expected.

[0359] Overall, a long shelf life of, for example, 12 months or more than 24 months can be assumed.

[0360] Examples 9A - 9E Coating composition The formulations of the agomelatine - containing coating compositions of Examples 9a - 9g are summarized in Table 9.1 below. As also shown in Table 9.1, the formulations are based on weight percentages.

[0361]

Table 38

[0362] Preparation of the coating composition In the case of Example 9a, the beaker was charged with agomelatine. Ethanol and polyvinylpyrrolidone were added, and the mixture was allowed to stand for 3 hours. A silicone acrylic hybrid PSA adhesive was added, and the mixture was stirred at 1000 rpm. A white homogeneous mixture was obtained.

[0363] In the case of Example 9b, the beaker was charged with agomelatine. Ethanol and a pressure-sensitive adhesive (Q7-4202) were added, and the mixture was stirred. Polyvinylpyrrolidone was added with stirring, and the mixture was further stirred. A turbid homogeneous solution was obtained.

[0364] In the case of Example 9c, the beaker was charged with agomelatine. A polyisobutylene adhesive and ethyl acetate were added, and the mixture was allowed to stand for 1 hour. Polyvinylpyrrolidone was added, and the mixture was stirred at 250 rpm. After 0.5 hour, ethanol was added. A transparent solution with visible small bubbles was obtained.

[0365] In the case of Example 9d, the beaker was charged with agomelatine and dissolved in 1.5 g of ethanol. Polyvinylpyrrolidone was added, and the mixture was allowed to stand for about 1 hour. A styrene isoprene styrene adhesive was added, and the mixture was stirred at 200 rpm. Finally, the remaining ethanol and n-heptane were added, and the mixture was stirred at 200 rpm. A slightly turbid solution without visible crystals was obtained.

[0366] In the case of Example 9e, the beaker was charged with agomelatine. Dipropylene glycol was added, and the mixture was stirred. Ethyl acetate and a pressure-sensitive adhesive (Q7-4301) were added. Then, the mixture was further stirred. After stirring for about 2.5 hours, a transparent solution was obtained.

[0367] Coating of the coating composition The resulting agomelatine-containing coating compositions of Examples 9a to 9d were coated onto a polyester film (74 μm thick, which can function as a release liner coated with a fluoropolymer) and dried at room temperature for about 10 minutes and at 70 °C for 10 minutes. The thickness of the coating was 45.5 g / m2 (Example 9a), 47.0 g / m 2 (Example 9b), 57.6 g / m 2 (Example 9c), and 50.4 g / m 2 (Example 9d) gave the basis weights. A polyethylene terephthalate backing layer (23 μm thick in Examples 9a, 9b, 9c and 9d) was laminated onto the dried films to obtain agomelatine-containing self-adhesive layer structures.

[0368] Microscopic observation The agomelatine-containing layers of Examples 9a to 9e were observed using a microscope (Leica DM6000M microscope equipped with a digital camera DFC450 and Leica Application Suite version 4.5) immediately after production (1 - 3 days) (Examples 9a and 9b), or after storage for about 2 weeks (Example 9c), 3 weeks (Example 9d), or 2.5 months (Example 9e). All of these layers contained crystals. Figures 9a - 9e show micrographs of the agomelatine-containing layers of Examples 9a to 9e, respectively.

[0369] Preparation of TTS See Example 1.

[0370] The present invention specifically relates to the following further items.

[0371] 1. A transdermal therapeutic system for the transdermal administration of agomelatine, comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, wherein said self-adhesive layer structure comprises A) a backing layer, and B) i) agomelatine; ii) a hydrophobic polymer; and iii) an agomelatine-containing layer comprising at least 1% by weight of a crystallization inhibitor selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone-polyvinyl acetate copolymers and The transdermal therapeutic system, wherein the hydrophobic polymer is selected from the group consisting of polyisobutylene, styrene-isoprene-styrene block copolymer, silicone acrylic hybrid polymer, a pressure-sensitive adhesive based on polysiloxane, and any mixture thereof.

[0372] 2. A transdermal therapeutic system for transdermal administration of agomelatine, comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, wherein the self-adhesive layer structure A) a backing layer; and B) i) agomelatine; and ii) an agomelatine-containing layer containing a hydrophobic polymer and wherein the hydrophobic polymer is selected from the group consisting of polyisobutylene, styrene-isoprene-styrene block copolymer, silicone acrylic hybrid polymer, a pressure-sensitive adhesive based on polysiloxane, and any mixture thereof, the transdermal therapeutic system, wherein the agomelatine-containing layer is of the microreservoir type.

