RU2839934C1 - Transmucosal therapeutic system containing agomelatine - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention relates to transmucosal therapeutic systems for transmucosal administration of agomelatine, having a mucoadhesive layered structure containing a therapeutically effective amount of agomelatine, such agomelatine-based transmucosal therapeutic systems for use in a method of treatment, comprising the use of such agomelatine-based transmucosal therapeutic systems, and methods of making such transmucosal therapeutic systems.

EFFECT: preferential penetration and release of agomelatine.

15 cl, 21 dwg, 11 tbl

Description

FIELD OF TECHNICAL INVENTION

[0001] The present invention relates to a transmucosal therapeutic system for transmucosal administration into the general circulation and methods for its manufacture, methods of treatment and use.

LEVEL OF TECHNOLOGY

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

[0003] As a melatonergic agonist stimulating both MT1 and MT2 receptors, agomelatine is able to mediate circadian rhythm synchronisation similar to melatonin. However, in addition and in contrast to melatonin, agomelatine is also a 5-HT2B/5-HT2C antagonist, and blockade of serotonergic 5HT2C receptors causes increased release of dopamine and norepinephrine in the prefrontal cortex. An unexpected synergistic effect was observed with MT1/MT2 agonism and 5HT2C antagonism, and this synergy is believed to underlie the antidepressant action and unique clinical profile of agomelatine.

[0004] Agomelatine has been approved in Europe under the trade names Valdoxan®, Melitor® and Timanax® and is indicated for the treatment of major depressive disorder (MDD). The currently available formulation is a film-coated tablet containing a dose of 25 mg, prescribed as an initial dose of one tablet taken at bedtime, with the option of doubling the dose if there is no improvement. Agomelatine is the only antidepressant on the market with the mechanism of action described above.

[0005] Orally administered agomelatine undergoes extensive first-pass and systemic metabolism, primarily via cytochrome CYP1A2. Although agomelatine is well absorbed orally (>80%), its overall bioavailability is very low (<5%) with marked inter-individual variability. Both the time to peak plasma concentration and the half-life tm range from 1 to 2 hours and the volume of distribution at steady state is 35 litres with plasma protein binding of 95%.

[0006] Compared with other antidepressants, agomelatine has an earlier onset of effect (usually within a week) and the main side effects known for other antidepressants, such as weight gain, sexual dysfunction, anticholinergic symptoms and cardiotoxicity, are reduced. However, agomelatine carries a risk of hepatotoxicity, the mechanism of which remains unclear, manifested by an increase in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) values, and in a few exceptional cases the result has been fatal or has led to liver transplantation. In addition, liver failure has also been reported in association with a strong increase in agomelatine exposure, with up to 140-fold increases in AUC and Smake values observed in patients with moderate hepatic impairment compared to healthy subjects.

[0007] Efforts have been made by Servier and Novartis to develop a sublingual formulation of agomelatine, presumably to avoid first pass metabolism and the associated problems outlined above (low oral bioavailability and hepatotoxicity), resulting in placebo-controlled randomised trials of 1 and 2 mg (Servier) or 0.5 and 1 mg (Novartis) sublingual tablets of agomelatine. In the case of the 2008/2009 Servier trial, no publicly available results have been published. The Novartis trials conducted in 2011/2011 were generally unsuccessful in that the efficacy of agomelatine sublingual tablets was no better than placebo and there was no clear dose-response relationship, although at least liver toxicity was shown to be rare. One of the reasons for the failure of the studies was the pronounced irritation caused by agomelatine when in contact with the oral mucosa. As a result, the FDA decided not to approve the drug in the US, despite its advantages over other active substances in the treatment of MDD.

[0008] Several patent applications from Servier show that the first attempt to create such new dosage forms, also called "orodispersible formulations", such as tablets, was to provide rapid disintegration within a few minutes, such as less than three minutes or even less than one minute, presumably with the aim of providing a very rapid onset of release and avoiding, as far as possible, enteral delivery and the associated problem of hepatic presystemic effect. A more recent approach has included buccal formulations, such as lozenges, which are designed to dissolve or disintegrate more slowly in the mouth in order to keep the concentration of agomelatine in the mouth low enough to limit the burning sensation. However, this carries the risk of the patient swallowing the tablet prematurely, i.e. before all the active substance has been released. Then, bi- or multi-layer tablets were proposed, containing, for example, a placebo core, so that the release of most of the active substance occurs over time, leaving only a placebo core containing no active substance, to ensure virtually complete release of the active substance even if the patient swallows the tablet prematurely.

[0009] However, these orodispersible formulations have not completely solved the problem of patient compliance, possibly related to the irritant sensation caused by agomelatine, and have also failed to prevent premature tablet swallowing, only reducing its effect. Incomplete release of the active substance still poses a risk, depending on the time of unintentional tablet swallowing. In addition, sucking the tablet over a long period of time means that the patient must keep the irritant object in the mouth, which is a problem in terms of patient compliance. Finally, the mechanism of drug delivery in the case of such orodispersible formulations relies on the active substance being dissolved first in saliva (open system), making the drug concentration and thus the drug delivery very difficult to control. All these reasons may have led to the lack of agomelatine formulations on the market today other than the traditional oral tablets described above.

[0010] Transmucosal therapeutic systems or transmucosal delivery systems (also referred to by some as buccal patches) consist of one or more layers that are applied to and adhere to the oral mucosa, providing delivery of the drug over a period of time. Thin film dosage forms for use in the oral cavity are also sometimes referred to as "oral thin films" or OTFs, but OTFs are not necessarily designed to adhere to the mucosa. In a transmucosal therapeutic system, the active agent is contained in a soluble layer, and by adhering the film to the mucosa, active delivery is achieved by a combination of direct release of the active agent from the transmucosal therapeutic system into the mucosa and indirect delivery of the active agent through dissolution in saliva, as in the case of the orodispersible formulations described above. In order to prevent the indirect delivery of the active substance, which is typical of open systems, a protective layer can be used, which serves to separate the layer containing the active substance from the rest of the oral cavity, in particular from the surrounding saliva. In any case, OTPs have the advantage over orodispersible formulations intended for resorption in that they do not cause any unpleasant sensation of the presence of an irritating object in the mouth, since the film attached to the mucous membrane cannot move freely in the oral cavity and since the film is usually thin enough that the patient cannot feel it after application.

[0011] However, transmucosal therapeutic systems are a relatively new form of drug delivery, meaning that there is limited information on formulation technology. The formulation of suitable dosage forms for transmucosal delivery via TDPs is complicated by a number of aspects that need to be taken into account and problems that need to be solved. The main requirements for such transmucosal therapeutic systems are good adhesion and active penetration in combination with appropriate disintegration behaviour and time. Also important is tactility, i.e. good mouth feel, as well as film stability (i.e. low abrasion) prior to application. The low solubility of agomelatine makes formulation difficult and, as described above, a major problem is the irritant sensation that the active substance causes in the oral cavity. Furthermore, since agomelatine is primarily used for circadian rhythm resynchronisation, the required drug release profile is a rapid initial increase in drug delivery followed by a subsequent and preferably tapering release only during the night.

[0012] To date, to the best of the applicant's knowledge, there is no commercially available agomelatine-based transmucosal therapeutic system and no studies or trials of such agomelatine-based transmucosal therapeutic systems are being conducted.

[0013] Overall, there is a great need for an alternative route of administration of agomelatine that overcomes the disadvantages of the oral as well as the sublingual routes of administration. As noted above, a transmucosal therapeutic system could overcome these disadvantages.

[0014] Therefore, there is a need in the art for a transmucosal therapeutic system based on agomelatine.

OBJECTIVES AND ESSENCE OF THE INVENTION

[0015] The aim of the present invention is to provide a transmucosal therapeutic system based on agomelatine as an alternative option for administering agomelatine, overcoming all the above-mentioned disadvantages of the currently available administration of agomelatine.

[0016] It is therefore an object of the present invention to provide a transmucosal therapeutic system based on agomelatine for the transmucosal administration of agomelatine, providing an exceptionally high level of penetration, which is thus sufficient to provide a therapeutically effective dose.

[0017] A further object of the present invention is to provide a transmucosal therapeutic system based on agomelatine for the transmucosal administration of agomelatine, providing a drug release profile with a rapid initial rise and allowing for overnight use, for example suitable for administration shortly before bedtime.

[0018] It is also a further object of the present invention to provide a transmucosal therapeutic system based on agomelatine for transmucosal administration of agomelatine, which does not cause an irritating sensation on the mucous membrane or elsewhere in the oral cavity.

[0019] Another object of the present invention is to provide a transmucosal therapeutic system based on agomelatine for transmucosal administration of agomelatine, ensuring adequate adhesion to the mucosa, for example initially but also over time.

[0020] One further object of the present invention is to provide a transmucosal therapeutic system based on agomelatine for the transmucosal administration of agomelatine, which ensures an appropriate disintegration pattern, for example in terms of disintegration time, but also in terms of the integrity of the transmucosal therapeutic system (without premature separation of layers in the case of multiple layers).

[0021] Another object of the present invention is to provide a transmucosal therapeutic system based on agomelatine for transmucosal administration of agomelatine, for which hepatotoxicity and individual variability are reduced and bioavailability is increased compared to oral administration.

[0022] It is also an object of the present invention to provide a transmucosal therapeutic system based on agomelatine for transmucosal administration of agomelatine, providing good haptics, i.e. a pleasant sensation in the mouth.

[0023] A further object of the present invention is to provide a transmucosal therapeutic system based on agomelatine for transmucosal administration of agomelatine, which satisfies the requirements for convenient use and handling in terms of size and thickness, ensures good patient compliance and/or the manufacture of which is simple and cost-effective.

[0024] These and other objects are achieved by the present invention, which in one aspect relates to a transmucosal therapeutic system for the transmucosal administration of agomelatine, having a mucoadhesive layered structure, said mucoadhesive layered structure comprising:

A) agomelatine-containing layer containing:

i) agomelatine; and

ii) soluble film-forming agent.

[0025] According to certain embodiments of the invention, the transmucosal therapeutic system of the invention is for use in a method of treatment, preferably for use in a method of treating major depression.

[0026] According to other embodiments, the present invention relates to a method of treatment, and in particular to a method of treating major depression, comprising applying a transmucosal therapeutic system according to the invention to the mucosa of a human patient.

[0027] According to other embodiments, the present invention relates to the use of the transmucosal therapeutic system of the invention for the manufacture of a medicament for treatment, preferably for the treatment of major depression.

[0028] According to another aspect, the invention relates to a method for producing an agomelatine-containing layer, comprising the steps of:

i) combining at least agomelatine and a soluble film-forming agent in a solvent to form a first coating composition;

ii) applying the coating composition to the release substrate; and

iii) drying the applied coating composition to form an agomelatine-containing layer.

[0029] According to certain embodiments, the invention also relates to a transmucosal therapeutic system for the transmucosal administration of agomelatine obtainable by such a manufacturing process.

[0030] According to certain embodiments, the invention also relates to a transmucosal therapeutic system for the transmucosal administration of agomelatine, having a mucoadhesive layered structure, wherein said mucoadhesive layered structure comprises at least:

A) agomelatine-containing layer containing:

i) 3-10% by weight, agomelatine;

ii) soluble film-forming agent;

iii) 5-15% by weight of fatty acid;

iv) 0.1-2% by weight of one or more sweeteners; and

v) 0.2-2.0% by weight of flavoring;

moreover

the soluble polymer is selected from the group consisting of polyvinylpyrrolidone and hydroxypropyl cellulose, and

The mass per unit area of the agomelatine-containing layer is in the range from 100 to 150 g/ ^m2 .

[0031] In the context of this invention, the term "transmucosal therapeutic system" or "transmucosal delivery system" refers to a system by which the active agent (agomelatine) is introduced into the general circulation by transmucosal delivery by application to the oral mucosa, and refers to a single dosage unit that is applied to the mucosa of a patient and that contains a therapeutically effective amount of agomelatine in a mucoadhesive layered structure and, optionally, an additional top layer on top of the agomelatine-containing mucoadhesive layered structure. The mucoadhesive layered structure may be on a release liner (peel-off backing layer), thus the transmucosal therapeutic system may further comprise a backing liner. In the context of this invention, the term "transmucosal therapeutic system" refers in particular to a system that provides passive transmucosal delivery, excluding active transport, as in methods involving microporation. Also, unlike some oral thin films that are not necessarily mucoadhesive and that are designed to disintegrate very quickly in saliva (sometimes called "flash films"), enteral delivery is not entirely provided for in transmucosal therapeutic systems.

[0032] In the context of the present invention, the term "agomelatine-containing mucoadhesive layered structure" or "mucoadhesive layered structure containing a therapeutically effective amount of agomelatine" refers to a structure containing the active agent which, upon administration, provides a release area for asenapine. Any additional top layer increases the overall size of the transmucosal therapeutic system but does not increase the release area. The agomelatine-containing mucoadhesive layered structure comprises at least one agomelatine-containing layer.

[0033] In the context of this invention, the term "therapeutically effective amount" refers to an amount of active agent in a transmucosal therapeutic system sufficient to provide, when administered to a patient via the transmucosal therapeutic system, blood levels of agomelatine in a similar range (e.g., from about 10% to about 1000% of the AUC) compared to blood levels obtained following a single oral administration of 25 mg agomelatine.

[0034] In the context of this invention, the terms "active substance", "active agent" and the like, as well as the term "agomelatine" refer to agomelatine in any pharmaceutically acceptable chemical and morphological form and any physical state. These forms include, without limitation, agomelatine in its free dissociated or any associated form, such as hydrates, solvates, etc., as well as agomelatine in particulate form, which may be in micronized form, crystalline form and, in particular, in one of its polymorphic forms, and/or in amorphous form, and in any form of a hybrid type of any of the above-mentioned forms or a mixture thereof. When agomelatine is contained in a medium such as a solvent, it may be dissolved or dispersed, or partly dissolved and partly dispersed.

[0035] When agomelatine is said to be used in a particular form in the manufacture of a transmucosal therapeutic system, this does not exclude interactions between this form of agomelatine and the other ingredients of the agomelatine-containing self-adhesive lamellar structure such that the active substance is in a different form in the final transmucosal therapeutic system. This means that even if agomelatine is included in free dissociated form, it may be present in the final transmucosal therapeutic system in the form of a hydrate or a solvate, or if it is included in one of its polymorphic forms, it may be present in amorphous form in the final transmucosal therapeutic system. Unless otherwise stated, in particular, the amount of agomelatine in the mucoadhesive lamellar structure refers to the amount of agomelatine incorporated into the transmucosal therapeutic system during the manufacture of the transmucosal therapeutic system and calculated taking into account agomelatine in free form, i.e. when agomelatine is included in an amount of 0.1 mmol, the amount of agomelatine in the self-adhesive layered structure is in the context of this invention 24.3 mg (the molecular weight of agomelatine is 243 g/mol) regardless of whether agomelatine was included in the transmucosal therapeutic system during manufacture in its free form or in any associated form.

[0036] The agomelatine starting material incorporated into the transmucosal therapeutic system during the manufacture of the transmucosal therapeutic system may be in particulate form. Agomelatine may, for example, be in the mucoadhesive layered structure in particulate form in dispersed and/or dissolved form.

[0037] In the context of this invention, the term "particles" refers to a solid particulate material comprising individual particles whose sizes are insignificant compared to the material. In particular, the particles are solid, including plastic/deformable solids, including amorphous and crystalline materials.

[0038] In the context of this invention, the term "dispersing" refers to a step or combination of steps during which the starting material (e.g. agomelatine) is not completely dissolved. Dispersing in the context of the invention includes dissolving a portion 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).

[0039] There are two main types of transmucosal therapeutic systems, i.e. those that use a backing layer and those that do not. As also noted in the introductory section of the prior art, the active delivery of an open-type transmucosal therapeutic system without the use of a backing layer will always be a combination of direct delivery from the transmucosal therapeutic system through the mucosa at the site of adhesion and indirect delivery due to dissolution of the active substance from the transmucosal therapeutic system in saliva and from saliva through the mucosa. The proportion of the different delivery routes depends mainly on factors such as the solubility of the active substance and the disintegration time of the transmucosal therapeutic system. With greater solubility and faster disintegration of the transmucosal therapeutic system, dissolution in saliva will prevail over direct delivery to the mucosa at the site of adhesion. A huge advantage of such indirect delivery is a practical increase by several times of the surface area of the mucosa through which the systemic release of the active substance occurs. On the other hand, dissolution in saliva means that the concentration of the active substance and therefore the final amount delivered is difficult to control and there may be a risk of enteral delivery if saliva is inadvertently swallowed. In particular, for agomelatine, this is also due to the problem of free dissolution of the active substance, which is known to potentially cause an irritant sensation, throughout the oral cavity.

[0040] Transmucosal therapeutic systems that use a protective layer are characterized by a completely different approach, i.e. in such systems the loss of the limitation of the area of drug release (the actual size of the patch) is accepted in exchange for the limitation of the delivery route by direct transmucosal delivery, which can be controlled much better. Thus, in the context of the present invention, a "protective layer" is any layer in a transmucosal therapeutic system that is capable of preventing the dissolution of (at least a significant amount of) the active substance contained in the transmucosal therapeutic system in saliva. Such a protective layer may be insoluble or dissolve over a period of time. In the latter case, the time required for the dissolution of the protective layer is at least the same as that required for the delivery of (at least a significant amount of) the active substance through the mucosa.

[0041] In this context it also becomes clear that such terms as “dissolution”, “soluble”, “to dissolve”, etc. in relation to any of the layers of the transmucosal therapeutic system (for example, the protective layer containing the active substance of the layer) and in relation to the film-forming agent in the case of its formation into a film should be understood in a very broad sense, and not strictly in the scientific sense of chemical dissolution of a molecule in a solvent. Any transformation of the solid state of the layer in question into the liquid state, such as dispersion, suspension, gelation of a film and disintegration into smaller gel particles, etc., shall be considered as "dissolution" in the context of the present invention, provided that the "dissolved" material is free to move in the liquid (e.g. saliva) so that whatever is underneath the layer in question (i.e. the mucosa when the mucosal contact layer dissolves, or e.g. the active substance-containing layer when the protective layer in front of the active substance-containing layer dissolves) becomes accessible to a liquid other than the "dissolved" material. In preferred embodiments, this meaning is limited to the usual chemical sense of dissolving a molecule in a solvent. It should be noted that the term "dissolve" in relation to the substances themselves, such as the active agent agomelatine, or any excipients, will hereinafter be used in the usual chemical sense of dissolving a molecule in a solvent. For example, agomelatine in dissolved form obviously does not include agomelatine in dispersed form. The film-forming agent itself may be present in the coating composition during the manufacture of the transmucosal therapeutic system in dissolved form in the usual chemical sense (e.g. not in dispersed form, fine gel particle form, etc.), but if the film-forming agent is formed into a film, "dissolution" of such a film also includes gelation of the film and disintegration into smaller gel particles.

[0042] The active agent-containing layer is the last cured layer, for example obtained after coating and drying the coating composition. The active agent-containing layer can also be produced by laminating two or more such cured layers (for example, dried layers) with the same composition to provide the required mass per unit area. The active agent-containing layer can be mucoadhesive (in the form of a mucoadhesive layer) or the transmucosal therapeutic system can contain an additional mucosal contact layer of a mucoadhesive substance to provide sufficient adhesion. In particular, the active agent-containing layer is a mucoadhesive layer.

[0043] In the context of this invention, the term "mucoadhesive" refers to a material which, in particular, adheres to the mucous membrane after contact therewith, but which is preferably not sticky and which can be touched, for example with the fingers, and handled, for example for application in the oral cavity, without inadvertently adhering to the skin of the fingers in a dry state. The mucoadhesive layer is "self-adhesive" upon contact with the mucous membrane, i.e. it ensures adhesion to the mucous membrane such that, as a rule, no additional means for fixation are required. The degree of adhesion is preferably high enough such that normal movements in the oral cavity are not sufficient to displace the mucoadhesive layer adhered to the mucous membrane. The "mucoadhesive" layered structure comprises a mucoadhesive layer for contact with the mucosa, which may be provided in the form of a layer containing a mucoadhesive active agent or in the form of an additional layer, i.e. a mucoadhesive mucosal contact layer. A mucoadhesive top layer may be used to improve adhesion.

[0044] In the context of this invention, the term "mucosal contact layer" refers to a layer included in a transmucosal therapeutic system that is intended to directly contact the mucosa of a patient upon administration. When a transmucosal therapeutic system comprises a mucosal contact layer, the other layers do not contact the mucosa and do not necessarily have mucoadhesive properties. The release area is provided by the area of the active agent-containing layer. The mucosal contact layer can be used to improve adhesion. The dimensions of the additional mucosal contact layer and the active agent-containing layer are typically the same and correspond to the release area.

[0045] In the context of this invention, the term "weight per unit area" refers to the dry weight of a layer, for example an active agent-containing layer, expressed in g/ ^m2 . The permissible deviations in the values of weight per unit area due to manufacturing variability are ±10%, preferably ±7.5%.

[0046] Unless otherwise stated, "%" refers to mass %.

[0047] In the context of this invention, the term "polymer" refers to any substance consisting of so-called repeating units obtained by polymerization of one or more monomers, and includes homopolymers, which consist of a single type of monomer, and copolymers, which consist of two or more types of monomers. The polymers can have any structure, for example, linear polymers, star polymers, comb polymers, brush polymers with any arrangement of monomers in the case of copolymers, for example alternating, random, block copolymers or graft polymers. The minimum molecular weight varies depending on the type of polymer and is known to those skilled in the art. For example, the polymers can have a molecular weight of more than 2,000, preferably more than 5,000, and more preferably more than 10,000 daltons. Accordingly, compounds with a molecular weight of less than 2000, preferably less than 5000, or more preferably less than 10000 daltons are generally referred to as oligomers.

[0048] In the context of this invention, the term "cross-linking agent" refers to a substance that is capable of cross-linking functional groups contained in a polymer.

