Agomelatine transmucosal therapeutic system for use in a method of treating a human subject

Abstract

The present invention relates to a transmucosal therapeutic system for use in a method of treating a human subject, comprising a mucoadhesive layer structure comprising a therapeutically effective amount of agomelatine and providing a fast release profile with a time to maximum plasma concentration of agomelatine of less than 2 h.

Description

AGOMELATINE TRANSMUCOSAL THERAPEUTIC SYSTEM FOR USE IN AMETHOD OF TREATING A HUMAN SUBJECTTECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to an agomelatine-containing transmucosal therapeutic system for use in a method of treating a human subject, and processes of manufacture thereof.BACKGROUND OF THE INVENTION

[0002] The majority of patients, more than 80% of those who suffer from classical mood disorders (major depression, depressive phases of bipolar disorder, or generalized anxiety disorder) show disruptions of the sleep-wake cycle and of the sleep architecture.Characteristically, difficulty falling asleep (increased sleep latency) followed by fitful sleep results in a pronounced daytime sleepiness that further compromises their ability to function properly in daily life, establishing a vicious cycle. As concerns depression, although there are no specific treatment guidelines, available options generally base themselves on the premise that depression and sleep disturbances share a bidirectional relationship and so, the successful treatment of one of the conditions will reciprocally benefit the other.

[0003] In recent years it has become increasingly clear that circadian rhythm disruption -maladjustment and dysfunction of the "body clock" that locks core physiological functions such as body temperature and blood pressure, but also very complex neurotransmitter responses, to the time of the day - is a major factor in major depressive disorder that would warrant therapeutic attention. Malfunctioning of the link between the suprachiasmatic nucleus, the pineal gland, and the neurohormone it produces - melatonin - has been suggested as the main cause for these phenomena. Melatonin has been heavily advocated (and marketed) as a “non-photic circadian rhythm resynchronizing agent” to treat jet lag and insomnia associated with shift working, and a lot has been published on the antidepressant and anxiolytic effects of melatonin. Because the oral bioavailability is low for melatonin, synthetic melatonin receptor agonists have been investigated; the most prominent of which is agomelatine.

[0004] While agomelatine is approved for the treatment of depression, treatment of other indications such as bipolar disorders, generalized anxiety disorder, Smith-Magenis syndrome, periventricular leukomalacia and OCD has been suggested.

[0005] The active agent agomelatine (N-(2-(7-Methoxy-l-naphthyl)ethyl)acetamide) is a melatonergic antidepressant developed by Les Laboratoires Servier. The chemical structure is very similar to that of melatonin.Melatonin Agomelatine

[0006] As a melatonergic agonist stimulating the MT1 and MT2 receptors, agomelatine is able to mediate synchronization of the circadian rhythm, much like melatonin. However, in addition and in contrast to melatonin, agomelatine is also a 5-HT2B / 5-HT2C antagonist, and blocking the serotonergic 5HT2C receptors causes enhanced release of dopamine and norepinephrine in the prefrontal cortex. Unexpected synergistic actions have been observed for the MT1 / MT2 agonism and 5HT2C antagonism, and it is supposed that this synergy accounts for the antidepressant actions and unique clinical profile of agomelatine.

[0007] Agomelatine has been approved in Europe under the trade names Valdoxan®, Melitor® and Thymanax® and is indicated for the treatment of major depressive disorder (MDD). The currently available form is a film tablet containing a dose of 25 mg, which is prescribed with an initial dose of one tablet to be taken at bedtime, with the option of doubling the dose if no improvement is seen. Agomelatine is the only antidepressant on the market with the mechanism of action described above.

[0008] Oral agomelatine undergoes extensive first pass and systemic metabolism, mainly via the cytochrome CYP1 A2. Although agomelatine is well absorbed orally (> 80 %), overall bioavailability is very low (less than 5 %), with pronounced inter-individual variability. Both the time to reach maximal blood plasma concentration as well as elimination half-life ti / 2 is about 1 to 2 hours, and in steady state, the volume of distribution is 35 liters, with a plasma protein binding of 95 %.

[0009] When compared to other antidepressants, agomelatine seems to have a more rapid onset of effects (usually within a week), and major side effects commonly known for other antidepressants such as weight gain, sexual dysfunction, anticholinergic symptoms and cardiotoxicity appear to be reduced. However, agomelatine bears the risk of hepatotoxicity of which the mechanism remains unclarified, manifesting as increased alanine aminotransferase (ALAT) and / or aspartate aminotransferase (ASAT) values, and in few exceptional cases, the outcome was fatal or necessitated liver transplantation. In addition, hepatic impairment was also reported to be related to a huge increase in agomelatine exposure, with up to 140-fold AUC and Cmax values observed for patients with moderate hepatic impairment compared to healthy subjects.

[0010] Efforts were made by Servier and Novartis to establish a sublingual dosage form of agomelatine, supposedly in order to avoid the first-pass metabolism and the associated drawbacks as outlined above (low oral bioavailability and hepatotoxicity), resulting in placebocontrolled randomized studies with 1 and 2 mg (Servier) or 0.5 and 1 mg agomelatine sublingual tablets (Novartis). No result is publicly available for the 2008 / 2009 Servier trial. The Novartis studies, commenced in 2011 / 2011, were essentially unsuccessful in that the efficacy of the agomelatine sublingual tablets was not better than placebo, and in that there was no clear dose response relationship, though at least liver toxicity was shown to be rare. One of the reasons for the unsuccessful trials appears to have been the pronounced irritant sensation caused by agomelatine when administered to the oral mucosa. As a consequence, the FDA decided not to grant approval of the drug in the USA, despite the advantages over other actives in the treatment ofMDD.

[0011] Several patent applications from Servier indicate that the first approach of providing such novel dosage forms, referred to also as “orodispersible” formulations, e.g. tablets, was directed to achieving a rapid disintegration of a few minutes, such as less than three or even less than one minute(s), assumedly in order to obtain a very fast onset of release and to avoid as good as possible enteral delivery and the associated disadvantage of hepatic first-pass effect. A more recent approach included buccal formulations such as tablets to be sucked, that are intended to dissolve or disintegrate more slowly in the mouth, in order to keep the agomelatine concentration in the oral cavity low enough to limit the stinging sensation. This, however, bears the risk of the tablet being swallowed by the patient prematurely, i.e. before all of the active having been released, and the onset of action is consequently delayed, which is unfavorable for a medication that is intended to promote sleep. Bi- or multilayer tablets comprising e.g. a placebo core have then been proposed so that most part of the active will have been released after some time, leaving only the active-free placebo core, to ensure that active release is near complete even if the patient swallows the tablet prematurely.

[0012] Nonetheless, these orodispersible formulations appear not to have solved completely the issue of patient compliance possibly induced by agomelatine causing an irritant sensation, and premature tablet swallowing has not been prevented, but only the effect thereof mitigated.Incomplete active release still is a risk, depending on the timing of unintended tablet swallowing. In addition, sucking a tablet over a prolonged period of time means that the patient has to keep a disturbing object in the oral cavity and has also to take the tablets in advance, i.e., needs to consider correct timing of sucking the tablet, which is disadvantageous in terms of patient compliance. Finally, the drug delivery mechanism of such orodispersible formulations depend on the active being first dissolved in the saliva (open system), which is why the drug concentration and in consequence the drug delivery is very difficult to control. All these reasons may have led to currently no agomelatine formulations being on the market besides the conventional oral tablets outlined above.

[0013] Transmucosal therapeutic systems, or transmucosal delivery systems (also termed buccal patches by some), consist of one or more thin layers which are applied and adhere to the mucosa of the oral cavity to deliver the drug over a period of time. Dosage forms in the form of thin films for application in the oral cavity are also sometimes referred to as “Oral Thin Film” or OTF, however, OTFs are not necessarily intended to adhere to the mucosa. In a transmucosal therapeutic system, the active is contained in a dissolvable layer, and due to the film adhering to the mucosa, active delivery is achieved by a combination of direct active release from the transmucosal therapeutic system to the mucosa, and by an indirect active delivery via dissolutionin the saliva, as in the orodispersible formulations outlined above. In order to prevent the indirect active delivery inherent to open systems, a backing layer may be employed, which serves to shield the active-containing layer from the remaining parts of the oral cavity, in particular from the saliva of the environment. In any case are OTFs advantageous when compared to orodispersible formulations intended to be sucked in that they do not provoke any negative sensation of having a disturbing object in the mouth, since the film, adhered to the mucosa, does not freely move around in the oral cavity, and since the film is usually thin enough not to be perceived by the patient once applied.

[0014] However, transmucosal therapeutic systems are a relatively new form of drug delivery, meaning that knowledge on formulation technology is limited. Formulating appropriate dosage forms for the transmucosal delivery by OTFs is challenging due to a multitude of aspects to be considered and issues to be solved. Up to date, there are no commercially available agomelatine transmucosal therapeutic systems. The main requirements for such transmucosal therapeutic systems are good adhesion and active permeation, combined with an appropriate behavior and time of disintegration. Also important are haptics, i.e. a good feeling in the mouth, as well as stability of the film (i.e. low friability) before application.

[0015] Thus, while such a new form of agomelatine medication would avoid the first-pass effect (with which the low oral bioavailability and hepatotoxicity of the agomelatine tablets are associated, see discussion above), the low solubility of agomelatine makes it difficult to formulate and the irritating sensation caused by the active substance in the oral cavity needs to be addressed in any agomelatine treatment to ensure patient compliance, while at the same time providing for an appropriate release of the treatment to be effective, which is notoriously difficult, as outlined above. In addition, since agomelatine is mainly used to re-synchronize the circadian rhythm, another major concern is the timing of taking the medication. Ideally, to offer a convenient administration for the patient and to improve patient compliance, there will be no need for the patient to plan ahead of going to bed when to take the medicament. If the medicament has to be taken, e.g., one or two hours in advance, this will mean that the patient has to wait for the sleep-promoting effect to set in for a long time before being able to sleep if the medicament was not taken in time, which is a substantial drawback.

[0016] The Applicant is not aware of any research or investigation on in vivo human clinical studies with an agomelatine transmucosal therapeutic system or any other forms of agomelatine medication that avoids the first pass metabolism and would provide such convenience to the patient comparable to the commercially available tablets.

[0017] In summary, an alternative form of agomelatine treatment that is convenient for human patients, and overcomes the disadvantages of the oral as well as sublingual administration routes is much needed. As outlined above, a form of agomelatine treatment using a transmucosal therapeutic system that provides an appropriate release profile would be able to address these disadvantages.

[0018] There is thus a need in the art for an alternative form of treatment with agomelatine.OBJECTS AND SUMMARY OF THE INVENTION

[0019] It is an object of the present invention to provide a treatment with agomelatine overcoming the above-mentioned disadvantages of current agomelatine administration.

[0020] Thus, it is an object of the present invention to provide a treatment with agomelatine which avoids the first-pass effect and promotes patient compliance by offering a convenient administration.

[0021] It is also an object of the present invention to provide a treatment with agomelatine using a transmucosal therapeutic system which promotes patient compliance by offering a convenient administration, and at the same time causes no, or only mild to moderate irritating sensation at the mucosa or otherwise in the oral cavity.

[0022] It is another object of the present invention to provide a treatment with agomelatine using a transmucosal therapeutic system that has an appropriate drug release profile comparable to the one of the commercial tablet and overcomes the disadvantages of the oral and sublingual administration routes.

[0023] It is a further object of the present invention to provide a treatment with agomelatine using a transmucosal therapeutic system having a drug release profile which provides fast release and fast decrease in plasma concentration of active similar to the commercially available tablets, and which is appropriate for an administration shortly before going to bed.

[0024] It is also a further object of the present invention to provide a treatment with agomelatine using a transmucosal therapeutic system providing a rapid completion of drug release with very little residual drug content in the bloodstream of most human subjects 8 hours after administration.

[0025] It is also a further object of the present invention to provide a treatment with agomelatine using a transmucosal therapeutic system, wherein hepatotoxicity and the interindividual variability is reduced and the bioavailability is increased when compared to oral administration.

[0026] One further object of the present invention is to provide a treatment with agomelatine using a transmucosal therapeutic system that provides appropriate disintegration behavior, e.g. in terms of the disintegration time but also in terms of integrity of the transmucosal therapeutic system (no premature falling apart of the layers in case multiple layers are present).

[0027] It is also one object of the present invention to provide a treatment with agomelatine using a transmucosal therapeutic system that provides good haptics, i.e. a good feeling in the mouth.

[0028] It is further an object of the present invention to provide a treatment with agomelatine using a transmucosal therapeutic system that complies with the needs of a convenient application and handling in view of size and thickness, provides for good patient compliance and / or which is easy and cost-efficient to manufacture.

[0029] These objects and others are accomplished by the present invention, which according to one aspect relates to a transmucosal therapeutic system for use in a method of treating a human subject,wherein the transmucosal therapeutic system provides a time to maximum plasma concentration of agomelatine (tmax) of less than 2 h, andwherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least an agomelatine-containing layer comprising:i) 3 to 10 wt % agomelatine; andii) a dissolvable film-forming agent.

[0030] According to this aspect, the present invention also relates to a use of a transmucosal therapeutic system for the manufacture of a medicament for treating a human subject, wherein the transmucosal therapeutic system provides a time to maximum plasma concentration of agomelatine (tmax) of less than 2 h, andwherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least an agomelatine-containing layer comprising i) 3 to 10 wt % agomelatine; andii) a dissolvable film-forming agent.

[0031] Still according to this aspect, the present invention also relates to a method of treating a human subject, wherein a transmucosal therapeutic system is administered to the human subject, wherein the transmucosal therapeutic system provides a time to maximum plasma concentration of agomelatine (tmax) of less than 2 h, andwherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least an agomelatine-containing layer comprising i) 3 to 10 wt % agomelatine; andii) A dissolvable film-forming agent.

[0032] According to another aspect, the present invention relates to a transmucosal therapeutic system for use in a method of treating a human subject,wherein the transmucosal therapeutic system provides a ratio of the plasma concentration of agomelatine at 8 hours after administration (Csh) to the maximum plasma concentration of agomelatine (Cmax) of at most 0.01, of at most 0.008, of at most 0.005, of at most 0.003 or of at most 0.002, andwherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least an agomelatine-containing layer comprising i) 3 to 10 wt % agomelatine; andii) a dissolvable film-forming agent.

[0033] According to this aspect, the present invention also relates to a use of a transmucosal therapeutic system for the manufacture of a medicament for treating a human subject, wherein the transmucosal therapeutic system provides a ratio of the plasma concentration of agomelatine at 8 hours after administration (Csh) to the maximum plasma concentration of agomelatine (Cmax) of at most 0.01, of at most 0.008, of at most 0.005, of at most 0.003 or of at most 0.002, and wherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least an agomelatine-containing layer comprising i) 3 to 10 wt % agomelatine; andii) a dissolvable film-forming agent.

[0034] Still according to this aspect, the present invention also relates to a method of treating a human subject, wherein a transmucosal therapeutic system is administered to the human subject, wherein the transmucosal therapeutic system provides a ratio of the plasma concentration of agomelatine at 8 hours after administration (Csh) to the maximum plasma concentration of agomelatine (Cmax) of at most 0.01, of at most 0.008, of at most 0.005, of at most 0.003 or of at most 0.002, andwherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least an agomelatine-containing layer comprisingi) 3 to 10 wt % agomelatine; andii) a dissolvable film-forming agent.

[0035] According to yet another aspect, the present invention relates to a transmucosal therapeutic system for use in a method of treating a human subject,wherein the transmucosal therapeutic system provides a ratio of the maximum plasma concentration of metabolites of agomelatine to the maximum plasma concentration of agomelatine of less than 1, of less than 0.1 or of less than of 0.01, andwherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least an agomelatine-containing layer comprising i) 3 to 10 wt % agomelatine; andii) a dissolvable film-forming agent.

[0036] According to this aspect, the present invention also relates to a use of a transmucosal therapeutic system for the manufacture of a medicament for treating a human subject, wherein the transmucosal therapeutic system provides a ratio of the maximum plasma concentration of metabolites of agomelatine to the maximum plasma concentration of agomelatine of less than 1, of less than 0.1 or of less than of 0.01, andwherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least an agomelatine-containing layer comprising i) 3 to 10 wt % agomelatine; andii) a dissolvable film-forming agent.

[0037] Still according to this aspect, the present invention also relates to a method of treating a human subject, wherein a transmucosal therapeutic system is administered to the human subject, wherein the transmucosal therapeutic system provides a ratio of the maximum plasma concentration of metabolites of agomelatine to the maximum plasma concentration of agomelatine of less than 1, of less than 0.1 or of less than of 0.01, andwherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least an agomelatine-containing layer comprising i) 3 to 10 wt % agomelatine; andii) a dissolvable film-forming agent.

[0038] According to certain embodiments, the alternative form of treatment with agomelatine is provided using a transmucosal therapeutic system, wherein the transmucosal therapeutic system provides• a tmax of at most 1.5 h,• a ratio of Csh to C max of at most 0.008,• a ratio of Cmax of metabolites of agomelatine to Cmax of agomelatine of less thanl,• a Cmax in the range from 40 to 200 ng / mL,wherein the transmucosal therapeutic system• comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprisingat least an agomelatine-containing layer comprising i) 3 to 10 wt % agomelatine; andii) a dissolvable film-forming agent• has a total agomelatine content from 1 to 20 mg, and• consists of one, two or more agomelatine-containing layers.