[0373] 3. The transdermal therapeutic system according to claim 2, wherein the agomelatine-containing layer further comprises a crystallization inhibitor or contains at least 1% by weight of a crystallization inhibitor.

[0374] 4. The transdermal therapeutic system according to claim 3, wherein the crystallization inhibitor is selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone-polyvinyl acetate copolymer.

[0375] 5. The transdermal therapeutic system according to any one of claims 1, 3, and 4, wherein the agomelatine-containing layer contains at least 1.5% by weight, at least 2.5% by weight, at least 4% by weight, or at least 5% by weight of the crystallization inhibitor.

[0376] 6. The crystallization inhibitor is polyvinylpyrrolidone or The percutaneous therapeutic system according to any one of items 1 and 3 to 5, wherein the crystallization inhibitor is selected from soluble polyvinylpyrrolidone.

[0377] 7. The crystallization inhibitor is 9 to 15, preferably 10.2 to 13.8, 15 to 20, preferably 15.3 to 18.4, 20 to 27, preferably 22.5 to 27.0, 27 to 35, preferably 27.0 to 32.4, and The percutaneous therapeutic system according to any one of items 1 and 3 to 6, which is selected from polyvinylpyrrolidone having a K value within a range selected from the group consisting of 75 to 110, preferably 81.0 to 97.2.

[0378] 8. The agomelatine-containing layer contains a solubilizing agent selected from the group consisting of dipropylene glycol, lauryl lactate, a mixture of propylene glycol monoester and diester of fatty acid, levulinic acid, polyethylene glycol ether, and diethylene glycol monoethyl ether, and is the percutaneous therapeutic system according to any one of items 1 to 7.

[0379] 9. The agomelatine-containing layer contains at least 1.5% by weight, at least 2.5% by weight, at least 4% by weight, or at least 5% by weight of the solubilizing agent, or The agomelatine-containing layer does not contain a solubilizing agent selected from the group consisting of dipropylene glycol, lauryl lactate, a mixture of propylene glycol monoester and diester of fatty acid, levulinic acid, polyethylene glycol ether, and diethylene glycol monoethyl ether, and is the percutaneous therapeutic system according to item 8.

[0380] 10. The agomelatine-containing layer contains a crystallization inhibitor, and the total amount of the crystallization inhibitor and the solubilizing agent present in the agomelatine-containing layer is at least 2.5% by weight, at least 3.5% by weight, at least 4% by weight, or at least 5% by weight, or The ratio of the total amount of the crystallization inhibitor and solubilizer present in the agomelatine-containing layer to the amount of agomelatine present in the agomelatine-containing layer is at least 1:2, at least 1:1, or at least 2:1, the transdermal therapeutic system according to any one of items 1 and 3 to 9.

[0381] 11. The agomelatine-containing layer contains at least 0.5% by weight of agomelatine, at least 1% by weight of agomelatine, or at least 1.5% by weight of agomelatine, or The agomelatine-containing layer contains 8% by weight or less of agomelatine, 6% by weight or less of agomelatine, or 5% by weight or less of agomelatine, or The agomelatine-containing layer contains 0.5 to 8% by weight of agomelatine, 1 to 6% by weight of agomelatine, or 1.5 to 5% by weight of agomelatine, the transdermal therapeutic system according to any one of items 1 to 10.

[0382] 12. The hydrophobic polymer is selected from pressure-sensitive adhesive polymers, the transdermal therapeutic system according to any one of items 1 to 11.

[0383] 13. The hydrophobic polymer is a pressure-sensitive adhesive based on polysiloxane, the transdermal therapeutic system according to any one of items 1 to 12.

[0384] 14. The pressure-sensitive adhesive based on polysiloxane is a soluble silicate resin polycondensed with silanol-terminated polydimethylsiloxane, the transdermal therapeutic system according to item 13.

[0385] 15. The pressure-sensitive adhesive based on polysiloxane is a soluble silicate resin polycondensed with silanol-terminated polydimethylsiloxane having a resin-to-polymer ratio of 65:35, 60:40, or 55:45, the transdermal therapeutic system according to item 14.

[0386] 16. The percutaneous therapeutic system according to item 15, wherein the silanol groups of the polydimethylsiloxane not bonded to the soluble silicate resin are free silanol groups or are trimethylsilylated.

