Transmucosal therapeutic system containing agomelatine

Abstract

The present invention relates to a transmucosal therapeutic system for transmucosal administration of agomelatine comprising a mucoadhesive layer structure containing a therapeutically effective amount of agomelatine, e.g., an agomelatine transmucosal therapeutic system for use in a treatment method, a treatment method comprising applying such an agomelatine transmucosal therapeutic system, and a process for manufacturing such a transmucosal therapeutic system.

Description

Technical Field

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

Background Art

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

Chemical Formula

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

[0004] 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-coated tablet containing a 25 mg dose, which is prescribed as an initial dose of 1 tablet taken at bedtime, with the option to double the dose if no improvement is seen. Agomelatine is the only antidepressant on the market with the above-mentioned mechanism of action.

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

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

[0007] Servier and Novartis made efforts to establish a sublingual dosage form of agomelatine, probably to avoid first-pass metabolism and the associated drawbacks outlined above (low oral bioavailability and hepatotoxicity). A placebo-controlled randomized trial was conducted using 1 and 2 mg (Servier) or 0.5 and 1 mg of sublingual tablets of agomelatine (Novartis). There are no published results regarding the Servier trial in 2008 / 2009. The Novartis study, which started in 2011 / 2011, showed that the efficacy of sublingual tablets of agomelatine was not superior to placebo and that at least hepatotoxicity was less, but it essentially ended in failure in that there was no clear dose-response relationship. One of the reasons for the failure of the trial seems to have been the marked irritating sensation caused by agomelatine when administered to the oral mucosa. As a result, the FDA decided not to approve this drug in the United States, even though it is superior to other active substances in the treatment of MDD.

[0008] Some patent applications from Servier indicate that the first approach to providing a novel dosage form, such as a tablet, also called an "orally dispersible" formulation, aimed to achieve rapid disintegration in a few minutes, such as less than 3 minutes or even less than 1 minute, probably to obtain a very rapid start of release and avoid, as much as possible, the disadvantages associated with enteral delivery and the liver's first-pass effect. A more recent approach included buccal formulations, such as suckable tablets, aimed at dissolving or disintegrating more slowly in the mouth to keep the concentration of agomelatine in the oral cavity at a low enough level to limit the stinging sensation. However, this bears the risk that the tablet will be swallowed prematurely by the patient, i.e., before all the active substance has been released. Next, bilayer or multilayer tablets containing a placebo core, for example, were proposed so that most of the active substance is released after some time and only the placebo core without the active substance remains, ensuring that active substance release is almost complete even if the patient swallows prematurely.

[0009] However, these orally dispersible formulations do not seem to completely solve the potential patient compliance problems induced by agomelatine, which causes a feeling of irritation, and premature tablet swallowing is not prevented, but only the effect is reduced. Depending on the timing of unintentional tablet swallowing, incomplete active substance release remains a risk. In addition, sucking on the tablet over a long period means that the patient has to hold an intrusive object in the mouth, which is disadvantageous in terms of patient compliance. Finally, the drug delivery mechanism of such orally dispersible formulations depends on the active substance that dissolves first in saliva (open system), which is the reason why it is very difficult to control drug concentration and, as a result, drug delivery. For all these reasons, currently, there may be no agomelatine formulations on the market other than the conventional oral tablets outlined above.

[0010] A transmucosal therapeutic system, or transmucosal delivery system (also sometimes called a buccal patch), consists of one or more thin layers that are applied to the oral mucosa, adhere, and deliver the drug over a period of time. The dosage form in the form of a thin film for application in the oral cavity may also be called an "oral thin film" or OTF, but an OTF is not necessarily intended to adhere to the mucosa. In a transmucosal therapeutic system, the active substance is contained in a soluble layer, and since the film adheres to the mucosa, active substance delivery is achieved by a combination of direct active substance release from the transmucosal therapeutic system to the mucosa and indirect active substance delivery via dissolution in saliva, as in the orally dispersible formulations outlined above. To prevent the indirect active substance delivery inherent in the open system, a backing layer may be employed, which helps to protect the active substance-containing layer from the rest of the oral cavity, particularly the environmental saliva. In any case, the OTF is advantageous compared to the orally dispersible formulations intended to be sucked, in that the film adhering to the mucosa does not move freely in the oral cavity, and the film is thin enough that it is usually not perceptible to the patient once applied, so it does not cause a negative feeling of having an intrusive object in the mouth.

[0011] However, the transmucosal treatment system is a relatively new form of drug delivery, which means that the knowledge of formulation technology is limited. Formulating a suitable dosage form for transmucosal delivery by OTF is difficult due to many aspects to be considered and problems to be solved. The main requirements of such a transmucosal treatment system are good adhesion and permeation of the active substance, combined with appropriate behavior and disintegration time. Also, the tactile sensation, i.e., the good feel in the mouth, and the stability of the film before application (i.e., low friability) are important. Due to the low solubility of agomelatine, it is difficult to formulate the substance, and as outlined above, the key problem is to address the irritating sensation caused by the active substance in the oral cavity. In addition, since agomelatine is mainly used for resynchronizing the circadian rhythm, the desired drug release profile is a rapid initial increase in drug delivery, followed by a preferably decreasing release only overnight.

[0012] To date, there is no commercially available agomelatine transmucosal treatment system, and the applicant is not aware of any research or investigation regarding such an agomelatine transmucosal treatment system.