[0039] Within the meaning of this invention, the term “transmucosal therapeutic system” or “transmucosal delivery system” refers to a system by which the active agent (agomelatine) is administered to the systemic circulation via transmucosal delivery by application to the mucosa of the oral cavity, and refers to the entire individual dosing unit that is applied to the mucosa of a subject, and which comprises a therapeutically effective amount of agomelatine in a mucoadhesive layer structure and optionally an additional overlay on top of the agomelatine-containing mucoadhesive layer structure. The mucoadhesive layer structure may be located on a release liner (a detachable protective layer), thus, the transmucosal therapeutic system may further comprise a release liner. Within the meaning of this invention, the term “transmucosal therapeutic system” in particular refers to a system providing passive transmucosal delivery excluding active transport as in methods including microporation. Also, in contrast to certain oral thin films which are not necessarily mucoadhesive and which are intended to disintegrate very fast in the saliva (sometimes referred to as “flash wafers”), enteral delivery is entirely unintended in transmucosal therapeutic systems.

[0040] Within the meaning of this invention, the term “agomelatine-containing mucoadhesive layer structure” or “mucoadhesive layer structure containing a therapeutically effective amount of agomelatine” refers to the active agent-containing structure providing the area of release for agomelatine during administration. Any additional overlay adds to the overall size of the transmucosal therapeutic system but does not add to the area of release. The agomelatine-containing mucoadhesive layer structure comprises at least one agomelatine-containing layer.

[0041] Within the meaning of this invention, the term “therapeutically effective amount” refers to a quantity of active agent in the transmucosal therapeutic system sufficient to provide, if administered by the transmucosal therapeutic system to a subject, agomelatine blood levels of a similar range (e.g. of about 10 % to about 1000 % as measured as an AUC) when compared to blood levels obtained in a one-time administration of 25 mg oral agomelatine.

[0042] Within the meaning of this invention, the terms “active”, “active agent”, and the like, as well as the term “agomelatine” refer to agomelatine in any pharmaceutically acceptable chemical and morphological form and physical state. These forms include without limitation agomelatine in its free, dissociated or any associated form such as hydrates, solvates and so on, as well as agomelatine in the form of particles which may be in micronized form, crystalline form, and in particular in one of its polymorph forms, and / or in amorphous form, and in any hybrid type form of any of the aforementioned forms or a mixture thereof. The agomelatine, where contained in a medium such as a solvent, may be dissolved or dispersed or in part dissolved and in part dispersed.

[0043] When agomelatine is mentioned to be used in a particular form in the manufacture of the transmucosal therapeutic system, this does not exclude interactions between this form of agomelatine and other ingredients of the agomelatine-containing self-adhesive layer structure so that the active is present in another form in the final transmucosal therapeutic system. This means that, even if agomelatine is included in a 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 polymorph forms, it may be present in amorphous form in the final transmucosaltherapeutic system. Unless otherwise indicated, in particular the amount of agomelatine in the mucoadhesive layer structure relates to the amount of agomelatine included in the transmucosal therapeutic system during manufacture of the transmucosal therapeutic system and is calculated based on agomelatine in the free form, i.e. when agomelatine is included in an amount of 0.1 mmol, the amount of agomelatine in the self-adhesive layer structure is, within the meaning of the invention, considered to be 24.3 mg (the molecular weight of agomelatine is 243 g / mol), regardless of whether the agomelatine has been included in the transmucosal therapeutic system during manufacture in its free form or in any associated form.

[0044] The agomelatine starting material included in the transmucosal therapeutic system during manufacture of the transmucosal therapeutic system may be in the form of particles. Agomelatine may e.g. be present in the mucoadhesive layer structure in the form of particles, dispersed and / or dissolved.

[0045] Within the meaning of this invention, the term “particles” refers to a solid, particulate material comprising individual particles, the dimensions of which are negligible compared to the material. In particular, the particles are solid, including plash c / deformable solids, including amorphous and crystalline materials.

[0046] Within the meaning of this invention, the term “dispersing” refers to a step or a combination of steps wherein a starting material (e.g. agomelatine) is not totally dissolved. Dispersing in the sense of the invention comprises the dissolution of a part 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).

[0047] There are two main types of transmucosal therapeutic systems, i.e. those using backing layers, and those without. As also outlined in the introductory background section, active delivery of an open system type transmucosal therapeutic system using no backing layer will always be a combination of direct delivery from the transmucosal therapeutic system through the mucosa at the adhesion site, and indirect delivery via dissolution of the active from the transmucosal therapeutic system into the saliva, and from the saliva through the mucosa. The proportion of the different delivery routes depends mainly on factors such as the solubility of the active and the disintegration time of the transmucosal therapeutic system. The higher the solubility and the faster disintegration of the transmucosal therapeutic system, dissolution into the saliva will be favored over direct delivery into the mucosa at the adhesion site. Such an indirect delivery has the huge advantage of providing a practical increase by several factors of the mucosal surface area through which the active is released systemically. Dissolution into the saliva on the other hand means that the active concentration, and thus the final delivered amount is difficult to control, and that there may be a risk of enteral delivery by unintended swallowing of the saliva. In particular with respect to agomelatine, this also poses the problem of an active, which has proven to potentially provide irritating sensation, is freely dissolved in the whole oral cavity.

[0048] Transmucosal therapeutic systems using a backing layer have a completely different approach, i.e. in such systems, the loss of being restricted in the drug release area (to the actual size of the patch) is accepted in exchange for limiting the delivery route to the direct transmucosal delivery, which can be much better controlled. Thus, in the sense of the present invention, a “backing layer” is any layer within a transmucosal therapeutic system which is ableto prevent (at least a substantial amount of) the active contained within the transmucosal therapeutic system to be dissolved into the saliva. Such a backing layer can be non-dissolvable, or dissolvable over time. In the latter case, the time the backing layer takes for dissolution is at least as long as (a substantial amount of) the active takes to be delivered through the mucosa.

[0049] In this context, it also becomes clear that terms such as “dissolution”, “dissolvable”, “dissolve” and the like with respect to any of the layers of a transmucosal therapeutic system (e.g. backing layer, active-containing layer) and with respect to the film-forming agent when casted into a film, are to be understood very broadly, and not in the strict scientific sense of chemically dissolving a molecule in a solvent. Any transformation of the solid state of the layer concerned to a liquid state, such as dispersing, forming of a suspension, gelling of the film and disintegrating into smaller parts of gel, etc. has to be regarded as “dissolving” in the sense of the present invention, as long as the “dissolved” material is able to freely move around in the liquid (e.g. saliva) so that anything that was present below the layer concerned (i.e. the mucosa if a mucosa-contacting layer was dissolved, or e.g. the active-containing layer if a backing layer was dissolved before the active-containing layer) becomes accessible to liquid other than the “dissolved” material. In preferred embodiments, the meaning is limited to the usual chemical sense of dissolving a molecule in a solvent. It should be noted that the term “dissolve” with respect to substances per se, such as the active agent agomelatine, or any excipients, will continue to be used in the usual chemical sense of dissolving a molecule in a solvent. E.g., agomelatine in dissolved form obviously does not include agomelatine in dispersed form. The film-forming agent per se can be present in the coating composition during manufacture of the transmucosal therapeutic system in dissolved form in the common chemical sense (e.g. is not dispersed, in form of small parts of gel, etc.), but where the film-forming agent is casted into a film, “dissolving” such a film also includes gelling of the film and disintegrating into smaller parts of gel.

[0050] The active agent-containing layer is the final, solidified layer e.g. obtained after coating and drying the solvent-containing coating composition. The active agent-containing layer may also be manufactured by laminating two or more such solidified layers (e.g. dried layers) of the same composition to provide the desired area weight. The active agent-containing layer may be mucoadhesive (in the form of a mucoadhesive layer) or the transmucosal therapeutic system may comprise an additional mucosa-contacting layer of a mucoadhesive for providing sufficient adhesion. In particular, the active agent-containing layer is a mucoadhesive layer.

[0051] Within the meaning of this invention, the term “mucoadhesive” refers to a material that in particular adheres to and upon contact with a mucosa, but which preferably is non-tacky and can be touched e.g. with the fingers and manipulated, e.g. for application into the oral cavity, without unintentionally adhering to the skin of the fingers, when in dry state. A mucoadhesive layer, when in contact with the mucosa, is “self-adhesive”, i.e. provides adhesion to the mucosa so that typically no further aid for fixation is needed. The adhesion strength is preferably strong enough that typical movements in the oral cavity are not sufficient to displace a mucoadhesive layer adhered to the mucosa. A “mucoadhesive” layer structure includes a mucoadhesive layer for mucosa contact which may be provided in the form of a mucoadhesive active agentcontaining layer or in the form of an additional layer, i.e. a mucoadhesive mucosa-contacting layer. A mucoadhesive overlay may still be employed to advance adhesion.

[0052] Within the meaning of this invention, the term “mucoadhesive polymer” refers to a polymer which is able to further improve the basic mucoadhesivity of the mucoadhesive layer as provided by the dissolvable film-forming agent and thus is different from any dissolvable filmforming agent.

[0053] Within the meaning of this invention, the term “mucosa-contacting layer” refers to a layer included in the transmucosal therapeutic system to be in direct contact with the mucosa of the subject during administration. When the transmucosal therapeutic systems comprises a mucosa-contacting layer, the other layers do not contact the mucosa and do not necessarily have mucoadhesive properties. The area of release is provided by the area of the active agentcontaining layer. A mucosa-contacting layer may be used to enhance adherence. The sizes of an additional mucosa-contacting layer and the active agent-containing layer are usually coextensive and correspond to the area of release.

[0054] Within the meaning of this invention, the term “area weight” refers to the dry weight of a specific layer, e.g. of the active agent-containing layer, provided in g / m2. The area weight values are subject to a tolerance of ± 10 %, preferably ± 7.5 %, due to manufacturing variability.

[0055] If not indicated otherwise “%” refers to weight-%.

[0056] Within the meaning of this invention, the term “polymer” refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, and includes homopolymers which consist of one type of monomer and copolymers which consist of two or more types of monomers. Polymers may be of any architecture such as linear polymers, star polymer, comb polymers, brush polymers, of any monomer arrangements in case of copolymers, e.g. alternating, statistical, block copolymers, or graft polymers. The minimum molecular weight varies depending on the polymer type and is known to the skilled person. Polymers may e.g. have a molecular weight above 2,000, preferably above 5,000 and more preferably above 10,000 Dalton. Correspondingly, compounds with a molecular weight below 2,000, preferably below 5,000 or more preferably below 10,000 Dalton are usually referred to as oligomers.

[0057] Within the meaning of this invention, the term “cross-linking agent” refers to a substance which is able to cross-link functional groups contained within the polymer.

[0058] Within the meaning of this invention, the term “mucoadhesive overlay” refers to a mucoadhesive layer, which is located on top of the agomelatine-containing mucoadhesive layer structure, free of active agent, larger in area than the active agent-containing structure and which provides additional area adhering to the mucosa, but no area of release of the active agent. It enhances thereby the overall adhesive properties of the transmucosal therapeutic system.

[0059] Within the meaning of this invention, the term “administration” refers to the application of the dosage form, i.e. the transmucosal therapeutic system, to the oral mucosa of the subject, which is then maintained on the mucosa until the agomelatine-containing layer structure is dissolved.

[0060] For a continuous treatment with agomelatine, the transmucosal therapeutic system will be usually administered once daily, and preferably at bedtime. The transmucosal therapeutic system may in particular be applied to the mucosa of the subject shortly (e.g. 5 to 30 minutes) before going to bed in order to account for the delay in drug onset. Since it appears for agomelatine that an around-the-clock maintenance of blood plasma concentration at therapeuticlevel is not necessary, or may be even contraindicated for re-synchronization of the circadian rhythm, 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 away, e.g. the next morning, so that the patient does not need to have a transmucosal therapeutic system applied thereafter, e.g. during the whole daytime.

[0061] Within the meaning of this invention, the term “room temperature” refers to the unmodified temperature found indoors in the laboratory where the experiments are conducted and usually lies within 15 to 35 °C, preferably about 18 to 25 °C.

[0062] Within the meaning of this invention, the term “patient” or “subject” refers to a human subject (unless explicitly indicated to the contrary) who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, who is treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated.

[0063] The transmucosal therapeutic system for use in a method of treating a human subject according to the present invention can be characterized by certain parameters as measured in an in vivo human clinical study.

[0064] Within the meaning of this invention the term “pharmacokinetic parameters” refers to parameters describing the blood plasma curve, e.g. Cmax, Ct and AUCti-t2 obtained in a clinical study, e.g. by single-dose or multi-dose administration of the agomelatine transmucosal therapeutic system to healthy human subjects. The pharmacokinetic parameters of the individual subjects are summarized using arithmetic and geometric means, e.g. a mean Cmax, a mean AUCt and a mean AUCINF, and additional statistics such as the respective standard deviations and standard errors, the minimum value, the maximum value, and the middle value when the list of values is ranked (Median). In the context of the present invention, pharmacokinetic parameters, e.g. the Cmax, Ct and AUCti-t2 refer to arithmetic or geometric mean values and preferably refer to geometric mean values. It cannot be precluded that the absolute mean values obtained for a certain transmucosal therapeutic system in a clinical study vary to a certain extent from study to study. To allow a comparison of absolute mean values between studies, a reference formulation, e.g. in the future any product based on the invention, may be used as internal standard. A comparison of the AUC per area of release of the respective reference product in the earlier and later study can be used to obtain a correction factor to take into account differences from study to study.

[0065] Clinical studies according to the present invention refer to studies performed in full compliance with the International Conference for Harmonization of Clinical Trials (ICH) and all applicable local Good Clinical Practices (GCP) and regulations.

[0066] Within the meaning of this invention, the term “healthy human subject” refers to a male or female subject with a body weight ranging from 47.0 kg to 79.6 kg and a body mass index (BMI) ranging from 19.9 to 26.2 and normal physiological parameters, such as blood pressure, etc. Healthy human subjects for the purposes of the present invention are selected according to inclusion and exclusion criteria which are based on and in accordance with recommendations of the ICH.

[0067] Within the meaning of this invention, the term “subject population” refers to at least ten individual healthy human subjects.

[0068] Within the meaning of this invention, the term “geometric mean” refers to the mean of the log transformed data back-transformed to the original scale.

[0069] Within the meaning of this invention, the term “arithmetic mean” refers to the sum of all values of observation divided by the total number of observations.

[0070] Within the meaning of this invention, the parameter “AUC” corresponds to the area under the plasma concentration-time curve. The AUC value is proportional to the amount of active agent absorbed into the blood circulation in total and is hence a measure for the bioavailability.

[0071] Within the meaning of this invention, the parameter “AUCti-t2” is provided in (ng / ml) h and relates to the area under the plasma concentration-time curve from hour tl to t2 and is calculated by the linear trapezoidal method.

[0072] Within the meaning of this invention, the parameter “AUCiast” is provided in (ng / ml) h and relates to the area under the plasma concentration-time curve from the start of application to the time of the last measurable concentration and is calculated by the linear trapezoidal method.

[0073] Within the meaning of this invention, the parameter “Cmax” is provided in (ng / ml) and relates to the maximum observed blood plasma concentration of the active agent.

[0074] Within the meaning of this invention, the parameter “Ct” is provided in (ng / ml) and relates to the blood plasma concentration of the active agent observed at hour t. For example, Csh is the blood plasma concentration of the active agent observed at 8 hours after application.

[0075] Within the meaning of this invention, the parameter “tmax” is provided in h and relates to the time point at which the Cmax value is reached. In other words, tmax is the time point of the maximum observed plasma concentration.

[0076] Within the meaning of this invention, the term “mean plasma concentration” is provided in (ng / ml) and is a mean of the individual plasma concentrations of active agent, e.g. agomelatine, at each point in time.

[0077] Within the meaning of this invention, the term “coating composition” refers to a composition comprising all components of the drug-containing layer in a solvent, which may be coated onto the backing layer or release liner to form the drug-containing layer upon drying.

[0078] Within the meaning of this invention, the term “dissolve” in the context of the preparation of the coating composition, e.g. dissolving components of the coating composition such as the active agent, refers to the process of obtaining a solution, which is clear and does not contain any particles, as visible to the naked eye.

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

[0080] Within the meaning of this invention, and unless otherwise specified, the term “about” refers to an amount that is ± 10 % of the disclosed amount. In some embodiments, the term “about” refers to an amount that is ± 5 % of the disclosed amount. In some embodiments, the term “about” refers to an amount that is ± 2 % of the disclosed amount.BRIEF DESCRIPTION OF THE DRAWINGS

[0081] Fig. 1 depicts the agomelatine blood plasma concentration from 0 to 3 hours after administration of transmucosal therapeutic systems prepared according to Examples la to Id, obtained in a human clinical study as described in Example 2.

[0082] Fig. 2 depicts the agomelatine blood plasma concentration from 0 to 12 hours after administration of transmucosal therapeutic systems prepared according to Examples la to Id, obtained in a human clinical study as described in Example 2.