[0387] 17. The pressure-sensitive adhesive based on polysiloxane is preferably characterized in that when measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 rpm, the solution viscosity at 60% solids in 25 °C and n-heptane exceeds about 150 mPa s, or is from about 200 mPa s to about 700 mPa s, or at 30 °C and 0.01 rad / s is about 1x10 9 less than Pa s or about 1x10 5 to about 9x10 8 characterized by the complex viscosity of Pa s, or The pressure-sensitive adhesive based on polysiloxane is preferably characterized in that when measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 rpm, the solution viscosity at 60% solids in 25 °C and ethyl acetate exceeds about 350 mPa s, or is from about 400 mPa s to about 1500 mPa s, or at 30 °C and 0.01 rad / s is about 1x10 5 to about 1x10 7 Pa s or about 5x10 6 characterized by the complex viscosity of Pa s, of the percutaneous therapeutic system according to any one of items 13 to 16.

[0388] 18. The percutaneous therapeutic system according to any one of items 1 to 12, wherein the hydrophobic polymer is polyisobutylene.

[0389] 19. The hydrophobic polymer has a viscosity average molecular weight M v of 1,110,000, a weight average molecular weight M w of 1,550,000, and an average molecular weight distribution M w / M n of 2.9 high molecular weight polyisobutylene, or a viscosity average molecular weight M v of 40,000, a weight average molecular weight Mw is 53,000, and the average molecular weight distribution M w / M n is a low molecular weight polyisobutylene with a value of 3.2, or a mixture thereof, or The hydrophobic polymer is a mixture of low molecular weight polyisobutylene and high molecular weight polyisobutylene, and the ratio of the low molecular weight polyisobutylene to the high molecular weight polyisobutylene is from 100:1 to 1:100, or from 60:40 to 20:80, or from 50:50 to 30:70. The transdermal therapeutic system according to item 18.

[0390] 20. The hydrophobic polymer is a styrene-isoprene-styrene block copolymer. The transdermal therapeutic system according to any one of items 1 to 12.

[0391] 21. The hydrophobic polymer is a silicone acrylate hybrid polymer. The transdermal therapeutic system according to any one of items 1 to 12.

[0392] 22. The agomelatine-containing layer substantially does not contain isopropanol. The transdermal therapeutic system according to any one of items 1 to 21.

[0393] 23. The agomelatine-containing layer contains 5% by weight or less, 3% by weight or less, or 1% by weight or less of isopropanol. The transdermal therapeutic system according to item 22.

[0394] 24. The agomelatine-containing layer substantially does not contain a volatile solvent, The volatile solvent is selected from the group consisting of linear and branched alcohols having 1 to 3 carbon atoms, ethyl acetate, hexane, n-heptane, and any mixture thereof. The transdermal therapeutic system according to any one of items 1 to 23.

[0395] 25. The agomelatine-containing layer contains 5% by weight or less, 3% by weight or less, or 1% by weight or less of a volatile solvent. The transdermal therapeutic system according to item 24.

[0396] 26. The transdermal therapeutic system according to any one of items 1 to 25, wherein the agomelatine-containing layer does not contain an acrylic polymer in an amount exceeding 70% by weight, exceeding 50% by weight, or exceeding 30% by weight of the agomelatine-containing layer.

[0397] 27. The transdermal therapeutic system according to any one of items 1 to 26, wherein the agomelatine-containing layer is of a microreservoir type or a matrix type, and the agomelatine is completely dissolved or in a dispersed form.

[0398] 28. The agomelatine-containing layer a) has an outer phase having a pressure-sensitive adhesive composition containing the hydrophobic polymer, and b) has an inner phase having a composition containing the agomelatine, and is a dry two-phase layer, wherein the inner phase forms deposits dispersed in the outer phase. The transdermal therapeutic system according to any one of items 1 to 26.

[0399] 29. The composition of the inner phase contains a crystallization inhibitor and / or the pressure-sensitive adhesive composition of the outer phase substantially does not contain a crystallization inhibitor. The transdermal therapeutic system according to item 28.

[0400] 30. The pressure-sensitive adhesive composition of the outer phase contains a crystallization inhibitor of 5% by weight or less, 3% by weight or less, or 1% by weight or less. The transdermal therapeutic system according to item 29.

[0401] 31. The composition of the inner phase substantially does not contain a hydrophobic polymer. The transdermal therapeutic system according to item 28.

[0402] 32. The composition of the inner phase contains a hydrophobic polymer of 5% by weight or less, 3% by weight or less, or 1% by weight or less. The transdermal therapeutic system according to item 31.

[0403] 33. The average particle size of the dispersed deposit is 0.1 to 100 μm, or 0.5 to 50 μm. The transdermal therapeutic system according to any one of items 28 to 32.

[0404] 34. The agomelatine-containing layer does not contain agomelatine crystals. The transdermal therapeutic system according to any one of items 1 to 33.