[0049] In the context of this invention, the term "mucoadhesive top layer" refers to a mucoadhesive layer that is on top of the agomelatine-containing mucoadhesive layered structure, does not contain the active agent, is larger in area than the active agent-containing structure, and which provides additional area of adhesion to the mucosa, but not area of release of the active agent. It thereby improves the overall adhesive properties of the transmucosal therapeutic system.

[0050] The transmucosal therapeutic systems according to the present invention can be characterized by certain parameters measured in an in vitro permeation test.

[0051] An in vitro penetration test is carried out with human or animal mucosa and preferably with porcine mucosa with intact barrier function obtained using a dermatome split to a thickness of 400 μm, with a phosphate buffer of pH 5.5 or 7.4 as a receptor medium (37°C) with or without the addition of a maximum of 40 vol.% organic solvent, such as ethanol, acetonitrile, isopropanol, dipropylene glycol, PEG 400, so that the receptor medium may, for example, contain 60 vol.% phosphate buffer of pH 5.5, 30 vol.% dipropylene glycol and 10 vol.% acetonitrile.

[0052] Unless otherwise specified, an in vitro permeation test is performed using 400 µm thick dermatomed porcine mucosa (esophageal mucosa) with intact barrier function and a phosphate buffer at pH 7.4 as the receptor medium (37°C). The amount of active substance penetrating the receptor medium is determined at regular intervals using an HPLC method with a UV photometric detector by withdrawing a sample volume. The measured amount of active substance permeated refers to the amount permeating between the last two sampling times and not to the total amount permeating.

[0053] Thus, in the context of this invention, the parameter "penetration amount" is presented in μg/ ^cm2 and refers to the permeation amount of the active substance for a certain elapsed time in the sampling interval based on the release area. For example, in the in vitro permeation test described above, in which the amount of active substance penetrating into the receptor environment is measured, for example, after 0, 2, 4, 8, 12 and 24 hours, the "penetration amount" of the active substance may, for example, be presented for the sampling interval from 8 hours to 12 hours and correspond to the measurement at 12 hours.

[0054] The permeation amount may also be represented as a "cumulative permeation amount" corresponding to the cumulative amount of active substance permeated at a certain point in time. For example, in the in vitro permeation test described above, in which the amount of active substance permeating into the receptor environment was measured, for example, after 0, 2, 4, 8, 12 and 24 hours, the "cumulative permeation amount" of the active substance at 12 hours corresponds to the sum of the permeation amounts from 0 to 2 hours, from 2 to 4 hours, from 4 to 8 hours and from 8 to 12 hours.

[0055] In the context of this invention, the parameter "mucosal penetration rate" for a given sampling interval over a given time is presented in μg/( ^cm2⋅h ) and is calculated from the amount penetrated in the said sampling interval, as measured in the in vitro penetration test described above, in μg/ ^cm2 , divided by the number of hours in the said sampling interval. For example, the mucosal penetration rate in the in vitro penetration test described above, in which the amount of active substance penetrated into the receptor environment was measured, for example, after 0, 2, 4, 8, 12 and 24 hours, the "mucosal penetration rate" after 12 hours is calculated as the amount penetrated in the sampling interval from 8 hours to 12 hours, divided by 4 hours.

[0056] The "cumulative mucosal penetration rate" can be calculated from the corresponding cumulative penetration amount by dividing the cumulative penetration amount by the elapsed time. For example, in the in vitro penetration test described above, in which the amount of active substance that penetrated into the receptor environment was measured, for example, after 0, 2, 4, 8, 12 and 24 hours, the "cumulative mucosal penetration rate" after 12 hours is calculated as the cumulative penetration amount up to 12 hours (see above) divided by 12 hours.

[0057] In the context of this invention, the above-described parameters "penetrating amount" and "mucosal penetration rate" (as well as "cumulative penetrating amount" and "cumulative mucosal penetration rate") refer to average values calculated from the results of 3 experiments in the in vitro penetration test.

[0058] The transmucosal therapeutic systems according to the present invention can also be characterized by certain parameters measured in an in vivo clinical study.

[0059] In the context of this invention, the term "administering" refers to the application of the dosage form, i.e. the transmucosal therapeutic system, to the oral mucosa of a patient, which is then retained on the mucosa until the agomelatine-containing layered structure dissolves.

[0060] In conventional continuous treatment of BDD, the frequency of administration of the drug is kept high enough to maintain a therapeutically effective concentration in the blood plasma. The interval between two administrations of the dosage form, also referred to as the administration interval, must be selected accordingly. In the context of this invention, the term "administration interval" refers to the period of time between two successive administrations, i.e., the interval between two successive applications of the transmucosal therapeutic system, to the oral mucosa of the patient. In order to continuously maintain the blood plasma concentration at a therapeutic level, the transmucosal therapeutic system must be replaced as soon as the active agent-containing layer of the previous transmucosal therapeutic system dissolves or shortly thereafter, when a new transmucosal therapeutic system is applied. In this regimen (constant plasma level around the clock), the administration interval corresponds approximately to the disintegration time of the active agent-containing layer and can be, for example, 6 hours, 8 hours or 12 hours. After this time, the active agent-containing layer of the transmucosal therapeutic system dissolves, any residues (e.g., insoluble protective layer) are removed from the oral cavity and a new transmucosal therapeutic system is applied. Thus, with an administration interval of 12 hours, a regimen of replacing the transmucosal therapeutic system twice a day for round-the-clock treatment is possible.

[0061] In the case of continuous treatment with agomelatine, however, the transmucosal therapeutic system will typically be administered once daily (24-hour administration interval) and preferably at bedtime, and the disintegration time will preferably be shorter than the administration interval. In particular, the transmucosal therapeutic system may be applied to the patient's mucosa shortly (e.g. 5-30 minutes) before bedtime to account for the delay in the onset of action of the drug. Since it has been shown that for agomelatine, 24-hour maintenance of plasma concentrations at a therapeutic level is not necessary or may even be contraindicated for circadian rhythm resynchronization, it is not necessary to apply another transmucosal therapeutic system as soon as the active agent-containing layer of the previous transmucosal therapeutic system has dissolved, e.g. the following morning, so that the patient does not need to apply the transmucosal therapeutic system thereafter, e.g. throughout the day.

[0062] In the context of this invention, the term "room temperature" refers to the unaltered temperature inherent in the rooms in the laboratory where the experiments are carried out, and is typically in the range of 15-35°C, preferably about 18-25°C.

[0063] In the context of this invention, the term "patient" refers to a subject who exhibits a clinical manifestation of a particular symptom or symptoms suggesting a need for treatment, who is being treated preventively or prophylactically for a pathological condition, or who has been diagnosed with a pathological condition to be treated.

[0064] In the context of this invention, the term "pharmacokinetic parameters" refers to parameters describing the plasma curve, such as C _max , C _t and AUC _t1-t2 , obtained in a clinical study, such as single or multiple administration of an agomelatine-based transmucosal therapeutic system to healthy human subjects. The pharmacokinetic parameters of individual subjects are summarized using arithmetic and geometric mean values, such as the mean C _max , the mean AUC _t and the mean AUC _BESC , as well as using additional statistical indicators such as the corresponding standard deviations and standard errors, the minimum value, the maximum value and the average value when ranking a list of values (median). In the context of this invention, the pharmacokinetic parameters, such as C _max , C _t and AUC _{t1-t2 ,} refer to arithmetic or geometric mean values, and preferably refer to geometric mean values. It cannot be excluded that the absolute mean values obtained for a given transmucosal therapeutic system in a clinical study may vary to a certain extent between studies. In order to be able to compare the absolute mean values between studies in the future, a reference composition, for example of any product according to the invention, can be used as an internal standard. A comparison of the AUC for each unit release area of the corresponding reference product in an earlier and a subsequent study can be used to obtain a correction factor taking into account the differences between the studies.

[0065] Clinical studies in accordance with the present invention refer to studies conducted in full compliance with the recommendations of the International Conference on Harmonization of Clinical Trials (ICH) and all applicable local Good Clinical Practice (GCP) and regulatory requirements.

[0066] In the context of this invention, the term "healthy human subject" refers to male and female subjects with a body weight of 55 kg to 100 kg and a body mass index (BMI) of 18 to 29 and normal physiological parameters such as blood pressure, etc. Healthy human subjects for the purposes of the present invention are selected in accordance with inclusion and exclusion criteria that are based on ICH recommendations.

[0067] In the context of this invention, the term "subject population" refers to at least ten healthy human subjects.

[0068] In the context of this invention, the term "geometric mean" refers to the mean value of log-transformed data that has been transformed back to the original scale.

[0069] In the context of this invention, the term "arithmetic mean" refers to the sum of the values from all observations divided by the total number of observations.

[0070] In the context of this invention, the parameter "AUC" corresponds to the area under the plasma concentration-time curve. The AUC value is proportional to the total amount of active agent absorbed into the bloodstream and is therefore an indicator of bioavailability.

[0071] In the context of this invention, the parameter "AUC _t1-t2 " is represented in (ng/mL)⋅h and refers to the area under the plasma concentration-time curve from time t1 to t2 and is calculated using the linear trapezoidal method.

[0072] In the context of the present invention, the parameter “C _max ” is represented in (ng/ml) and refers to the maximum observed concentration of the active agent in blood plasma.

[0073] In the context of this invention, the parameter “C _t ” is represented in (ng/ml) and refers to the concentration of the active agent in the blood plasma observed at time t.

[0074] In the context of this invention, the parameter "t _max " is represented in h and refers to the time at which the C _max value is reached. In other words, t _max is the time at which the maximum observed plasma concentration is reached.

[0075] In the context of this invention, the parameter "t _lag " is represented in h and refers to the delay between the time of administration (in the case of a transmucosal therapeutic system, the time when the transmucosal therapeutic system is first applied to the oral mucosa, i.e. t = 0) and the time of appearance of a measurable concentration in the blood plasma. The t _lag indicator can be calculated approximately as the arithmetic mean of the first time point when a measurable (i.e. non-zero) concentration of the active agent in the blood plasma is obtained or when it is represented by the median value.

[0076] In the context of this invention, the term "mean plasma concentration" is expressed in (ng/ml) and represents the average of the individual concentrations of the active agent, such as agomelatine, in plasma at each time point.

[0077] In the context of this invention, the term "coating composition" refers to a composition comprising all the components of a drug-containing layer in a solvent, which can be applied to a protective layer or a release liner to form a drug-containing layer after drying.

[0078] In the context of this invention, the term "dissolve" in the context of preparing a coating composition, such as dissolving components of the coating composition, such as an active agent, refers to the process of obtaining a solution that is clear and does not contain any particles visible to the naked eye.

[0079] In the context of this invention, the term "solvent" refers to any liquid substance, which is preferably a volatile organic liquid such as methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, hexane, n-heptane, heptanes, toluene and mixtures thereof.

[0080] In the context of this invention, unless otherwise indicated, the term "about" refers to an amount that is ±10% of the amount described. In some embodiments, the term "about" refers to an amount that is ±5% of the amount described. In some embodiments, the term "about" refers to an amount that is ±2% of the amount described.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

[0081] Fig. 1a illustrates the rate of penetration of agomelatine through the mucosa for the transmucosal therapeutic system prepared according to Examples 1a-1f for the period 0-7 hours.

[0082] Fig. 1b illustrates the consumption of agomelatine for the transmucosal therapeutic system prepared according to Examples 1a-1f after 7 hours.

[0083] Fig. 2a illustrates the rate of penetration of agomelatine through the mucosa for the transmucosal therapeutic system prepared according to Examples 1a, 2 and 3a for the period 0-7 hours.

[0084] Fig. 2b illustrates the consumption of agomelatine for the transmucosal therapeutic system prepared according to Examples 1a, 2 and 3a after 7 hours.

[0085] Fig. 3a illustrates the mucosal penetration rate of agomelatine for the transmucosal therapeutic system prepared according to Examples 3a-3d for the period 0-6 hours.

[0086] Fig. 3b illustrates the mucosal penetration rate of agomelatine for the transmucosal therapeutic system prepared according to Examples 3b and 3e-3h for the period 0-6 hours.

[0087] Fig. 3c illustrates the consumption of agomelatine for the transmucosal therapeutic system prepared according to Examples 3a-3h after 6 hours.

[0088] Fig. 4a illustrates the permeation rate of agomelatine through the mucosa for the transmucosal therapeutic system prepared according to Examples 4a-4f for a period of 0-6 hours.

[0089] Fig. 4b illustrates the consumption of agomelatine for the transmucosal therapeutic system prepared according to Examples 4a-4f after 6 hours.

[0090] Fig. 5a illustrates the permeation rate of agomelatine through the mucosa for the transmucosal therapeutic system prepared according to Examples 4b and 5a-5d for the period 0-6 hours.

[0091] Fig. 5b illustrates the uptake of agomelatine for the transmucosal therapeutic system prepared according to Examples 4b and 5a-5d after 6 hours.

[0092] Fig. 6a illustrates the permeation rate of agomelatine through the mucosa for the transmucosal therapeutic system prepared according to Examples 6a-6d for the period 0-6 hours.

[0093] Fig. 6b illustrates the consumption of agomelatine for the transmucosal therapeutic system prepared according to Examples 6a-6d after 6 hours.

[0094] Fig. 7a illustrates the permeation rate of agomelatine across the mucosa for the transmucosal therapeutic system prepared according to Examples 4b, 6b, 6c, 6d, 7e and 7g for the period 0-4 hours.

[0095] Fig. 7b illustrates the mucosal penetration rate of agomelatine for the transmucosal therapeutic system prepared according to Examples 4b, 7a-7d and 7f for the period 0-4 hours.

[0096] Fig. 7c illustrates the consumption of agomelatine for the transmucosal therapeutic system prepared according to examples 4b, 6b, 6c, 6d and 7a-7g after 7 hours.

[0097] Fig. 8a illustrates the plasma concentration of agomelatine obtained in an in vivo clinical study of transmucosal therapeutic systems prepared according to Examples 8a-8c for the period 0-8 hours.

[0098] Fig. 9a illustrates the permeation rate of agomelatine through the mucosa for the transmucosal therapeutic system prepared according to Examples 4b and 9a-9f for the period 0-4 hours.

[0099] Fig. 9b illustrates the uptake of agomelatine for the transmucosal therapeutic system prepared according to Examples 4b and 9a-9f after 4 hours.

[0100] Fig. 9c illustrates the sum of possible degradation products and the amount of agomelatine detected in the storage stability test at 25°C and 60% RH, as well as at 40°C and 75% RH at different time points for the TTS obtained according to Example 9a.

[0101] Fig. 9d illustrates the sum of possible degradation products and the amount of agomelatine detected in the storage stability test at 25°C and 60% RH and at 40°C and 75% RH at different time points for the TTS obtained according to Example 9c.

DETAILED DESCRIPTION

STRUCTURE OF THE TRANSMUCOSALS THERAPEUTIC SYSTEM

[0102] The present invention relates to a transmucosal therapeutic system for transmucosal administration of agomelatine, having a mucoadhesive layered structure containing agomelatine.

[0103] The mucoadhesive layered structure comprises therapeutically effective amounts of agomelatine and comprises an agomelatine-containing agent comprising i) agomelatine and ii) a soluble film-forming agent.

[0104] Thus, the transmucosal therapeutic system for transmucosal administration of agomelatine has a mucoadhesive layered structure containing a therapeutically effective amount of agomelatine, wherein said mucoadhesive layered structure contains:

A) agomelatine-containing layer containing:

i) agomelatine; and

ii) soluble film-forming agent.

[0105] The transmucosal therapeutic system of the present invention is designed to provide an exceptionally high degree of delivery of the active substance in order to ensure that the amount of the drug delivered is sufficient to provide a therapeutically effective dose. As described in detail in the introduction, so-called open systems, in which the delivery of the active substance is ensured by a combination of direct release of the active substance from the transmucosal therapeutic system into the mucosa and indirect delivery of the active substance due to dissolution in saliva, have exceptional advantages in terms of a high rate of penetration of the active substance.

[0106] Thus, in certain embodiments of the present invention, the transmucosal therapeutic system does not comprise a protective layer. As noted above, a protective layer in the context of the present invention is any layer in the transmucosal therapeutic system that is capable of preventing the dissolution of (at least a significant amount of) the active substance contained in the transmucosal therapeutic system in saliva. Thus, in particular embodiments, the time required for the dissolution of the protective layer is at least the same as that required to deliver (a significant amount of) the active substance across the mucosa, for example, that required to dissolve the layer containing the active substance. Thus, in certain embodiments, the protective layer does not dissolve in less than 15 minutes, less than 10 minutes, or less than 5 minutes after administration of the transmucosal therapeutic system to a human patient. In some embodiments, the protective layer does not completely dissolve in water, artificial or natural saliva, or any other aqueous medium at 37°C and 150 rpm in less than 30 minutes, less than 15 minutes, or less than 10 seconds.

[0107] In some specific embodiments, the mucoadhesive layered structure may further comprise one or more additional layers selected from:

B) the layer in contact with the mucous membrane and

C) cosmetic layer.

[0108] Thus, in particular embodiments, the mucoadhesive layered structure according to the invention comprises an additional mucosal contact layer. In other embodiments, the mucoadhesive layered structure according to the invention does not comprise an additional mucosal contact layer. In such embodiments, but also in particular embodiments, the agomelatine-containing layer may be mucoadhesive. The additional mucosal contact layer, if present, is mucoadhesive and provides (improved) adhesion between the mucoadhesive layered structure and the mucosa of the patient during use. The mucosal contact layer is located immediately below the active agent-containing layer and thus forms an adhesive layer between the mucosa and the agomelatine-containing layer during use. From the point of view of ease of manufacture and limitation of the overall size of the patch, the size of the agomelatine-containing layer and the size of the layer in contact with the mucous membrane are preferably matched.

[0109] As noted above, the mucoadhesive layered structure may also comprise a cosmetic layer. In another embodiment, the mucoadhesive layered structure does not comprise a cosmetic layer.

[0110] Unlike the mucosal contact layer, the cosmetic layer is located on top of the agomelatine-containing layer and is not (necessarily) intended for contact with the mucosa.

[0111] As a result, in some specific embodiments, the mucoadhesive layered structure may further comprise one or more additional layers selected from:

B) the layer in contact with the mucous membrane and

C) cosmetic layer,

moreover

additional layers are adjacent to the agomelatine-containing layer, and

the mucosal contact layer and the cosmetic layer, if both are present, are adjacent to the agomelatine-containing layer on opposite sides.

[0112] The cosmetic layer may provide decorative aspects such as color or printing, or simply prevent patients from touching the agomelatine-containing layer during use of the transmucosal therapeutic system. In the case of such a protective function, it is preferred that the cosmetic layer completely covers the agomelatine-containing layer. Thus, in certain embodiments, the mucoadhesive layered structure further comprises a cosmetic layer, and the size of the agomelatine-containing layer and the size of the cosmetic layer are comparable or the cosmetic layer is larger in size and exceeds the agomelatine-containing layer in surface area.

[0113] On the other hand, the cosmetic layer should not be confused with the protective layer. This is not the function of the cosmetic layer, and in fact it would be undesirable if the cosmetic layer interfered with the release of the active substance into the saliva. Accordingly, the cosmetic layer dissolves quickly enough so as not to interfere with the dissolution of the active substance in the saliva, and, in certain embodiments, the cosmetic layer dissolves in water, in artificial or natural saliva, or in any other aqueous medium at 37°C and 150 rpm in less than 3 minutes, less than 1 minute, or less than 30 seconds.

[0114] An elegant solution for the transmucosal therapeutic system in terms of ease of manufacture and also in terms of simplicity is that the agomelatine-containing layer itself is the transmucosal therapeutic system. In other words, in certain preferred embodiments, the transmucosal therapeutic system according to the present invention does not comprise a mucosal contact layer nor a cosmetic layer, and in particular the mucoadhesive layered structure may simply consist of the agomelatine-containing layer.

[0115] Thus, according to certain embodiments of the invention, the transmucosal therapeutic system may further comprise a mucoadhesive top layer or not comprise a mucoadhesive top layer, and preferably does not comprise a mucoadhesive top layer. This mucoadhesive top layer is, in particular, larger in size than the agomelatine-containing mucoadhesive layered structure and is attached thereto to increase the adhesive properties of the entire transmucosal therapeutic system. The area of said mucoadhesive top layer increases the overall size of the transmucosal therapeutic system, but does not increase the release area. The mucoadhesive top layer comprises a mucoadhesive polymer or a mixture of mucoadhesive polymers selected from the group consisting of hydroxyethyl cellulose and hydroxypropyl cellulose, which may be identical to or different from any soluble film-forming agent included in the active agent-containing mucoadhesive layered structure.

[0116] As also noted above, the transmucosal therapeutic system is comprised of one or more thin layers, thus, in certain embodiments, the transmucosal therapeutic system is in the form of a film. Such a film may be round, rectangular, or square in shape.

[0117] The film preferably has some degree of thickness, since it would otherwise be difficult to incorporate the required amount of active substance and since very thin films are not easy to produce, in particular with regard to ensuring a uniform thickness. Thus, in certain embodiments, the transmucosal therapeutic system is in the form of a thin film having a weight per unit area of at least 25 g/ ^m2 , preferably at least 35 g/ ^m2 or more preferably at least 40 g/ ^m2 . Or, if converted into units of thickness, the transmucosal therapeutic system is in the form of a thin film having a layer thickness of at least 15 μm, preferably at least 25 μm and most preferably at least 35 μm. On the other hand, very thick films will be perceived by the patient as an irritant in the oral cavity and therefore this is a disadvantage in the context of patient compliance. Thus, in certain embodiments, the transmucosal therapeutic system is in the form of a thin film having a weight per unit area of less than or equal to 300 g/ ^m2 , preferably less than or equal to 250 g/ ^m2 , or more preferably less than or equal to 200 g/ ^m2 . Or, in terms of thickness, the transmucosal therapeutic system is in the form of a thin film having a layer thickness of less than 550 μm, preferably less than 400 μm, and more preferably less than 300 μm. In preferred embodiments, the transmucosal therapeutic system is in the form of a thin film having a weight per unit area of 25 to 300 g/ ^m2 , preferably 35 to 250 g/ ^m2 , or more preferably 40 to 200 g/ ^m2 , or having a layer thickness of 15 to 550 μm, preferably 25 to 400 μm, and more preferably 35 to 300 μm.