[0083] Fig. 3 depicts the hydroxylated agomelatine blood plasma concentration from 0 to 3 hours after administration of transmucosal therapeutic systems prepared according to Examples la to Id, obtained in a human clinical study as described in Example 2.DETAILED DESCRIPTION MEDICAL USE

[0084] The present invention in one aspect is related to a transmucosal therapeutic system for use in a method of treating a human subject. Likewise, the present invention in such an aspect is related to a method of treating a human subject, wherein a transmucosal therapeutic system is administered to the human subject. The present invention in such an aspect is also related to a use of a transmucosal therapeutic system for the manufacture of a medicament for treating a human subject. In accordance with such an aspect, the present invention, whether related to a transmucosal therapeutic system for use in a method of treatment, or to a method of treatment, or to a use of a transmucosal therapeutic system for the manufacture of a medicament for treating, is characterized by the medical use or medical treatment, using a transmucosal therapeutic system to treat a human subject. Thus, where such a transmucosal therapeutic system or such a treatment is described in further detail below, it is understood that such details are equally applicable to (i) the transmucosal therapeutic system for use in a method of treating a human subject, (ii) the method of treating a human subject as well as (iii) the use of a transmucosal therapeutic system for the manufacture of a medicament for treating a human subject as referred to above.

[0085] In certain embodiments, the transmucosal therapeutic system for use in a method of treating a human subject according to the invention is for use in a method of treating major depression in a human subject. Likewise, in certain other embodiments, the invention is related to a method of treating major depression, wherein the transmucosal therapeutic system for use in a method of treating a human subject according to the invention is administered to a human subject. In certain embodiments, the transmucosal therapeutic system according to the invention is also used for the manufacture of a medicament for treating major depression in a human subject.

[0086] In certain embodiments, the transmucosal therapeutic system for use in a method of treating a human subject according to the invention is for use in a method of treating a human subject by applying the mucoadhesive layer structure to the mucosa of the oral cavity of the human subject and maintaining it on the mucosa until dissolved. Likewise, in certain embodiments, the invention is related to a method of treating a human subject, wherein the mucoadhesive layer structure of the transmucosal therapeutic system according to the inventionis applied to the mucosa of the oral cavity of the human subject and maintained on the mucosa until dissolved. In certain embodiments, the transmucosal therapeutic system according to the invention is also used for the manufacture of a medicament for treating a human subject by applying the mucoadhesive layer structure to the mucosa of the oral cavity of the human subject and maintaining it on the mucosa until dissolved.

[0087] In certain embodiments, the transmucosal therapeutic system for use in a method of treating a human subject according to the invention is for use in a method of treating a human subject by applying the mucoadhesive layer structure to the mucosa, in particular to the buccal, sublingual, gingival or palatal mucosa, of the oral cavity of the human subject and maintaining it on the mucosa until dissolved. Likewise, in certain embodiments, the invention is related to a method of treating a human subject, wherein the mucoadhesive layer structure of the transmucosal therapeutic system according to the invention is applied to the mucosa, in particular to the buccal, sublingual, gingival or palatal mucosa, of the oral cavity of the human subject and maintained on the mucosa until dissolved. In certain embodiments, the transmucosal therapeutic system according to the invention is also used for the manufacture of a medicament for treating a human subject by applying the mucoadhesive layer structure to the mucosa, in particular to the buccal, sublingual, gingival or palatal mucosa, of the oral cavity of the human subject and maintaining it on the mucosa until dissolved.

[0088] The treatment of depression, or major depression, also called major depressive disorder, may include treatment of conditions such as major depressive episodes, anxiety symptoms, sleep-wake cycle disturbances, daytime sleepiness and insomnia (the majority of MDD patients, i.e. over 80 % suffer from depression combined with insomnia) in depressive / MDD patients. In other embodiments, the treatment in general may also refer to treating bipolar disorder, generalized anxiety disorder, Smith-Magenis syndrome, periventricular leukomalacia, or OCD.

[0089] As outlined above, transmucosal delivery avoids the first-pass effect and thus, administering the transmucosal therapeutic system according to the invention has a lower risk of hepatotoxicity, unlike oral agomelatine dosage forms. Thus, there is no limitation with respect to the patient group to be treated. The treatment includes the treatment of human patients with or without hepatic impairment, including those patients with at least mild or at least moderate hepatic impairment.

[0090] Also, in a certain embodiment, treatment with the inventive transmucosal therapeutic system provides a reduction in at least one agomelatine-related side effect relative to an equivalent oral dose of agomelatine. As outlined above, in certain specific embodiments, such an agomelatine-related side effect is hepatotoxicity. Relative to an equivalent oral dose of agomelatine should be understood as a comparison in the incidence and intensity of side effects in a clinical study when using a dose of transmucosal and oral agomelatine that leads substantially to the same blood plasma exposure of agomelatine. The incidence of the at least one agomelatine-related side effect relative to an equivalent oral dose of agomelatine may be reduced by at least about 30 %, at least about 40 %, at least about 70 % or at least about 80 %, and / or the intensity of the at least one agomelatine-related side effect relative to an equivalent oral dose of agomelatine may be reduced. The intensity of a side effect can be determined e.g. by classifying the side effects on a scale indicating “mild”, “moderate” or “severe” intensity, and a reduction of the intensity can be quantified by comparing the median intensity.

[0091] In any of the treatments outlined for the above aspects and embodiments, the transmucosal therapeutic system is preferably administered by applying the mucoadhesive layer structure to the mucosa of the oral cavity of a human subject and maintained on the mucosa until dissolved. In preferred embodiments, the transmucosal therapeutic system is administered by applying the mucoadhesive layer structure to the buccal, sublingual, gingival or palatal mucosa of the oral cavity of a human subject and maintained on the mucosa until dissolved.

[0092] In yet preferred embodiments, the transmucosal therapeutic system is administered in the evening or at night time before going to bed. In further preferred embodiments, the transmucosal therapeutic system according to the invention is administered less than 2 hours before going to bed, less than 1 hour before going to bed, less than 30 minutes before going to bed or directly before going to bed.

[0093] In another embodiment, the transmucosal therapeutic system may also reduce, in a subject, at least one agomelatine-related side effect relative to an equivalent oral dose of agomelatine.

[0094] The invention is also related to a method of reducing at least one agomelatine-related side effect in a subject being treated with oral agomelatine therapy, the method comprising a) discontinuing oral agomelatine therapy; andb) administering a transmucosal therapeutic system for use in a method of treating a human subject according to the invention to the mucosa of the oral cavity of a human subject, wherein the transmucosal therapeutic system provides a reduction in at least one agomelatine-related side effect relative to an equivalent oral dose of agomelatine.

[0095] In such a method, the transmucosal therapeutic system according to the invention may deliver an amount of agomelatine equivalent to the amount of agomelatine originally provided by the oral agomelatine therapy.DRUG RELEASE CHARACTERISTICS

[0096] The transmucosal therapeutic system in accordance with the invention offers a fast onset of action and an advantageous release profile upon transmucosal administration of a certain amount of agomelatine to the systemic circulation, which is in particular beneficial for administration shortly before going to bed, and which will be characterized in the following in more detail.

[0097] In one aspect, the transmucosal therapeutic system in accordance with the invention provides a time to maximum plasma concentration of agomelatine (tmax) of less than 2 hours when administered to human subjects.

[0098] In certain aspects of the present invention, the transmucosal therapeutic system in accordance with the invention provides a ratio of the plasma concentration of agomelatine at 8 hours after administration (Csh) to the maximum plasma concentration of agomelatine (Cmax) of at most 0.01, at most 0.008, at most 0.005, at most 0.003 or at most 0.002 when administered to human subjects.

[0099] In yet another aspect of the present invention, the transmucosal therapeutic system in accordance with the invention provides a ratio of the maximum plasma concentration of metabolites of agomelatine to the maximum plasma concentration of agomelatine of less than 1,of less than 0.1 or of less than of 0.01, when administered to human subjects. In certain embodiments, the metabolites of agomelatine are a total of hydroxylated and demethylated agomelatine.

[0100] In specific embodiments of the invention, the transmucosal therapeutic system according to the invention further provides a tmax of at most 1.5 h, at most 1.25 h, or at most 1.0 h when administered to human subjects.

[0101] In specific embodiments of the invention, the transmucosal therapeutic system according to the invention further provides a Cmax in the range from 3 to 300 ng / mL, from 40 to 200 ng / mL, or from 60 to 200 ng / mL when administered to human subjects.

[0102] In specific embodiments of the invention, the transmucosal therapeutic system according to the invention further provides a Csh of at most 1.0 ng / mL, or at most 0.4 ng / mL when administered to human subjects.

[0103] In specific embodiments of the invention, the transmucosal therapeutic system according to the invention further provides an AUCiast from 5 to 300 (ng h) / mL, or from 50 to 200 (ng h) / mL when administered to human subjects.

[0104] In specific embodiments of the invention, the transmucosal therapeutic system according to the invention further provides a ratio of AUC to total dose in the range from 1 to 50 (ng h) / (mL mg), or from 10 to 25 (ng h) / (mL mg) when administered to human subjects.STRUCTURE OF THE TRANSMUCOSAL THERAPEUTIC SYSTEM

[0105] The transmucosal therapeutic system according to the present invention comprises a mucoadhesive layer structure containing agomelatine.

[0106] The mucoadhesive layer structure comprises an agomelatine-containing layer comprising i) agomelatine and ii) a dissolvable film-forming agent. In certain embodiments, the mucoadhesive layer structure contains therapeutically effective amounts of agomelatine.

[0107] Thus, the transmucosal therapeutic system according to the invention comprises a mucoadhesive layer structure comprising:A) at least an agomelatine-containing layer comprising:i) 3 to 10 wt-% agomelatine; andii) a dissolvable film-forming agent.

[0108] The transmucosal therapeutic system of the present invention attempts to achieve a particularly high active delivery in order to ensure that the drug amount delivered is sufficient for enabling a therapeutically effective dose. As outlined in detail in the introductory section, so-called open systems, wherein active delivery is achieved by a combination of direct active release from the transmucosal therapeutic system to the mucosa, and by an indirect active delivery via dissolution in the saliva, are particularly advantageous in terms of high active permeation rates and improved drug release profile.

[0109] Thus, in certain embodiments of the present invention, the transmucosal therapeutic system does not comprise a backing layer. As outlined above, a backing layer in the sense of the present invention is any layer within a transmucosal therapeutic system which is able to prevent (at least a substantial amount of) the active contained within the transmucosal therapeutic system to be dissolved into the saliva. Thus, in particular embodiments, the time the backing layer takes for dissolution is at least as long as (a substantial amount of) the active takes to be deliveredthrough the mucosa, e.g. as long as the active-containing layer takes for dissolving. Thus, in certain embodiments, the backing layer does not dissolve in less than 15 minutes, in less than 10 minutes, or in less than 5 minutes upon administration of the transmucosal therapeutic system to a human subject. In some embodiments, the backing 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, in less than 15 minutes, or in less than 10 minutes.

[0110] In some specific embodiments, the mucoadhesive layer structure may further comprise one or more further layers selected from:B) a mucosa-contacting layer, andC) a cosmetic layer.[OHl] Thus, in specific embodiments, the mucoadhesive layer structure according to the invention comprises an additional mucosa-contacting layer. In other embodiments, the mucoadhesive layer structure according to the invention does not comprise an additional mucosa-contacting layer. In such embodiments, but also in specific other embodiments, the agomelatine-containing layer may be mucoadhesive. The additional mucosa-contacting layer, if present, is mucoadhesive and provides for (improved) adhesion between the mucoadhesive layer structure and the mucosa of the subject during administration. A mucosa-contacting layer is provided just below the active-agent containing layer, and thus, forms an adhesive layer between the mucosa and the agomelatine-containing layer during administration. In view of convenience of manufacture and restricting the overall patch size, the size of the agomelatine-containing layer and the size of the mucosa-contacting layer are preferably coextensive.

[0112] As indicated above, the mucoadhesive layer structure may also comprise a cosmetic layer. In another embodiment, the mucoadhesive layer structure does not comprise a cosmetic layer.

[0113] In contrast to the mucosa-contacting layer, a cosmetic layer is located on top of the agomelatine-containing layer and is not (necessarily) intended to contact the mucosa.

[0114] As a result, in some specific embodiments, the mucoadhesive layer structure may further comprise one or more further layers selected from:B) a mucosa-contacting layer, andC) a cosmetic layer,whereinthe further layers adjoin the agomelatine-containing layer, andthe mucosa-contacting layer and the cosmetic layer, if both are present, adjoin the agomelatine-containing layer on opposite sides.

[0115] The cosmetic layer may provide for a decorative means such as coloring or imprinting, or may simply prevent the subject from touching the agomelatine-containing layer during administration of the transmucosal therapeutic system. For such a protective function, it is preferable that the cosmetic layer covers the agomelatine-containing layer completely. Thus, in certain embodiments, the mucoadhesive layer structure further comprises a cosmetic layer, and the size of the agomelatine-containing layer and the size of the cosmetic layer are coextensive, or the cosmetic layer is larger in size than and extends the surface area of the agomelatine-containing layer.

[0116] On the other hand, a cosmetic layer is not to be confused with a backing layer. It is not a function of a cosmetic layer and would indeed be undesirable if the cosmetic layer posed an obstacle for the active to be released into the saliva. Thus, a cosmetic layer dissolves fast enough not to hinder the active to be dissolved into 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 in less than 30 seconds.

[0117] An elegant solution for a transmucosal therapeutic system, in terms of ease of manufacture and also in terms of simplicity, is, however, when the agomelatine-containing layer is the transmucosal therapeutic system itself. In other words, in certain preferred embodiments, a transmucosal therapeutic system of the present invention does neither comprise a mucosacontacting layer, nor a cosmetic layer, and in particular, the mucoadhesive layer structure may simply consist of the agomelatine-containing layer.

[0118] Thus, according to certain embodiments of the invention, the transmucosal therapeutic system may further comprise a mucoadhesive overlay or does not comprise a mucoadhesive overlay, and preferably does not comprise a mucoadhesive overlay. This mucoadhesive overlay is in particular larger than the agomelatine-containing mucoadhesive layer structure and is attached thereto for enhancing the adhesive properties of the overall transmucosal therapeutic system. The area of said mucoadhesive overlay adds to the overall size of the transmucosal therapeutic system but does not add to the area of release. The mucoadhesive overlay comprises hydroxyethyl cellulose, hydroxypropyl cellulose, or mixture thereof, which may be identical to or different from any dissolvable film-forming agent included in the active agent-containing mucoadhesive layer structure.

[0119] As outlined also above, a transmucosal therapeutic system consists 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 have a circular, rectangular or square shape.

[0120] The film preferably has a certain degree of thickness, as otherwise it will be difficult to incorporate the required amount of active, and as very thin films are not easy to manufacture, in particular with respect to providing an even thickness. Thus, in certain embodiments, the transmucosal therapeutic system is in the form of a thin film having an area weight of at least 25 g / m2, preferably at least 35 g / m2, or more preferably at least 40 g / m2Or, put into thickness, the transmucosal therapeutic system is in the form of a thin film having a layer thickness of at least 15 pm, preferably at least 25 pm, and more preferably at least 35 pm. On the other hand, very thick films will be perceived by the patient as a disturbing object in the oral cavity, and thus are disadvantageous in terms of patient compliance. Thus, in certain embodiments, the transmucosal therapeutic system is in the form of a thin film having an area weight of less than or equal to 275 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 pm, preferably less than 400 pm, and more preferably less than 300 pm. In preferred embodiments, the transmucosal therapeutic system is in the form of a thin film having an area weight of from 25 to 275 g / m2, preferably from 35 to 250 g / m2, or more preferably from 40 to 200 g / m2, or having a layer thickness from 15 to 550 pm, preferably from 25 to 400 pm, and more preferably from 35 to 300 pm.

[0121] Where the thickness is insufficient to provide for the desired dose of agomelatine within the maximum acceptable size (area of release) of the transmucosal therapeutic system, the transmucosal therapeutic system according to the present invention can be folded onto itself to provide for a folded system having half the original size and double the original thickness. Thus, in certain embodiments of the present invention, the transmucosal therapeutic system consists of one, two or more agomelatine-containing layers, or the transmucosal therapeutic system consisting of two or more agomelatine-containing layer is obtainable by folding an agomelatine-containing layer onto itself.

[0122] The transmucosal therapeutic system according to the invention is normally stored in a seam-sealed pouch without any further means of protection. However, the mucoadhesive layer structure may also be located on a detachable protective layer (release liner) from which it is removed immediately before application to the mucosa of the subject’s oral cavity. Thus, the transmucosal therapeutic system may or may not further comprise a release liner. A transmucosal therapeutic system protected by a release liner is usually also stored in a seam-sealed pouch. The packaging may be child resistant and / or senior friendly.AGOMELATINE-CONTAINING LAYER

[0123] As outlined in more detail above, the transmucosal therapeutic system according to the present invention comprises a mucoadhesive layer structure comprising an agomelatine-containing layer.

[0124] Further, the agomelatine-containing layer comprises:i) 3 to 10 wt-% agomelatine; andii) a dissolvable film-forming agent.

[0125] The area weight of the agomelatine-containing layer is one of the factors decisive for the amount of active. A certain thickness is required in order to obtain a sufficient amount of active, and it is also difficult to coat very thin layers in particular with sufficient accuracy. On the other hand, thick layers may not only provoke an uncomfortable feeling in the oral cavity, but are also difficult to manufacture, and may result in the layer taking too long to dissolve for the desired release profile. On balance, in certain preferred embodiments of the present invention, the agomelatine-containing layer has an area weight of at least 125 g / m2or of at least 150 g / m2, or has an area weight of less than or equal to 275 g / m2or of less than or equal to 250 g / m2, or has an area weight of from 125 to 275 g / m2or of from 150 tol50 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 150 pm or at least 200 pm, or has a layer thickness of less than 480 pm or less than 400 pm.