[0405] 35. The agomelatine-containing layer has an area weight of at least 25 g / m 2 , at least 35 g / m 2 , or at least 40 g / m 2 , or the area weight is 150 g / m 2 or less, 120 g / m 2 or less, or 90 g / m 2 or less, or the area weight is 25 to 150 g / m 2 , 35 to 120 g / m 2 , or 40 to 90 g / m 2 . The transdermal therapeutic system according to any one of items 1 to 34.

[0406] 36. The transdermal therapeutic system has a release area of at least 1 cm 2 , at least 5 cm 2 , or at least 10 cm 2 , or the release area is 100 cm 2 or less, 60 cm 2 or less, or 50 cm 2 or less, or the release area is 1 to 100 cm 2 , 5 to 60 cm 2 , or 10 to 50 cm 2 . The transdermal therapeutic system according to any one of items 1 to 35.

[0407] 37. The agomelatine-containing layer has at least 0.04 mg / cm 2 , at least 0.06 mg / cm 2 , at least 0.08 mg / cm 2 , or at least 0.1 mg / cm 2containing agomelatine, or the agomelatine-containing layer is 0.4 mg / cm 2 or less, 0.3 mg / cm 2 or less, 0.25 mg / cm 2 or less, or 0.2 mg / cm 2 or less of agomelatine, the transdermal therapeutic system according to any one of items 1 to 36.

[0408] 38. The agomelatine-containing layer can be obtained by drying a coated composition containing the agomelatine, the hydrophobic polymer, optionally the crystallization inhibitor, and ethanol, the transdermal therapeutic system according to any one of items 1 to 37.

[0409] 39. The agomelatine-containing layer can be obtained by drying a coated composition containing less than 1% by weight, less than 0.5% by weight, or less than 0.1% by weight of water, the transdermal therapeutic system according to any one of items 1 to 38.

[0410] 40. The agomelatine is contained in the agomelatine-containing layer in a dissolved form, a dispersed form, a crystalline form, particularly one of its polymorphic forms, an amorphous form, a hydrate, a solvate, a hybrid type form of any of these forms, or a mixed form thereof, the transdermal therapeutic system according to any one of items 1 to 39.

[0411] 41. The agomelatine-containing layer can be obtained by incorporating the agomelatine in a dissolved form, a dispersed form, a crystalline form, particularly one of its polymorphic forms, an amorphous form, a hydrate, a solvate, a hybrid type form of any of these forms, or a mixed form thereof, the transdermal therapeutic system according to any one of items 1 to 40.

[0412] 42. The agomelatine in the agomelatine-containing layer is present in a dissolved or dispersed form, the transdermal therapeutic system according to any one of items 1 to 41.

[0413] 43. The transdermal therapeutic system according to any one of items 1 to 42, wherein at least 90 mol%, at least 95 mol%, at least 98 mol%, or at least 99 mol% of the agomelatine in the agomelatine-containing layer is present in a dissolved form.

[0414] 44. The transdermal therapeutic system according to any one of items 1 to 43, wherein the agomelatine has a purity of at least 95%, preferably at least 98%, more preferably at least 99%, as determined by quantitative HPLC.

[0415] 45. The transdermal therapeutic system according to any one of items 1 to 44, wherein the agomelatine-containing layer is a pressure-sensitive adhesive layer.

[0416] 46. The transdermal therapeutic system according to any one of items 1 to 45, wherein the amount of the hydrophobic polymer is at least 75% by weight, at least 80% by weight, or at least 75% by weight, or the amount of the hydrophobic polymer is 98% by weight or less, 94% by weight or less, or 90% by weight or less, or the amount of the hydrophobic polymer is 75 to 98% by weight, 80 to 94% by weight, or 85 to 90% by weight of the agomelatine-containing layer.

[0417] 47. The transdermal therapeutic system according to any one of items 1 to 46, wherein the amount of agomelatine contained in the transdermal therapeutic system is at least 0.5 mg, at least 1 mg, or at least 2 mg, or the amount of agomelatine contained in the transdermal therapeutic system is 15 mg or less, 10 mg or less, or 8 mg or less, or the amount of agomelatine contained in the transdermal therapeutic system is 0.5 to 15 mg, 1 to 10 mg, or 2 to 8 mg.

[0418] 48. The transdermal therapeutic system according to any one of items 1 to 47, wherein the agomelatine-containing layer contains a further excipient or additive selected from the group consisting of a crosslinking agent, a further solubilizing agent, a filler, a tackifier, a plasticizer, a stabilizer, a softening agent, a skin care substance, a permeation enhancer, a pH adjuster, and a preservative.

[0419] 49. The transdermal therapeutic system according to item 48, wherein the tackifier is selected from triglycerides, dipropylene glycol, resins, resin esters, terpenes and their derivatives, ethylene vinyl acetate adhesives, dimethylpolysiloxane, and polybutene.