[0118] The transmucosal therapeutic system according to the invention is usually stored in a sealed, hermetically sealed package without any additional protective means. In this case, the mucoadhesive layered structure can also be on a detachable protective layer (e.g. a release liner), from which it is removed immediately before application to the oral mucosa of the patient. Thus, the transmucosal therapeutic system can additionally contain a release liner or not. The transmucosal therapeutic system protected by a release liner is usually also stored in a sealed, hermetically sealed package. The packaging can have a child-resistant and/or easy-to-handle feature for the elderly.

AGOMELATINE-CONTAINING LAYER

[0119] As described in more detail above, the transmucosal therapeutic system according to the present invention has a mucoadhesive layered structure comprising an agomelatine-containing layer.

[0120] In addition, the agomelatine-containing layer contains:

i) agomelatine; and

ii) soluble film-forming agent.

[0121] The mass per unit area of the agomelatine-containing layer is one of the factors determining the amount of active substance. A certain thickness is necessary to obtain a sufficient amount of active substance, and it is also difficult to apply a very thin layer, in particular with sufficient precision. On the other hand, thick layers not only cause discomfort in the oral cavity, but are also difficult to manufacture and can lead to too long a dissolution of the layer for the required release profile. Taking this into account, it is preferred that the agomelatine-containing layer has a weight per unit area of at least 25 g/ ^m2 , more preferably at least 35 g/ ^m2 or most preferably at least 40 g/ ^m2 , or has a weight per unit area of less than or equal to 300 g/ ^m2 , more preferably less than or equal to 250 g/ ^m2 or most preferably less than or equal to 200 g/ ^m2 , or has a weight per unit area of from 25 to 300 g/ ^m2 , more preferably from 35 to 250 g/ ^m2 or most preferably from 40 to 200 g/ ^m2 . In terms of the thickness of the agomelatine-containing layer, it is preferred that the agomelatine-containing layer has a layer thickness of at least 15 μm, preferably at least 25 μm and more preferably at least 35 μm, or has a layer thickness of less than 550 μm, preferably less than 400 μm and more preferably less than 300 μm.

[0122] In an open transmucosal therapeutic system without a backing layer, which is particularly preferred in the present invention (see above), the delivery of the active substance is controlled by a combination of direct and indirect delivery, as explained above, so that in preferred embodiments the release area, i.e. the surface area of the agomelatine-containing layer, plays an insignificant role in controlling the effective dose. However, in order to ensure that the patch does not prematurely detach from the mucosa and also that it is able to contain a sufficient amount of the active substance without the need for very thick films, a certain minimum size is necessary. On the other hand, if the release area is too large, the transmucosal therapeutic system will be huge in size, inconvenient to apply and use, which will lead to poor patient compliance. Taking this into account, in certain embodiments of the invention, the transmucosal therapeutic system has a release area of at least 0.1 ^cm2 , preferably at least 0.2 ^cm2 or more preferably at least 0.5 ^cm2 , or has a release area of less than or equal to 10 ^cm2 , preferably less than or equal to 7 ^cm2 or more preferably less than or equal to 5 ^cm2 , or has a release area of from 0.1 to 10 ^cm2 , preferably from 0.2 to 7 ^cm2 or more preferably from 0.5 to 5 ^cm2 .

[0123] As also set out above and without being limited by theory, it is believed that a sufficient amount of active substance contained in the transmucosal therapeutic system is necessary to provide certain advantageous features of the transmucosal therapeutic system according to the present invention, such as good in vitro penetration. On the other hand, if the amount of active substance is too high, this may lead not only to undesirable storage problems, such as recrystallization of the active substance when agomelatine is in dissolved form, but also to irritating sensations in the oral cavity due to too high a concentration of the drug. The amount of agomelatine contained in the transmucosal therapeutic system can be controlled in two ways by adjusting the concentration and/or the mass per unit area of the agomelatine-containing layer. Details regarding the mass per unit area are set out above. In terms of concentration, the agomelatine-containing layer comprises at least 1% by weight of agomelatine, preferably at least 2% by weight of agomelatine and more preferably at least 3% by weight of agomelatine, or the agomelatine-containing layer comprises less than or equal to 25% by weight of agomelatine, preferably less than or equal to 20% by weight of agomelatine and more preferably less than or equal to 10% by weight of agomelatine, or the agomelatine-containing layer comprises from 1 to less than or equal to 25% by weight of agomelatine, preferably from 2 to less than or equal to 20% by weight of agomelatine and more preferably from 3 to less than or equal to 10% by weight of agomelatine.

[0124] Thus, in certain embodiments of the invention, the agomelatine-containing layer comprises at least 0.1 mg/ ^cm2 , preferably at least 0.2 mg/ ^cm2 or more preferably at least 0.4 mg/ ^cm2 of agomelatine, or the agomelatine-containing layer comprises less than or equal to 2.0 mg/ ^cm2 , preferably less than or equal to 1.5 mg/ ^cm2 or more preferably less than or equal to 1.2 mg/ ^cm2 of agomelatine, or the agomelatine-containing layer comprises from 0.1 to 2.0 mg/ ^cm2 , preferably from 0.2 to 1.5 mg/ ^cm2 or more preferably from 0.4 to 1.2 mg/ ^cm2 of agomelatine per release area.

[0125] In terms of the amount of active substance, the mucoadhesive layered structure may comprise at least 0.1 mg, preferably at least 0.2 mg or more preferably at least 0.4 mg agomelatine, or less than or equal to 20 mg, preferably less than or equal to 15 mg or more preferably less than or equal to 10 mg agomelatine, or from 0.1 mg to 20 mg, preferably from 0.2 mg to 15 mg or more preferably from 0.4 mg to 10 mg agomelatine.

[0126] As described in more detail above, the correct dissolution pattern of the agomelatine-containing layer is very important for the control of the delivery routes. The faster the dissolution of the transmucosal therapeutic system, the more dissolution in saliva will predominate over direct delivery to the mucosa at the site of adhesion. Since one of the objectives of the present invention is to provide an exceptionally high permeation rate, indirect delivery, in which the entire mucosa is used to deliver the drug, is very important and will predominate over direct delivery. This means that the transmucosal therapeutic system must dissolve relatively quickly. Thus, the mucoadhesive layered structure can, for example, dissolve in water, in artificial or natural saliva or in any other aqueous medium at 37°C and 150 rpm in less than 5 hours, preferably in less than 3 hours and more preferably in less than 2 hours. On the other hand, if the dissolution is too rapid, the risk of inadvertent ingestion of a significant portion of the active substance becomes high. The so-called "flash-plates" are films designed to disintegrate very quickly in order to ensure enteral delivery when swallowing is intentional (and easier compared to tablets). The transmucosal therapeutic system therefore differs from the flash-plates in its delivery mechanism and generally dissolves more slowly than the flash-plates. In the specific situation where the active substance is agomelatine, high concentrations of the active substance are also undesirable since there is a risk of irritant sensations, which is another reason why the dissolution should preferably not be too rapid. Thus, the mucoadhesive laminated structure can, for example, dissolve in water, in artificial or natural saliva or in any other aqueous medium at 37°C and 150 rpm in more than 30 seconds, preferably in more than 1 minute and more preferably in more than 2 minutes. In preferred embodiments, the mucoadhesive layered structure dissolves in water, artificial or natural saliva or any other aqueous medium at 37°C and 150 rpm in more than 30 seconds and less than 5 hours, preferably in more than 1 minute and less than 3 hours, and more preferably in more than 2 minutes and less than 2 hours.

[0127] Since it is preferable that the agomelatine-containing layer can directly adhere to the mucosa, in certain preferred embodiments of the invention the agomelatine-containing layer is mucoadhesive.

[0128] As will be further explained in more detail below, in certain embodiments, it is preferable to use ethanol rather than water as a solvent in the coating composition for producing the agomelatine-containing layer. Thus, the agomelatine-containing layer according to the present invention can be obtained (and/or is obtained) by drying the applied coating composition comprising agomelatine, a soluble film-forming agent and ethanol. On the other hand, some soluble film-forming agents have high solubility in water but limited solubility in other solvents. Thus, the use of water as a solvent is also advantageous, so that the agomelatine-containing layer can be obtained (and/or is obtained) by drying the applied coating composition comprising agomelatine, a soluble film-forming agent and water. A combination of ethanol and water is also possible, i.e. The agomelatine-containing layer can also be obtained (and/or is obtained) by drying an applied coating composition comprising agomelatine, a soluble film-forming agent, ethanol and water. In terms of the amount of water, the agomelatine-containing layer can be obtained (and/or is obtained) by drying an applied coating composition comprising less than 50% by weight, or less than 20% by weight, or less than 10% by weight, or less than 5% by weight of water.

[0129] Taking into account the stability of the agomelatine-containing layer with respect to its composition, it is preferable that the agomelatine-containing layer does not contain any volatile constituents that carry the risk of evaporation and compositional change during storage. Thus, in certain embodiments, the agomelatine-containing layer is substantially free of volatile solvent. In this sense, the volatile solvent can be selected from the group consisting of C1-C3 linear and branched alcohols, ethyl acetate, hexane, n-heptane and any mixtures thereof. From the point of view of a transmucosal therapeutic system applied in the oral cavity, volatile solvents include, in particular, those that are better not to be swallowed, such as methanol, ethyl acetate, hexane, n-heptane and mixtures thereof. In particular, the agomelatine-containing layer contains less than or equal to 5% by weight, preferably less than or equal to 3% by weight, and more preferably less than or equal to 1% by weight of a volatile solvent.

[0130] Since agomelatine has low solubility in water, significant amounts of water in the agomelatine-containing layer carry a risk of recrystallization if the active substance is in a dissolved state. Thus, in certain embodiments, the agomelatine-containing layer is substantially free of water, such as containing less than or equal to 12% by weight, less than or equal to 8% by weight, less than or equal to 5% by weight, or less than or equal to 4% by weight of water.

AGOMELATINE

[0131] According to the invention, the mucoadhesive layered structure comprises agomelatine in a therapeutically effective amount and the mucoadhesive layered structure comprises an agomelatine-containing layer.

[0132] Although according to the present invention the active agent agomelatine may be present in the transmucosal therapeutic system and in particular in the agomelatine-containing layer in any form, i.e. in its free, dissociated or any associated form such as hydrates, solvates, etc., as well as in the form of particles, which may be in micronized form, crystalline form and in particular in one of the polymorphic forms, and/or in amorphous form, and in any form of a hybrid type of any of the above forms or a mixture thereof, it is preferred that agomelatine is present in free dissociated form.

[0133] Furthermore, in certain embodiments, agomelatine is included in the agomelatine-containing layer in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorphic forms, in amorphous form, as a hydrate, a solvate, a hybrid form of any of the above forms, or a mixture thereof.

[0134] In certain embodiments, the agomelatine-containing layer is obtained (and/or prepared) by including agomelatine in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorphic forms, in amorphous form, as a hydrate, solvate, hybrid type form of any of the above forms, or a mixture thereof.

[0135] The agomelatine in the agomelatine-containing layer may be (completely) dissolved or the agomelatine-containing layer may comprise agomelatine particles, preferably consisting of agomelatine in its free dissociated form, such that the agomelatine is in dispersed form. It goes without saying that if agomelatine is in dispersed form, the agomelatine-containing layer may still comprise agomelatine in dissolved form, depending on the solubility of the active substance in the agomelatine-containing layer (which is, for example, saturated or supersaturated).

[0136] In a preferred embodiment, agomelatine is substantially completely dissolved, such as at least 90 mol%, preferably at least 95 mol%, more preferably at least 98 mol% or most preferably at least 99 mol% of the agomelatine in the agomelatine-containing layer is in dissolved form. It is also preferred that the agomelatine-containing layer does not contain agomelatine crystals.

[0137] As noted above, the amount of agomelatine in the transmucosal therapeutic system is considered important for proper release of the active substance, and can, for example, be adjusted by the concentration of agomelatine. Thus, in certain embodiments, the concentration of agomelatine in the agomelatine-containing layer is in the range of from 1 to 25% by weight of agomelatine, preferably from 2 to 20% by weight of agomelatine, and more preferably from 3 to 10% by weight of agomelatine of the agomelatine-containing layer.

[0138] In certain embodiments, agomelatine has a purity of at least 95%, preferably at least 98%, and more preferably at least 99%, as determined by quantitative HPLC. Quantitative HPLC can be carried out by reversed-phase HPLC with UV detection. In particular, the following conditions can be used when isocratically performing HPLC:

[0139] The transmucosal therapeutic systems according to the present invention advantageously exhibit improved stability in terms of agomelatine content as well as agomelatine degradation.

[0140] Thus, in certain embodiments, the agomelatine-containing layer initially comprises (i.e. shortly after manufacture, such as within one week) an amount of agomelatine that is 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 incorporated into the agomelatine-containing layer. The theoretical amount of agomelatine is calculated from the amount of agomelatine used in the coating composition and the (actual) weight per unit area of the applied and dried agomelatine-containing layer of the transmucosal therapeutic system under study.

[0141] The agomelatine-containing layer may also initially contain a total amount of agomelatine degradation products of less than 0.5%, preferably less than 0.2%, more preferably less than 0.1%, and even more preferably less than 0.05%.

[0142] In certain other embodiments, the transmucosal therapeutic systems of the present invention are stable upon storage, i.e., they may retain their original agomelatine content or exhibit low amounts of degradation products, as shown below.

[0143] In one such embodiment, after storage at 25°C and a relative humidity of 60% 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 comprises an amount of agomelatine of 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 included in the agomelatine-containing layer.

[0144] After storage at 25°C and a relative humidity of 60% 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 may also contain a total amount of substances associated with the degradation of agomelatine of less than 0.5%, preferably less than 0.2%, more preferably less than 0.1% and most preferably less than 0.05%.

[0145] In one such embodiment, after storage at 40°C/75% RH for at least 3 months, and preferably at least 6 months, the agomelatine-containing layer comprises an amount of agomelatine of 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 incorporated into the agomelatine-containing layer.

[0146] After storage at 40°C/75% RH for at least 3 months and preferably at least 6 months, the agomelatine-containing layer may also contain a total amount of agomelatine-related degradation substances of less than 0.5%, preferably less than 0.2%, more preferably less than 0.1% and even more preferably less than 0.05%.

[0147] The method for determining the content of agomelatine and the total amount of substances associated with the degradation of agomelatine, as well as the adhesion force and the detachment force, is preferably carried out as described in Examples 9a and 9c.

SOLUBLE FILM-FORMING AGENT

[0148] As described above, the transmucosal therapeutic system according to the present invention has a mucoadhesive layered structure comprising an agomelatine-containing layer comprising a soluble film-forming agent.

[0149] This soluble film-forming agent ensures sufficient cohesion of the agomelatine-containing layer while it is in a dry state. According to certain embodiments, the soluble film-forming agent can also ensure sufficient adhesion to the mucosa after wetting, i.e. upon contact with the mucosa. In such embodiments, but also in general, the soluble film-forming agent can be selected from mucoadhesive polymers.

[0150] The film-forming agent provides the primary control over the dissolution pattern of the agomelatine-containing layer. For this reason, the film-forming agent is "soluble". In certain specific embodiments, this means that the first soluble film-forming agent, when formed into a film having a weight per unit area of from 30 to 100 g/ ^m2 or 50 g/ ^m2 , dissolves in water, in artificial or natural saliva or in any other aqueous medium at 37°C and 150 rpm in less than 5 hours, preferably less than 3 hours, more preferably less than 2 hours and most preferably less than 1 hour. The soluble film-forming agent, when formed into a film having a weight per unit area of from 30 to 100 g/ ^m2 or 50 g/ ^m2 , can also dissolve in water, in artificial or natural saliva or in any other aqueous medium at 37°C and 150 rpm in more than 5 seconds, preferably more than 30 seconds, more preferably more than 1 minute and most preferably more than 2 minutes. It should be noted that the soluble film-forming agent, when formed into a film having a weight per unit area of 30 to 100 g/ ^m2 or 50 g/ ^m2 , can dissolve in more than 5 seconds and less than 5 hours, preferably in more than 30 seconds and less than 3 hours, more preferably in more than 1 minute and less than 2 hours, and most preferably in more than 2 minutes and less than 1 hour.

[0151] Film-forming agents suitable as the soluble film-forming agent according to the invention are selected, for example, from the group consisting of polymers such as polyvinylpyrrolidone (commercially available as Kollidon® 30F from BASF), methylcellulose (commercially available as Methocel® from Colorcon), ethylcellulose (commercially available as Ethocel® from Colorcon), hydroxyethylcellulose (commercially available as Natrosol® 250 L from Ashland Industries), hydroxypropylcellulose (commercially available as Klucel® from Ashland Industries), hydroxypropylmethylcellulose (also known as hypromellose, commercially available as Pharmacoat® from Shin-Etsu), sodium carboxymethylcellulose (non-crosslinked sodium salt of carboxymethylcellulose, also called CMC or carmellose, commercially available as Blanose® from Ashland Industries), graft copolymers based on polyethylene glycol, polyvinyl acetate and polyvinylcaprolactam (commercially available as Soluplus® from BASF), polyvinyl alcohol (commercially available as Mowiol® 4-88 from Kuraray), copolymers of polyvinyl alcohol and polyethylene glycol (commercially available as Kollicoat® IR from BASF), copolymers of polyvinylpyrrolidone and polyvinyl acetate (also called copovidones and commercially available, for example, as Kollidon® VA64 from BASF), polyethylene oxides, polyethylene glycols, copolymers of methacrylic acid and methyl methacrylate (commercially available as Eudragit® L100, Eudragit® Y2,5, Eudragit® S100 and Eudragit® S 12,5 from Evonik) and copolymers of methacrylic acid and ethyl methacrylate (commercially available as Eudragit® L100-55 and Eudragit® L30D55 from Evonik), and natural film-forming agents such as shellac, pectin, gelatin, alginate, pullulan and starch derivatives, and any mixtures thereof.

[0152] The film-forming agent should be capable of not only providing sufficient cohesion of the agomelatine-containing layer, but preferably providing a film that is not sticky in the dry state, so that the patient can touch and manipulate the agomelatine-containing layer, for example, apply it to the oral mucosa, without it sticking to the fingers. In addition, since the soluble film-forming agent provides the main control over the dissolution pattern of the agomelatine-containing layer, which should be neither too fast nor too slow, the soluble film-forming agent is preferably soluble, dispersible or otherwise disintegrating in an aqueous medium, in particular in saliva, or, in a simplified version, in water. On the other hand, in terms of ease of manufacture and the possibility of a water-free manufacturing process, which is preferable in the context of avoiding crystal formation or recrystallization of the active agent, film-forming agents that are soluble in other solvents, such as C1-C3 alcohols, in particular ethanol, are also preferred. Although it is preferable that the film-forming agent is soluble in both water and ethanol, high solubility may result in too rapid dissolution of the agomelatine-containing layer. Thus, the choice of a film-forming agent is not a simple task.

[0153] The inventors have unexpectedly found that, in view of the above, polymers such as polyvinylpyrrolidone, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, graft copolymers based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam, polyvinyl alcohol, copolymers of polyvinyl alcohol and polyethylene glycol, copolymers of polyvinylpyrrolidone and polyvinyl acetate, polyethylene oxides, polyethylene glycols and any mixtures thereof are preferred for soluble film-forming agents. Particularly preferred for the soluble film-forming agent are polymers such as polyvinylpyrrolidone, hydroxypropyl cellulose, graft copolymers based on polyethylene glycol, polyvinyl acetate and polyvinylcaprolactam, copolymers of polyvinylpyrrolidone and polyvinyl acetate and any mixtures thereof, and most preferably the soluble film-forming agent is hydroxypropyl cellulose or polyvinylpyrrolidone, or a mixture thereof.

[0154] Hydroxypropyl cellulose is commercially available from Ashland under the trade name Klucel™ and comes in several grades.

[0155] The grades differ from each other in molecular weight MM (measured by SEC-SEC) and Brookfield viscosity (25°C, LPH, moisture-free) and are as follows:

HF grade has a MW of 1150000 and a Brookfield viscosity of 1500-3000 (1% in water),

MF grade has a MM of 850,000 and a Brookfield viscosity of 4000-6500 (2% in water),

GF grade has a MM of 370,000 and a Brookfield viscosity of 150-400 (2% in water),

JF grade has a MM of 140,000 and a Brookfield viscosity of 150-400 (5% in water),

LF grade has a MM of 95000 and a Brookfield viscosity of 75-150 (5% in water),

EF grade has a MM of 80000 and a Brookfield viscosity of 300-600 (10% in water),

ELF grade has a MW of 40,000 and a Brookfield viscosity of 150-300 (10% in water).

[0156] Thus, in certain embodiments, the hydroxypropyl cellulose has a molecular weight (measured by SEC-SEC) of from 30,000 to 1,500,000, and more preferably, the hydroxypropyl cellulose has a molecular weight (measured by SEC-SEC) selected from

from 35,000 to 45,000, in particular 40,000,

from 75,000 to 85,000, in particular 80,000,

from 90,000 to 100,000, in particular 95,000,

from 130,000 to 150,000, in particular 140,000,

from 350,000 to 400,000, in particular 370,000,

from 800,000 to 900,000, in particular 850,000,

from 1,100,000 to 1,200,000, in particular 1,150,000. Particularly preferred is hydroxypropyl cellulose having a molecular weight (measured by SEC-size exclusion chromatography) of from 75,000 to 85,000, in particular 80,000.

[0157] The polyvinylpyrrolidone is preferably soluble polyvinylpyrrolidone.