[0126] In an open system transmucosal therapeutic system comprising no backing layer, which is preferred in the present invention (see above), the active delivery is controlled by a combination of direct and indirect delivery as explained above, which is why in preferred embodiments, the area of release, i.e. the surface area of the agomelatine-containing layer, plays a minor role in the control of the effective dose. However, a certain minimum size is required in order to ensure that the patch does not detach prematurely from the mucosa, and also for being able to include a sufficient amount of active without having to use very thick films. On the other hand, if the area of release is too large, the transmucosal therapeutic system will be huge in size,uncomfortable to apply and to wear, leading to low patient compliance. Considering this, in certain embodiments of the invention, the agomelatine-containing layer has an area of release of at least 0.5 cm2, preferably at least 1 cm2, or has an area of release of less than or equal to 6 cm2, preferably less than or equal to 4 cm2, or has an area of release of from 0.5 to 6 cm2, preferably of from 1 to 4 cm2.

[0127] As outlined also above and without wishing to be bound by theory, it is believed that a sufficient amount of active agent contained in the transmucosal therapeutic system is necessary to achieve certain advantageous features of the transmucosal therapeutic system according to the present invention, such as good in vitro permeation. On the other hand, if the amount of active is too high, this might lead not only to undesirable storage stability issues such as re-crystallization of the active where the agomelatine is present in dissolved form, but also to potential irritating sensations in the oral cavity due to the drug concentration being too high. The amount of agomelatine contained in the transmucosal therapeutic system can be controlled two-way by adjusting concentration and / or the area weight of the agomelatine-containing layer. Details concerning the area weight are outlined above. With respect to the concentration, the agomelatine-containing layer comprises at least 3 wt-% agomelatine, at least 4 wt-% agomelatine, or at least 5 wt-% agomelatine, or the agomelatine-containing layer comprises less than or equal to 10 wt-% agomelatine, less than or equal to 9 wt-% agomelatine, or less than or equal to 8 wt-% agomelatine, or the agomelatine-containing layer comprises from 3 to less than or equal to 10 wt-% agomelatine, from 4 to less than or equal to 9 wt-% agomelatine, or from 5 to less than or equal to 8 wt-% agomelatine.

[0128] Thus, in certain embodiments of the invention, the agomelatine-containing layer comprises at least 0.6 mg / cm2, at least 0.8 mg / cm2, at least 1.0 mg / cm2or at least 1.2 mg / cm2agomelatine, or wherein the agomelatine-containing layer comprises less than or equal to 2.0 mg / cm2, less than or equal to 1.8 mg / cm2, less than or equal to 1.7 mg / cm2or less than or equal to 1.6 mg / cm2agomelatine, or wherein the agomelatine-containing layer comprises from 0.6 to 2.0 mg / cm2, from 0.8 to 1.8 mg / cm2, from 1.0 to 1.7 mg / cm2, or from 1.2 to 1.6 mg / cm2agomelatine per area of release.

[0129] In terms of active amount, the mucoadhesive layer structure may comprise at least 1 mg or at least 2 mg, agomelatine, or less than or equal to 20 mg or less than or equal to 10 mg agomelatine, or from 1 mg to 20 mg or from 2 mg to 10 mg agomelatine.

[0130] As outlined in more detail above, a correct dissolving behavior of the agomelatine-containing layer is very important for controlling the delivery routes. The faster the disintegration of the transmucosal therapeutic system, the more dissolution into the saliva will be favored over direct delivery into the mucosa at the adhesion site. As it is one of the objects of the present invention to achieve a particularly rapid release of the active, indirect delivery, which will be able to make use of the whole mucosa for drug delivery, is very important and to be favored over direct delivery. This means that the transmucosal therapeutic system should disintegrate relatively quickly. Thus, the mucoadhesive layer structure may e.g. 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 4 hours, more preferably in less than 3 hours, and most preferably in less than 2 hours. On the other hand, if dissolving too fast, the risk of unintentionally swallowing a substantial part of the active becomes high. So-called “flashwafers” are films designed to disintegrate very fast in order to achieve enteral delivery, wherein swallowing is intentional (and easier when compared to tablets). Thus, transmucosal therapeutic systems differ from flash wafers by way of its delivery mechanism, and usually take longer than flash wafers to dissolve. In the particular situation of agomelatine as active, high concentrations of active are also undesirable as there is the risk of irritating sensations, which is another reason why the dissolution preferably is not too fast. Thus, the mucoadhesive layer structure may e.g. 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, more preferably in more than 2 minutes, and most preferably in more than 4 minutes. In preferred embodiments, the mucoadhesive layer structure dissolves in water, in artificial or natural saliva, or in 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 4 hours, more preferably in more than 2 minutes and less than 3 hours, and most preferably in more than 4 minutes and less than 2 hours.

[0131] As it is preferred that the agomelatine-containing layer is able to directly adhere to the mucosa, in certain preferred embodiments of the invention, the agomelatine-containing layer is mucoadhesive.

[0132] As will be appreciated further below in more detail, in certain embodiments, it is preferable that the coating composition for preparing the agomelatine-containing layer makes use of ethanol as solvent, but substantially no water. Thus, the agomelatine-containing layer according to the present invention may be obtainable (and / or is obtained) by drying a coated coating composition comprising the agomelatine, the dissolvable film-forming agent, and ethanol. On the other hand, certain dissolvable film-forming agents have a high solubility in water, but limited solubility in other solvents. Thus, there is also an advantage to use water as a solvent, which is why the agomelatine-containing layer may be obtainable (and / or is obtained) by drying a coated coating composition comprising the agomelatine, the dissolvable filmforming agent, and water. A combination of ethanol and water is also possible, i.e. the agomelatine-containing layer may also be obtainable (and / or is obtained) by drying a coated coating composition comprising the agomelatine, the dissolvable film-forming agent, ethanol and water. In terms of the amount of water, the agomelatine-containing layer may be obtainable (and / or is obtained) by drying a coated coating composition comprising less than 50 wt-%, or less than 20 wt-%, or less than 10 wt-%, or less than 5 wt-% water.

[0133] Considering the stability of the agomelatine-containing layer with respect to its composition, it is preferable that the agomelatine-containing layer does not substantially comprise any volatile constituents, which bear the risk of evaporating and changing the composition upon storage. Thus, in certain embodiments, the agomelatine-containing layer comprises substantially no volatile solvent. A volatile solvent in this sense may be selected from the group consisting of Cl to C3 linear and branched alcohols, ethyl acetate, hexane, n-heptane, and any mixtures thereof. In view of the transmucosal therapeutic system being applied in the oral cavity, the volatile solvents include particularly those which should better not be digested such as methanol, ethyl acetate, hexane, n-heptane, and mixtures thereof. In particular, the agomelatine-containing layer comprises less than or equal to 5 wt-%, preferably less than or equal to 3 wt-%, and more preferably less than or equal to 1 wt-% volatile solvent.

[0134] As agomelatine has a low solubility in water, substantial amounts of water in the agomelatine-containing layer bear the risk of re-crystallization where the active is present in dissolved state. Thus, in certain embodiments, the agomelatine-containing layer comprises substantially no water, e.g. comprises less than or equal to 12 wt-%, less than or equal to 8 wt-%, less than or equal to 5 wt-%, or less than or equal to 4 wt-% water.

[0135] In certain embodiments, it is preferable that the agomelatine-containing layer does not comprise poly(acrylic acid), and preferably does not comprise a crosslinked polymer.

[0136] In certain embodiment, the agomelatine-containing layer does not comprise 1.50 wt-% or more of a mucoadhesive polymer. In particular, the mucoadhesive polymer is selected from the group consisting of poly(acrylic acid), polyhydroxyethylmethylacrylate, polyethylenepropylene glycol copolymer, xanthan gum, amylopectin, chitosan, and lectin.AGOMELATINE

[0137] In accordance with the invention, the mucoadhesive layer structure contains agomelatine in a therapeutically effective amount, and the mucoadhesive layer structure comprises an agomelatine-containing layer.

[0138] While in accordance with 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 and so on, as well as in the form of particles which may be in micronized form, crystalline form, and in particular in one of its polymorph forms, and / or in amorphous form, and in any hybrid type form of any of the aforementioned forms or a mixture thereof, it is preferred that the agomelatine is present in the free, dissociated form.

[0139] Further, in certain embodiments, the agomelatine is included in the agomelatine-containing layer in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorph forms, in an amorphous form, as a hydrate, a solvate, a hybrid type form of any of the foregoing forms or a mixture thereof.

[0140] In certain embodiments, the agomelatine-containing layer is obtainable (and / or is obtained) by incorporating the agomelatine in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorph forms, in an amorphous form, as a hydrate, a solvate, a hybrid type form of any of the foregoing forms or a mixture thereof.

[0141] The agomelatine in the agomelatine-containing layer may be (completely) dissolved, or the agomelatine-containing layer may comprise agomelatine particles, preferably constituted of agomelatine in its free, dissociated form, so that the agomelatine is present in dispersed form. Needless to say, if the agomelatine is present in dispersed form, the agomelatine-containing layer nonetheless may comprise agomelatine also in dissolved form, depending on the solubility of the active in the agomelatine-containing layer (which is e.g. saturated or super-saturated).

[0142] In a preferred embodiment, the agomelatine is completely dissolved, e.g. 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 present in dissolved form. It is also preferred that the agomelatine-containing layer is free of agomelatine crystals.

[0143] As outlined above, the amount of agomelatine in the transmucosal therapeutic system is believed to be important for a good release of the active, and can be e.g. adjusted by theagomelatine concentration. Thus, in certain embodiments, the concentration of agomelatine in the agomelatine-containing layer ranges from 3 to 10 wt-% agomelatine, from 4 to 9 wt-% agomelatine, or from 5 to 8 wt-% agomelatine of the agomelatine-containing layer.

[0144] In certain embodiments, the agomelatine has a purity of at least 95 %, preferably of at least 98 % and more preferably of at least 99 % as determined by quantitative HPLC.Quantitative HPLC may be performed with Reversed-Phase-HPLC with UV detection. In particular, the following conditions can be used if HPLC is performed isocratically:Column: RP Octadecyl phaseXTerra RP18 100 mm x 3.9 mm; 3.5 pm or equivalent Mobile phase: 0.06 molar KH2PO4 Buffer / acetonitril (60:40; v:v); pH 2.5 Gradient: isocraticFlux: 1.0 mlInjection volume: 20 plColumn temperature: 23 °CWavelength: 229 nm and 275 nmRun time: 5 min

[0145] The transmucosal therapeutic systems according to the present invention advantageously show an improved stability in terms of the agomelatine content as well as agomelatine degradation.

[0146] Thus, in certain embodiments, the agomelatine-containing layer contains initially (i.e. shortly after manufacture e.g. within one week) an amount of agomelatine of at least 95 %, preferably of at least 97 %, more preferably of at least 98 % and even more preferably of at least 99 % of the theoretical amount of agomelatine included in the agomelatine-containing layer. The theoretical amount of agomelatine is calculated from the agomelatine amount used for the coating composition and the (actual) area weight of the coated and dried agomelatine-containing layer of the tested transmucosal therapeutic system.

[0147] The agomelatine-containing layer may also contain initially a total amount of agomelatine-related degradation substances of less than 0.5 %, preferably of less than 0.2 %, more preferably of less than 0.1 % and even more preferably of less than 0.05 %.

[0148] In certain other embodiments, the transmucosal therapeutic system according to the present invention are stable upon storage, i.e. they may maintain the initial agomelatine content values or present low amounts of degradation products, as follows:

[0149] In one of such embodiments, the agomelatine-containing layer contains, after having been stored at 30 °C and 65 % relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, even more preferably at least 12 months and most preferably at least 18 months, an amount of agomelatine of at least 95 %, preferably of at least 97 % and more preferably of at least 98 % of the theoretical amount of agomelatine included in the agomelatine-containing layer.

[0150] The agomelatine-containing layer may also contain, after having been stored at 30 °C and 65 % relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, even more preferably at least 12 months and most preferably at least 18 months, a total amount of agomelatine-related degradation substances of less than 0.5 %, preferably ofless than 0.2 %, more preferably of less than 0.1 % and even more preferably of less than 0.05 %.

[0151] In one of such embodiments, the agomelatine-containing layer contains, after having been stored at 40 °C / 75 % RH for at least 3 months and preferably at least 6 months, an amount of agomelatine of at least 95 %, preferably of at least 96 %, more preferably of at least 97 % and even more preferably of at least 98 % of the theoretical amount of agomelatine included in the agomelatine-containing layer.

[0152] The agomelatine-containing layer may also contain, after having been stored at 40 °C / 75 % RH for at least 3 months and preferably at least 6 months, a total amount of agomelatine -related degradation substances of less than 0.1 % and even more preferably of less than 0.05 %.

[0153] The method for determining the agomelatine content and the total amount of agomelatine-related degradation substances is preferably conducted as described for Example 1.DISSOLVABLE FILM-FORMING AGENT

[0154] As outlined above, the transmucosal therapeutic system according to the present invention comprises a mucoadhesive layer structure comprising an agomelatine-containing layer comprising a dissolvable film-forming agent.

[0155] This dissolvable film-forming agent provides for sufficient cohesion of the agomelatine-containing layer as long as it is kept in dry state. According to certain embodiments, the dissolvable film-forming agent may also provide for sufficient adhesion to the mucosa once wet, i.e. when having been brought in contact with the mucosa. In such embodiments, but also in general, dissolvable film-forming agent may be selected from polymers providing for such properties. In such embodiments, the agomelatine-containing layer does not comprise 1.50 wt-% or more of poly(acrylic acid), or does not comprise poly(acrylic acid) at all. Further, in some embodiments, the agomelatine-containing layer does not comprise 1.50 wt-% or more of a mucoadhesive polymer selected from the group consisting of poly(acrylic acid), polyhydroxyethylmethylacrylate, polyethylene-propylene glycol copolymer, xanthan gum, amylopectin, chitosan, and lectin, or does not comprise any of such mucoadhesive polymers at all. Further, in some embodiments, the agomelatine-containing layer does not comprise 1.50 wt-% or more of a mucoadhesive polymer.

[0156] The film-forming agent is the primary control over the dissolution behavior of the agomelatine-containing layer. This is why the film-forming agent is “dissolvable”. This means in certain specific embodiments that the dissolvable film-forming agent, if casted into a film having an area weight of from 30 to 100 g / m2, or 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. The dissolvable film-forming agent, if casted into a film having an area weight of from 30 to 100 g / m2, or of 50 g / m2, may 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.Notably, the dissolvable film-forming agent, if casted into a film having an area weight of from 30 to 100 g / m2, or of 50 g / m2, may dissolve in more than 5 seconds and less than 5 hours,preferably in more than 30 seconds and less than 3 hours, more preferably more than 1 minute and less than 2 hours, and most preferably in more than 2 minutes and less than 1 hour.

[0157] Film-forming agents which are suitable as the dissolvable film-forming agent in accordance with the invention are e.g. selected from the group consisting of polymers such as polyvinylpyrrolidone (commercially available as Kollidon® 3 OF from BASF), methyl cellulose (commercially available as Methocel® from Colorcon), ethyl cellulose (commercially available as Ethocel® from Colorcon), hydroxyethyl cellulose (commercially available as Natrosol® 250 L from Ashland Industries), hydroxypropyl cellulose (commercially available as Klucel® from Ashland Industries), hydroxypropylmethyl cellulose (also known as hypromellose, commercially available as Pharmacoat® from Shin-Etsu), carboxymethyl cellulose sodium (uncrosslinked sodium salt of carboxymethyl cellulose also referred to as CMC or carmellose, commercially available as Blanose® from Ashland Industries), polyethylene glycol- polyvinyl acetate- and polyvinylcaprolactame-based graft copolymers (commercially available as Soluplus® from BASF), polyvinyl alcohol (commercially available as Mowiol® 4-88 from Kuraray), polyvinyl alcohol-polyethylene glycol copolymers (commercially available as Kollicoat® IR from BASF), polyvinylpyrrolidone-polyvinylacetate copolymers (also referred to as copovidones and commercially available e.g. as Kollidon® VA64 from BASF), polyethylene oxides, polyethylene glycols, methacrylic acid - methyl methacrylate copolymers (commercially available as Eudragit® LI 00, Eudragit® LI 2, 5, Eudragit® SI 00 and Eudragit® SI 2, 5 from Evonik), and methacrylic acid - ethyl methacrylate copolymers (commercially available as Eudragit® LI GO-55 and Eudragit® L30D55 from Evonik), and natural film-forming agents such as shellac, pectin, gelatine, alginate, pullulan and starch derivatives, and any mixtures thereof.