[0420] 50. The transdermal therapeutic system according to item 48, wherein the stabilizer is selected from sodium metabisulfite, tocopherol and its ester derivatives, such as tocopherol acetate and tocopherol linoleate, ascorbic acid and its ester derivatives, particularly ascorbyl esters of fatty acids such as ascorbyl palmitate, butylated hydroxytoluene, and any combination thereof.

[0421] 51. The transdermal therapeutic system according to item 48, wherein the permeation enhancer is selected from caprylic acid, glycerol, 2,5 - dimethylisosorbide, dimethylethyleneurea, N,N - diethyl - meta - toluamide, polyethylene glycol, propylene glycol monocaprylate, 2 - methoxy - 4-(prop - 2 - en - 1 - yl)phenol, lactic acid, and laurocapram.

[0422] 52. Measured using Franz diffusion cells with excised human skin, at 2 hours, from 0.5 μg / cm 2 -hr to 15 μg / cm 2 -hr, at 4 hours, from 1 μg / cm 2 -hr to 20 μg / cm 2 -hr, at 8 hours, from 2 μg / cm 2 -hr to 25 μg / cm 2 -hr, and at 16 hours, from 1 μg / cm 2 -hr to 15 μg / cm 2 -hr, providing the skin permeation rate of agomelatine, the transdermal therapeutic system according to any one of items 1 to 51.

[0423] 53. At least 0.01 mg / cm measured by a Franz diffusion cell using excised human skin at 8 hours 2 , at least 0.015 mg / cm 2 , or at least 0.02 mg / cm 2 , or 0.2 mg / cm 2 or less, 0.15 mg / cm 2 or less, or 0.1 mg / cm 2 or less, or 0.01 mg / cm 2 ~0.2 mg / cm 2 , 0.015 mg / cm 2 ~0.15 mg / cm 2 , or 0.02 mg / cm 2 ~0.1 mg / cm 2 The transdermal therapeutic system according to any one of items 1 to 52, which provides a cumulative permeation amount of agomelatine of

[0424] 54. After 8 hours, the transdermal therapeutic system according to any one of items 1 to 53, which provides an agomelatine utilization rate of at least 10%, or at least 15%, or at least 20% measured by a Franz diffusion cell using excised human skin.

[0425] 55. The transdermal therapeutic system according to any one of items 1 to 54, further comprising a release liner, an adhesive overlay, or both.

[0426] 56. The transdermal therapeutic system according to any one of items 1 to 55, wherein the backing layer is substantially impermeable to agomelatine.

[0427] 57. The transdermal therapeutic system according to any one of items 1 to 56, wherein the self-adhesive layer structure does not include an additional skin contact layer.

[0428] 58. The transdermal therapeutic system according to any one of items 1 to 57, wherein the self-adhesive layer structure consists of the backing layer and the agomelatine-containing layer.

[0429] 59. The transdermal therapeutic system according to any one of claims 1 to 56, wherein the self-adhesive layer structure includes an additional skin contact layer.

[0430] 60. The transdermal therapeutic system according to any one of claims 1 to 59 for use in a treatment method.

[0431] 61. The transdermal therapeutic system according to claim 60 for use in a method of treating major depressive disorder.

[0432] 62. The transdermal therapeutic system according to claim 60 or 61 for use in a treatment method, wherein the transdermal therapeutic system is applied to the skin of a human patient and is maintained on the skin for at least 2 hours, at least 4 hours or at least 6 hours, or 24 hours or less, 18 hours or less, or 14 hours or less, or 2 to 24 hours, 4 to 18 hours, or 6 to 14 hours.

[0433] 63. A treatment method of applying the transdermal therapeutic system according to any one of claims 1 to 59 to the skin of a human patient.

[0434] 64. A method of treating major depressive disorder of applying the transdermal therapeutic system according to any one of claims 1 to 59 to the skin of a human patient.

[0435] 65. The treatment method according to claim 63 or 64, wherein the transdermal therapeutic system according to any one of claims 1 to 61 is applied to the skin of a human patient and is maintained on the skin for at least 2 hours, at least 4 hours or at least 6 hours, or 24 hours or less, 18 hours or less, or 14 hours or less, or 2 to 24 hours, 4 to 18 hours, or 6 to 14 hours.

[0436] 66. The following steps: i) A step of combining at least agomelatine, a hydrophobic polymer, and a crystallization inhibitor selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone-polyvinyl acetate copolymer in a solvent to obtain a coating composition. ii) coating the coating composition onto a backing layer, a release liner, or any intermediate layer; iii) drying the coated coating composition to form an agomelatine-containing layer; A process for producing an agomelatine-containing layer, comprising: The hydrophobic polymer is selected from the group consisting of polyisobutylene, styrene-isoprene-styrene block copolymer, silicone acrylic hybrid polymer, and pressure-sensitive adhesives based on polysiloxane, said manufacturing process.