[0158] The term "soluble polyvinylpyrrolidone" refers to polyvinylpyrrolidone, also known as povidone, which is soluble by more than 10% in at least ethanol, preferably also in water, diethylene glycol, methanol, n-propanol, 2-propanol, n-butanol, chloroform, methylene chloride, 2-pyrrolidone, macrogol 400, 1,2-propylene glycol, 1,4-butanediol, glycerol, triethanolamine, propionic acid and acetic acid. Examples of commercially available polyvinylpyrrolidones include Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® 25, Kollidon® 30 and Kollidon® 90 F, available from BASF, or Povidone K90F. The different grades of Kollidone® are defined in terms of the K-value, which represents the average molecular weight of the polyvinylpyrrolidone grades. Kollidon® 12 PF has a K-value in the range of 10.2 to 13.8, corresponding to a nominal K-value of 12. Kollidon® 17 PF has a K-value in the range of 15.3 to 18.4, corresponding to a nominal K-value of 17. Kollidon® 25 has a K-value in the range of 22.5 to 27.0, corresponding to a nominal K-value of 25, Kollidon® 30 has a K-value in the range of 27.0 to 32.4, corresponding to a nominal K-value of 30. Kollidon® 90 F has a K-value in the range of 81.0 to 97.2, corresponding to a nominal K-value of 90. Preferred grades of Kollidon® are Kollidon® 12 PF, Kollidon® 30 and Kollidon® 90 F. For all grades and types of polyvinylpyrrolidone, it is preferred that the amount of peroxides be within certain limits, in particular, the amount of peroxide be equal to or less than 500 ppm, more preferably equal to or less than 150 ppm, and most preferably equal to or less than 100 ppm.

[0159] In the context of this invention, the term "K-value" refers to a value calculated from the relative viscosity of polyvinylpyrrolidone in water in accordance with the European Pharmacopoeia (Ph.Eur.) and USP monographs for "povidone".

[0160] Thus, in certain embodiments, the polyvinylpyrrolidone is selected from polyvinylpyrrolidones having a K-value in a range selected from the group of ranges consisting of

from 9 to 15 and preferably from 10.2 to 13.8,

from 15 to 20 and preferably from 15.3 to 18.4,

from 20 to 27 and preferably from 22.5 to 27.0,

from 27 to 35 and preferably from 27.0 to 32.4 and

from 75 to 110 and preferably from 81.0 to 97.2, or any mixtures thereof, and more preferably is polyvinylpyrrolidone having a K-value in the range from 27.0 to 32.4 or from 81.0 to 97.2 and any mixtures thereof, and most preferably is polyvinylpyrrolidone having a K-value in the range from 81.0 to 97.2.

[0161] In order to ensure that the agomelatine-containing layer is sufficiently cohesive, it is necessary to include a certain amount of soluble film-forming agent. Thus, in certain preferred embodiments, the amount of soluble film-forming agent is at least 65% by weight, more preferably at least 75% by weight, and most preferably at least 85% by weight. On the other hand, the amount of soluble film-forming agent may also be less than or equal to 98% by weight, less than or equal to 94% by weight, or less than or equal to 90% by weight. In certain embodiments, the amount of soluble film-forming agent is in the range of from 65 to 98% by weight, from 75 to 94% by weight, or from 80 to 90% by weight, of the agomelatine-containing layer.

[0162] Such a film-forming agent may be present as a soluble film-forming agent in the agomelatine-containing layer and layer, but may also be contained in an optional top layer.

ADDITIONAL ADDITIVES

[0163] The agomelatine-containing layer of the transmucosal therapeutic system according to the invention may contain additional excipients or additives selected from the group consisting of fatty acids, sweeteners, flavors, colorants, penetration enhancers, solubilizers, stabilizers, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffering agents and additional film-forming agents.

[0164] 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 a range is given for the amount of a particular additive, such range refers to the amount per individual additive.

[0165] It should be noted that in pharmaceutical formulations, the components of the formulation are classified according to their physicochemical and physiological properties and according to their function. This means in particular that a substance or compound falling into one category is not excluded from being classified into another category of formulation components. For example, a certain polymer may be a crystallization inhibitor, but also a tackifier. Some substances may, for example, be typical emollients, but at the same time act as penetration enhancers. A person skilled in the art is able to determine, based on his general knowledge, to which category or categories of formulation components a certain substance or compound belongs. Detailed information on excipients and additives is provided below, which, however, should not be taken as exclusive. Other substances not explicitly listed in the present description can also be used in accordance with the present invention, and substances and/or compounds explicitly listed for one category of formulation components are not excluded from being used as another formulation component in the context of the present invention.

[0166] Due to the potential burning or irritating effects of agomelatine, substances that are capable of masking or modifying taste or that can mitigate the effect of agomelatine are particularly preferred. For example, researchers have shown that certain fatty acids can reduce capsaicin-induced effects such as pain/itching.

[0167] Thus, in certain preferred embodiments, the agomelatine-containing layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners and flavoring agents.

[0168] The fatty acid may in particular be a saturated or unsaturated, linear or branched carboxylic acid containing 4-24 carbon atoms, and in particular may be selected from the group consisting of caprylic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoleic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid. Particularly preferred are oleic acid and linoleic acid.

[0169] In terms of amount, the agomelatine-containing layer preferably comprises one or more fatty acids in an amount of at least 1% by weight, more preferably at least 3% by weight, and more preferably at least 4% by weight. The agomelatine-containing layer may also comprise one or more fatty acids in an amount of less than or equal to 15% by weight, preferably less than or equal to 12% by weight, and more preferably less than or equal to 10% by weight. Finally, the agomelatine-containing layer may also comprise one or more fatty acids in an amount of from 1 to 15% by weight, preferably from 3 to 12% by weight, and more preferably from 4 to 10% by weight.

[0170] In certain preferred embodiments, the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of sucrose, glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidin, neotame, steviol glycosides, thaumatin, and sodium saccharin. It is particularly preferred that the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of sucrose, sucralose, and sodium saccharin. In such a particularly preferred embodiment, i.e. when the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of sucrose, sucralose and sodium saccharin, the amount of sweetener is at least 0.05% by weight, preferably at least 0.1% by weight, and more preferably at least 0.3% by weight, and/or is less than or equal to 2.0% by weight, preferably less than or equal to 1.5% by weight, and more preferably less than or equal to 1.0% by weight, and/or is from 0.05 to 2.0% by weight, preferably from 0.1 to 1.5% by weight, and more preferably from 0.3 to 1.0% by weight, of each.

[0171] Also in preferred embodiments, the agomelatine-containing layer comprises one or more natural or artificial flavors selected from the group consisting of vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetyl propionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethyl vanillin, and eucalyptol, as well as flavoring compositions such as peppermint flavor. Vanillin, methyl salicylate, menthol, peppermint flavor, and eucalyptol are particularly preferred. In such a particularly preferred embodiment, i.e. when the agomelatine-containing layer comprises one or more natural or artificial flavourings selected from the group consisting of vanillin, methyl salicylate, menthol, peppermint flavouring and eucalyptol, the amount of flavouring is at least 0.1% by weight, preferably at least 0.3% by weight, and more preferably at least 0.4% by weight, and/or is less than or equal to 10% by weight, preferably less than or equal to 6% by weight, and more preferably less than or equal to 4% by weight, and/or is between 0.1 and 10% by weight, preferably between 0.3 and 6% by weight, and more preferably between 0.4 and 4% by weight, each, or the amount is at least 0.1% by weight, preferably at least 0.5% by weight, and more preferably at least 0.7% by weight, and/or is less than or equal to 15% by weight, preferably less than or equal to 10% by weight, and more preferably less than or equal to 8% by weight, and/or constitutes from 0.1 to 15% by weight, preferably from 0.5 to 10% by weight, and more preferably from 0.7 to 8% by weight, in total. Suitable flavors are also commercially available from Mane, and any of them identifiable by an odor such as apple, caramel, chocolate, lemon, mint, etc., can be used as a flavor in the present invention.

[0172] In certain embodiments, the agomelatine-containing layer comprises one or more colorants. Any colorant for use in the pharmaceutical/food industry may be included, in particular those approved for use by the US FDA or the European EFSA/EMA. Such dyes may be, for example, selected from the group consisting of titanium dioxide, brilliant blue FCF, indigo carmine, fast green FCF, erythrosine, allura red AC, tartracene and sunset yellow FCF, curcumin, riboflavin, riboflavin-5'-phosphate, quinoline yellow, orange yellow S, cochineal, carminic acid, azorubin, carmoisine, amaranth, crimson 4R, cochineal red A, patent blue V, indigotin, chlorophylls, chlorophyllins, copper complexes of chlorophyll and chlorophyllins, green S, plain caramel, caustic sulphate caramel, ammonia caramel, ammonia sulphate caramel, brilliant black BN, black PN, vegetable carbon, brown HT, carotenes, annatto, bixin, norbixin, paprika extract, capsanthin, capsorubin, lycopene, beta-apo-8'-carotenal, lutein, canthaxanthin, beet red, betanin, anthocyanins, calcium carbonate, oxides and hydroxides of iron, aluminum, silver, gold and litholrubin BK.

[0173] The agomelatine-containing layer may contain one or more additional film-forming agents in addition to those described above for the soluble film-forming agent. Such additional film-forming agent differs from those previously described for the soluble film-forming agent. One or more additional film-forming agents may be contained in the agomelatine-containing layer in an amount of at least 2% by weight, preferably at least 5% by weight, and more preferably at least 10% by weight, and/or in an amount of less than or equal to 40% by weight, preferably less than or equal to 30% by weight, and more preferably less than or equal to 25% by weight, and/or in an amount of from 2 to 40% by weight, preferably from 5 to 30% by weight, and more preferably from 10 to 25% by weight each, and/or in an amount of at least 5% by weight, preferably at least 15% by weight, and more preferably at least 20% by weight, or in an amount of less than or equal to 40% by weight, preferably less than or equal to 30% by weight, and more preferably less than or equal to 25% by weight, and/or in an amount of from 5 to 40% by weight, preferably from 15 to 30% by weight, and more preferably from 20 to 25% by weight, in total.

[0174] In certain embodiments, the agomelatine-containing layer comprises one or more solubilizers. Suitable solubilizers can be, for example, selected from the group consisting of ethoxylated sorbitol esterified with fatty acids, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan monooleate (commercially available as Tween 80 or polysorbate 80), safflower oleasomes, propanediol and polyethoxylated castor oil. Such solubilizers may be contained in the agomelatine-containing layer in an amount of at least 0.3% by weight, preferably at least 0.5% by weight and more preferably at least 1.0% by weight, and/or in an amount less than or equal to 5% by weight, preferably less than or equal to 4% by weight and more preferably less than or equal to 3% by weight, and/or in an amount of from 0.3 to 5% by weight, preferably from 0.5 to 4% by weight and more preferably from 1.0 to 3% by weight, each.

[0175] The agomelatine-containing layer may also contain one or more emulsifiers. Such emulsifiers may be, for example, selected from the group consisting of soya lecithin, sodium phosphates, mono- and diglycerides of fatty acids, sodium stearoyl lactylate, diacetyl tartaric acid esters of mono- and diglycerides, and polyethoxylated hydrogenated castor oil (commercially available as Cremophor RH 40 from BASF). The emulsifiers may, for example, be contained in the agomelatine-containing layer in an amount of at least 1% by weight, preferably at least 3% by weight, and more preferably at least 5% by weight, and/or in an amount of less than or equal to 25% by weight, preferably less than or equal to 20% by weight, and more preferably less than or equal to 15% by weight, and/or in an amount of from 1 to 25% by weight, preferably from 3 to 20% by weight, and more preferably from 5 to 15% by weight each.

[0176] In particular embodiments, the agomelatine-containing layer comprises one or more plasticizers. The one or more plasticizers may be selected from the group consisting of mono-, di-, oligo- and polysaccharides and derivatives such as sorbitol (commercially available as Sorbidex™ from Cargill), polyethylene glycol, triacetin, triethyl citrate, propylene glycol, glycerol and medium chain triglycerides. The agomelatine-containing layer may comprise one or more plasticizers in an amount of at least 0.5% by weight, preferably at least 1% by weight and more preferably at least 5% by weight, and/or in an amount less than or equal to 25% by weight, preferably less than or equal to 20% by weight or more preferably less than or equal to 15% by weight, and/or in an amount of from 0.5 to 25% by weight, preferably from 1 to 20% by weight and more preferably from 5 to 15% by weight each.

[0177] The agomelatine-containing layer may also comprise a penetration enhancer. In one embodiment, the agomelatine-containing layer comprises a penetration enhancer selected from the group consisting of diethylene glycol monoethyl ether (transcutol), dipropylene glycol, levulinic acid, 2,5-dimethyl isosorbide (dottisol), lauryl lactate, lactic acid, dimethylethylene urea, N,N'-dimethylpropylene urea, N,N-diethyl metatoluamide (DETA), propylene glycol monocaprylate, 2-methoxy-4-(prop-2-en-1-yl)phenol and laurocapram. Such penetration enhancers may be contained in the agomelatine-containing layer in an amount of at least 1% by weight, preferably at least 2% by weight, and more preferably at least 5% by weight, and/or in an amount less than or equal to 20% by weight, preferably less than or equal to 15% by weight, and more preferably less than or equal to 10% by weight, and/or in an amount of from 1 to 20% by weight, preferably from 2 to 15% by weight, and more preferably from 5 to 10% by weight, each.

[0178] On the other hand, certain compounds that can be considered as penetration enhancers are not preferred. Thus, in some embodiments, the agomelatine-containing layer does not comprise a penetration enhancer selected from the group consisting of bile acid, bile salts, bile acid derivatives, acylcarnitines, sodium dodecyl sulfate, dimethyl sulfoxide, sodium lauryl sulfate, terpenes, cyclodextrins, cyclodextrin derivatives, saponins, saponin derivatives, chitosan, EDTA, citric acid and salicylates, in an amount of more than 5% by weight, preferably more than 1% by weight, more preferably more than 0.2% by weight, and most preferably more than 0.1% by weight.

[0179] The agomelatine-containing layer according to the invention may comprise a pH regulator. Preferably, the pH regulator is selected from mono- and polytropic acids, mono-, di- and triacid bases, buffer solutions with mixtures of a weak acid and its conjugate base, amine derivatives, inorganic alkaline derivatives, polymers with basic and acidic functional groups, respectively.

RELEASE CHARACTERISTICS

[0180] Transmucosal therapeutic systems according to the invention are designed for transmucosal administration of a certain amount of agomelatine into the general circulation, in particular at night.

[0181] The use of the transmucosal therapeutic system according to the invention generally and preferably consists of applying the mucoadhesive layered structure (after removing the optionally present release liner) to the oral mucosa of a human patient and maintaining it on the mucosa until it dissolves. The site of application may be the inner surface of the cheek, the sublingual space, the gingiva or the palate, i.e. in a preferred embodiment, the use of the transmucosal therapeutic system consists of applying the mucoadhesive layered structure to the mucosa of the cheek, the sublingual space, the gingiva or the palate, and preferably the buccal mucosa of the oral cavity of a human patient and maintaining it on the mucosa until it dissolves.

[0182] In specific embodiments of the invention, the above-described transmucosal therapeutic system according to the invention provides a mucosal penetration rate of agomelatine, as measured with porcine esophageal mucosa, of 10 μg/cm2- ^hr to 150 μg/cm2- ^hr after 1 hour.

[0183] In certain embodiments, the transmucosal therapeutic system of the invention provides a cumulative release of agomelatine as measured in porcine oesophageal mucosa of at least 0.02 mg/ ^cm2 , preferably at least 0.05 mg/ ^cm2 , and more preferably at least 0.1 mg/ ^cm2 , and/or less than or equal to 0.5 mg/ ^cm2 , preferably less than or equal to 0.4 mg/ ^cm2 , and more preferably less than or equal to 0.3 mg/ ^cm2 , and/or from 0.02 mg/ ^cm2 to 0.5 mg/ ^cm2 , preferably from 0.05 mg/ ^cm2 to 0.4 mg/ ^cm2 , and more preferably from 0.1 mg/ ^cm2 to 0.3 mg/ ^cm2 over a period of 8 hours.

METHOD OF TREATMENT/MEDICAL USE

[0184] According to a particular aspect of the present invention, the transmucosal therapeutic system according to the invention is for use in a method of treatment, and in particular in a method of treating a human patient. According to another aspect, the present invention relates to a method of treatment in which the transmucosal therapeutic system according to the invention is administered to a human patient. In another aspect, the present invention relates to the use of the transmucosal therapeutic system according to the invention for the manufacture of a medicament for treatment, preferably for treating a human patient.

[0185] Most patients, more than 80% of those suffering from classic mood disorders (major depression, depressive phases of bipolar disorder, or generalized anxiety disorder) exhibit disturbances in the sleep-wake cycle and sleep architecture. Typically, difficulty falling asleep (increased latent sleepiness) followed by restless sleep leads to significant daytime sleepiness, which further impairs their ability to function properly in daily life, resulting in a vicious cycle. With regard to depression, although there are no specific treatment guidelines, available options are often based on the assumption that depression and sleep disturbances are interrelated and that successful treatment of one condition will therefore benefit the other.

[0186] In recent years, it has become increasingly clear that circadian rhythm disruption—misalignment and dysfunction of the "biological clock" that aligns basic physiological functions such as body temperature and blood pressure, but also highly complex neurotransmitter responses, with the time of day—is a major factor in major depressive disorder that requires therapeutic attention. Disruption of communication between the suprachiasmatic nucleus, the pineal gland, and the neurohormone melatonin it produces has been proposed as a major cause of these phenomena. Melatonin has been actively promoted (and marketed) as a "non-photic circadian resynchronizing agent" for the treatment of jet lag and shift work-related insomnia, and much data has been published on the antidepressant and anxiolytic effects of melatonin. Since oral bioavailability of melatonin is low, synthetic melatonin receptor agonists have been investigated, the most prominent of which is agomelatine.

[0187] Although agomelatine is approved for the treatment of depression, potential for the treatment of other indications has been suggested, including bipolar disorder, generalized anxiety disorder, Smith-Magenis syndrome, periventricular leukomalacia, and OCD.

[0188] Thus, in certain embodiments, the transmucosal therapeutic system of the invention is preferably for use in a method of treating major depression. Similarly, in certain other embodiments, the invention relates to a method of treating major depression, wherein the transmucosal therapeutic system of the invention is administered to a human patient. In other embodiments, the present invention relates to the use of the transmucosal therapeutic system of the invention for the manufacture of a medicament for treating major depression.

[0189] Treatment of depression or major depression, also referred to as major depressive disorder, may include treatment of conditions such as major depressive episodes, anxiety symptoms, sleep-wake cycle disturbances, daytime sleepiness, and insomnia (most patients with MDD, i.e., over 80%, suffer from depression in combination with insomnia) in patients with depression/MDD. In other embodiments, treatment in general may also refer to treatment of bipolar disorder, generalized anxiety disorder, Smith-Magenis syndrome, periventricular leukomalacia, or OCD.

[0190] As noted above, transmucosal delivery avoids presystemic metabolism and thus the transmucosal therapeutic system according to the invention is characterized by a lower risk of hepatotoxicity compared to oral dosage forms of agomelatine. Thus, there are no restrictions on the group of patients for treatment. Treatment includes treatment of human patients with or without liver failure, including patients with at least mild or at least moderate liver failure.

[0191] Also in certain embodiments, treatment with the transmucosal therapeutic system of the invention provides a reduction in at least one agomelatine-related side effect compared to an equivalent oral dose of agomelatine. As noted above, in certain specific embodiments, such agomelatine-related side effect is hepatotoxicity. The comparison with an equivalent oral dose of agomelatine is to be understood as a comparison with respect to the frequency and intensity of side effects in a clinical study using a dose of transmucosal and oral agomelatine that results in substantially the same plasma exposure of agomelatine. The incidence of at least one agomelatine-associated side effect, compared to an equivalent oral dose of agomelatine, may be reduced by at least about 30%, preferably by at least about 40%, more preferably by at least about 70% and most preferably by at least about 80%, and/or the intensity of at least one agomelatine-associated side effect, compared to an equivalent oral dose of agomelatine, may be reduced. The intensity of the side effect may be determined, for example, by classifying the side effects on a scale indicating "mild", "moderate" or "severe" intensity, and the reduction in intensity may be quantified by comparing the median intensity.

[0192] In any of the treatment options set forth for the above aspects, the transmucosal therapeutic system is preferably applied by applying the mucoadhesive layered structure to the oral mucosa of a human patient and maintaining it on the mucosa until it dissolves. In preferred embodiments, the transmucosal therapeutic system is applied by applying the mucoadhesive layered structure to the buccal, sublingual, gingival or palatal mucosa of the oral cavity of a human patient and maintaining it on the mucosa until it dissolves. In other preferred embodiments, the transmucosal therapeutic system is applied in the evening or at night before bedtime.

[0193] In another embodiment, the transmucosal therapeutic system according to the invention may also be intended for use in a method of reducing at least one agomelatine-associated side effect compared to an equivalent oral dose of agomelatine in a patient.

[0194] The invention also relates to a method for reducing at least one agomelatine-associated side effect in a patient undergoing treatment with oral agomelatine, comprising

a) discontinuation of agomelatine therapy; and

b) applying a transmucosal therapeutic system according to the invention to the oral mucosa of a human patient, wherein the transmucosal therapeutic system provides a reduction in at least one agomelatine-associated side effect compared to an equivalent oral dose of agomelatine.

[0195] In such a manner, the transmucosal therapeutic system can deliver an amount of agomelatine equivalent to the amount of agomelatine provided initially by oral agomelatine therapy.

METHOD OF MANUFACTURING

[0196] The invention further relates to a method for producing an agomelatine-containing layer for use in a transmucosal therapeutic system and a corresponding mucoadhesive layered structure comprising the agomelatine-containing layer and a corresponding transmucosal therapeutic system. [0197] According to the invention, the method for producing an agomelatine-containing layer comprises the following steps:

i) combining at least agomelatine and a soluble film-forming agent in a solvent to form a first coating composition;

ii) applying the coating composition to the release substrate; and

iii) drying the applied coating composition to form an agomelatine-containing layer.