[0158] The dissolvable film-forming agent should be able not only to provide sufficient cohesion to the agomelatine-containing layer, but preferably provides a film that is not tacky in dry state so that the subject is able to touch and manipulate the agomelatine-containing layer, e.g. apply it to the oral mucosa, without the same adhering to the fingers. In addition, since the dissolvable film-forming agent is the primary control over the dissolution behavior of the agomelatine-containing layer which needs to be neither too fast nor too slow, the dissolvable film-forming agent is preferably soluble, dispersible or otherwise disintegrable in aqueous media, specifically in saliva, or, simplified, in water. On the other hand, in terms of ease of manufacture and for allowing a water-free process of manufacture, which is advantageous in terms of avoiding crystals, or re-crystallization of the active agent, film-forming agents that are soluble in other solvents such as C1-C3 alcohols, in particular ethanol, are also preferred. While it is therefore particularly preferable that the film-forming agent is soluble in both, water and ethanol, a high solubility may lead to the agomelatine-containing layer dissolving too quickly. Thus, selecting the film-forming agent is not a simple task.

[0159] The inventors have surprisingly found that, in view of the above, in certain embodiments, polymers such as polyvinylpyrrolidone, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose sodium, polyethylene glycol- polyvinyl acetate- and polyvinylcaprolactame-based graft copolymers, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymers, polyvinylpyrrolidone-polyvinylacetate copolymers, polyethylene oxides, polyethylene glycols, and any mixtures thereof are preferred for the dissolvable film-forming agents. Particularly preferred for thedissolvable film-forming agent are polymers such as polyvinylpyrrolidone, hydroxypropyl cellulose, polyethylene glycol- polyvinyl acetate- and polyvinylcaprolactame-based graft copolymers, polyvinylpyrrolidone-polyvinylacetate copolymers, and any mixtures thereof, and most preferably, the dissolvable film-forming agent is a hydroxypropyl cellulose or a polyvinylpyrrolidone, or a mixture thereof.

[0160] Hydroxypropyl cellulose is commercially available from Ashland under the brand name Klucel™ and is provided in several grades.

[0161] The grades differ from each other by molecular weight MW (as measured by GPC-size exclusion chromatography) and Brookfield viscosity (25 °C, LVF, Moisture Free), and are as follows:The HF grade has a MW of 1,150,000 and a Brookfield Viscosity of 1500-3000 (1 % in water), the MF grade has a MW of 850,000 and a Brookfield Viscosity of 4000-6500 (2 % in water), the GF grade has a MW of 370,000 and a Brookfield Viscosity of 150-400 (2 % in water), the JF grade has a MW of 140,000 and a Brookfield Viscosity of 150-400 (5 % in water), the LF grade has a MW of 95,000 and a Brookfield Viscosity of 75-150 (5 % in water), the EF grade has a MW of 80,000 and a Brookfield Viscosity of 300-600 (10 % in water), the ELF grade has a MW of 40,000 and a Brookfield Viscosity of 150-300 (10 % in water).

[0162] Thus, in certain embodiments, the hydroxypropyl cellulose has a molecular weight (as measured by GPC-size exclusion chromatography) of from 30,000 to 1,500,000, and more preferably, the hydroxypropyl cellulose has a molecular weight (as measured by GPC-size exclusion chromatography) selected frombetween 35,000 and 45,000, in particular 40,000between 75,000 and 85,000, in particular 80,000between 90,000 and 100,000, in particular 95,000between 130,000 and 150,000, in particular 140,000between 350,000 and 400,000, in particular 370,000,between 800,000 and 900,000, in particular 850,000between 1,100,000 and 1,200,000, in particular 1,150,000. Particularly preferred is hydroxypropyl cellulose having a molecular weight (as measured by GPC-size exclusion chromatography) of between 75,000 and 85,000, in particular 80,000.

[0163] The polyvinylpyrrolidone is preferably a soluble polyvinylpyrrolidone.

[0164] The term “soluble polyvinylpyrrolidone” refers to polyvinylpyrrolidone, also known as povidone, which is soluble with more than 10 % in at least ethanol, preferably also in water, diethylene glycol, methanol, n-propanol, 2-propanol, n-butanol, chloroform, methylene chloride, 2 -pyrrolidone, macrogol 400, 1,2 propylene glycol, 1,4 butanediol, glycerol, triethanolamine, propionic acid and acetic acid. Examples of polyvinylpyrrolidones which are commercially available include Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® 25, Kollidon® 30 and Kollidon® 90 F supplied by BASF, or povidone K90F. The different grades of Kollidon® are defined in terms of the K-Value reflecting the average molecular weight of the polyvinylpyrrolidone grades. Kollidon® 12 PF is characterized by a K-Value range of 10.2 to 13.8, corresponding to a nominal K-Value of 12. Kollidon® 17 PF is characterized by a K-Value range of 15.3 to 18.4, corresponding to a nominal K-Value of 17. Kollidon® 25 is characterized by a K-Value range of 22.5 to 27.0, corresponding to a nominal K-Value of 25, Kollidon® 30 ischaracterized by a K- Value range of 27.0 to 32.4, corresponding to a nominal K- Value of 30. Kollidon® 90 F is characterized by a K-Value range of 81.0 to 97.2, corresponding to a nominal K-Value of 90. Preferred Kollidon® grades are Kollidon® 12 PF, Kollidon® 30 and Kollidon® 90 F. For all grades and types of polyvinylpyrrolidone, it is preferred that the amount of peroxides is within certain limits, in particular, the peroxide amount is 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.

[0165] Within the meaning of this invention, the term “K-Value” refers to a value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the European Pharmacopoeia (Ph.Eur.) and USP monographs for “Povidone”.

[0166] Thus, in certain embodiments, the polyvinylpyrrolidone is selected from polyvinylpyrrolidones having a K-Value within a range selected from the group of ranges consisting of9 to 15, and preferably 10.2 to 13.8,15 to 20, and preferably 15.3 to 18.4,20 to 27, and preferably 22.5 to 27.0,27 to 35, and preferably 27.0 to 32.4, and75 to 110, and preferably 81.0 to 97.2,or any mixtures thereof, and more preferably is a polyvinylpyrrolidone having a K-Value within a range of 27.0 to 32.4 or of 81.0 to 97.2, and any mixtures thereof, and most preferably is a polyvinylpyrrolidone having a K-Value within range of 81.0 to 97.2.

[0167] In order to be able to provide sufficient cohesion to the agomelatine-containing layer, a certain amount of the dissolvable film-forming agent should be included. Thus, in certain preferred embodiments, the amount of the dissolvable film-forming agent is at least 65 wt-%, at least 70 wt-%, or at least 75 wt-%. On the other hand, the amount of the dissolvable filmforming agent may also be less than or equal to 90 wt-%, or less than or equal to 85 wt-%,. In certain embodiments, the amount of the dissolvable film-forming agent ranges from 65 to 90 wt-%, or from 75 to 85 wt-% of the agomelatine-containing layer.

[0168] Such a film-forming agent may be present as the dissolvable film-forming agent in the agomelatine-containing layer, but may also be contained in an optional overlay.FURTHER ADDITIVES

[0169] The agomelatine-containing layer of the transmucosal therapeutic system according to the invention may comprise further excipients or additives selected from the group consisting of fatty acids, sweeteners, flavoring agents, colorants, permeation enhancers, solubilizers, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffer reagents and further film-forming agents.

[0170] Such additives may be present in the agomelatine-containing layer in an amount of from 0.001 to 15 wt-% of the agomelatine-containing layer per additive. In a certain embodiment, the total amount of all additives is from 0.001 to 25 wt-% of the agomelatine-containing layer. Hereinafter, where a range for an amount of a specific additive is given, such a range refers to the amount per individual additive.

[0171] It should be noted that in pharmaceutical formulations, the formulation components are categorized according to their physicochemical and physiological properties, and in accordance with their function. This means in particular that a substance or a compound falling into one category is not excluded from falling into another category of formulation component. E.g. a certain polymer can be a crystallization inhibitor but also a tackifier. Some substances may e.g. be a typical softener but at the same time act as a permeation enhancer. The skilled person is able to determine based on his general knowledge in which category or categories of formulation component a certain substance or compound belongs to. In the following, details on the excipients and additives are provided which are, however, not to be understood as being exclusive. Other substances not explicitly listed in the present description may be as well used in accordance with the present invention, and substances and / or compounds explicitly listed for one category of formulation component are not excluded from being used as another formulation component in the sense of the present invention.

[0172] In view of the potentially stinging or irritating effect of agomelatine, substances that are able to mask or modify the taste, or which might alleviate the effect of agomelatine, are particularly preferred. For example, researchers have shown that certain fatty acids may reduce capsaicin-induced effects such as pain / itch.

[0173] 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.

[0174] The fatty acid may in particular be a saturated or unsaturated, linear or branched carboxylic acid comprising 4 to 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, linoelaidic acid, a -linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid. Particularly preferred are oleic acid or linoleic acid.

[0175] In terms of amount, the agomelatine-containing layer preferably comprises one or more fatty acids in an amount of at least 1 wt-%, more preferably at least 3 wt-%, and more preferably at least 4 wt-%. The agomelatine-containing layer may also comprise one or more fatty acids in an amount of less than or equal to 15 wt-%, preferably less than or equal to 12 wt-%, and more preferably less than or equal to 10 wt-%. Finally, the agomelatine-containing layer may also comprise one or more fatty acids in an amount of from 1 to 15 wt-%, preferably of from 3 to 12 wt-%, and more preferably of from 4 to 10 wt-%.

[0176] In certain preferred embodiments, the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of saccharose, glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidine, neotame, steviol glycosides, thaumatin and saccharin sodium. Particularly preferably, the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of saccharose, sucralose and saccharin sodium. In such a particularly preferred embodiment, i.e. wherein the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of sucralose, saccharose and saccharin sodium, the amount of the sweetener is at least 0.1 wt-%, at least 0.2 wt-% or at least 0.5 wt-%, and / or is less than or equal to 2.0 wt-%, lessthan or equal to 1.8 wt-% or less than or equal to 1.5 wt-%, and / or is from 0.1 to 2.0 wt-%, from 0.2 to 1.8 wt-%, or from 0.5 to 1.5 wt-% each.

[0177] In also preferred embodiments, the agomelatine-containing layer comprises one or more natural or artificial flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethylvanillin 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. wherein the agomelatine-containing layer comprises one or more flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, peppermint flavor and eucalyptol, the amount of the flavoring agent is at least 0.1 wt-%, preferably at least 0.3 wt-% and more preferably at least 0.4 wt-%, and / or is less than or equal to 10 wt-%, preferably less than or equal to 6 wt-%, and more preferably less than or equal to 4 wt-%, and / or is from 0.1 to 10 wt-%, preferably from 0.3 to 6 wt-%, and more preferably from 0.4 to 4 wt-% each, or the amount is at least 0.1 wt-%, preferably at least 0.5 wt-% and more preferably at least 0.7 wt-%, and / or is less than or equal to 15 wt-%, preferably less than or equal to 10 wt-%, and more preferably less than or equal to 8 wt-%, and / or is from 0.1 to 15 wt-%, preferably from 0.5 to 10 wt-%, and more preferably from 0.7 to 8 wt-% in total. Suitable flavoring agents are also commercially available from the company Mane, and any of those, which are identified by tonalities such as apple, caramel, chocolate, lemon, mint, etc. can be used as a flavoring agent in the present invention.

[0178] In certain embodiments, the agomelatine-containing layer comprises one or more colorants. Any colorant suitable for use in pharmaceutical / food applications can be included, in particular those admitted for use by the US FDA or by the European Agencies EFSA / EMA. Such colorants may be e.g. selected from the group consisting of titanium dioxide, brilliant blue FCF, indigo carmine, fast green FCF, erythrosine, allura red AC, tartrazine and sunset yellow FCF, curcumin, riboflavin, rivoflavin-5’ -phosphate, quinoline yellow, orange yellow S, cochineal, carminic acid, azorubine, carmoisine, amaranth, ponceau 4R, cochineal red A, patent blue V, indigotine, chlorophylls, chlorophyllins, copper complexes of chlorophyll and chlorophyllins, green S, plain caramel, caustic sulphite caramel, ammonia caramel, sulphite ammonia caramel, brilliant black BN, black PN, vegetable carbon, brown HT, carotenes, annatto, bixin, norbixin, paprika extract, capsanthian, capsorubin, lycopene, beta-apo-8’-carotenal, lutein, canthaxanthin, beetroot red, betanin, anthocyanins, calcium carbonate, iron oxides and hydroxides, aluminium, silver, gold and litholrubine BK.

[0179] The agomelatine-containing layer may comprise one or more further film-forming agents in addition to those disclosed for the dissolvable film-forming agent above. Such a further film-forming agent is different from those disclosed previously for the dissolvable film-forming agent. The one or more further film-forming agents may be comprised in the agomelatine-containing layer in an amount of at least 2 wt-%, preferably at least 5 wt-% and more preferably at least 10 wt-%, and / or in an amount of less than or equal to 40 wt-%, preferably less than or equal to 30 wt-%, and more preferably less than or equal to 25 wt-%, and / or in an amount of from 2 to 40 wt-%, preferably from 5 to 30 wt-%, and more preferably from 10 to 25 wt-% each,and / or in an amount of at least 5 wt-%, preferably at least 15 wt-% and more preferably at least 20 wt-%, or in an amount of less than or equal to 40 wt-%, preferably less than or equal to 30 wt-%, and more preferably less than or equal to 25 wt-%, and / or in an amount of from 5 to 40 wt-%, preferably from 15 to 30 wt-%, and more preferably from 20 to 25 wt-% in total.

[0180] In certain embodiments, the agomelatine-containing layer comprises one or more solubilizers. Suitable solubilizers may be e.g. selected from the group consisting of ethoxylated sorbitan 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 oleosomes, propanediol and poly ethoxylated castor oil. Such solubilizers may be comprised in the agomelatine-containing layer in an amount of at least 0.3 wt-%, preferably at least 0.5 wt-% and more preferably at least 1.0 wt-%, and / or in an amount of less than or equal to 5 wt-%, preferably less than or equal to 4 wt-%, and more preferably less than or equal to 3 wt-%, and / or in an amount of from 0.3 to 5 wt-%, preferably of from 0.5 to 4 wt-%, and more preferably of from 1.0 to 3 wt-% each.

[0181] The agomelatine-containing layer may also comprise one or more emulsifiers. Such emulsifiers may for example be selected from the group consisting of soy 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 Chremophor RH 40 from BASF). Emulsifiers may be e.g. comprised in the agomelatine-containing layer in an amount of at least 1 wt-%, preferably at least 3 wt-% and more preferably at least 5 wt-%, and / or in an amount of less than or equal to 25 wt-%, preferably less than or equal to 20 wt-%, and more preferably less than or equal to 15 wt-%, and / or in an amount of from 1 to 25 wt-%, preferably of from 3 to 20 wt-%, and more preferably of from 5 to 15 wt-% each.

[0182] In specific embodiments, the agomelatine-containing layer comprises one or more plasticizers. The one or more plasticizer 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 wt-%, preferably at least 1 wt-% and more preferably at least 5 wt-%, and / or in an amount of less than or equal to 25 wt-%, preferably less than or equal to 20 wt-%, or more preferably less than or equal to 15 wt-%, and / or in an amount of from 0.5 to 25 wt-%, preferably of from 1 to 20 wt-%, and more preferably of from 5 to 15 wt-% each.

[0183] The agomelatine-containing layer may also comprise a permeation enhancer. In one embodiment, the agomelatine-containing layer comprises a permeation 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-Diethyl-meta-toluamide (DEET), propylene glycol monocaprylate, 2 -methoxy -4-(prop-2-en-l-yl)phenol and laurocapram. Such permeation enhancers can be comprised in the agomelatine-containing layer in an amount of at least 1 wt-%, preferably at least 2 wt-% and more preferably at least 5 wt-%, and / or in an amount of less than or equal to 20 wt-%, preferablyless than or equal to 15 wt-%, and more preferably less than or equal to 10 wt-%, and / or in an amount of from 1 to 20 wt-%, preferably of from 2 to 15 wt-%, and more preferably of from 5 to 10 wt-% each.

[0184] On the other hand, certain compounds which may be regarded as permeation enhancers are not preferable. Thus, in some embodiments, the agomelatine-containing layer does not comprise a permeation enhancer selected from the group consisting of bile acid, bile acid salts, bile acid derivatives, acyl carnitines, sodium dodecyl sulfate, dimethyl sulfoxide, sodium laurylsulfate, terpenes, cyclodextrins, cyclodextrin derivatives, saponins, saponin derivatives, chitosan, EDTA, citric acid, and salicylates in an amount of more than 5 wt-%, preferably more than 1 wt-%, more preferably more than 0.2 wt-%, and most preferably more than 0.1 wt-%.

[0185] 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 triacidic bases, buffer solutions with mixtures of a weak acid and its conjugate base, amine derivatives, inorganic alkali derivatives, polymers with basic and acidic functionality, respectively.PROCESS OF MANUFACTURE

[0186] The invention further relates to a process of manufacture of an agomelatine-containing layer for use in a transmucosal therapeutic system and a corresponding mucoadhesive layer structure comprising the agomelatine-containing layer and a corresponding transmucosal therapeutic system.

[0187] In accordance with the invention, the process of manufacture of an agomelatine-containing layer comprises the steps of:i) combining at least agomelatine and a dissolvable film-forming agent in a solvent to obtain a coating composition;ii) coating the coating composition onto a release liner; andiii) drying the coated coating composition to form the agomelatine-containing layer.