[0437] 67. The process according to item 70, wherein in step i), the agomelatine is dissolved or dispersed.

[0438] 68. The process according to item 70 or 71, wherein the solvent comprises an alcohol solvent selected from methanol, ethanol, isopropanol, and mixtures thereof.

[0439] 69. The process according to item 72, wherein the solvent contains ethanol or consists of ethanol.

[0440] 70. The process according to any one of items 66 to 69, wherein the solvent is substantially free of water.

[0441] 71. The process according to any one of items 66 to 70, wherein the solvent contains less than 1% by weight, less than 0.5% by weight, or less than 0.1% by weight of water.

[0442] 72. The process according to any one of items 66 to 71, wherein drying is carried out at a temperature of 40 to 90 °C or 50 to 70 °C.

[0443] 73. The crystallization inhibitor is polyvinylpyrrolidone or The crystallization inhibitor is selected from soluble polyvinylpyrrolidone, the process according to any one of items 66 to 72.

[0444] 74. The crystallization inhibitor is 9 to 15, preferably 10.2 to 13.8, 15 to 20, preferably 15.3 to 18.4, 20 to 27, preferably 22.5 to 27.0, 27 to 35, preferably 27.0 to 32.4, and 75 to 110, preferably having a K value within the range selected from the group consisting of 81.0 to 97.2, and is selected from polyvinylpyrrolidone, and the process according to any one of items 66 to 73.

[0445] 75. Step i) comprises combining at least agomelatine, a hydrophobic polymer, polyvinylpyrrolidone, and a solubilizer selected from the group consisting of dipropylene glycol, lauryl lactate, a mixture of propylene glycol monoester and diester of fatty acid, levulinic acid, polyethylene glycol ether, and diethylene glycol monoethyl ether in a solvent to obtain a coating composition, and the process according to any one of items 66 to 74.

[0446] 76. The hydrophobic polymer is selected from pressure-sensitive adhesive polymers, and the process according to any one of items 66 to 75.

[0447] 77. The hydrophobic polymer is a pressure-sensitive adhesive based on polysiloxane, and the process according to any one of items 66 to 76.

[0448] 78. The pressure-sensitive adhesive based on polysiloxane is a soluble silicate resin polycondensed with silanol-terminated polydimethylsiloxane, and the process according to item 77.

[0449] 79. The pressure-sensitive adhesive based on polysiloxane is a soluble silicate resin polycondensed with silanol-terminated polydimethylsiloxane and having a resin-to-polymer ratio of 65:35, 60:40, or 55:45, and the process according to item 78.

[0450] The process according to paragraph 79, wherein the silanol groups of the polydimethylsiloxane that are not bonded to the soluble silicate resin are free silanol groups or are trimethylsilylated.

[0451] 81. The pressure-sensitive adhesive based on polysiloxane is preferably characterized in that when measured using a Brookfield RVT viscometer equipped with spindle number 5 at 50 rpm, the solution viscosity at 60% solids in 25 °C and n-heptane exceeds about 150 mPa s, or is from about 200 mPa s to about 700 mPa s, or at 30 °C and 0.01 rad / s is about 1x10 9 less than poise or about 1x10 5 to about 9x10 8 The process according to any one of paragraphs 77 to 80, characterized by the complex viscosity of poise.

[0452] 82. The process according to any one of paragraphs 66 to 76, wherein the hydrophobic polymer is polyisobutylene.

[0453] 83. The hydrophobic polymer is a high molecular weight polyisobutylene having a viscosity average molecular weight M v of 1,110,000, a weight average molecular weight M w of 1,550,000, and an average molecular weight distribution M w / M n of 2.9, or a low molecular weight polyisobutylene having a viscosity average molecular weight M v of 40,000, a weight average molecular weight M w of 53,000, and an average molecular weight distribution M w / M n of 3.2, or a mixture thereof. The process according to paragraph 82.

[0454] 84. The hydrophobic polymer is a mixture of low molecular weight polyisobutylene and high molecular weight polyisobutylene, and the ratio of the low molecular weight polyisobutylene to the high molecular weight polyisobutylene is from 100:1 to 1:100, or from 60:40 to 20:80, or from 50:50 to 30:70. The process according to paragraph 83.

[0455] 85. The process according to any one of paragraphs 66 to 76, wherein the hydrophobic polymer is a styrene-isoprene-styrene block copolymer.