[0198] In such a method, suitable soluble film-forming agents are the same as those mentioned previously. Thus, in certain embodiments, the soluble film-forming agent, when formed into a film having a weight per unit area of 50 g/ ^m2 , dissolves in water, in artificial or natural saliva, or in any other aqueous medium at 37°C and 150 rpm in less than 5 hours, preferably less than 3 hours, more preferably less than 2 hours and most preferably less than 1 hour, and/or in more than 5 seconds, preferably more than 30 seconds, more preferably more than 1 minute and most preferably more than 2 minutes, and/or in more than 5 seconds and less than 5 hours, preferably more than 30 seconds and less than 3 hours, more preferably more than 1 minute and less than 2 hours and most preferably more than 2 minutes and less than 1 hour.

[0199] The soluble film-forming agent may also be selected from the group consisting of polymers such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, graft copolymers based on polyethylene glycol, polyvinyl acetate and polyvinylcaprolactam, polyvinyl alcohol, copolymers of polyvinyl alcohol and polyethyleneglycol, copolymers of polyvinylpyrrolidone and polyvinyl acetate, polyethylene oxides, polyethyleneglycols, copolymers of methacrylic acid and methyl methacrylate and copolymers of methacrylic acid and ethyl methacrylate, natural film-forming agents such as shellac, pectin, gelatin, alginate, pullulan and starch derivatives, and any mixtures thereof. The soluble film-forming agent is preferably selected from the group consisting of polymers such as polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, graft copolymers based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam, polyvinyl alcohol, copolymers of polyvinyl alcohol and polyethylene glycol, copolymers of polyvinylpyrrolidone and polyvinyl acetate, polyethylene oxides, polyethylene glycols and any mixtures thereof, and is more preferably selected from the group consisting of polymers such as polyvinylpyrrolidone, hydroxypropyl cellulose, graft copolymers based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam, copolymers of polyvinylpyrrolidone and polyvinyl acetate and any mixtures thereof.

[0200] In particular embodiments, the soluble film-forming agent may be hydroxypropyl cellulose, preferably hydroxypropyl cellulose having a molecular weight of 50,000 to 1,500,000, and more preferably the soluble film-forming agent is hydroxypropyl cellulose having a molecular weight of 80,000, 95,000, 370,000, or 1,150,000.

[0201] In other particular embodiments, the soluble film-forming agent is a polyvinylpyrrolidone, preferably selected from soluble polyvinylpyrrolidone and, in particular, from polyvinylpyrrolidones having a K-value in a range selected from the group of ranges consisting of

from 9 to 15 and preferably from 10.2 to 13.8,

from 15 to 20 and preferably from 15.3 to 18.4,

from 20 to 27 and preferably from 22.5 to 27.0,

from 27 to 35 and preferably from 27.0 to 32.4 and

from 75 to 110 and preferably from 81.0 to 97.2.

[0202] In this manufacturing method, in step i), agomelatine may be dissolved or may be dispersed to obtain a coating composition.

[0203] Since agomelatine is poorly soluble in water and therefore there is a risk of recrystallization, it is preferable not to use water. Thus, in a preferred embodiment, the solvent does not contain water in an amount of more than 5% by weight, preferably more than 2% by weight, more preferably more than 1% by weight, and most preferably more than 0.5% by weight. On the other hand, depending on the solubility of the soluble film-forming agent for use in different solvents, the use of water may provide an advantage. Thus, in some embodiments, the solvent comprises water.

[0204] Thus, in the above-described method, the solvent preferably comprises an alcohol solvent selected from methanol, ethanol, isopropanol and mixtures thereof, and more preferably the solvent comprises ethanol or consists of ethanol.

[0205] The preferences for the soluble film-forming agent and the other constituents of the agomelatine-containing layer are the same as set out above. Thus, in one embodiment, step i) consists of combining at least agomelatine, a soluble film-forming agent and one or more excipients selected from the group consisting of fatty acids, sweeteners and flavourings in a solvent to obtain a coating composition. Also in step i), agomelatine can be used to combine in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorphic forms, in amorphous form, as a hydrate, a solvate, a hybrid type form of any of the above forms or a mixture thereof.

[0206] In step iii) drying is preferably carried out in one or more cycles at room temperature and/or at a temperature of 40-90°C, more preferably 60-80°C.

[0207] The mucoadhesive layered structure comprising the agomelatine-containing layer and the corresponding transmucosal therapeutic system can be manufactured using the above method using additional manufacturing steps such as stamping a separate transmucosal therapeutic system and packaging it, for example by sealing in a bag made of a base packaging material, as known to those skilled in the art. Such additional steps preferably result in the mucoadhesive layered structure or the transmucosal therapeutic system described in the previous sections.

[0208] In particular, the present invention also relates to agomelatine-containing layers, as well as mucoadhesive layered structures and a transmucosal therapeutic system obtainable (and/or produced) by the above-described method.

EXAMPLES

[0209] The present invention will now be described in more detail with reference to the accompanying examples. It should be understood that the following description is merely illustrative and should in no way be taken as limiting the present invention. The numerical values presented in the examples with respect to the amount of ingredients in the composition or the weight per unit area may vary slightly due to variability in the manufacturing process.

EXAMPLES 1A-1F Coating composition

[0210] The compositions of the agomelatine-containing coating compositions for the examples la If are summarized in Table 1.1 below. The compositions are based on weight percent, which is also shown in Table 1.1.

Obtaining the first coating composition (agomelatine-containing layer)

[0212] For Examples 1a-1f, the first beaker was loaded with agomelatine. Approximately one-third of the ethanol, eucalyptol, menthol, methyl salicylate, Novamint fresh peppermint flavor, Collifor RH 40, FD&C Red #40, and sucralose were added and mixed. Polyvinylpyrrolidone was added while mixing. The second beaker was loaded with distilled water. Polysorbate 80 was added and the mixture was mixed. The remaining ethanol was added while mixing. The contents of the two beakers were combined while stirring to produce a reddish solution with a visible crystalline precipitate.

Obtaining the second coating composition (protective layer)

[0213] For Examples 1b-1f, the beaker was charged with ethanol and then stirred. While stirring, ethylcellulose and castor oil were added to form a cloudy mixture.

[0214] The resulting protective composition was applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 10 min at room temperature and 20 min at 70°C. The coating thickness gave a mass per unit area of 20.9 g/ ^m2 (Ex. 1b, 1e and 1f) and 20.8 g/ ^m2 (Ex. 1c and 1d).

[0215] The release liner was removed prior to application of the protective layer to the agomelatine-containing layer.

Application of the first coating composition

[0216] The obtained agomelatine-containing first coating composition from Example 1a was applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 5 min at room temperature and 10 min at 50°C (Ex. 1a). In the case of Example 1a, the dried film is the final agomelatine-containing mucoadhesive laminate structure.

[0217] The coating thickness gave a mass per unit area of 57.9 g/ ^m2 (Ex. 1a).

[0218] The obtained agomelatine-containing first coating compositions of Examples 1b-1f were applied over the dried protective layer and dried for about 5 min at room temperature, 10 min at 50°C and 4 min at 90°C (Ex. 1b and Ex. 1f), for about 5 min at room temperature and 10 min at 50°C (Ex. 1c), for about 6 min at room temperature, 12 min at 50°C and 4 min at 90°C (Ex. 1d) and for about 5 min at room temperature, 10 min at 50°C and 2 min at 90°C (Ex. 1e), respectively.

[0219] The coating thickness yielded a mass per unit area of 57.9 g/ ^m2 (Ex. 1a), 53.9 g/ ^m2 (Ex. 1b), 34.9 g/ ^m2 (Ex. 1c), 72.1 g/ ^m2 (Ex. 1d), 50.5 g/ ^m2 (Ex. 1e) and 53.4 g/ ^m2 (Ex. 1f), respectively, for the agomelatine-containing layer.

Receiving a transmucosal therapeutic system (applies to all examples)

[0220] Individual transmucosal therapeutic systems were stamped from the agomelatine-containing mucoadhesive layer structure. This is advantageous when the PTP does not adhere sufficiently to the mucosa based on its physical properties alone and/or when the agomelatine-containing layer has pronounced angles (has a square or rectangular shape) to avoid excessive loss. The transmucosal therapeutic systems are then stamped and the transmucosal therapeutic systems are sealed in pouches made of primary packaging material, as is customary in the art, for example in a protective atmosphere with nitrogen gas purging.

Measurement of the rate of penetration through the mucous membrane

[0221] The penetrating amount and the corresponding mucosal penetration rates for the transmucosal therapeutic systems according to Examples la 1f were determined by in vitro experiments according to the OECD Guideline (adopted on April 13, 2004) using porcine mucosa (esophageal mucosa). A dermatome was used to obtain a 400 μm thick mucosa with an intact barrier function for all transmucosal therapeutic systems. Pieces of 0.798 ^cm2 were punched from the transmucosal therapeutic systems, applied to the mucosa and the mucosa with the transmucosal therapeutic system on the upper side was immersed in artificial saliva (the lower side was in contact with the receptor environment and the upper side was placed on the mucosa of 1.145 ^cm2 ). The amount of agomelatine penetrating the receptor environment (phosphate buffer solution, pH 7.4) at 37 ± 1°C was measured and the corresponding mucosal penetration rate was calculated. The results are presented in Table 1.2 and Fig. 1a.

Agomelatine consumption

[0223] Agomelatine uptake at 7 hours was calculated based on the cumulative penetration at 7 hours and the initial agomelatine content. The results are presented in Table 1.3 and Fig. 1b.

[0224] Table 1.3

[0225] In vitro experiments have shown good mucosal penetration rate and good uptake. In particular, it has been shown that example 1a without a protective layer has the advantage of rapid release of the active substance compared to examples with a protective layer. Examples 1b-1d demonstrate that increasing the mass per unit area (and therefore increasing the amount of active substance) also increases the penetration rate. Likewise, increasing the amount of active substance by changing the concentration of the active substance also leads to an increase in the penetration rate (examples 1e and 1f).

EXAMPLE 2

Obtaining a sample for penetration determination

[0226] In Example 2, the mucosal penetration rate was determined for pure agomelatine in natural saliva for the transmucosal therapeutic systems of Examples 1a and 3a. For this purpose, in Example 2, instead of the transmucosal therapeutic systems, an agomelatine-containing solution was prepared from 0.877 mg agomelatine in 300 μl of natural saliva.

Measurement of the rate of penetration through the mucous membrane

[0227] The penetrating amount and the corresponding mucosal penetration rates for the transmucosal therapeutic systems according to Examples 1a (containing some crystalline material), 3a (without crystals) and the agomelatine-containing solution described above (Ex. 2) were determined by in vitro experiments according to the OECD Guideline (adopted on 13 April 2004) using porcine mucosa (oesophageal mucosa). A dermatome was used to obtain a 400 μm thick mucosa with an intact barrier function for all transmucosal therapeutic systems. For Examples 1a and 3a, 0.798 ^cm2 pieces were punched from the transmucosal therapeutic systems and applied to the mucosa. The mucosa with the transmucosal therapeutic system was immersed on the upper side in 300 μl of natural saliva (the lower side was in contact with the receptor environment and the upper side was placed on the mucosa with an area of 1.595 cm ² ). In the case of Example 2, instead of applying the transmucosal therapeutic system and adding natural saliva, the above-described permeation sample was directly applied to the mucosa (also with an area of 1.595 cm ² ) so that the API content on the mucosa was about 0.55 mg/cm ² . The amount of agomelatine penetrating the receptor environment (phosphate buffer solution, pH 7.4) at a temperature of 37 ± 1 °C was measured and the corresponding permeation rate through the mucosa was calculated. The results are presented in Table 2.1 and Fig. 2a.

Agomelatine consumption

[0229] Agomelatine uptake at 7 hours was calculated based on the cumulative amount absorbed at 7 hours and the initial agomelatine content. The results are presented in Table 2.2 and Fig. 2b.

[0230]

[0231] In vitro experiments have shown good mucosal penetration and satisfactory uptake.

EXAMPLES OF ZA-ZN Coating composition

[0232] The compositions of the agomelatine-containing coating compositions for Examples 3a-3h are summarized in Tables 3.1 and 3.2 below. The compositions are based on weight percent, as also shown in Tables 3.1 and 3.2.

Obtaining the first coating composition (agomelatine-containing layer)

[0235] For example, agomelatine was loaded into a beaker. Ethanol, eucalyptol, menthol, methyl salicylate, Novamint fresh peppermint flavor, Colliphor RH 40, FD&C red #40, sucralose, and polysorbate 80 were added and the mixture was stirred. Polyvinylpyrrolidone was added while stirring to obtain a clear red solution after approximately 2.5 hours of stirring.

[0236] For Examples 3b-3h, the same agomelatine-containing layer coating composition was used, which was prepared as follows: A beaker was loaded with agomelatine. Ethanol, menthol, eucalyptol, methyl salicylate, Colliphor RH 40, FD&C Red No. 40, sucralose, and polysorbate 80 were added, and the mixture was then stirred. A clear solution was obtained. Polyvinylpyrrolidone was added, and after stirring overnight, Novamint fresh peppermint flavor was added dropwise to obtain a clear red solution.

Obtaining the second coating composition (protective layer)

[0237] For Example 3c, a beaker was loaded with ethylcellulose. Ethanol was added, and then the mixture was stirred. While stirring, castor oil was added to produce a cloudy mixture.

[0238] For Examples 3e-3h, the beaker was charged with ethanol. Purified water and kollidon were added and the mixture was then stirred to form a solution. Eudragit and glycerol were added while stirring to form a clear mixture. For Examples 3f and 3g, sodium hydroxide solution was added to obtain the pH indicated in Table 3.2 above.

[0239] The obtained second coating composition from Examples 3c and 3e-3h was applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 10 min at room temperature and 20 min at 70°C (Ex. 3c) and for about 5 min at room temperature, 10 min at 35°C and 2 min at 80°C (Ex. 3e-3h), respectively. The coating thickness yielded a mass per unit area of 12.3 g/ ^m2 (Ex. 3c), 26.8 g/ ^m2 (Ex. 3e), 26.0 g/ ^m2 (Ex. 3f), 20.5 g/ ^m2 (Ex. 3g), and 22.9 g/ ^m2 (Ex. 3h), respectively. In the case of Example 3d, a commercially available polyethylene terephthalate film with a thickness of 15 μm was used as the protective layer.

Application of the first coating composition

[0240] The obtained agomelatine-containing first coating composition from Examples 3a and 3b was applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 15 min at room temperature and 5 min at 70°C (Ex. 3a) or for about 5 min at room temperature, 10 min at 50°C and 2 min at 90°C (Ex. 3b), respectively. In the case of Examples 3a and 3b, the dried film is the final agomelatine-containing mucoadhesive laminate structure.

[0241] The obtained agomelatine-containing first coating compositions from Examples 3c and 3e 3h were applied over the dried protective layer and dried for about 5 min at room temperature, 10 min at 50°C and 2 min at 90°C (Ex. 3c and 3e-3h).

[0242] The coating thickness yielded a mass per unit area of 55.4 g/ ^m2 (Ex. 3a) and 50.0 g/ ^m2 (3b, 3c, and 3e 3h), respectively. The coating process 3d was identical to Examples 3b, 3c, and 3e-3h, except that the coating composition was applied to a 15 μm thick polyethylene terephthalate film, thereby providing the transmucosal therapeutic system with a protective layer (made of polyethylene terephthalate film).

Receiving a transmucosal therapeutic system

[0243] The transmucosal therapeutic systems of Examples 3b, 3c and 3e-3h were prepared by laminating the protective layers with the agomelatine-containing layers. The release liner was removed prior to lamination.

[0244] Additional steps (e.g. stamping of individual devices) were carried out as in Example 1.

Measurement of the rate of penetration through the mucous membrane

[0245] The penetrating amount and the corresponding mucosal penetration rates for the transmucosal therapeutic systems according to Examples 3a-3h were determined by in vitro experiments according to the OECD Guideline (adopted on April 13, 2004) using porcine mucosa (esophageal mucosa). A dermatome was used to obtain a 400 μm thick mucosa with an intact barrier function for all transmucosal therapeutic systems. Pieces of 0.522 ^cm2 were punched from the transmucosal therapeutic systems, applied to the mucosa, and the mucosa with the transmucosal therapeutic system on the upper side was immersed in artificial saliva (the lower side was in contact with the receptor environment and the upper side was placed on the mucosa of 1.145 ^cm2 ). The amount of agomelatine penetrating the receptor environment (phosphate buffer solution, pH 7.4) at 37 ± 1°C was measured and the corresponding mucosal penetration rate was calculated. The results are presented in Tables 3.3 and 3.4 and in Figs. 3a and 3b.

Agomelatine consumption

[0248] Agomelatine uptake at 6 hours was calculated based on the cumulative penetration at 6 hours and the initial agomelatine content. The results are presented in Table 3.5 and Fig. 3c.

[0250] In vitro experiments have shown good mucosal penetration and good uptake.

EXAMPLES 4A-4F Coating composition

[0251] The compositions of the agomelatine-containing coating compositions for Examples 4a-4f are summarized in Tables 4.1 and 4.2 below. The compositions are based on weight percent, as also shown in Tables 4.1 and 4.2.

[0252] Table 4.1

Obtaining the first coating composition (agomelatine-containing layer)

[0254] For Example 4a, a beaker was loaded with agomelatine. Ethanol, menthol, eucalyptol, methyl salicylate, Colliphor RH 49, FD&C Red No. 40, sucralose, and polysorbate 80 were added and the mixture was stirred. While stirring, polyvinylpyrrolidone and Novamint fresh peppermint flavor were added to form a viscous mixture.

[0255] For Example 4b, a beaker was loaded with ethanol. Eucalyptol, menthol, methyl salicylate, Colliphor RH 49, FD&C Red No. 40, sucralose, and polysorbate 80 were added, and the mixture was then stirred. While stirring, hydroxypropyl cellulose, Novamint fresh peppermint flavor, and agomelatine were added to form a viscous mixture.

[0256] For Example 4, a beaker was loaded with ethanol. Eucalyptol, menthol, methyl salicylate, Novamint fresh peppermint flavor, Colliphor RH 49, FD&C red #40, sucralose, and polysorbate 80 were added, and the mixture was then mixed. Soluplus, Miglyol 812, and agomelatine were added while mixing to obtain a low viscosity mixture.

[0257] For Examples 4d, 4e, and 4f, a beaker was loaded with agomelatine. Ethanol, eucalyptol, menthol, methyl salicylate, Novamint fresh peppermint flavor, Collifor RH 49, FD&C Red No. 40, sucralose, and polysorbate 80 were added and the mixture was stirred. While stirring, propylene glycol was added to form a viscous mixture.

Obtaining the second coating composition (protective layer)

[0258] For Examples 4e and 4f, the beaker was loaded with ethanol. Purified water and FD&C Blue No. 1 were added, and then the mixture was stirred. While stirring, kollidon, eudragit, and glycerin were added to form a mixture.

[0259] The resulting second coating composition from Examples 4e and 4f was applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 5 min at room temperature, 10 min at 35°C and 2 min at 80°C. The coating thickness gave a weight per unit area of 47.4 g/ ^m2 .

Obtaining an adhesive composition

[0260] For Example 4, a beaker was loaded with ethanol. Purified water and menthol were added, and the mixture was then stirred. While stirring, hydroxyethylcellulose, castor oil, and polysorbate 80 were added to form a cloudy mixture.

[0261] For Example 4f, a beaker was charged with ethanol. Menthol was added, and then the mixture was stirred. While stirring, hydroxypropyl cellulose and castor oil were added to form a viscous mixture.

[0262] The resulting adhesive composition of Examples 4e and 4f was applied over the above-described protective layer and dried for about 5 min at room temperature, 10 min at 50°C, and 2 min at 90°C. The coating thickness yielded a mass per unit area of 25.2 g/ ^m2 (Ex. 4e) and 23.5 g/ ^m2 (Ex. 4f), respectively. Pieces of 1.1 ^cm2 in size were stamped from the adhesive protective layer.

Application of the first coating composition

[0263] The obtained agomelatine-containing coating composition of Examples 4a-4f was applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 5 min at room temperature, 10 min at 50°C and 2 min at 90°C (Ex. 4a-4c) and for about 5 min at room temperature, 15 min at 50°C and 2 min at 90°C (Ex. 4d-4f), respectively. The coating thickness gave a mass per unit area of 49.5 g/m ² (Ex. 4a), 48.6 g/m ² (Ex. 4b), 58.5 g/m ² (Ex. 4c) and 115.4 g/m ² (Ex. 4d, Ex. 4e and Ex. 4f), respectively.

[0264] In the case of Examples 4a-4d, the dried film is the final agomelatine-containing mucoadhesive laminate structure. In the case of Examples 4e and 4f, pieces of 0.28 ^cm2 in size were punched out of the dried film and laminated with the above-described pieces of adhesive backing layer so that the backing layer extends uniformly on all sides of the agomelatine-containing layer, thereby obtaining the agomelatine-containing mucoadhesive laminate structure.

Receiving a transmucosal therapeutic system

[0265] See example 1.

Measurement of the rate of penetration through the mucous membrane

[0266] The penetrating amount and the corresponding mucosal penetration rates for the transmucosal therapeutic systems according to Examples 4a-4e were determined by in vitro experiments according to the OECD Guideline (adopted on April 13, 2004) using porcine mucosa (esophageal mucosa). A dermatome was used to obtain a 400 μm thick mucosa with an intact barrier function for all transmucosal therapeutic systems. Pieces of 0.522 ^cm2 area, stamped from the transmucosal therapeutic systems of Examples 4a-4d and the above-described agomelatine-containing mucoadhesive layered structures of Examples 4e and 4f, were applied to the mucosa and the mucosa with the transmucosal therapeutic system on the upper side was immersed in artificial saliva (the lower side was in contact with the receptor environment, and the upper side was placed on the mucosa of 1.145 ^cm2 area). The amount of agomelatine penetrating into the receptor environment (phosphate buffer solution, pH 7.4) at a temperature of 37 ± 1 °C was measured and the corresponding permeation rate through the mucosa was calculated. The results are presented in Table 4.3 and in Fig. 4a.

Agomelatine consumption

[0268] Agomelatine uptake at 6 hours was calculated based on the cumulative amount absorbed at 6 hours and the initial agomelatine content. The results are presented in Table 4.4 and Fig. 4b.