[0188] In such a process, suitable dissolvable film-forming agents are the same as those mentioned previously. Thus, in certain embodiments, the dissolvable film-forming agent, if casted into a film having an area weight 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 in less than 3 hours, more preferably in less than 2 hours, and most preferably in less than 1 hour, and / or in more than 5 seconds, preferably in more than 30 seconds, more preferably in more than 1 minute, and most preferably in more than 2 minutes, and / or 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.

[0189] The dissolvable film-forming agent may also be selected from the group consisting of polymers such as polyvinylpyrrolidone, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium, polyethylene glycol- polyvinyl acetate- and polyvinylcaprolactame-based graft copolymers, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymers, polyvinylpyrrolidone-polyvinylacetate copolymers, polyethylene oxides, polyethylene glycols, methacrylic acid -methyl methacrylate copolymers, and methacrylic acid - ethyl methacrylate copolymers, natural film-forming agents such as shellac, pectin, gelatine, alginate, pullulan and starch derivatives, and any mixtures thereof. The dissolvable film-forming agent preferably is selected from the group consisting of polymers such as polyvinylpyrrolidone, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium, polyethylene glycol- polyvinyl acetate- and polyvinylcaprolactame-based graft copolymers, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymers, polyvinylpyrrolidone-polyvinylacetate copolymers, polyethylene oxides, polyethylene glycols, and any mixtures thereof, and more preferably is selected from the group consisting of polymers such as polyvinylpyrrolidone, hydroxypropyl cellulose, polyethylene glycol- polyvinyl acetate-and polyvinylcaprolactame-based graft copolymers, polyvinylpyrrolidone-polyvinylacetate copolymers, and any mixtures thereof.

[0190] In particular embodiments, the dissolvable film-forming agent may be a hydroxypropyl cellulose, preferably a hydroxypropyl cellulose having a molecular weight of from 50,000 to 1,500,000, and more preferably the dissolvable film-forming agent is a hydroxypropyl cellulose having a molecular weight of 80,000, 95,000, 370,000 or 1,150,000.

[0191] In other particular embodiments, the dissolvable film-forming agent is a polyvinylpyrrolidone, preferably is selected from soluble polyvinylpyrrolidones, and in particular from polyvinylpyrrolidones having a K-Value within a range selected from the group of ranges consisting of9 to 15, and preferably 10.2 to 13.8,15 to 20, and preferably 15.3 to 18.4,20 to 27, and preferably 22.5 to 27.0,27 to 35, and preferably 27.0 to 32.4, and75 to 110, and preferably 81.0 to 97.2.

[0192] In this process of manufacture, in step i) the agomelatine may be dissolved or may be dispersed to obtain a coating composition.

[0193] Since agomelatine is poorly soluble in water and thus would be at risk of recrystallizing, it is preferred that no water is used. Thus, in a preferred embodiment, the solvent does not comprise water in an amount of more than 5 wt-%, preferably of more than 2 wt-%, more preferably of more than 1 wt-% and most preferably of more than 0.5 wt-%. On the other hand, depending on the solubility of the dissolvable film-forming agent to be used in different solvents, it may be of advantage to use water. Thus, in some embodiments, the solvent comprises water.

[0194] Thus, in the above described process, the solvent preferably comprises an alcoholic solvent selected from methanol, ethanol, isopropanol and mixtures thereof, and more preferably, the solvent comprises ethanol, or consists of ethanol.

[0195] The preferences for the dissolvable film-forming agent and other constituents of the agomelatine-containing layer are as outlined above. Thus, in one embodiment, step i) consists of combining at least agomelatine, a dissolvable film-forming agent, and one or more excipients selected from the group consisting of fatty acids, sweeteners, and flavoring agents, in a solvent to obtain a coating composition. Also, in step i), the agomelatine may be combined in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorph forms, in anamorphous form, as a hydrate, a solvate, a hybrid type form of any of the foregoing forms or a mixture thereof.

[0196] In step iii), drying is performed preferably in one or more cycles at room temperature and / or at a temperature of from 40 to 90 °C, more preferably of from 60 to 80 °C.

[0197] A mucoadhesive layer structure comprising the agomelatine-containing layer and a corresponding transmucosal therapeutic system can be manufactured using the above-outlined process, using further manufacturing steps such as punching out individual transmucosal therapeutic system and packaging, e.g. by sealing in a pouch of a primary packaging material, as known to the skilled person. Such further steps preferably lead to a mucoadhesive layer structure or a transmucosal therapeutic system as described in the previous chapters.

[0198] The present invention in particular also relates to agomelatine-containing layers as well as mucoadhesive layer structures and transmucosal therapeutic system obtainable (and / or obtained) by the above-described processes.EXAMPLES

[0199] The present invention will now be more fully described with reference to the accompanying examples. It should be understood, however, that the following description is illustrative only and should not be taken in any way as a restriction of the invention. Numerical values provided in the examples regarding the amount of ingredients in the composition or the area weight may vary slightly due to manufacturing variability.EXAMPLE 1: PREPARATION OF A TRANSMUCOSAL THERAPEUTIC SYSTEM Coating composition

[0200] The formulations of the agomelatine-containing coating compositions of Examples la, lb, 1c and Id are summarized in Table 1.1 below. The formulations are based on weight percent, as also indicated in Table 1.1.

[0201] For Examples la, lb and 1c, a vessel was loaded with Vanilla flavor, Sucralose, and Brilliant blue FCF. One part of the ethanol was added and the mass was stirred for at least 10 minutes. The Oleic acid and Hydroxypropyl cellulose EFP were then added while stirring and homogenized. Finally, agomelatine and the second part of the ethanol were added and the mixture was stirred. For Example Id, a vessel was loaded with Vanilla flavor, Sucralose and Brilliant blue FCF. One part of the ethanol was added and the mass was stirred for at least 10 minutes. The Oleic acid and an ethanolic / aqueous Carbopol solution were added and stirred. Hydroxypropyl cellulose EFP was then added while stirring and homogenized. An ethanolic Hydroxypropyl cellulose GFP solution was added and stirred for approximately 2 hours. Finally, agomelatine and the second part of the ethanol were added and the mixture was stirred.

[0202] Table 1.1Ingredient Ex. la Ex. lb Ex. 1c Ex. Id (Trade Name)Amt Solids Amt Solids Amt Solids Amt Solids [g] [%] [g] [%] [g] [%] [g] [%] Agomelatine 41.00 10.00 41.00 10.00 13.00 5.00 29.00 10.00 HPC EFP 315.29 76.90 315.29 76.90 212.94 81.90 176.09 60.72 HPC GFP - - - - - - 43.98 15.18 Vanilla flavor 8.20 2.00 8.20 2.00 5.20 2.00 5.80 2.00 Sucralose 4.10 1.00 4.10 1.00 2.60 1.00 2.90 1.00 Oleic acid 41.00 10.00 41.00 10.00 26.00 10.00 29.00 10.00 Brilliant blue FCF 0.41 0.10 0.410 0.10 0.26 0.10 0.29 0.10 Carbopol - - - - - - 2.90 1.00 Ethanol, absolute 1201.00 q.s. 1201.00 q.s. 761.61 q.s. 929.87 q.s. Aqua purificata - - - - - - 14.21 q.s. Total 1611.00 100.00 1611.00 100.00 1021.61 100.00 1234.04 100.00 Area weight [g / m2] 134 134 134 134 Dose per OTF [mg] 4 8 4 8 Agomelatine content 1.34 1.34 0.67 1.34 [mg / cm2]Di 3 6 6 6ecut size [cm2]Coating of the coating composition

[0203] The resulting agomelatine-containing coating composition of Examples la, lb, 1c and Id was coated on a polyester film (polyethylene terephthalate film, one side siliconized, 75 pm thickness, which may function as release liner) and dried for approx. 10 min at room temperature, 15 min at 40 °C, and 10 min at 70 °C. The coating thickness gave an area weight (without moisture) of 134 g / m2.

[0204] For Examples la, lb, 1c and Id, the dried film is the final agomelatine-containing mucoadhesive layer structure.Preparation of the transmucosal therapeutic system (concerning all examples)

[0205] Individual transmucosal therapeutic systems were then punched out from the agomelatine-containing mucoadhesive layer structure and sealed into pouches of the primary packaging material as conventional in the art.Storage stability measurements

[0206] A long term storage stability test was conducted for Examples la, lb, 1c and Id under the test condition of at 30 °C and 65 % relative humidity (RH). Samples were taken from the transmucosal therapeutic systems after 3 months, 6 months, 9 months, 12 months and 18 months storage at 30 °C and 65 % RH, the ethanol and water content was determined, and the amount of agomelatine, as well as various possible degradation substances was determined by a specific quantitative HPLC method based on the agomelatine content calculated from the (actual) area weight of the tested transmucosal therapeutic systems. The results are shown in Tables 1.2 to 1.5.

[0207] Table 1.2Ex. la Initial 3 months 6 months 9 months 12 months 18 months 30°C / 65 % RHDetected amounts: 96 98 98 98 98 96 Agomelatine [%]Detected amounts: n.d. n.d. n.d. n.d. n.d. n.d. Sum of possibledegradationsubstances [%]Ethanol (residual 0 n.t. n.t. n.t. n.t. n.t. solvent) [%]Water [wt-%] 3.1 3.5 3.5 3.3 3.1 3.6n.d. = not detected, n.t. = not tested, limit of quantitation = 0.05 %

[0208] Table 1.3Ex. lb Initial 3 months 6 months 9 months 12 months 18 months 30°C / 65 % RHDetected amounts: 97 96 97 97 98 97 Agomelatine [%]Detected amounts: n.d. n.d. n.d. n.d. n.d. n.d. Sum of possibledegradationsubstances [%]Ethanol (residual 1 n.t. n.t. n.t. n.t. n.t. solvent) [%]Water [wt-%] 2.7 3.1 2.9 3.6 3.2 3.3* n.d. = not detected, n.t. = not tested, limit of quantitation = 0.05 %

[0209] Table 1.4Ex. 1c Initial 3 months 6 months 9 months 12 months 18 months 30°C / 65 % RHDetected amounts: 96 97 97 97 98 96 Agomelatine [%]Detected amounts: n.d. n.d. n.d. n.d. n.d. n.d. Sum of possibledegradationsubstances [%]Ethanol (residual 1 n.t. n.t. n.t. n.t. n.t. solvent) [%]Water [wt-%] 3.2 3.1 3.0 3.3 3.4 3.4n.d. = not detected, n.t. = not tested, limit of quantitation = 0.05 %

[0210] Table 1.5Ex. Id Initial 3 months 6 months 9 months 12 months 18 months 30°C / 65 % RHDetected amounts: 95 98 97 96 97 95 Agomelatine [%]Detected amounts: n.d. n.d. n.d. n.d. n.d. n.d. Sum of possibledegradationsubstances [%]Ethanol (residual 1 n.t. n.t. n.t. n.t. n.t. solvent) [%]Water [wt-%] 3.1 3.1 3.2 3.6 3.5 3.5n.d. = not detected, n.t. = not tested, limit of quantitation = 0.05 %

[0211] A long term storage stability test was conducted for Examples la, lb, 1c and Id under the test condition of at 40 °C and 75 % relative humidity (RH). Samples were taken from the transmucosal therapeutic systems after 3 months and 6 months storage at 40 °C and 75 % RH, the ethanol and water content was determined, and the amount of agomelatine, as well as various possible degradation substances was determined by a specific quantitative HPLC method based on the agomelatine content calculated from the (actual) area weight of the tested transmucosal therapeutic systems. The results are shown in Tables 1.6 to 1.9.

[0212] Table 1.6Ex. la Initial 3 months 6 months 40 °C / 75 % RHDetected amounts: Agomelatine [%] 96 97 98 Detected amounts: Sum of possible n.d. n.d. n.d. degradation substances [%]Ethanol (residual solvent) [%] 0 n.t. n.t.3.1 3.1 3.4Water [wt-%]n.d. = not detected, n.t. = not tested, limit of quantitation = 0.05 %

[0213] Table 1.7Ex. lb Initial 3 months 6 months 40 °C / 75 % RHDetected amounts: Agomelatine [%] 97 96 97 Detected amounts: Sum of possible n.d. n.d. n.d. degradation substances [%]Ethanol (residual solvent) [%] 1 n.t. n.t.Water [wt-%] 2.7 3.3 3.0n.d. = not detected, n.t. = not tested, limit of quantitation = 0.05 %

[0214] Table 1.8Ex. 1c Initial 3 months 6 months 40 °C / 75 % RHDetected amounts: Agomelatine [%] 96 97 97 Detected amounts: Sum of possible n.d. n.d. n.d. degradation substances [%]Ethanol (residual solvent) [%] 1 n.t. n.t.Water [wt-%] 3.2 3.1 3.2n.d. = not detected, n.t. = not tested, limit of quantitation = 0.05 %

[0215] Table 1.9Ex. Id Initial 3 months 6 months 40 °C / 75 % RHDetected amounts: Agomelatine [%] 95 96 96 Detected amounts: Sum of possible n.d. n.d. n.d. degradation substances [%]Ethanol (residual solvent) [%] 1 n.t. n.t.Water [wt-%] 3.1 3.4 3.5n.d. = not detected, n.t. = not tested, limit of quantitation = 0.05 %

[0216] The stability data show that the initial as well as storage stability is excellent for the agomelatine-containing coating composition of Examples la to Id, both in terms of the amount of agomelatine (in particular with respect to the amount of agomelatine remaining after storage) as well as the sum of possible degradation substances.EXAMPLE 2: CLINICAL STUDY WITH TRANSMUCOSAL THERAPEUTIC SYSTEMS

[0217] In order to evaluate the delivery of agomelatine, phase I clinical studies were carried out with twenty healthy adult subjects (eleven males and nine females) under fasting condition. Preparation of Dose FormulationsDose Formulations Preparation (for transmucosal therapeutic systems)

[0218] The transmucosal therapeutic systems of Example la, lb, 1c and Id were used.Test systemSubjects enrolled in the study

[0219] Twenty subjects were enrolled in the fasting trial. All subjects were screened according to the inclusion and exclusion criteria, and all subjects signed informed consent prior to medical screening.

[0220] There was no subject withdrawal or substitution.Experimental design

[0221] A randomized, open, four-formulation, four-period, self-crossover design with a two-day washout period between periods was used. Twenty subjects were randomized into four groups, five subjects per group according to the sequence of administration, i.e.Ex.1 a-Ex. Ib-Ex.1 c-Ex.1 d group, Ex.1 d-Ex.1 a-Ex. Ib-Ex.1 c group, Ex.1 c-Ex.1 d-Ex.1 a-Ex. lb group and Ex. Ib-Ex.1 c-Ex. Id-Ex. la group.Dose ProcedureAdministration per period — Transmucosal therapeutic systems

[0222] Subjects were under fasting for at least 10 hours before administration. Subjects did not drink water within 1 hour before and after administration except for 20 mL room temperature water to moisten the mouth before administration.

[0223] A single dose of transmucosal therapeutic systems of Examples la to Id, prepared as described above, were folded prior to the application to reduce the size while increasing the area weight: size and area weight of the transmucosal therapeutic systems according to Ex. la, Ex. lb, Ex.lc and Ex. Id in clinical studies were therefore 3 cm2and 268 g / m2, 1.5 cm2and 268 g / m2, 3 cm2and 268 g / m2and 3 cm2and 268 g / m2, respectively. The folded transmucosal therapeutic systems were then administered sublingually to five subjects each for Examples la to Id (one system per subject) for each period.Sample collection, processing and analysis

[0224] Blood samples of approximately 4 mL were collected at 21 time points following application of the transmucosal therapeutic systems, as indicated in Table 2.1 below.

[0225] Blood plasma concentrations of agomelatine and hydroxylated agomelatine were determined using a validated LC-MS / MS method. The results are illustrated in Fig. 1 to 3. Results and discussion

[0226] There was no serious adverse event happened while five mild sub-adverse events that are possibly unrelated to the medication were observed in four subjects.

[0227] There were no breaches of deviations from the program.

[0228] Blood plasma concentrations of demethylated agomelatine were not detectable and therefore no valid pharmacokinetic parameters were obtained.

[0229] To reduce variability in results, samples from the same subject were analyzed in the same analytical batch.

[0230] For agomelatine, pharmacokinetic parameters of Cmax, tmax, ti / 2, AUCiast, AUCinf, and AUC(%ExtraP) were determined using non-compartmental modeling analysis (NCA) with the WinNonlin computer program and summarized in Table 2.1.