[0456] 86. The process according to any one of paragraphs 66 to 76, wherein the hydrophobic polymer is a silicone acrylate hybrid polymer.

[0457] 87. In step i), the agomelatine is combined in a dissolved form, a dispersed form, a crystalline form, in particular one of its polymorphic forms, an amorphous form, a hydrate, a solvate, a hybrid type form of any of these forms, or a mixed form thereof, the process according to any one of paragraphs 66 to 86.

[0458] 88. A transdermal therapeutic system for the transdermal administration of agomelatine obtainable by the manufacturing process according to any one of paragraphs 66 to 87.

[0459] 89. A transdermal therapeutic system for the transdermal administration of agomelatine comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, said self-adhesive layer structure comprising A) a backing layer and B) i) 2 to 6% by weight of agomelatine; ii) a hydrophobic polymer; iii) 2 to 7% by weight of polyvinylpyrrolidone; and iv) an agomelatine-containing layer containing 2 to 7% by weight of a permeation enhancer selected from levulinic acid and polyethylene glycol ether and wherein the hydrophobic polymer is selected from pressure-sensitive adhesives based on polysiloxane, and the areal weight of the agomelatine-containing layer is in the range of 35 to 70 g / m 2 of the transdermal therapeutic system.

[0460] A transdermal therapeutic system for the transdermal administration of agomelatine, comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, wherein the self-adhesive layer structure comprises A) a backing layer, and B) i) 2 to 6% by weight of agomelatine; ii) a hydrophobic polymer; and iii) an agomelatine-containing layer containing 7 to 15% by weight of polyvinylpyrrolidone and the hydrophobic polymer is selected from pressure-sensitive adhesives based on polysiloxane, the areal weight of the agomelatine-containing layer ranges from 35 to 70 g / m 2 of the transdermal therapeutic system.

Claims

1. A transdermal therapeutic system for the transdermal administration of agomelatine, comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, wherein the self-adhesive layer structure comprises A) a backing layer, and B) i) agomelatine; ii) a hydrophobic polymer; and iii) an agomelatine-containing layer comprising at least 1% by weight of a crystallization inhibitor selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone-polyvinyl acetate copolymer and the hydrophobic polymer consists of a pressure-sensitive adhesive based on polysiloxane, the transdermal therapeutic system.

2. The transdermal therapeutic system according to claim 1, wherein the agomelatine-containing layer is of the microreservoir type.

3. The agomelatine-containing layer comprises at least 1.5% by weight, at least 2.5% by weight, at least 4% by weight, or at least 5% by weight of the crystallization inhibitor, and / or the crystallization inhibitor is polyvinylpyrrolidone, and / or the crystallization inhibitor is selected from soluble polyvinylpyrrolidone, the transdermal therapeutic system according to claim 1 or 2.

4. The agomelatine-containing layer comprises a solubilizer selected from the group consisting of dipropylene glycol, lauryl lactate, a mixture of propylene glycol monoester and diester of fatty acid, levulinic acid, polyethylene glycol ether, and diethylene glycol monoethyl ether, the transdermal therapeutic system according to any one of claims 1 to 3.

5. The agomelatine-containing layer comprises at least 1.5% by weight, at least 2.5% by weight, at least 4% by weight, or at least 5% by weight of the solubilizer, the transdermal therapeutic system according to claim 4.

6. The agomelatine-containing layer comprises a crystallization inhibitor, and the total amount of the crystallization inhibitor and the solubilizer present in the agomelatine-containing layer is at least 2.5% by weight, at least 3.5% by weight, at least 4% by weight, or at least 5% by weight, and / or the ratio of the total amount of the crystallization inhibitor and the solubilizer present in the agomelatine-containing layer to the amount of agomelatine present in the agomelatine-containing layer is at least 1:2, at least 1:1, or at least 2:1, and / or The agomelatine-containing layer contains at least 0.5% by weight of agomelatine, at least 1% by weight of agomelatine, or at least 1.5% by weight of agomelatine, or The agomelatine-containing layer contains 8% by weight or less of agomelatine, 6% by weight or less of agomelatine, or 5% by weight or less of agomelatine, or The agomelatine-containing layer contains 0.5 to 8% by weight of agomelatine, 1 to 6% by weight of agomelatine, or 1.5 to 5% by weight of agomelatine, and / or The agomelatine-containing layer substantially does not contain isopropanol, and / or the agomelatine-containing layer does not contain an amount of acrylic polymer exceeding 70% by weight, 50% by weight, or 30% by weight of the agomelatine-containing layer, and / or The agomelatine-containing layer does not contain agomelatine crystals, and / or The agomelatine-containing layer has an areal weight of at least 25 g / m 2 , at least 35 g / m 2 , or at least 40 g / m 2 , or an areal weight of 150 g / m 2 or less, 120 g / m 2 or less, or 90 g / m 2 or less, or an areal weight of 25 to 150 g / m 2 , 35 to 120 g / m 2 , or 40 to 90 g / m 2 The transdermal therapeutic system according to any one of claims 1 to 5, wherein the areal weight is as defined above.