[0270] In vitro experiments have shown a good mucosal penetration rate and satisfactory uptake. In particular, the mucosal penetration is unexpectedly high compared to the same formulations having a protective layer (Example 4d compared to Examples 4e and 4f). Hydroxypropyl cellulose has also been shown to have functional characteristics similar to polyvinylpyrrolidone (see Examples 4a and 4b), which are even better than in the case of systems having a protective layer, which have more than twice the active substance content (Examples 4a and 4b compared to 4e and 4f).

EXAMPLES 5A-5D Coating composition

[0271] The compositions of the agomelatine-containing coating compositions for Examples 4b and 5a-5d are summarized in Tables 4.1 above and Table 5.1 below. The compositions are based on weight percent, as also shown in Tables 4.1 and 5.1.

Obtaining the first coating composition (agomelatine-containing layer)

[0273] For Examples 5a and 5b, a beaker was loaded with agomelatine. Vanilla flavor, ethanol, sucralose, sodium saccharin, oleic acid, FD&C yellow #5, and hydroxypropyl cellulose were added, and the mixture was then stirred to obtain a clear mixture.

[0274] For example 5 s, the beaker was loaded with agomelatine. Polyvinyl alcohol was added and the mixture was stirred to produce a white mixture.

Obtaining the second coating composition (protective layer)

[0275] For Examples 5b and 5c, the beaker was loaded with purified water or ethanol, respectively. FD&C Red No. 40 and hydroxypropyl cellulose were added while stirring to form a cloudy mixture.

[0276] For Example 5d, a beaker was loaded with ethanol. Purified water and FD&C Blue No. 1 were added, and then the mixture was stirred. While stirring, kollidon, eudragit, and glycerin were added to obtain a mixture.

[0277] The obtained second coating composition from Examples 5b, 5c and 5d was applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 15 min at 40°C and 15 min at 70°C (Ex. 5b) and about 10 min at room temperature, 15 min at 40°C and 10 min at 70°C (Ex. 5c) and about 5 min at room temperature, 10 min at 35°C and 2 min at 80°C (Ex. 5d), respectively. The coating thickness yielded a mass per unit area of 105.1 g/ ^m2 (Ex. 5b), 99.6 g/ ^m2 (Ex. 5c) and 78.3 g/ ^m2 (Ex. 5d), respectively. In the case of Example 5c, pieces measuring 0.8 ^cm2 were stamped from the dried protective layer.

Obtaining an adhesive composition

[0278] For Example 5d, a beaker was loaded with ethanol. Purified water and methanol were added, and the mixture was then stirred. While stirring, hydroxyethyl cellulose, castor oil, and polysorbate 80 were added to obtain a homogeneous mixture.

[0279] The resulting adhesive composition of Example 5d was applied over the above-described protective layer and dried for approximately 5 min at room temperature, 10 min at 50°C, and 2 min at 90°C. The coating thickness yielded a mass per unit area of 95.6 g/ ^m2 (Ex. 5d).

[0280] Pieces measuring 0.8 ^cm2 were stamped from the adhesive protective layer. Application of the first coating composition

[0281] The obtained agomelatine-containing coating composition of Examples 5a, 5c and 5d was applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 10 min at room temperature, 15 min at 40°C and 10 min at 70°C (Ex. 5a) and 5 min at 70°C (Ex. 5c) and for about 5 min at room temperature, 15 min at 50°C and 2 min at 90°C (Ex. 5d), respectively. In the case of Example 5a, the dried film is the final agomelatine-containing mucoadhesive laminate structure. In the case of Examples 5c and 5d, pieces of 0.28 ^cm2 in size were punched out from the dried film and laminated with the above-described pieces of the protective layer or the adhesive protective layer so that the protective layer extended uniformly on all sides of the agomelatine-containing layer, thereby obtaining an agomelatine-containing mucoadhesive laminate structure.

[0282] The resulting agomelatine-containing first coating composition from Example 5b was applied over the dried protective layer and dried for approximately 10 min at room temperature, 15 min at 40°C and 10 min at 70°C.

[0283] The coating thickness yielded a mass per unit area of 95.7 g/ ^m2 (Ex. 5a), 95.9 g/ ^m2 (Ex. 5b), 82.9 g/ ^m2 (Ex. 5c), and 115.4 g/ ^m2 (5d), respectively. Obtaining a transmucosal therapeutic system

[0284] See example 1.

Measurement of the rate of penetration through the mucous membrane

[0285] The penetrating amount and the corresponding mucosal penetration rates for the transmucosal therapeutic systems according to Examples 4b and 5a-5d were determined by in vitro experiments according to the OECD Guideline (adopted on 13 April 2004) using porcine mucosa (esophageal mucosa). A dermatome was used to obtain a 400 μm thick mucosa with an intact barrier function for all transmucosal therapeutic systems. Pieces of 0.28 ^cm2 (Example 4b) and 0.8 ^cm2 (Examples 5a and 5b) stamped from the transmucosal therapeutic systems and the agomelatine-containing mucoadhesive layered structures described in Examples 5c and 5d above were applied to the mucosa and the mucosa with the transmucosal therapeutic system on the upper side was immersed in artificial saliva (the lower side was in contact with the receptor environment and the upper side was placed on a mucosa of 1.145 ^cm2 ). The amount of agomelatine penetrating the receptor environment (phosphate buffer solution, pH 7.4) at 37 ± 1 °C was measured and the corresponding mucosal penetration rate was calculated. The results are presented in Table 5.2 and Fig. 5a.

[0286] Table 5.2

Agomelatine consumption

[0287] Agomelatine uptake at 6 hours was calculated based on the cumulative penetration at 8 hours and the initial agomelatine content. The results are presented in Table 5.3 and Fig. 5b.

[0289] In vitro experiments showed good mucosal penetration rates and satisfactory uptake. Although all formulations demonstrated a good penetration profile, comparison of Example 4b (release area 0.28 ^cm2 , mucosal area 1.145 ^cm2 ) with Examples 5a and 5b (release area 0.8 ^cm2 , mucosal area 1.145 ^cm2 ) demonstrates the important role of total mucosal area for penetration in open systems.

EXAMPLES 6A-6D

Coating composition

[0290] The compositions of the agomelatine-containing coating compositions for Examples 6a-6d are summarized in Table 6.1 below. The compositions are based on weight percent, which is also shown in Table 6.1.

Manufacturing of coating composition

[0292] For Examples 6a-6c, the beaker was loaded with agomelatine. Vanilla flavor, ethanol, sucralose, Na saccharin, and oleic acid (Ex. 6b and 6c) were added, and the mixture was then stirred. While stirring, hydroxypropyl cellulose was added to obtain a clear solution.

[0293] For Example 6d, a beaker was loaded with agomelatine. Vanilla flavor, ethanol, sucralose, Na saccharin, and oleic acid were added, and then the mixture was stirred. While stirring, titanium dioxide and hydroxypropyl cellulose were added to obtain a white mixture.

Application of the coating composition

[0294] The obtained agomelatine-containing coating composition of Examples 6a-6d was applied to a polyester film (siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 10 min at room temperature, 15 min at 40°C and 10 min at 70°C. The coating thickness gave a mass per unit area of 93.8/ ^m2 (Ex. 6a), 93.6 g/ ^m2 (Ex. 6b), 94.3 g/ ^m2 (Ex. 6c) and 98.3 g/ ^m2 (Ex. 6d), respectively. The dried film was not further laminated with an additional protective layer, as was the final agomelatine-containing mucoadhesive laminate structure.

Receiving a transmucosal therapeutic system

[0295] See example 1.

Measurement of the rate of penetration through the mucous membrane

[0296] The penetrating amount and the corresponding mucosal penetration rates for the transmucosal therapeutic systems according to Examples 6a-6d were determined by in vitro experiments according to the OECD Guideline (adopted April 13, 2004) using porcine mucosa (esophageal mucosa). A dermatome was used to obtain a 400 μm thick mucosa with an intact barrier function for all transmucosal therapeutic systems. Pieces of 0.524 ^cm2 were punched from the transmucosal therapeutic systems, applied to the mucosa, and the mucosa with the transmucosal therapeutic system on the upper side was immersed in artificial saliva (the lower side was in contact with the receptor environment and the upper side was placed on the mucosa of 1.145 ^cm2 ). The amount of agomelatine penetrating the receptor environment (phosphate buffer solution, pH 7.4) at 37 ± 1°C was measured and the corresponding mucosal penetration rate was calculated. The results are presented in Table 6.2 and Fig. 6a.

Agomelatine consumption

[0298] Agomelatine uptake at 6 hours was calculated based on the cumulative penetration at 6 hours and the initial agomelatine content. The results are presented in Table 6.3 and Fig. 6b.

[0299]

[0300] In vitro experiments have shown a good mucosal penetration rate and satisfactory uptake. These examples show that a satisfactory penetration profile can be obtained even at a lower concentration of agomelatine and that the functional characteristics of hydroxypropylcellulose are comparable to polyvinylpyrrolidone. It has also been shown that some fatty acid probably also increases the penetration rate (see example 6b in combination with examples 6a and 6c).

EXAMPLES 7A-7G

Coating composition

[0301] The compositions of the agomelatine-containing coating compositions for Examples 4b and 6b-6d are summarized in Tables 4.1 and 6.1 above. The compositions of the agomelatine-containing coating compositions for Examples 7a-7g are summarized in Tables 7.1 and 7.2 below. The compositions are based on weight percent, as also indicated in these tables.

[0303]

Obtaining the first coating composition (agomelatine-containing layer)

[0304] The first coating composition for Example 7g was prepared in analogy to Example 4b.

[0305] For Examples 7a-7c, the beaker was loaded with agomelatine. Ethanol was added and then the mixture was stirred. While stirring, povidone K90 and povidone K30 (Ex. 7a), hydroxypropyl cellulose (Ex. 7b) and povidone K90 (Ex. 7c), respectively, were added to form a viscous mixture.

[0306] For example 7d, a beaker was loaded with agomelatine. Polyvinyl alcohol was added and the mixture was stirred to produce a white mixture.

[0307] For Example 7e, a beaker was loaded with polyvinyl alcohol. Purified water was added, and the mixture was then stirred and heated to 95°C. Vanilla flavoring, sucralose, Na saccharin, oleic acid, and agomelatine were added while stirring to form a viscous mixture.

[0308] For Example 7f, a beaker was loaded with agomelatine. Ethanol, vanilla flavor, sucralose, sodium saccharin, oleic acid, and FD&C yellow #5 were added, and the mixture was then stirred. While stirring, hydroxypropyl cellulose was added to form a viscous mixture.

Application of the first coating composition

[0309] The obtained agomelatine-containing coating composition of Examples 7a-7f was applied to a polyester film (siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 10 min at room temperature, 15 min at 40°C and 10 min at 70°C (Ex. 7a-7c and 7f) and 5 min at 70°C (Ex. 7d) and 15 min at 70°C (Ex. 7e), respectively. The thickness of the coating gave a mass per unit area of 104.4 g/m ² (Ex. 7a), 103.2 g/m ² (Ex. 7b), 100.7 g/m ² (Ex. 7c), 82.9 g/m ² (Ex. 7d), 98.4 g/m ² (Ex. 7e) and 95.7 g/m ² (Prov. 71).

[0310] The resulting agomelatine-containing coating composition from Example 7g was applied to a polyester film (siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 5 min at room temperature, 15 min at 50°C and 2 min at 90°C. The coating thickness gave a mass per unit area of 115.4 g/ ^m2 .

[0311] Pieces measuring 0.28 ^cm2 were punched out from the dried agomelatine-containing layers.

Obtaining the second coating composition (protective layer)

[0312] For Examples 7a-7d and 7g (same backing layer) and for Examples 7e and 7f (same backing layer), the beaker was loaded with vanilla flavor. Sucralose, saccharin, oleic acid, ethanol, purified water, FD&C red and polyethylene glycol (Examples 7a-7d and 7g) and glycerin (Examples 7e and 7f), respectively, were added and the mixture was stirred. Kollidon and Eudragit were added while stirring to obtain a clear solution.

[0313] The resulting second coating composition was applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 10 min at room temperature, 15 min at 40°C and 5 min at 70°C. The coating thickness gave a mass per unit area of 92.2 g/ ^m2 (7a-7d and 7g) and 81.2 g/ ^m2 (examples 7e and 7f), respectively.

[0314] Pieces measuring 0.8 ^cm2 were stamped from the dried protective layers. Obtaining a transmucosal therapeutic system

[0315] In the case of Examples 7a, 7d and 7g, pieces of agomelatine-containing layers were attached to pieces of the respective protective layers using small amounts of 23.5% PVP90 solution in ethanol, such that the protective layer extended uniformly on all sides of the agomelatine-containing layer, and then laminated to obtain an agomelatine-containing mucoadhesive layered structure. In the case of Examples 7e and 7f, the dried film was laminated with the respective protective layer, also such that the protective layer extended uniformly on all sides of the agomelatine-containing layer, to obtain an agomelatine-containing mucoadhesive layered structure.

[0316] Additional steps (e.g. stamping of individual devices) were carried out as in Example 1.

Measurement of the rate of penetration through the mucous membrane

[0317] The permeation amount and the corresponding mucosal permeation rates for the transmucosal therapeutic systems according to Examples 4b, 6b-6d and 7a-7g were determined by in vitro experiments according to the OECD Guideline (adopted on 13 April 2004) using porcine mucosa (esophageal mucosa). A dermatome was used to obtain a 400 μm thick mucosa with an intact barrier function for all transmucosal therapeutic systems. The above-described agomelatine-containing mucoadhesive layered structures were applied to the mucosa and the mucosa with the transmucosal therapeutic system on the upper side was immersed in artificial saliva (the lower side was in contact with the receptor environment and the upper side was placed on a mucosa area of 1.145 ^cm2 ). The amount of agomelatine penetrating the receptor environment (phosphate buffer solution, pH 7.4) at 37 ± 1°C was measured and the corresponding mucosal penetration rate was calculated. The results are presented in Tables 7.3 and 7.4 and in Figs. 7a and 7b.

Agomelatine consumption

[0320] Agomelatine uptake at 4 hours was calculated based on the cumulative amount absorbed at 4 hours and the initial agomelatine content. The results are presented in Table 7.5 and Fig. 7c.

[0322] In vitro experiments have shown good mucosal penetration rates and satisfactory absorption. These examples show that a satisfactory penetration profile can be obtained even at lower agomelatine concentrations and that the functional characteristics of hydroxypropyl cellulose and polyvinyl alcohol are comparable to polyvinylpyrrolidone (see examples 7b, 7c and 7d).

EXAMPLES 8A-8C

Coating composition

[0323] The compositions of the agomelatine-containing coating compositions for Examples 4b, 8a and 8b are summarized in Tables 4.1 above and 8.1 below. The compositions are based on weight percent, as also shown in Tables 4.1 and 8.1.

[0324]

Obtaining the first coating composition (agomelatine-containing layer)

[0325] For Examples 8a-8c, the beaker was loaded with agomelatine. Ethanol, eucalyptol, menthol, methyl salicylate, Novamint fresh peppermint flavor, Colliphor RH 40, sucralose, FD&C red #40, and polysorbate 80 were added and the mixture was mixed. Povidone was added while mixing to form a viscous mixture.

Application of the first coating composition

[0326] The obtained agomelatine-containing coating composition from Examples 8a-8c was applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 10 min at room temperature, 15 min at 50°C and 2 min at 90°C. The coating thickness gave a mass per unit area of 109.7 g/ ^m2 .

[0327] In the case of Example 8a, the dried film is the final agomelatine-containing mucoadhesive layer structure. In the case of Examples 8b and 8c, pieces of 1.6 cm ² in size were punched out from the dried agomelatine-containing layers.

Obtaining the second coating composition (protective layer)

[0328] For Example 8b, a beaker was loaded with ethanol. FD&C Green No. 3 was added, and then the mixture was stirred. While stirring, ethylcellulose N50F, castor oil, and glycerin were added to form a mixture.

[0329] The second coating composition of Example 8c was prepared in analogy to Example 5d above.

[0330] The resulting second coating composition was applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 10 min at room temperature and 20 min at 70°C (Ex. 8b) and about 5 min at room temperature, 10 min at 35°C and 2 min at 80°C (Ex. 8c). The coating thickness gave a mass per unit area of 19.2 g/ ^m2 (Ex. 8b) and 78.3 g/ ^m2 (Ex. 8c), respectively.

Obtaining an adhesive composition

[0331] The beaker was loaded with ethanol. Purified water and menthol were added, and the mixture was then stirred. While stirring, hydroxyethyl cellulose, castor oil, and polysorbate 80 were added to obtain a homogeneous mixture.

[0332] The resulting adhesive composition was applied over the dried protective layer and dried for about 5 min at room temperature, 10 min at 50°C, and 2 min at 90°C. The coating thickness yielded a mass per unit area of 42.9 g/ ^m2 (Ex. 8b) and 95.7 g/ ^m2 (Ex. 8c), respectively. Pieces of 5.5 ^cm2 in size were stamped from the dried adhesive protective layer.

Receiving a transmucosal therapeutic system

[0333] In the case of Examples 8b and 8c, the dried film was laminated with a suitable adhesive backing layer to form an agomelatine-containing mucoadhesive laminate structure.

[0334] Additional steps (e.g. stamping of individual devices) were carried out as in Example 1.

In vivo studies with Goettingens minipigs

[0335] To evaluate the delivery of agomelatine, in vivo experiments were performed in Goettingens minipigs (female, approximately 6-7 months old, body weight at study entry 13.8-14.3 kg). Four minipigs were used. The transmucosal therapeutic systems of Examples 8a, 8b and 8c, prepared as described above, were applied to the buccal mucosa of one animal for Examples 8a and 8b and two animals for Example 8c (one system per animal). The total use time of the transmucosal therapeutic systems was approximately 4 hours (after 4 hours, the application area was cleaned to remove potential residues of the transmucosal therapeutic system). No residues were observed for Ex. 8a and negligible residues were observed for Ex. 8b and 8c with a protective layer.

[0336] During the study, the miniature pigs were kept under anesthesia.

[0337] Blood samples were collected at 8 time points following application of the transmucosal therapeutic systems. Samples were obtained at 0 (prior to treatment), 0.5, 1, 1.5, 2, 4 (immediately prior to removal of the test product), 5, and 8 hours. Plasma samples were analyzed in accordance with the OECD Principles of Good Laboratory Practice (revised 1997). These principles are consistent with other international GLP guidelines.

[0338] Plasma agomelatine concentrations in minipig animals were determined using a validated liquid-liquid extraction followed by LC-MS/MS analysis. Measurements for all pre-treatment samples were below the limit of quantification (0.100 ng/mL).

[0339] The measured plasma concentrations of agomelatine are summarized in Table 8.2 and illustrated in Fig. 8a.

[0340] Additionally, the mucosal condition was determined microscopically and the Draize score was obtained based on the scoring scheme below, which is in accordance with the OECD Guideline for Testing Chemicals No. 404, adopted on July 28, 2015: "Acute Dermal Irritation/Corrosion", immediately after removal of the PRP, 4 hours after application and cleaning of the side of application of the PRP.

[0341] None of the formulations demonstrated any irritant effects 4 hours after removal of the transmucosal therapeutic system (see Table 8.2).

[0343] The maximum plasma concentration was measured 2-4 hours after the start of treatment and ranged from 9.0 to 11.8 ng/mL for the PTP according to Ex. 8b and 8c with a protective layer and 57.2 ng/mL for the PTP according to Ex. 8a without a protective layer. In the case of the transmucosal therapeutic system according to Ex. 8a without a protective layer, very high PK data values can be achieved, which can be explained by the open system, which allows delivery of the API through the mucosa of the entire oral cavity. The high delivery rate still provides an advantage, since the patch size and/or the concentration of the active substance can be lower compared to systems containing a protective layer. Transmucosal therapeutic systems with a protective layer, although limited by a penetration area of 1.6 cm ² , show a lower, but still high, penetration over 4 hours. Since agomelatine was quantifiable 4 hours after removal of transmucosal therapeutic systems with higher PK data, residual agomelatine could potentially be present in the mucosa.

EXAMPLES 9A-9F Coating composition

[0344] The compositions of the agomelatine-containing coating compositions for Examples 4b and 9a 9f are summarized in Tables 4.1 above and 9.1 below. The compositions are based on weight percent, as also shown in Tables 4.1 and 9.1.

Obtaining the first coating composition (agomelatine-containing layer)

[0346] For the TiO ₂ solution, the beaker was charged with 2.80 g of TiO ₂ . Oleic acid was added, and

The mixture was then stirred to obtain a TiO ₂ solution.

[0347] For Examples 9b, 9c and 9d, the beaker was loaded with vanilla flavor. Sucralose, saccharin Na, ethanol, hydroxypropylcellulose GF, hydroxypropylcellulose EF, carbopol solution and agomelatine were added and the mixture was then stirred. While stirring, the _TiO2 solution was added to form a viscous mixture.

[0348] For Example 9a, a beaker was loaded with vanilla flavoring. Sucralose, Na saccharin, agomelatine, and ethanol were added, and the mixture was then stirred. While stirring, a TiO ₂ solution and hydroxypropyl cellulose were added to form a viscous mixture.

[0349] For Examples 9e and 9f, the beaker was loaded with vanilla flavor. Sucralose, Na saccharin, and ethanol were added and the mixture was then stirred. While stirring, carbopol solution, ethylcellulose, hydroxypropylcellulose, agomelatine, and _TiO2 solution were added to form a viscous mixture.

Application of the first coating composition

[0350] The obtained agomelatine-containing coating composition was applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for about 10 min at room temperature, 15 min at 40°C and 10 min at 70°C. The coating thickness gave a mass per unit area of 117.0 g/ ^m2 (Ex. 9a-9d), 123.5 g/ ^m2 (Ex. 9e) and 117.5 g/ ^m2 (Ex. 9f), respectively.