[0231] Table 2.1Elapsed time Agomelatine blood plasma concentration*[h] [ng / ml]Example la Example lb Example 1c Example Id (n = 20) (n = 20) (n = 20) (n = 20) Rate Rate Rate Rate 0.00 0.000 0.000 0.000 0.000 0.08 8.142 12.44 6.797 8.822 0.17 26.45 41.46 23.30 25.52 0.33 51.86 83.83 54.06 52.90 0.50 55.94 100.7 62.80 71.40 0.75 47.63 88.00 50.24 84.17 1.00 31.14 60.68 34.76 74.03 1.25 19.56 41.60 23.68 58.99 1.50 13.61 28.87 17.32 48.12 1.75 9.503 20.13 12.26 36.99 2.00 7.485 15.00 8.628 26.84 2.25 5.863 10.99 6.464 20.42 2.33 5.279 10.35 5.728 18.91 2.67 4.063 7.259 4.412 13.25 3.00 3.219 5.872 3.451 10.02 3.50 2.335 4.257 2.494 7.179 4.00 1.856 3.324 1.982 5.503 5.00 0.7493 1.328 0.7485 1.952 6.00 0.3452 0.6996 0.3967 0.8739 8.00 0.1239 0.2421 0.1201 0.2637 12.00 0.07386 0.09663 0.08448 0.07592 Cmax [ng / mL] 64.47±18.34 109.63±45.05 66.02±13.81 91.22±30.130.50 (0.17, 0.50 (0.17, 0.50 (0.33, 0.75 (0.33, tmax [h]** 0.75) 0.75) 1.00) 1.50) tl / 2 [h] 1.03±0.29 0.99±0.21 1.07±0.27 1.12±0.29 AUC(iast) [(ng / ml) h] 65.26±22.34 120.87±50.63 71.77±21.63 137.38±49.54 AUC(inf) [(ng / ml) h] 65.45±22.32 121.17±50.69 71.94±21.65 137.65±49.61 AUC(%Extrap) [%] 0.34±0.26 0.31±0.24 0.24±0.11 0.25±0.26 0.0019 0.0022 0.0018 0.0029Csh / Cmax* The lower limit of quantification for the assay of agomelatine is 0.05 ng / mL. if the measured blood concentration is below the lower limit of quantification, the value is taken as zero until the peak concentration is reached.** tmax is expressed as a median (min, max) value.

[0232] The maximum plasma concentrations of agomelatine were 64.47, 109.63, 66.02 and 91.22 ng / mL for the transmucosal therapeutic systems according to Example la, lb, 1c and Id, respectively.

[0233] Time to reach the maximum plasma concentrations of agomelatine was well below 1 hour for all formulations.

[0234] The area under the dose-response curve to the last measurable plasma concentration for the transmucosal therapeutic systems according to Examples la, lb, 1c and Id was 65.26, 120.87, 71.77 and 137.38 (ng / ml) h, respectively. The area under the dose-response curve extrapolated to infinity for the systems according to Examples la, lb, 1c and Id was 65.45, 121.17, 71.94 and 137.65 (ng / ml) h, respectively.

[0235] Ratio of the plasma concentration of agomelatine at 8 hours after administration (Csh) to the maximum plasma concentration of agomelatine (Cmax) for the transmucosal therapeutic systems according to Examples la, lb, 1c and Id was 0.0019, 0.0022, 0.0018 and 0.0029, respectively.

[0236] For hydroxylated agomelatine, the pharmacokinetic parameters of Cmax, tmax, ti / 2, AUCiast, AUCinf, and AUC(%ExtraP) were determined in the same way.

[0237] The maximum plasma concentrations of hydroxylated agomelatine were 0.03, 0.21, 0.03 and 0.10 ng / mL for the transmucosal therapeutic systems according to Example la, lb, 1c and Id, respectively.

[0238] Hydroxylated agomelatine was only detectable in four subjects and demethylated agomelatine could not be detected in any of the subjects. Significantly lower metabolites of agomelatine after administration of transmucosal therapeutic systems were observed compared with the data of Fang Tang et al. (Acta Pharmaceutics Sinica B (2016) 6(1), 71-78;“Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products of agomelatine in Chinese subjects”) obtained with forty -four healthy fasted Chinese adult male subjects after a single 25-mg oral dose of an agomelatine tablet, Valdoxan®.

[0239] The maximum plasma concentrations of agomelatine for the transmucosal therapeutic systems according to Example la, lb, 1c and Id were significantly higher than that of 5.74 (ng / mL) achieved for the single 25-mg dose of agomelatine tablets reported in Fang Tang et al.. The absence of multiple peaks on the agomelatine pharmacokinetic figure in most subjects in Fig. 1 and 2 indicates that the irregularity of peak attainment observed in agomelatine tablets in Fang Tang et al. was reduced.

[0240] The ratio of the maximum plasma concentration of the metabolites of agomelatine, a total of hydroxylated and demethylated agomelatine, to the maximum plasma concentration of agomelatine for the transmucosal therapeutic systems according to Examples la, lb, 1c and Id was 0.0005, 0.002, 0.0005 and 0.001, respectively. This is significantly lower than that of 8.2 achieved for the single 25-mg dose of agomelatine tablets reported in Fang Tang et al..

[0241] Time to reach the maximum plasma concentrations for the transmucosal therapeutic systems according to Example la, lb, 1c and Id were significantly faster than that of 1.22 (h) achieved for the single 25-mg dose of agomelatine tablets reported in Fang Tang et al.. This demonstrates that the rate of absorption of agomelatine for the administration of transmucosaltherapeutic systems was accelerated and that the transmucosal therapeutic systems provide excellent active pharmaceutical ingredient delivery.

[0242] The area under the dose-response curve to the last measurable plasma concentration for the systems according to Examples la, lb, 1c and Id was significantly greater than that of 7.99 ((ng / ml) h) achieved for the single 25-mg dose of agomelatine tablets reported in Fang Tang et al..

[0243] Higher AUC values of the transmucosal therapeutic systems according to Example la, lb, 1c and Id compared to that of the tablets reported in Fang Tang et al. indicate a higher degree of exposure of agomelatine and can be explained by the open system that allows agomelatine to be delivered through the mucosa of the total oral cavity, highlighting the improved efficacy of the inventive transmucosal therapeutic systems. The improved utilization of agomelatine achieved by the transmucosal therapeutic system of the present invention requires a smaller amount of the active pharmaceutical ingredient to achieve the same or even better therapeutic effect than with tablets.

[0244] The inter-individual coefficient of variation of the transmucosal therapeutic systems decreased significantly compared with that of the single 25-mg dose of agomelatine tablets reported in Fang Tang et al.: The inter-individual variation of Cmax and AUC for the transmucosal therapeutic systems was about 20-45 % and 30-45 %, respectively, whereas that for the single 25-mg dose of agomelatine tablets reported in Fang Tang et al. was 80 % and 60.10 %, respectively.The invention relates in particular to the following further items:1. Transmucosal therapeutic system for use in a method of treating a human subject, wherein the transmucosal therapeutic system provides a time to maximum plasma concentration of agomelatine (tmax) of less than 2h,wherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprisingA) at least an agomelatine-containing layer comprisingi) 3 to 10 wt-% agomelatine; andii) a dissolvable film-forming agent.2. Transmucosal therapeutic system for use in a method of treating a human subject, wherein the transmucosal therapeutic system provides a ratio of the plasma concentration of agomelatine at 8 hours after administration (Csh) to the maximum plasma concentration of agomelatine (Cmax) of at most 0.01, at most 0.008, at most 0.005, at most 0.003 or at most 0.002, wherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprisingat least an agomelatine-containing layer comprisingi) 3 to 10 wt-% agomelatine; andii) a dissolvable film-forming agent.3. Transmucosal therapeutic system for use in a method of treating a human subject, wherein the transmucosal therapeutic system provides a ratio of the maximum plasma concentration of metabolites of agomelatine to the maximum plasma concentration of agomelatine of less than 1, of less than 0.1 or of less than of 0.01,wherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprisingat least an agomelatine-containing layer comprisingi) 3 to 10 wt-% agomelatine; andii) a dissolvable film-forming agent.4. Transmucosal therapeutic system for use in a method of treating a human subject according to item 3,wherein the metabolites of agomelatine are a total of hydroxylated and demethylated agomelatine.5. Transmucosal therapeutic system for use in a method of treating a human subject according to items 1 to 4,wherein the transmucosal therapeutic system is in the form of a film.6. Transmucosal therapeutic system for use in a method of treating a human subject according to items 1 to 5,wherein the transmucosal therapeutic system is administered less than 2 hours before going to bed, less than 1 hour before going to bed, less than 30 minutes before going to bed or directly before going to bed.7. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 6,wherein the transmucosal therapeutic system further provides a tmax of at most 1.5 h, at most 1.25 h or at most 1.0 h.8. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 6,wherein the transmucosal therapeutic system further provides a Cmax in the range from 3 to 300 ng / mL, from 40 to 200 ng / mL or from 60 to 200 ng / mL.9. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 6,wherein the transmucosal therapeutic system further provides a Csh of at most 1.0 ng / mL or at most 0.4 ng / mL.10. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 6,wherein the transmucosal therapeutic system further provides an AUCiast from 5 to 300(ng h) / mL or from 50 to 200 (ng h) / mL.11. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 6,wherein the transmucosal therapeutic system further provides a ratio of AUC to total dose in the range from 1 to 50 (ng h) / (mL mg) or from 10 to 25 (ng h) / (mL mg).12. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 11,wherein the transmucosal therapeutic system has a total agomelatine content from 1 to 20 mg or from 2 to 10 mg.13. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 12,wherein the agomelatine-containing layer comprises at least 0.60 mg / cm2, at least 0.8 mg / cm2, at least 1.0 mg / cm2or at least 1.2 mg / cm2agomelatine.14. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 13,wherein the agomelatine-containing layer has an area weight in the range from 125 to 275 g / m2or from 150 to 250 g / m2.15. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 14,wherein the agomelatine-containing layer has an area of release in the range from 0.5 to 6 cm2or from 1 to 4 cm2.16. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 15,wherein the mucoadhesive layer structure comprises or does not comprise a mucosa-contacting layer.17. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 16,wherein the mucoadhesive layer structure comprises or does not comprise a cosmetic layer.18. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 17,wherein the transmucosal therapeutic system does not comprise a backing layer, and the backing layer in particular does not dissolve in less than 15 minutes, in less than 10 minutes, or in less than 5 minutes upon administration of the transmucosal therapeutic system to a human patient.19. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 18,wherein the transmucosal therapeutic system consists of one, two or more agomelatine-containing layers, or wherein the transmucosal therapeutic system consisting of two or more agomelatine-containing layers is obtainable by folding an agomelatine-containing layer onto itself.20. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 19,wherein the dissolvable film-forming agent is a polymer selected from the group consisting of polyvinylpyrrolidone, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose sodium, polyethylene glycolpolyvinyl acetate- and polyvinylcaprolactame-based graft copolymers, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymers, polyvinylpyrrolidone-polyvinylacetate copolymers, polyethylene oxides, polyethylene glycols, methacrylic acid - methyl methacrylate copolymers, and methacrylic acid - ethyl methacrylate copolymers, natural film-forming agents, and any mixtures thereof.21. Transmucosal therapeutic system for use in a method of treating a human subject according to item 20,wherein the natural film-forming agent is selected from the group consisting of shellac, amylopectin, lectin, pectin, gelatine, alginate, chitosan, xanthan gum, pullulan and starch derivatives, and any mixtures thereof.22. Transmucosal therapeutic system for use in a method of treating a human subject according to item 20,wherein the dissolvable film-forming agent is selected from cellulose derivatives.23. Transmucosal therapeutic system for use in a method of treating a human subject according to item 22,wherein the cellulose derivatives are selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose sodium and mixtures thereof.24. Transmucosal therapeutic system for use in a method of treating a human subject according to item 23,wherein the dissolvable film-forming agent is hydroxypropyl cellulose.25. Transmucosal therapeutic system for use in a method of treating a human subject according to item 24,wherein the dissolvable film-forming agent is a hydroxypropyl cellulose having a molecular weight of from 50,000 to 1,500,000, or of 80,000, 95,000, 370,000 or 1,150,000.26. Transmucosal therapeutic system for use in a method of treating a human subject according to item 25,wherein the dissolvable film-forming agent is a hydroxypropyl cellulose having a molecular weight of 80,000.27. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 26,wherein the amount of the dissolvable film-forming agent is at least 65 wt-%, at least 70 wt-% or at least 75 wt-%, or the amount of the dissolvable film-forming agent is less than or equal to 90 wt-% or less than or equal to 85 wt-%, or the amount of the dissolvable film-forming agent ranges from 65 to 90 wt-% or from 75 to 85 wt-% of the agomelatine-containing layer.28. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 27,wherein the dissolvable film-forming agent, if casted into a film having an area weight of from 30 to 100 g / m2, or 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 more than 5 seconds and less than 5 hours, in more than 30 seconds andless than 3 hours, more than 1 minute and less than 2 hours, or in more than 2 minutes and less than 1 hour.29. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 28, wherein the agomelatine-containing layer does not comprise polycarbophil.30. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 29, wherein the agomelatine-containing layer does not comprise 1.50 wt-% or more of a mucoadhesive polymer.31. Transmucosal therapeutic system for use in a method of treating a human subject according to item 30, wherein the mucoadhesive polymer is selected from the group consisting of poly(acrylic acid), polyhydroxyethylmethylacrylate, polyethylene oxide, polyvinyl alcohol, polyvinylpyrrolidone, thiolated polymers, cellulose derivatives such as hydroxypropyl methylcellulose, poloxamere, xanthan gum, amylopectin, chitosan, alginates, pectins, and lectins.32. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 31,wherein the agomelatine-containing layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, flavoring agents, colorants, permeation enhancers, solubilizers, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffer reagents and further film-forming agents.33. Transmucosal therapeutic system for use in a method of treating a human subject according to item 32, wherein the agomelatine-containing layer further comprises one or more taste masking agents selected from the group consisting of fatty acids, sweeteners and flavoring agents.34. Transmucosal therapeutic system for use in a method of treating a human subject according to item 33,wherein the fatty acid is a saturated or unsaturated, linear or branched carboxylic acid comprising 4 to 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, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid.35. Transmucosal therapeutic system for use in a method of treating a human subject according to item 34, wherein the agomelatine-containing layer comprises oleic acid.36. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 33 to 35,wherein the agomelatine-containing layer comprises one or more fatty acids in an amount of at least 1 wt-%, at least 3 wt-% or at least 4 wt-%, or in an amount of less than or equal to 15 wt-%, less than or equal to 12 wt-%, or less than or equal to 10 wt-%, or in an amount of from 1 to 15 wt-%, from 3 to 12 wt-%, or from 4 to 10 wt-%.37. Transmucosal therapeutic system for use in a method of treating a human subject according to item 32,wherein the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of saccharose, glucose, fructose, sorbitol, mannitol, isomalt maltitol lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidine, neotame, steviol glycosides, thaumatin and saccharin sodium.38. Transmucosal therapeutic system for use in a method of treating a human subject according to item 37, wherein the agomelatine-containing layer comprises sucralose.39. Transmucosal therapeutic system for use in a method of treating a human subject according to item 37,wherein the agomelatine-containing layer comprises sucralose in an amount of at least 0.1 wt-%, at least 0.2 wt-% or at least 0.5 wt-%, or in an amount of less than or equal to 2.0 wt-%, less than or equal to 1.8 wt-% or less than or equal to 1.5 wt-%, or in an amount of from 0.1 to 2.0 wt-%, from 0.2 to 1.8 wt-%, or from 0.5 to 1.5 wt-% each.40. Transmucosal therapeutic system for use in a method of treating a human subject according to item 32,wherein the agomelatine-containing layer comprises one or more natural or artificial flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethylvanillin and eucalyptol and flavoring compositions.41. Transmucosal therapeutic system for use in a method of treating a human subject according to item 40, wherein the flavoring composition is vanillin.42. Transmucosal therapeutic system for use in a method of treating a human subject according to item 40,wherein the the agomelatine-containing layer comprises vanillin in an amount of at least 0.1 wt-%, at least 0.3 wt-% or at least 0.4 wt-%, or in an amount of less than or equal to 10 wt-%, less than or equal to 6 wt-%, or less than or equal to 4 wt-%, or in an amount of from 0.1 to 10 wt-%, from 0.3 to 6 wt-%, or from 0.4 to 4 wt-% each, orin an amount of at least 0.1 wt-%, at least 0.5 wt-% or at least 0.7 wt-%, or in an amount of less than or equal to 15 wt-%, less than or equal to 10 wt-%, or less than or equal to 8 wt-%, or in an amount of from 0.1 to 15 wt-%, from 0.5 to 10 wt-%, or from 0.7 to 8 wt-% in total.43. Transmucosal therapeutic system for use in a method of treating a human subject according to item 32,wherein the agomelatine-containing layer comprises one or more colorants selected from the group consisting of titanium dioxide, brilliant blue FCF, indigo carmine, fast green FCF, erythrosine, allura red AC, tartrazine and sunset yellow FCF, curcumin, riboflavin, rivoflavin-5’-phosphate, quinoline yellow, orange yellow S, cochineal, carminic acid, azorubine, carmoisine, amaranth, ponceau 4R, cochineal red A, patent blue V, indigotine, chlorophylls, chlorophyllins, copper complexes of chlorophyll and chlorophyllins, green S, plain caramel, caustic sulphite caramel, ammonia caramel, sulphite ammonia caramel, brilliant black BN, black PN, vegetable carbon, brown HT, carotenes, annatto, bixin, norbixin, paprika extract, capsanthian, capsorubin, lycopene, beta-apo-8’-carotenal, lutein, canthaxanthin, beetroot red, betanin, anthocyanins, calcium carbonate, iron oxides and hydroxides, aluminium, silver, gold and litholrubine BK.44. Transmucosal therapeutic system for use in a method of treating a human subject according to item 32,wherein the agomelatine-containing layer comprises one or more further film-forming agents, wherein the further film-forming agents are different from the dissolvable film-forming agent.45. Transmucosal therapeutic system for use in a method of treating a human subject according to item 44,wherein the agomelatine-containing layer comprises one or more further film-forming agents in an amount of at least 2 wt-%, at least 5 wt-% or at least 10 wt-%, or in an amount of less than or equal to 40 wt-%, less than or equal to 30 wt-%, or less than or equal to 25 wt-%, or in an amount of from 2 to 40 wt-%, from 5 to 30 wt-%, or from 10 to 25 wt-% each, or in an amount of at least 5 wt-%, at least 15 wt-% or at least 20 wt-%, or in an amount of less than or equal to 40 wt-%, less than or equal to 30 wt-%, or less than or equal to 25 wt-%, or in an amount of from 5 to 40 wt-%, from 15 to 30 wt-%, or from 20 to 25 wt-% in total.46. Transmucosal therapeutic system for use in a method of treating a human subject according to item 32,wherein the agomelatine-containing layer comprises one or more solubilizers selected from the group consisting of ethoxylated sorbitan esterified with fatty acids such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan monooleate, safflower oleosomes, propanediol and poly ethoxylated castor oil.47. Transmucosal therapeutic system for use in a method of treating a human subject according to item 46,wherein the agomelatine-containing layer comprises one or more solubilizers in an amount of at least 0.3 wt-%, at least 0.5 wt-% or at least 1.0 wt-%, or in an amount of less than or equal to 5 wt-%, less than or equal to 4 wt-%, or less than or equal to 3 wt-%, or in an amount of from 0.3 to 5 wt-%, from 0.5 to 4 wt-%, or from 1.0 to 3 wt-% each.48. Transmucosal therapeutic system for use in a method of treating a human subject according to item 32,wherein the agomelatine-containing layer comprises one or more emulsifiers selected from the group consisting of soy lecithin, sodium phosphates, mono- and diglycerides of fatty acids, sodium stearoyl lactylate, diacetyl tartaric acid esters of mono- and diglycerides, andpoly ethoxylated hydrogenated castor oil.49. Transmucosal therapeutic system for use in a method of treating a human subject according to item 48,wherein the agomelatine-containing layer comprises one or more emulsifiers in an amount of at least 1 wt-%, at least 3 wt-% or at least 5 wt-%, or in an amount of less than or equal to 25 wt-%, less than or equal to 20 wt-%, or less than or equal to 15 wt-%, or in an amount of from 1 to 25 wt-%, from 3 to 20 wt-%, or from 5 to 15 wt-% each.50. Transmucosal therapeutic system for use in a method of treating a human subject according to item 32,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.51. Transmucosal therapeutic system for use in a method of treating a human subject according to item 50,wherein the agomelatine-containing layer comprises one or more plasticizers in an amount of at least 0.5 wt-%, at least 1 wt-% or at least 5 wt-%, or in an amount of less than or equal to 25 wt-%, less than or equal to 20 wt-%, or less than or equal to 15 wt-%, or in an amount of from 0.5 to 25 wt-%, from 1 to 20 wt-%, or from 5 to 15 wt-% each.52. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 51,wherein the agomelatine-containing layer comprises a permeation 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-meta-toluamide, propylene glycol monocaprylate, 2-methoxy-4-(prop-2-en-l-yl)phenol, lactic acid and1 aurocapram.53. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 52,wherein the agomelatine-containing layer comprises a permeation enhancer in an amount of at least 1 wt-%, at least 2 wt-% or at least 5 wt-%, or in an amount of less than or equal to 20 wt-%, less than or equal to 15 wt-%, or less than or equal to 10 wt-%, or in an amount of from 1 to 20 wt-%, from 2 to 15 wt-%, or from 5 to 10 wt-% each.54. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 53,wherein the agomelatine-containing layer comprises substantially no water.55. Transmucosal therapeutic system for use in a method of treating a human subject according to item 54,wherein the agomelatine-containing layer comprises less than or equal to 12 wt-%, less than or equal to 8 wt-%, less than or equal to 5 wt-%, or less than or equal to 4 wt-% water.56. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 55,wherein the agomelatine-containing layer comprises substantially no volatile solvent.57. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 56,wherein the volatile solvent is selected from the group consisting of Cl to C3 linear and branched alcohols, ethyl acetate, hexane, n-heptane, and any mixtures thereof.58. Transmucosal therapeutic system for use in a method of treating a human subject according to item 57,wherein the agomelatine-containing layer comprises less than or equal to 5 wt-%, less than or equal to 3 wt-%, or less than or equal to 1 wt-% volatile solvent.59. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 58,wherein the the agomelatine-containing layer is obtainable by drying a coated coating composition comprisingthe agomelatine, the dissolvable film-forming agent, and ethanol, orthe agomelatine, the dissolvable film-forming agent, and water, and / orthe agomelatine, the dissolvable film-forming agent, ethanol and water.60. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 59,wherein the agomelatine-containing layer is obtainable by drying a coated coating composition comprising less than 50 wt-%, or less than 20 wt-%, or less than 10 wt-%, or less than 5 wt-% water.61. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 60,wherein the agomelatine-containing layer is obtainable by incorporating the agomelatine in dissolved form, in dispersed form, in crystalline form, in particular in one of its polymorph forms, in an amorphous form, as a hydrate, a solvate, a hybrid type form of any of the foregoing forms or a mixture thereof.62. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 61,wherein the agomelatine in the agomelatine-containing layer is dissolved or is present in dispersed form.63. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 62,wherein at least 90 mol%, at least 95 mol%, at least 98 mol% and at least 99 mol% of the agomelatine in the agomelatine-containing layer is present in dissolved form.64. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 63,wherein the agomelatine-containing layer is free of agomelatine crystals.65. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 64,wherein the agomelatine has a purity of at least 95%, preferably of at least 98% and more preferably of at least 99% as determined by quantitative HPLC.66. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 65,wherein the mucoadhesive layer structure further comprises one or more further layers selected fromB) a mucosa-contacting layer, andC) a cosmetic layer,whereinthe further layers adjoin the agomelatine-containing layer, andthe mucosa-contacting layer and the cosmetic layer, if both are present, adjoin the agomelatine-containing layer on opposite sides.67. Transmucosal therapeutic system for use in a method of treating a human subject according to item 66, wherein the mucoadhesive layer structure does not comprise a mucosa-contacting layer.68. Transmucosal therapeutic system for use in a method of treating a human subject according to items 66 and 67, wherein the mucoadhesive layer structure does not comprise a cosmetic layer.69. Transmucosal therapeutic system for use in a method of treating a human subject according to items 66 and 67,wherein the mucoadhesive layer structure further comprises a cosmetic layer,wherein the cosmetic layer prevents the subject from touching the agomelatine-containing layer during administration of the transmucosal therapeutic system.70. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 65, wherein the mucoadhesive layer structure consists of the agomelatine-containing layer.71. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 70, wherein the agomelatine-containing layer is mucoadhesive.72. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 71, wherein the mucoadhesive layer structure contains agomelatine in a therapeutically effective amount.73. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 72,wherein the mucoadhesive layer structure dissolves in water, in artificial or natural saliva, or in 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.74. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 73, wherein the transmucosal therapeutic system does not comprise a backing layer.75. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 74,wherein the transmucosal therapeutic system is in the form of a film having a circular, rectangular or square shape.76. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 75, wherein the method of treatment is a method of treating major depression.77. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 76, wherein the method of treatment comprises administration of the transmucosal therapeutic system to the human subject.78. Transmucosal therapeutic system for use in a method of treating a human subject according to any one of items 1 to 77,wherein the administration of the transmucosal therapeutic system consists of applying the mucoadhesive layer structure to the buccal, sublingual, gingival or palatal mucosa of the oral cavity of the human subject and maintaining the same on the mucosa until dissolved.79. A method of treatment, wherein the transmucosal therapeutic system according to any one of claims 1 to 78 is administered to a human subject.80. A method of treating major depression according to item 79,wherein the transmucosal therapeutic system according to any one of claims 1 to 78 is administered to a human subject.81. A method of treatment according to items 79 or 80,wherein the transmucosal therapeutic system according to any one of items 1 to 78 is administered by applying the mucoadhesive layer structure to the mucosa of the oral cavity of the human subject and maintained on the mucosa until dissolved.82. A method of treatment according to item 81,wherein the transmucosal therapeutic system according to any one of items 1 to 78 is administered by applying the mucoadhesive layer structure to the mucosa, in particular to the buccal, sublingual, gingival or palatal mucosa, of the oral cavity of the human subject and maintained on the mucosa until dissolved.83. Use of the transmucosal therapeutic system according to any one of items 1 to 78, for the manufacture of a medicament for treating a human subject.84. Use of the transmucosal therapeutic system according to item 83, for the manufacture of a medicament for treating major depression.85. Use of the transmucosal therapeutic system according to items 83 or 84, for the manufacture of a medicament for treating a human patient by applying the mucoadhesive layer structure to the mucosa of the oral cavity of the human subject and maintaining it on the mucosa until dissolved.86. Use of the transmucosal therapeutic system according to item 85, for the manufacture of a medicament for treating a human patient by applying the mucoadhesive layer structure to the mucosa, in particular to the buccal, sublingual, gingival or palatal mucosa, of the oral cavity of the human subject and maintaining it on the mucosa until dissolved.87. Process of manufacture of a transmucosal therapeutic system comprising an agomelatine- containing layer according to any one of items 1 to 78 comprising the steps of:i) combining at least agomelatine and a dissolvable film-forming agent in a solvent to obtain a coating composition;ii) coating the coating composition onto a release liner; andiii) drying the coated coating composition to form the agomelatine-containing layer.88. A transmucosal therapeutic system for the transmucosal administration of agomelatine, obtainable by the process of manufacture according to item 87.89. Transmucosal therapeutic system for use in a method of treating a human subject, wherein the method of treatment is a method of treating major depression,wherein the transmucosal therapeutic system provides• a tmax of at most 1.5 h,• a ratio of Csh to C max of at most 0.008,• a ratio of Cmax of metabolites of agomelatine to Cmax of agomelatine of less than 1, • a Cmax in the range from 40 to 200 ng / mL,wherein the transmucosal therapeutic system• comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least an agomelatine-containing layer comprisingi) 3 to 10 wt-% agomelatine; andii) a dissolvable film-forming agent• has a total agomelatine content from 1 to 20 mg, and• consists of one, two or more agomelatine-containing layer.