7. The hydrophobic polymer is a pressure-sensitive adhesive based on polysiloxane, and / or The amount of the hydrophobic polymer is at least 75% by weight, at least 80% by weight, or at least 75% by weight of the agomelatine-containing layer, or the amount of the hydrophobic polymer is 98% by weight or less, 94% by weight or less, or 90% by weight or less of the agomelatine-containing layer, or the amount of the hydrophobic polymer is 75 to 98% by weight, 80 to 94% by weight, or 85 to 90% by weight of the agomelatine-containing layer. The transdermal therapeutic system according to any one of claims 1 to 6.

8. The agomelatine-containing layer a) has an outer phase having a pressure-sensitive adhesive composition containing the hydrophobic polymer, and b) has an inner phase having a composition containing the agomelatine is a dry two-phase layer having, The transdermal therapeutic system according to any one of claims 1 to 7, wherein the inner phase forms a deposit dispersed in the outer phase.

9. The composition of the inner phase contains a crystallization inhibitor, and / or The pressure-sensitive adhesive composition of the outer phase substantially does not contain a crystallization inhibitor, and / or The composition of the inner phase substantially does not contain a hydrophobic polymer. The transdermal therapeutic system according to claim 8.

10. Measured with a Franz diffusion cell using excised human skin, At the second hour, from 0.5 μg / cm 2 -hr to 15 μg / cm 2 -hr, At the 4th hour, from 1 μg / cm 2 -hr to 20 μg / cm 2 -hr, At the 8th hour, 2 μg / cm 2 -hr to 25 μg / cm 2 -hr, and At the 16th hour, from 1 μg / cm 2 -hr to 15 μg / cm 2 -hr provides the skin permeation rate of agomelatine, and / or Measured in a Franz diffusion cell using excised human skin, at least 0.01 mg / cm 2 , at least 0.015 mg / cm 2 , or at least 0.02 mg / cm 2 , or 0.2 mg / cm 2 or less, 0.15 mg / cm 2 or less, or 0.1 mg / cm 2 or less, or 0.01 mg / cm 2 to 0.2 mg / cm 2 , 0.015 mg / cm 2 to 0.15 mg / cm 2 , or 0.02 mg / cm 2 to 0.1 mg / cm 2 The transdermal therapeutic system according to any one of claims 1 to 9, which provides a cumulative permeation amount of agomelatine of

11. The transdermal therapeutic system according to any one of claims 1 to 10 for use in a treatment method.

12. The transdermal therapeutic system according to claim 11, wherein the treatment method is a method for treating major depressive disorder, and / or the transdermal therapeutic system is applied to the skin of a human patient and is maintained on the skin for at least 2 hours, at least 4 hours, or at least 6 hours, or 24 hours or less, 18 hours or less, or 14 hours or less, or 2 to 24 hours, 4 to 18 hours, or 6 to 14 hours, said transdermal therapeutic system.

13. The following steps: i) combining at least agomelatine, a hydrophobic polymer, and a crystallization inhibitor selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone-vinyl acetate copolymer in a solvent to obtain a coating composition; ii) coating the coating composition on a backing layer or a release liner or any intermediate layer; iii) drying the coated coating composition to form an agomelatine-containing layer A process for producing an agomelatine-containing layer, comprising wherein the hydrophobic polymer consists of a pressure-sensitive adhesive based on polysiloxane, said production process.

14. A transdermal therapeutic system for the transdermal administration of agomelatine, comprising a self-adhesive layer structure containing a therapeutically effective amount of agomelatine, wherein the self-adhesive layer structure A) a backing layer; B) i) 2 to 6% by weight of agomelatine; ii) a hydrophobic polymer; iii) 2 to 7% by weight of polyvinylpyrrolidone; and iv) a 2 to 7% by weight permeation enhancer selected from levulinic acid and polyethylene glycol ether, an agomelatine-containing layer; or B) i) 2 to 6% by weight of agomelatine; ii) a hydrophobic polymer; and iii) an agomelatine-containing layer containing 7 to 15% by weight of polyvinylpyrrolidone comprising wherein the hydrophobic polymer is selected from pressure-sensitive adhesives based on polysiloxane, The areal weight of the agomelatine-containing layer is in the range of 35 to 70 g / m 2 of the transdermal therapeutic system.

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