[0351] In the case of examples 9a and 9b, the dried film is the final agomelatine-containing mucoadhesive layered structure. In the case of example 9d, a piece measuring 0.28 cm ² was punched out from the dried agomelatine-containing layers.

Obtaining the second coating composition (protective layer)

[0352] For Examples 9c-9f, the beaker was loaded with vanilla flavor. Sucralose, Na saccharin, oleic acid, FD&C red #40, ethanol, and purified water were added and the mixture was then stirred. While stirring, hydroxypropyl cellulose and hydroxyethyl cellulose were added to form a viscous mixture.

[0353] The resulting protective composition was applied twice on top of the dried agomelatine-containing layer (for Examples 9c, 9e and 9f) or on a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) (for Example 9d) and dried for about 10 min at room temperature, 15 min at 50°C and 10 min at 80°C. The coating thickness gave a total weight per unit area (agomelatine-containing layer and protective layer) of 382 g/ ^cm2 (Ex. 9c), 272.2 g/ ^m2 (Ex. 9d) or 388.1 g/ ^m2 (Ex. 9e and 9f).

[0354] For Examples 9c, 9e and 9f, 0.28 ^cm2 pieces were punched out from the dried layers to obtain an agomelatine-containing mucoadhesive layered structure.

[0355] In the case of Example 9d, a 0.28 ^cm2 piece was punched out from the protective layer and attached to the corresponding agomelatine-containing layer using a small amount of the second coating composition so that the protective layer extended uniformly on all sides of the agomelatine-containing layer, thereby obtaining an agomelatine-containing mucoadhesive layered structure.

Receiving a transmucosal therapeutic system

[0356] See example 1.

Measurement of the rate of penetration through the mucous membrane

[0357] The penetrating amount and the corresponding mucosal penetration rates for the transmucosal therapeutic systems according to Examples 4b and 9a-9f were determined by in vitro experiments according to the OECD Guideline (adopted on 13 April 2004) using porcine mucosa (esophageal mucosa). A dermatome was used to obtain a 400 μm thick mucosa with an intact barrier function for all transmucosal therapeutic systems. Pieces of 0.28 ^cm2 area, punched out from the transmucosal therapeutic systems of Examples 9a and 9b and the agomelatine-containing mucoadhesive laminated structures described above, were applied to the mucosa and the mucosa with the transmucosal therapeutic system on the upper side was immersed in artificial saliva (the lower side was in contact with the receptor environment, and the upper side was placed on the mucosa of 1.145 ^cm2 area). The amount of agomelatine penetrating into the receptor environment (phosphate buffer solution, pH 7.4) at a temperature of 37 ± 1 °C was measured and the corresponding permeation rate through the mucosa was calculated. The results are presented in Tables 9.2 and 9.3 and in Fig. 9a.

[0358] Table 9.2

Agomelatine consumption

[0360] Agomelatine uptake at 4 hours was calculated based on the cumulative amount absorbed at 4 hours and the initial agomelatine content. The results are presented in Table 9.4 and Fig. 9c.

[0362] In vitro experiments have shown good mucosal penetration rates and good uptake. These examples again demonstrate that open systems without a protective layer provide increased delivery of the active substance compared to systems with protective layers.

Storage stability measurements

[0363] For Examples 9a and 9c, long-term storage stability testing was performed under different test conditions, i.e., storage at 25°C and 60% relative humidity (RH) and at 40°C and 75% RH. Samples were taken from the transmucosal therapeutic systems after 3, 6, 9 and 12 months of storage at 25°C and 60% RH and after 3 and 6 months of storage at 40°C and 75% RH, the water and ethanol contents were determined, and the amount of agomelatine as well as various possible degradation products was determined by a specific quantitative HPLC method based on the agomelatine content calculated from the (actual) mass per unit area of the tested transmucosal therapeutic systems. The results are presented in Tables 9.5-9.8 and in Figs. 9c and 9d.

[0368] Stability data show that initial stability as well as stability on storage are excellent for examples 9a and 9c, both in terms of the amount of agomelatine (in particular in terms of the amount of agomelatine remaining after storage) and the total possible degradation products.

DISSOLUTION EXPERIMENT 10

[0369] As set out in more detail above, the soluble film-forming agent is preferably soluble, dispersible or otherwise disintegrating in an aqueous medium such as water, and on the other hand, film-forming agents that are soluble in, for example, ethanol are also preferred.

[0370] To observe the dissolution behavior of potential film-forming agents, 10 wt% (+/- 0.1% point) mixtures of the polymer were prepared in water, in ethanol, or in a 1:1 water/ethanol mixture and the dissolution behavior was recorded. Viscosity and other observations were also recorded. The results are presented in Table 10.1 below.

WATER ABSORPTION EXPERIMENT 11

[0372] Some soluble film-forming agents exhibit hygroscopic behavior. To evaluate the absorption of water over time, various coating compositions were prepared and films were produced by applying the coating compositions and drying the coated layers. The films were stored for 7 days at room temperature, either opened or packaged in a sealed bag. Details of the composition, drying conditions for the coated films, and the results obtained are presented in Table 11.1 below.

The invention relates, in particular, to the following additional points:

1. A transmucosal therapeutic system for the transmucosal administration of agomelatine, having a mucoadhesive layered structure, wherein said mucoadhesive layered structure comprises

A) agomelatine-containing layer containing

i) agomelatine; and

ii) soluble film-forming agent.

2. The transmucosal therapeutic system according to item 1,

moreover

the soluble film-forming agent, when formed into a film having a weight per unit area of 30 to 100 g/ ^m2 or 50 g/ ^m2 , dissolves in water, in artificial or natural saliva, or in any other aqueous medium at 37°C and 150 rpm in less than 5 hours, less than 3 hours, less than 2 hours, or less than 1 hour, or in more than 5 seconds, more than 30 seconds, more than 1 minute, or more than 2 minutes, or in more than 5 seconds and less than 5 hours, in more than 30 seconds and less than 3 hours, more than 1 minute and less than 2 hours, or in more than 2 minutes and less than 1 hour.

3. The transmucosal therapeutic system according to item 1 or item 2,

moreover

the soluble film-forming agent is selected from the group consisting of polymers such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, graft copolymers based on polyethyleneglycol, polyvinyl acetate and polyvinylcaprolactam, polyvinyl alcohol, copolymers of polyvinyl alcohol and polyethyleneglycol, copolymers of polyvinylpyrrolidone and polyvinyl acetate, polyethylene oxides, polyethylene glycols, copolymers of methacrylic acid and methyl methacrylate and copolymers of methacrylic acid and ethyl methacrylate, and natural film-forming agents such as shellac, pectin, gelatin, alginate, pullulan and starch derivatives, and any mixtures thereof.

4. The transmucosal therapeutic system according to item 3,

moreover

the soluble film-forming agent is selected from the group consisting of polymers such as polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, graft copolymers based on polyethyleneglycol, polyvinyl acetate and polyvinylcaprolactam, polyvinyl alcohol, copolymers of polyvinyl alcohol and polyethyleneglycol, copolymers of polyvinylpyrrolidone and polyvinyl acetate, polyethylene oxides, polyethyleneglycols and any mixtures thereof.

5. The transmucosal therapeutic system according to item 4,

moreover

the soluble film-forming agent is selected from the group consisting of polymers such as polyvinylpyrrolidone, hydroxypropyl cellulose, graft copolymers based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam, copolymers of polyvinylpyrrolidone and polyvinyl acetate and any mixtures thereof.

6. The transmucosal therapeutic system according to item 5,

wherein the soluble film-forming agent is hydroxypropyl cellulose.

7. The transmucosal therapeutic system according to item 6,

wherein the soluble film-forming agent is hydroxypropyl cellulose having a molecular weight of 50,000 to 1,500,000.

8. The transmucosal therapeutic system according to item 7,

wherein the soluble film-forming agent is hydroxypropyl cellulose having a molecular weight of 80,000, 95,000, 370,000 or 1,150,000.

9. The transmucosal therapeutic system according to item 5,

wherein the soluble film-forming agent is polyvinylpyrrolidone.

10. The transmucosal therapeutic system according to item 9,

wherein polyvinylpyrrolidone is selected from soluble polyvinylpyrrolidones.

wherein the polyvinylpyrrolidone is selected from polyvinylpyrrolidones having a K-value in a range selected from a group of ranges consisting of

from 9 to 15 and preferably from 10.2 to 13.8,

from 15 to 20 and preferably from 15.3 to 18.4,

from 20 to 27 and preferably from 22.5 to 27.0,

from 27 to 35 and preferably from 27.0 to 32.4 and

from 75 to 110 and preferably from 81.0 to 97.2.

12. A transmucosal therapeutic system according to any one of claims 1-11,

wherein the amount of soluble film-forming agent is at least 65% by weight, at least 75% by weight, or at least 85% by weight, or the amount of soluble film-forming agent is less than or equal to 98% by weight, less than or equal to 94% by weight, or less than or equal to 90% by weight, or the amount of soluble film-forming agent is in the range from 65 to 98% by weight, from 75 to 94% by weight, or from 80 to 90% by weight, of the agomelatine-containing layer.

13. A transmucosal therapeutic system according to any one of claims 1-12,

wherein the agomelatine-containing layer comprises at least 1% by weight of agomelatine, at least 2% by weight of agomelatine or at least 3% by weight of agomelatine.

14. A transmucosal therapeutic system according to any one of claims 1-13,

wherein the agomelatine-containing layer contains less than or 25% by weight of agomelatine, less than or 20% by weight of agomelatine, or less than or 10% by weight of agomelatine.

15. A transmucosal therapeutic system according to any one of claims 1-14,

wherein the agomelatine-containing layer comprises from 1 to less than or 25% by weight of agomelatine, from 2 to less than or 20% by weight of agomelatine, or from 3 to less than or 10% by weight of agomelatine.

16. A transmucosal therapeutic system according to any one of claims 1-15,

wherein the agomelatine-containing layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, flavors, colorants, penetration enhancers, solubilizers, stabilizers, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffering agents and additional film-forming agents.

17. The transmucosal therapeutic system of claim 16, wherein the agomelatine-containing layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners and flavoring agents.

18. The transmucosal therapeutic system of claim 17, wherein the fatty acid is a saturated or unsaturated, linear or branched carboxylic acid containing 4-24 carbon atoms, and in particular is selected from the group consisting of caprylic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaydic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid.

19. The transmucosal therapeutic system of claim 18, wherein the fatty acid is oleic acid or linoleic acid.

20. The transmucosal therapeutic system according to any one of claims 16 to 19, wherein the agomelatine-containing layer comprises one or more fatty acids in an amount of at least 1% by weight, at least 3% by weight, or at least 4% by weight, or in an amount less than or equal to 15% by weight, less than or equal to 12% by weight, or less than or equal to 10% by weight, or in an amount of from 1 to 15% by weight, from 3 to 12% by weight, or from 4 to 10% by weight.

21. The transmucosal therapeutic system of claim 16, wherein the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of sucrose, glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidin, neotame, steviol glycosides, thaumatin and sodium saccharin.

22. The transmucosal therapeutic system of claim 21, wherein the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of sucrose, sucralose and sodium saccharin.

23. The transmucosal therapeutic system of claim 22, wherein the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of sucralose, sucrose and sodium saccharin in an amount of at least 0.05% by weight, at least 0.1% by weight, or at least 0.3% by weight, or in an amount less than or equal to 2.0% by weight, less than or equal to 1.5% by weight, or less than or equal to 1.0% by weight, or in an amount of from 0.05 to 2.0% by weight, from 0.1 to 1.5% by weight, or from 0.3 to 1.0% by weight, each.

24. The transmucosal therapeutic system of claim 16, wherein the agomelatine-containing layer comprises one or more natural or artificial flavors selected from the group consisting of vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetyl propionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethyl vanillin and eucalyptol, as well as flavoring compositions such as peppermint flavor.

25. The transmucosal therapeutic system of claim 24, wherein the agomelatine-containing layer comprises one or more flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, peppermint flavoring agent and eucalyptol, in an amount of at least 0.1% by weight, at least 0.3% by weight, or at least 0.4% by weight, or in an amount less than or equal to 10% by weight, less than or equal to 6% by weight, or less than or equal to 4% by weight, or in an amount of from 0.1 to 10% by weight, from 0.3 to 6% by weight, or from 0.4 to 4% by weight, each, or in an amount of at least 0.1% by weight, at least 0.5% by weight, or at least 0.7% by weight, or in an amount less than or equal to 15% by weight, less than or equal to 10% by weight, or less than or equal to 8% by weight, or in an amount from 0.1 to 15% by weight, from 0.5 to 10% by weight, or from 0.7 to 8% by weight, in total.

26. The transmucosal therapeutic system of claim 16, wherein the agomelatine-containing layer comprises one or more dyes selected from the group consisting of titanium dioxide, brilliant blue FCF, indigo carmine, fast green FCF, erythrosine, allura red AC, tartracene and sunset yellow FCF, curcumin, riboflavin, riboflavin-5'-phosphate, quinoline yellow, orange-yellow S, cochineal, carminic acid, azorubin, carmoisine, amaranth, crimson 4R, cochineal red A, patent blue V, indigotine, chlorophylls, chlorophyllins, copper complexes of chlorophyll and chlorophyllins, green S, plain caramel, caustic sulphate caramel, ammonia caramel, sulphate caramel ammonia, brilliant black BN, black PN, vegetable carbon, brown NT, carotenes, annatto, bixin, norbixin, paprika extract, capsanthin, capsorubin, lycopene, beta-apo-8'-carotenal, lutein, canthaxanthin, beet red, betanin, anthocyanins, calcium carbonate, oxides and hydroxides of iron, aluminum, silver, gold and litholrubin VK.

27. The transmucosal therapeutic system of claim 16, wherein the agomelatine-containing layer comprises one or more additional film-forming agents, wherein the additional film-forming agents are different from the soluble film-forming agent.

28. The transmucosal therapeutic system of claim 27, wherein the agomelatine-containing layer comprises one or more additional film-forming agents in an amount of at least 2% by weight, at least 5% by weight, or at least 10% by weight, or in an amount less than or equal to 40% by weight, less than or equal to 30% by weight, or less than or equal to 25% by weight, or in an amount of from 2 to 40% by weight, from 5 to 30% by weight, or from 10 to 25% by weight each, or in an amount of at least 5% by weight, at least 15% by weight, or at least 20% by weight, or in an amount less than or equal to 40% by weight, less than or equal to 30% by weight, or less than or equal to 25% by weight, or in an amount of from 5 to 40% by weight, from 15 to 30% by weight, or from 20 to 25% by weight, generally.

29. The transmucosal therapeutic system of claim 16, wherein the agomelatine-containing layer comprises one or more solubilizers selected from the group consisting of ethoxylated sorbitol esterified with fatty acids, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan monooleate, safflower oleasomes, propanediol and polyethoxylated castor oil.

30. The transmucosal therapeutic system of claim 29, wherein the agomelatine-containing layer comprises one or more solubilizers in an amount of at least 0.3% by weight, at least 0.5% by weight, or at least 1.0% by weight, or in an amount less than or equal to 5% by weight, less than or equal to 4% by weight, or less than or equal to 3% by weight, or in an amount of from 0.3 to 5% by weight, from 0.5 to 4% by weight, or from 1.0 to 3% by weight, each.

31. The transmucosal therapeutic system of claim 16, wherein the agomelatine-containing layer comprises one or more emulsifiers selected from the group consisting of soya lecithin, sodium phosphates, mono- and diglycerides of fatty acids, sodium stearoyl lactylate, diacetyl tartaric acid esters of mono- and diglycerides, and polyethoxylated hydrogenated castor oil.

32. The transmucosal therapeutic system of claim 31, wherein the agomelatine-containing layer comprises one or more emulsifiers in an amount of at least 1% by weight, at least 3% by weight, or at least 5% by weight, or in an amount less than or equal to 25% by weight, less than or equal to 20% by weight, or less than or equal to 15% by weight, or in an amount of from 1 to 25% by weight, from 3 to 20% by weight, or from 5 to 15% by weight, each.

33. The transmucosal therapeutic system of claim 16, wherein the agomelatine-containing layer comprises one or more plasticizers selected from the group consisting of mono-, di-, oligo- and polysaccharides and derivatives such as sorbitol, polyethylene glycol, triacetin, triethyl citrate, propylene glycol, glycerol and medium chain triglycerides.

34. The transmucosal therapeutic system of claim 33, wherein the agomelatine-containing layer comprises one or more plasticizers in an amount of at least 0.5% by weight, at least 1% by weight, or at least 5% by weight, or in an amount less than or equal to 25% by weight, less than or equal to 20% by weight, or less than or equal to 15% by weight, or in an amount of from 0.5 to 25% by weight, from 1 to 20% by weight, or from 5 to 15% by weight, each.

35. The transmucosal therapeutic system according to any one of claims 1 to 34, wherein the agomelatine-containing layer does not contain a penetration enhancer selected from the group consisting of bile acid, bile salts, bile acid derivatives, acylcarnitines, sodium dodecyl sulfate, dimethyl sulfoxide, sodium lauryl sulfate, terpenes, cyclodextrins, cyclodextrin derivatives, saponins, saponin derivatives, chitosan, EDTA, citric acid and salicylates, in an amount of more than 0.1% by weight, more than 0.2% by weight, more than 1% by weight, or more than 5% by weight.

36. The transmucosal therapeutic system according to any one of claims 1 to 35, wherein the agomelatine-containing layer comprises a penetration enhancer selected from the group consisting of diethylene glycol monoethyl ether, dipropylene glycol, levulinic acid, 2,5-dimethyl isosorbide, lauryl lactate, dimethylethylene urea, N,N-diethyl metatoluamide, propylene glycol monocaprylate, 2-methoxy-4-(prop-2-en-1-yl)phenol, lactic acid and laurocapram.

37. The transmucosal therapeutic system according to any one of claims 16 to 36, wherein the agomelatine-containing layer comprises one or more penetration enhancers in an amount of at least 1% by weight, at least 2% by weight, or at least 5% by weight, or in an amount less than or equal to 20% by weight, less than or equal to 15% by weight, or less than or equal to 10% by weight, or in an amount of from 1 to 20% by weight, from 2 to 15% by weight, or from 5 to 10% by weight, each.

38. A transmucosal therapeutic system according to any one of claims 1 to 37, wherein the agomelatine-containing layer is substantially free of water.

39. The transmucosal therapeutic system of claim 38, wherein the agomelatine-containing layer comprises less than or equal to 12% by weight, less than or equal to 8% by weight, less than or equal to 5% by weight, or less than or equal to 4% by weight of water.

40. A transmucosal therapeutic system according to any one of claims 1-39, wherein the agomelatine-containing layer is substantially free of volatile solvent, wherein the volatile solvent is selected from the group consisting of C1-C3 linear and branched alcohols, ethyl acetate, hexane, n-heptane and any mixtures thereof.

41. The transmucosal therapeutic system of claim 40, wherein the agomelatine-containing layer comprises less than or equal to 5% by weight, less than or equal to 3% by weight, or less than or equal to 1% by weight of a volatile solvent.

42. A transmucosal therapeutic system according to any one of claims 1 to 41, wherein the agomelatine-containing layer can be obtained by drying the applied coating composition containing agomelatine, a soluble film-forming agent and ethanol.

43. A transmucosal therapeutic system according to any one of claims 1 to 42, wherein the agomelatine-containing layer can be obtained by drying the applied coating composition containing agomelatine, a soluble film-forming agent and water.

44. The transmucosal therapeutic system according to claim 42 or claim 43, wherein the agomelatine-containing layer can be obtained by drying the applied coating composition containing agomelatine, a soluble film-forming agent, ethanol and water.

45. A transmucosal therapeutic system according to any one of claims 42 to 44, wherein the agomelatine-containing layer can be obtained by drying the applied coating composition containing less than 50% by weight, or less than 20% by weight, or less than 10% by weight, or less than 5% by weight of water.

46. The transmucosal therapeutic system according to any one of claims 1 to 45, wherein the agomelatine-containing layer has a mass per unit area of at least 25 g/ ^m2 , at least 35 g/ ^m2 or at least 40 g/ ^m2 , or has a mass per unit area of less than or equal to 300 g/ ^m2 , less than or equal to 250 g/ ^m2 or less than or equal to 200 g/ ^m2 , or has a mass per unit area of from 25 to 300 g/ ^m2 , from 35 to 250 g/ ^m2 or from 40 to 200 g/ ^m2 .

47. The transmucosal therapeutic system according to any one of claims 1 to 46, wherein the agomelatine-containing layer comprises at least 0.1 mg/ ^cm2 , at least 0.2 mg/ ^cm2 or at least 0.4 mg/ ^cm2 of agomelatine, or the agomelatine-containing layer comprises less than or equal to 2.0 mg/ ^cm2 , less than or equal to 1.5 mg/ ^cm2 or less than or equal to 1.2 mg/ ^cm2 of agomelatine, or the agomelatine-containing layer comprises from 0.1 to 2.0 mg/ ^cm2 , from 0.2 to 1.5 mg/ ^cm2 or from 0.4 to 1.2 mg/ ^cm2 of agomelatine.

48. A transmucosal therapeutic system according to any one of claims 1 to 47, wherein agomelatine is included in the agomelatine-containing layer in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorphic forms, in amorphous form, as a hydrate, solvate, hybrid form of any of the above forms or a mixture thereof.

49. A transmucosal therapeutic system according to any one of claims 1 to 48, wherein the agomelatine-containing layer can be obtained by including agomelatine in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorphic forms, in amorphous form, as a hydrate, solvate, hybrid form of any of the above forms or a mixture thereof.

50. A transmucosal therapeutic system according to any one of claims 1 to 49, wherein the agomelatine in the agomelatine-containing layer is dissolved or in dispersed form.

51. The transmucosal therapeutic system according to claim 50, wherein the agomelatine in the agomelatine-containing layer is in dispersed form.

52. The transmucosal therapeutic system according to claim 50, wherein agomelatine is dissolved in the agomelatine-containing layer.

53. The transmucosal therapeutic system according to any one of claims 1 to 52, wherein 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 in dissolved form.