Claims

CLAIMS1. Transmucosal therapeutic system for use in a method of treating a human subject, wherein the transmucosal therapeutic system provides a time to maximum plasma concentration of agomelatine (tmax) of less than 2 h,wherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprisingat least an agomelatine-containing layer comprisingi) 3 to 10 wt % agomelatine; andii) a dissolvable film-forming agent.

2. Transmucosal therapeutic system for use in a method of treating a human subject, wherein the transmucosal therapeutic system provides a ratio of the plasma concentration of agomelatine at 8 hours after administration (Csh) to the maximum plasma concentration of agomelatine (Cmax) of at most 0.01, at most 0.008, at most 0.005, at most 0.003 or of at most 0.002,wherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprisingat least an agomelatine-containing layer comprisingi) 3 to 10 wt % agomelatine; andii) a dissolvable film-forming agent.

3. Transmucosal therapeutic system for use in a method of treating a human subject, wherein the transmucosal therapeutic system provides a ratio of the maximum plasma concentration of metabolites of agomelatine to the maximum plasma concentration of agomelatine of less than 1, of less than 0.1 or of less than of 0.01,wherein the transmucosal therapeutic system comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprisingat least an agomelatine-containing layer comprisingi) 3 to 10 wt-% agomelatine; andii) a dissolvable film-forming agent.

4. The transmucosal therapeutic system for the use of claim 3, wherein the metabolites of agomelatine are a total of hydroxylated and demethylated agomelatine.

5. The transmucosal therapeutic system for the use of any of the preceding claims, wherein the transmucosal therapeutic system is administered less than 2 hours before going to bed, less than 1 hour before going to bed, less than 30 minutes before going to bed or directly before going to bed.

6. The transmucosal therapeutic system for the use of any of the preceding claims, wherein the transmucosal therapeutic system further provides one or more of the characteristics selected from the group consisting of:• a tmax of at most 1.5 h, of at most 1.25 h, and of at most 1.0 h,• a Cmax in the range from 3 to 300 ng / mL, from 40 to 200 ng / mL, and from 60 to 200 ng / mL,• a Csh of at most 1.0 ng / mL, and of at most 0.4 ng / mL,• an AUCiast from 5 to 300 (ng h) / mL, from 50 to 200 (ng h) / mL, and• a ratio of AUC to total dose in the range from 1 to 50 (ng h) / (mL mg), and from 10 to 25 (ng h) / (mL mg).

7. The transmucosal therapeutic system for the use of any of the preceding claims, wherein the transmucosal therapeutic system has a total agomelatine content from 1 to 20 mg, preferably from 2 to 10 mg.

8. The transmucosal therapeutic system for the use of any of the preceding claims, wherein the agomelatine-containing layer has consisting of:• an area weight in the range from 125 to 275 g / m2, preferably from 150 to 250 g / m2, and / or• an area of release in the range from 0.5 to 6 cm2, preferably from 1 to 4 cm2.

9. The transmucosal therapeutic system for the use of any of the preceding claims, wherein • the mucoadhesive layer structure comprises or does not comprise a mucosacontacting layer, and / or• the mucoadhesive layer structure comprises or does not comprise a cosmetic layer, and / or• the transmucosal therapeutic system does not comprise a backing layer, and the backing layer in particular does not dissolve in less than 15 minutes, in less than 10 minutes, or in less than 5 minutes upon administration of the transmucosal therapeutic system to a human subject, and / or• the transmucosal therapeutic system consists of one, two or more agomelatine- containing layers, preferably wherein the transmucosal therapeutic system consisting of two or more agomelatine-containing layers is obtainable by folding an agomelatine-containing layer onto itself.

10. The transmucosal therapeutic system for the use of any of the preceding claims, wherein the dissolvable film-forming agent is selected from the group consisting of polymers such as polyvinylpyrrolidone, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose sodium, polyethylene glycolpolyvinyl acetate- and polyvinylcaprolactame-based graft copolymers, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymers, polyvinylpyrrolidone-polyvinylacetate copolymers, polyethylene oxides, polyethylene glycols, methacrylic acid - methyl methacrylate copolymers, and methacrylic acid - ethyl methacrylate copolymers, and natural film-formingagents such as shellac, pectin, gelatine, alginate, pullulan and starch derivatives, and any mixtures thereof,preferably wherein the dissolvable film-forming agent is selected from cellulose derivatives, more preferably methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose sodium and mixtures thereof, most preferably wherein the dissolvable film-forming agent is hydroxypropyl cellulose.

11. The transmucosal therapeutic system for the use of any of the preceding claims, wherein the agomelatine-containing layer does not comprise poly(acrylic acid), preferably does not comprise a crosslinked polymer.

12. The transmucosal therapeutic system for the use of any of the preceding claims, wherein the agomelatine-containing layer further comprisesa taste masking agent, preferably a fatty acid, more preferably wherein the fatty acid is a saturated or unsaturated, linear or branched carboxylic acid comprising 4 to 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, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid, and / orone or more sweeteners, preferably one or more natural or artificial sweeteners selected from the group consisting of saccharose, glucose, fructose, sorbitol, mannitol, isomalt maltitol lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidine, neotame, steviol glycosides, thaumatin and saccharin sodium, and / ora flavoring agent preferably one or more natural or artificial flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethylvanillin and eucalyptol as well as flavoring compositions such as peppermint flavor.

13. The transmucosal therapeutic system for the use of any of the preceding claims, wherein the agomelatine-containing layer is obtainable by drying a coated coating composition comprisingthe agomelatine, the dissolvable film-forming agent, and ethanol, orthe agomelatine, the dissolvable film-forming agent, and water, and / orthe agomelatine, the dissolvable film-forming agent, ethanol and water, and / or wherein the agomelatine-containing layer is obtainable by drying a coated coating composition comprising less than 50 wt-%, or less than 20 wt-%, or less than 10 wt-%, or less than 5 wt-% water.

14. The transmucosal therapeutic system for the use of any of the preceding claims, wherein the agomelatine in the agomelatine-containing layer is dissolved or is present in dispersed form, and / orwherein the agomelatine-containing layer is free of agomelatine crystals.

15. The transmucosal therapeutic system for the use of any of the preceding claims, wherein the method of treatment is a method of treating major depression.

16. The transmucosal therapeutic system for the use of any of the preceding claims, wherein the transmucosal therapeutic system is administered by applying the mucoadhesive layer structure to the mucosa, and in particular to the buccal, sublingual, gingival or palatal mucosa, of the oral cavity of a human subject and maintained on the mucosa until dissolved.

17. The transmucosal therapeutic system for the use according to any one of the preceding claims,wherein the method of treatment is a method of treating major depression,wherein the transmucosal therapeutic system provides• a tmax of at most 1.5 h,• a ratio of Csh to C max of at most 0.008,• a ratio of Cmax of metabolites of agomelatine to Cmax of agomelatine of less thanl, • a Cmax in the range from 40 to 200 ng / mL,wherein the transmucosal therapeutic system• comprises a mucoadhesive layer structure, said mucoadhesive layer structure comprisingat least an agomelatine-containing layer comprisingi) 3 to 10 wt % agomelatine; andii) a dissolvable film-forming agent• has a total agomelatine content from 1 to 20 mg, and• consists of one, two or more agomelatine-containing layers.

Images