54. A transmucosal therapeutic system according to any one of claims 1 to 53, wherein the agomelatine-containing layer does not contain agomelatine crystals.

55. A transmucosal therapeutic system according to any one of claims 1 to 54, wherein agomelatine has a purity of at least 95%, preferably at least 98% and more preferably at least 99% as determined by quantitative HPLC.

56. A transmucosal therapeutic system according to any one of claims 1-55, wherein the mucoadhesive layered structure further comprises one or more additional layers selected from

B) the layer in contact with the mucous membrane and

C) cosmetic layer, and

the additional layers are adjacent to the agomelatine-containing layer, and the mucosal contact layer and the cosmetic layer, if both are present, are adjacent to the agomelatine-containing layer on opposite sides.

57. The transmucosal therapeutic system of claim 56, wherein the mucoadhesive layered structure does not comprise a mucosal contact layer.

58. The transmucosal therapeutic system of claim 56, wherein the mucoadhesive layered structure further comprises a mucosal contact layer, and the mucosal contact layer is mucoadhesive.

59. The transmucosal therapeutic system of claim 58, wherein the mucoadhesive layered structure further comprises a mucosal contact layer,

wherein the size of the agomelatine-containing layer and the size of the mucosal contact layer are comparable.

60. A transmucosal therapeutic system according to any one of claims 56-59, wherein the mucoadhesive layered structure does not comprise a cosmetic layer.

61. The transmucosal therapeutic system of any one of claims 56-59, wherein the mucoadhesive layered structure further comprises a cosmetic layer, wherein the cosmetic layer prevents the patient from touching the agomelatine-containing layer during use of the transmucosal therapeutic system.

62. A transmucosal therapeutic system according to any one of claims 56-59 and 61, wherein the mucoadhesive layered structure additionally comprises a cosmetic layer, wherein the size of the agomelatine-containing layer and the size of the cosmetic layer are comparable or the cosmetic layer is larger in size and exceeds the agomelatine-containing layer in surface area.

63. A transmucosal therapeutic system according to any one of claims 56-59, 61 and 62, wherein the cosmetic layer dissolves in water, in artificial or natural saliva or in any other aqueous medium at 37°C and 150 rpm in less than 3 minutes, less than 1 minute or less than 30 seconds.

64. A transmucosal therapeutic system according to any one of claims 1-55, wherein the mucoadhesive layered structure consists of an agomelatine-containing layer.

65. A transmucosal therapeutic system according to any one of claims 1 to 64, wherein the agomelatine-containing layer is mucoadhesive.

66. A transmucosal therapeutic system according to any one of claims 1-65, wherein the mucoadhesive layered structure comprises agomelatine in a therapeutically effective amount.

67. The transmucosal therapeutic system according to any one of claims 1 to 66, wherein the mucoadhesive layered structure comprises at least 0.1 mg, at least 0.2 mg or at least 0.4 mg of agomelatine, or the agomelatine-containing layer comprises less than or equal to 20 mg, less than or equal to 15 mg or less than or equal to 10 mg of agomelatine, or the agomelatine-containing layer comprises from 0.1 mg to 20 mg, from 0.2 mg to 15 mg or from 0.4 mg to 10 mg of agomelatine.

68. The transmucosal therapeutic system of any one of claims 1 to 67, wherein the mucoadhesive layered structure dissolves in water, artificial or natural saliva, or any other aqueous medium at 37°C and 150 rpm in more than 30 seconds and less than 5 hours, or in more than 1 minute and less than 4 hours, or more than 2 minutes and less than 3 hours, or more than 4 minutes and less than 2 hours.

69. The transmucosal therapeutic system of any one of claims 1 to 68, wherein the transmucosal therapeutic system has a release area of at least 0.1 ^cm2 , at least 0.2 ^cm2 , or at least 0.5 ^cm2 , or has a release area less than or equal to 10 ^cm2 , less than or equal to 7 ^cm2 , or less than or equal to 5 ^cm2 , or has a release area of 0.1 to 10 ^cm2 , 0.2 to 7 ^cm2 , or 0.5 to 5 ^cm2 .

70. The transmucosal therapeutic system of any one of claims 1-69, wherein the transmucosal therapeutic system does not comprise a protective layer, and wherein the protective layer does not dissolve in less than 15 minutes, less than 10 minutes, or less than 5 minutes after administration of the transmucosal therapeutic system to a human patient.

71. A transmucosal therapeutic system according to any one of claims 1 to 70, wherein the transmucosal therapeutic system does not contain a protective layer, wherein the protective layer does not completely dissolve in water, in artificial or natural saliva or in any other aqueous medium at 37°C and 150 rpm in less than 30 minutes, less than 15 minutes or less than 10 seconds.

72. A transmucosal therapeutic system according to any one of claims 1-71, wherein the transmucosal therapeutic system does not contain a protective layer.

73. The transmucosal therapeutic system of any one of claims 1-72, further comprising a release substrate.

74. A transmucosal therapeutic system according to any one of claims 1-65, wherein the transmucosal therapeutic system does not comprise a protective liner.

75. A transmucosal therapeutic system according to any one of claims 1-74, wherein the transmucosal therapeutic system is in the form of a film.

76. The transmucosal therapeutic system of claim 75, wherein the transmucosal therapeutic system is in the form of a thin film having a mass per unit area of at least 25 g/ ^m2 , at least 35 g/ ^m2 or at least 40 g/ ^m2 , or has a mass per unit area of less than or equal to 300 g/ ^m2 , less than or equal to 250 g/ ^m2 or less than or equal to 200 g/ ^m2 , or has a mass per unit area of from 25 to 300 g/ ^m2 , from 35 to 250 g/ ^m2 or from 40 to 200 g/ ^m2 .

77. A transmucosal therapeutic system according to any one of claims 1-76, wherein the transmucosal therapeutic system has the form of a film having a round, rectangular or square shape.

78. A transmucosal therapeutic system according to any one of claims 1-77, wherein the use of the transmucosal therapeutic system consists of applying a mucoadhesive layered structure to the oral mucosa of a human patient and maintaining it on the mucosa until it dissolves.

79. The transmucosal therapeutic system of claim 78, wherein the use of the transmucosal therapeutic system consists of applying a mucoadhesive layered structure to the mucous membrane of the cheek, sublingual space, gum or palate in the oral cavity of a human patient and maintaining it on the mucous membrane until it dissolves.

80. A transmucosal therapeutic system according to any one of claims 1 to 79, wherein the transmucosal therapeutic system provides a mucosal penetration rate of agomelatine, as measured with pig esophageal mucosa, of 10 μg/cm2- ^h to 150 μg/ ^cm2 -h after 1 hour.

81. The transmucosal therapeutic system of any one of claims 1 to 80, wherein the transmucosal therapeutic system provides a cumulative release of agomelatine, as measured with the porcine oesophageal mucosa, of at least 0.02 mg/ ^cm2 , at least 0.05 mg/ ^cm2 or at least 0.1 mg/ ^cm2 , and/or less than or 0.5 mg/ ^cm2 , less than or 0.4 mg/ ^cm2 or less than or 0.3 mg/ ^cm2 , and/or from 0.02 mg/ ^cm2 to 0.5 mg/ ^cm2 , from 0.05 mg/ ^cm2 to 0.4 mg/ ^cm2 or from 0.1 mg/ ^cm2 to 0.3 mg/ ^cm2 over a period of 8 hours.

82. A transmucosal therapeutic system according to any one of claims 181 for use in a method of treating a human patient.

83. The transmucosal therapeutic system of claim 82 for use in a method for treating major depression.

84. A transmucosal therapeutic system according to claim 82 or claim 83 for use in a method of treatment,

wherein the transmucosal therapeutic system is applied by applying the mucoadhesive layered structure to the oral mucosa of a human patient and maintaining it on the mucosa until it dissolves.

85. The transmucosal therapeutic system of claim 84 for use in a method of treatment,

wherein the transmucosal therapeutic system is applied by applying the mucoadhesive layered structure to the mucous membrane of the cheek, sublingual space, gum or palate in the oral cavity of a human patient and maintaining it on the mucous membrane until it dissolves.

86. A transmucosal therapeutic system according to any one of claims 82-85 for use in a method of treatment, wherein the transmucosal therapeutic system is used in the evening or at night before bedtime.

87. Method of treatment,

wherein the transmucosal therapeutic system according to any one of paragraphs 1-81 is used for treating a human patient.

88. The method for treating major depression according to claim 88,

wherein the transmucosal therapeutic system according to any one of paragraphs 1-81 is used for treating a human patient.

89. The method of treatment according to item 88 or item 89,

wherein the transmucosal therapeutic system according to any one of paragraphs 1-81

applied by applying a mucoadhesive layered structure to the mucous membrane

oral cavity of a human patient and keeping it on the mucous membrane until it dissolves.

90. The method of treatment according to paragraph 89,

wherein the transmucosal therapeutic system according to any one of claims 1 to 82 is used by applying the mucoadhesive layered structure to the mucous membrane, in particular the mucous membrane of the cheek, sublingual space, gum or palate in the oral cavity of a human patient and maintaining it on the mucous membrane until it dissolves.

91. The method of treatment according to any of paragraphs 87-90,

Moreover, the transmucosal therapeutic system is used in the evening or at night before bedtime.

92. A method for producing an agomelatine-containing layer, comprising the following steps:

i) combining at least agomelatine and a soluble film-forming agent in a solvent to form a first coating composition;

ii) applying the coating composition to the release substrate; and

iii) drying the applied coating composition to form an agomelatine-containing layer.

93. The method according to item 92,

wherein in step i) agomelatine is dissolved.

94. The method according to item 92,

wherein in step i) agomelatine is dispersed.

95. The method according to any of paragraphs 92-94,

wherein the solvent comprises an alcohol solvent selected from methanol, ethanol, isopropanol and mixtures thereof.

96. The method according to item 95,

wherein the solvent contains ethanol or consists of ethanol.

97. The method according to any one of paragraphs 92-95, wherein the solvent comprises water.

98. The method according to any of paragraphs 92-96,

wherein the solvent does not contain water in an amount of more than 5% by weight, more than 2% by weight, more than 1% by weight, or more than 0.5% by weight.

99. The method according to any of paragraphs 92-98,

and drying is carried out at a temperature of 40-90°C or 60-80°C.

100. The method according to any of paragraphs 92-99,

wherein step i) consists of combining at least agomelatine, a soluble film-forming agent and one or more excipients selected from the group consisting of fatty acids, sweeteners and flavourings in a solvent to obtain a coating composition.

101. The method according to any of paragraphs 92-100,

wherein the soluble film-forming agent, when formed into a film having a mass per unit area of 50 g/ ^m2 , dissolves in water, in artificial or natural saliva, or in any other aqueous medium at 37°C and 150 rpm in less than 5 hours, less than 3 hours, less than 2 hours, or less than 1 hour, or in more than 5 seconds, more than 30 seconds, more than 1 minute, or more than 2 minutes, or in more than 5 seconds and less than 5 hours, in more than 30 seconds and less than 3 hours, more than 1 minute and less than 2 hours, or in more than 2 minutes and less than 1 hour.

102. The method according to any of paragraphs 92-101,

wherein the soluble film-forming agent is selected from the group consisting of polymers such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, graft copolymers based on polyethyleneglycol, polyvinyl acetate and polyvinylcaprolactam, polyvinyl alcohol, copolymers of polyvinyl alcohol and polyethyleneglycol, copolymers of polyvinylpyrrolidone and polyvinyl acetate, polyethylene oxides, polyethylene glycols, copolymers of methacrylic acid and methyl methacrylate and copolymers of methacrylic acid and ethyl methacrylate, natural film-forming agents such as shellac, pectin, gelatin, alginate, pullulan and starch derivatives, and any mixtures thereof.

103. Method according to item 102,

moreover

the soluble film-forming agent is selected from the group consisting of polymers such as polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, graft copolymers based on polyethyleneglycol, polyvinyl acetate and polyvinylcaprolactam, polyvinyl alcohol, copolymers of polyvinyl alcohol and polyethyleneglycol, copolymers of polyvinylpyrrolidone and polyvinyl acetate, polyethyleneoxides, polyethyleneglycols and any mixtures thereof.

104. Method according to item 103,

moreover

the soluble film-forming agent is selected from the group consisting of polymers such as polyvinylpyrrolidone, hydroxypropyl cellulose, graft copolymers based on polyethylene glycol, polyvinyl acetate and polyvinyl caprolactam, copolymers of polyvinylpyrrolidone and polyvinyl acetate and any mixtures thereof.

105. The method according to claim 104, wherein the soluble film-forming agent is hydroxypropyl cellulose.

106. Method according to paragraph 105,

wherein the soluble film-forming agent is hydroxypropyl cellulose having a molecular weight of 50,000 to 1,500,000.

107. Method according to item 106,

wherein the soluble film-forming agent is hydroxypropyl cellulose having a molecular weight of 80,000, 95,000, 370,000 or 1,150,000.

108. Method according to item 104,

wherein the soluble film-forming agent is polyvinylpyrrolidone.

109. Method according to paragraph 108,

wherein polyvinylpyrrolidone is selected from soluble polyvinylpyrrolidones.

110. The method according to paragraph 108 or paragraph 109,

wherein the polyvinylpyrrolidone is selected from polyvinylpyrrolidones having a K-value in a range selected from a group of ranges consisting of

from 9 to 15 and preferably from 10.2 to 13.8,

from 15 to 20 and preferably from 15.3 to 18.4,

from 20 to 27 and preferably from 22.5 to 27.0,

from 27 to 35 and preferably from 27.0 to 32.4 and

from 75 to 110 and preferably from 81.0 to 97.2.

111. The method according to any of paragraphs 92-110,

wherein in step 1) agomelatine is used to combine in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorphic forms, in amorphous form, in the form of a co-crystal, in the form of a hydrate, solvate, hybrid form of any of the above forms or a mixture thereof.

112. A transmucosal therapeutic system for the transmucosal administration of agomelatine, obtained by the manufacturing method according to any of claims 92-111.

113. A transmucosal therapeutic system for the transmucosal administration of agomelatine, having a mucoadhesive layered structure, wherein said mucoadhesive layered structure comprises at least

A) agomelatine-containing layer containing

i) 3-10% by weight, agomelatine;

ii) a soluble film-forming agent and

iii) 5-15% by weight of fatty acid,

iv) 0.1-2% by weight of one or more sweeteners and

v) 0.2-2.0% by weight of flavoring agent,

moreover

the soluble film-forming agent is selected from the group consisting of polyvinylpyrrolidone and hydroxypropyl cellulose, and

The mass per unit area of the agomelatine-containing layer is in the range from 100 to 150 g/ ^m2 .

Claims (62)

1. A transmucosal therapeutic system for the transmucosal administration of agomelatine, having a mucoadhesive layered structure, wherein said mucoadhesive layered structure comprises A) agomelatine-containing layer containing i) agomelatine; and ii) soluble film-forming agent, wherein the transmucosal therapeutic system is in the form of a film, and the soluble film-forming agent is selected from the group consisting of polyvinylpyrrolidone and hydroxypropyl cellulose. 2. The transmucosal therapeutic system according to item 1, in which the soluble film-forming agent, when formed into a film having a weight per unit area of 30 to 100 g/ ^m2 or 50 g/ ^m2 , dissolves in water, in artificial or natural saliva or in any other aqueous medium at 37°C and 150 rpm in less than 5 hours, less than 3 hours, less than 2 hours or less than 1 hour, or in more than 5 seconds, more than 30 seconds, more than 1 minute or more than 2 minutes, or in more than 5 seconds and less than 5 hours, in more than 30 seconds and less than 3 hours, more than 1 minute and less than 2 hours or in more than 2 minutes and less than 1 hour. 3. The transmucosal therapeutic system according to item 1 or 2, wherein the amount of soluble film-forming agent is at least 65% by weight, at least 75% by weight or at least 85% by weight, or the amount of soluble film-forming agent is less than or equal to 98% by weight, less than or equal to 94% by weight or less than or equal to 90% by weight, or the amount of soluble film-forming agent is in the range of 65 to 98% by weight, 75 to 94% by weight or 80 to 90% by weight of the agomelatine-containing layer. 4. A transmucosal therapeutic system according to any one of paragraphs 1-3, wherein the agomelatine-containing layer comprises at least 1% by weight of agomelatine, at least 2% by weight of agomelatine or at least 3% by weight of agomelatine, and/or wherein the agomelatine-containing layer comprises less than or 25% by weight of agomelatine, less than or 20% by weight of agomelatine, or less than or 10% by weight of agomelatine, and/or wherein the agomelatine-containing layer comprises from 1 to less than or 25% by weight of agomelatine, from 2 to less than or 20% by weight of agomelatine, or from 3 to less than or 10% by weight of agomelatine, and/or wherein agomelatine in the agomelatine-containing layer is dissolved or in dispersed form, and/or wherein the agomelatine-containing layer does not contain agomelatine crystals. 5. A transmucosal therapeutic system according to any one of paragraphs 1-4, wherein the agomelatine-containing layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, flavors, colorants, penetration enhancers, solubilizers, stabilizers, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, buffering agents and additional film-forming agents, wherein, in particular, the fatty acid is a saturated or unsaturated, linear or branched carboxylic acid containing 4-24 carbon atoms, and in particular is selected from the group consisting of caprylic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaydic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid, and/or wherein, in particular, the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of sucrose, glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidin, neotame, steviol glycosides, thaumatin and sodium saccharin, and/or wherein, in particular, the agomelatine-containing layer comprises one or more natural or artificial flavors selected from the group consisting of vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetyl propionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethyl vanillin and eucalyptol, as well as flavoring compositions such as peppermint flavor. 6. A transmucosal therapeutic system according to any one of paragraphs 1-5, wherein the agomelatine-containing layer contains virtually no water and/or wherein the agomelatine-containing layer contains less than or equal to 12% by weight, less than or equal to 8% by weight, less than or equal to 5% by weight, or less than or equal to 4% by weight of water. 7. A transmucosal therapeutic system according to any one of claims 1-6, wherein the agomelatine-containing layer can be obtained by drying the applied coating composition containing agomelatine, a soluble film-forming agent and ethanol, or agomelatine, a soluble film-forming agent and water, and/or agomelatine, soluble film-forming agent, ethanol and water, and/or wherein the agomelatine-containing layer can be obtained by drying the applied coating composition containing less than 50% by weight, or less than 20% by weight, or less than 10% by weight, or less than 5% by weight of water. 8. A transmucosal therapeutic system according to any one of paragraphs 1-7, wherein the agomelatine-containing layer has a mass per unit area of at least 25 g/ ^m2 , at least 35 g/ ^m2 or at least 40 g/ ^m2 , or has a mass per unit area of less than or equal to 300 g/ ^m2 , less than or equal to 250 g/ ^m2 or less than or equal to 200 g/ ^m2 , or has a mass per unit area of from 25 to 300 g/ ^m2 , from 35 to 250 g/ ^m2 or from 40 to 200 g/ ^m2 . 9. The transmucosal therapeutic system according to item 8, wherein the mucoadhesive layered structure contains or does not contain a mucosal contact layer, and/or wherein the mucoadhesive layered structure contains or does not contain a cosmetic layer, and/or Moreover, the transmucosal therapeutic system does not contain a protective layer. 10. A transmucosal therapeutic system according to any one of claims 1-9, in which the mucoadhesive layered structure dissolves in water, artificial or natural saliva or any other aqueous medium at 37°C and 150 rpm in more than 30 seconds and less than 5 hours, or in more than 1 minute and less than 4 hours, or more than 2 minutes and less than 3 hours, or more than 4 minutes and less than 2 hours. 11. A transmucosal therapeutic system according to any one of claims 1-10, wherein the transmucosal therapeutic system provides a mucosal penetration rate of agomelatine, as measured with the porcine oesophageal mucosa, of 10 μg/ ^cm2 -h to 150 μg/ ^cm2 -h after 1 hour and/or wherein the transmucosal therapeutic system provides a cumulative release of agomelatine, as measured with the porcine oesophageal mucosa, of at least 0.02 mg/ ^cm2 , at least 0.05 mg/ ^cm2 or at least 0.1 mg/ ^cm2 , and/or less than or 0.5 mg/ ^cm2 , less than or 0.4 mg/ ^cm2 or less than or 0.3 mg/ ^cm2 , and/or from 0.02 mg/ ^cm2 to 0.5 mg/ ^cm2 , from 0.05 mg/ ^cm2 to 0.4 mg/ ^cm2 or from 0.1 mg/ ^cm2 to 0.3 mg/ ^cm2 over a period of 8 hours. 12. Use of a transmucosal therapeutic system according to any one of claims 1-11 for the treatment of major depression in a human patient. 13. The use of a transmucosal therapeutic system for the treatment of major depression according to paragraph 12, wherein the transmucosal therapeutic system is applied by applying a mucoadhesive layered structure to a mucous membrane, and in particular to the mucous membrane of the cheek, sublingual space, gum or palate in the oral cavity of a human patient and maintaining it on the mucous membrane until it dissolves, and/or Moreover, the transmucosal therapeutic system is used in the evening or at night before bedtime. 14. A method for producing an agomelatine-containing layer, comprising the following steps: i) combining at least agomelatine and a soluble film-forming agent in a solvent to form a first coating composition; ii) applying the coating composition to the release substrate; and iii) drying the applied coating composition to form an agomelatine-containing layer, wherein the soluble film-forming agent is selected from the group consisting of polyvinylpyrrolidone and hydroxypropyl cellulose. 15. A transmucosal therapeutic system for the transmucosal administration of agomelatine, having a mucoadhesive layered structure, wherein said mucoadhesive layered structure comprises at least A) agomelatine-containing layer containing i) 3-10% by weight of agomelatine; ii) a soluble film-forming agent and iii) 5-15% by weight of fatty acid, iv) 0.1-2% by weight of one or more sweeteners and v) 0.2-2.0% by weight of flavoring agent, moreover the soluble film-forming agent is selected from the group consisting of polyvinylpyrrolidone and hydroxypropyl cellulose, and The mass per unit area of the agomelatine-containing layer is in the range from 100 to 150 g/ ^m2 .

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