[0013] In summary, there is a great need for an alternative administration of agomelatine that overcomes the disadvantages of the oral and sublingual administration routes. As outlined above, the transmucosal treatment system would be able to address these disadvantages.

[0014] Therefore, in the art, there is a need for an agomelatine transmucosal treatment system.

Summary of the Invention

[0015] An object of the present invention is to provide an agomelatine transmucosal treatment system as an alternative administration of agomelatine that overcomes the above-mentioned disadvantages of the current agomelatine administration.

[0016] Therefore, an object of the present invention is to provide an agomelatine transmucosal treatment system for the transmucosal administration of agomelatine that provides a particularly high permeation rate and is thus sufficient to achieve a therapeutically effective dose.

[0017] A further object of the present invention is to provide a drug release profile with a rapid initial increase and to provide an agomelatine transmucosal therapeutic system for the transmucosal administration of agomelatine that allows for overnight application suitable for administration just before bedtime, for example.

[0018] A further object of the present invention is also to provide an agomelatine transmucosal therapeutic system for the transmucosal administration of agomelatine that does not cause irritating sensations in the mucosa or otherwise in the oral cavity.

[0019] Another object of the present invention is to provide an agomelatine transmucosal therapeutic system for the transmucosal administration of agomelatine that provides appropriate adhesion to the mucosa, for example, not only initially but also over time.

[0020] One further object of the present invention is to provide an agomelatine transmucosal therapeutic system for the transmucosal administration of agomelatine that provides appropriate disintegration behavior not only with respect to, for example, disintegration time but also with respect to the integrity of the transmucosal therapeutic system (when multiple layers are present, the layers do not fall apart prematurely).

[0021] Another object of the present invention is to provide an agomelatine transmucosal therapeutic system for the transmucosal administration of agomelatine that has reduced hepatotoxicity and interindividual variability and increased bioavailability when compared to oral administration.

[0022] Also, one object of the present invention is to provide an agomelatine transmucosal therapeutic system for the transmucosal administration of agomelatine that provides a good tactile sensation, i.e., a good feel in the oral cavity.

[0023] A further object of the present invention is to provide good patient compliance and / or to be easy to manufacture and cost-effective, in accordance with the need for convenient application and handling from the perspective of size and thickness, for the transmucosal administration of agomelatine, to provide an agomelatine transmucosal therapeutic system.

[0024] These and other objects are achieved by the present invention according to one aspect related to a transmucosal therapeutic system for the transmucosal administration of agomelatine comprising a mucoadhesive layer structure, said mucoadhesive layer structure comprising A) a backing layer; and B) i) agomelatine; and ii) an agomelatine-containing layer comprising a first soluble film-forming agent.

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

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

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

[0028] According to yet another particular aspect, the present invention relates to a process for the manufacture of an agomelatine-containing layer, said process comprising i) combining at least agomelatine and a first soluble film-forming agent in a solvent to obtain a first coating composition; ii) coating the first coating composition onto a release liner; and iii) drying the first coated coating composition to form an agomelatine-containing layer.

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

[0030] According to certain embodiments, the invention also relates to a transmucosal therapeutic system for the transmucosal administration of agomelatine comprising a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least A) a backing layer; and B) i) 3 to 7% by weight of agomelatine; ii) a first soluble film-forming agent, and iii) 5 to 15% by weight of a fatty acid, iv) 0.1 to 2.0% by weight of one or more sweeteners, and v) 0.2 to 2.0% by weight of a flavoring agent, and wherein the first soluble polymer is hydroxypropyl cellulose or a mixture of one or more polymers selected from hydroxypropyl cellulose and ethyl cellulose, the areal weight of the agomelatine-containing layer ranges from 100 to 150 g / m 2 and the backing layer comprises 5 to 15% by weight of a fatty acid, 0.1 to 2.0% by weight of one or more sweeteners, 0.2 to 2.0% by weight of a flavoring agent, and a second soluble film-forming agent, and the second soluble film-forming agent is a mixture of hydroxyethyl cellulose and hydroxypropyl cellulose, the areal weight of the backing layer ranges from 100 to 300 g / m 2 and

[0031] Within the scope of the meaning of the present invention, the terms "transmucosal therapeutic system" or "transmucosal delivery system" refer to a system in which an active agent (agomelatine) is administered into the systemic circulation via transmucosal delivery by application to the oral mucosa, which is applied to the patient's mucosa and contains a therapeutically effective amount of agomelatine in a mucoadhesive layer structure, and optionally includes an additional overlay on top of the agomelatine-containing mucoadhesive layer structure, referring to the entire individual dosage unit. The mucoadhesive layer structure may be located on a release liner (removable protective layer), and thus, the transmucosal therapeutic system may further include a release liner. Within the scope of the meaning of the present invention, the term "transmucosal therapeutic system" refers particularly to a system that provides passive transmucosal delivery, excluding active substance transport similar to methods including micro-poration. Also, in contrast to certain oral thin films (sometimes called "flash wafers") that are not necessarily mucoadhesive and are intended to disintegrate very rapidly in saliva, enteral delivery is not at all intended in the transmucosal therapeutic system.

[0032] Within the scope of the meaning of the present invention, the terms "agomelatine-containing mucoadhesive layer structure" or "mucoadhesive layer structure containing a therapeutically effective amount of agomelatine" refer to an active agent-containing structure that provides a release area for agomelatine during administration. Any additional overlay increases the overall size of the transmucosal therapeutic system but does not increase the release area. The agomelatine-containing mucoadhesive layer structure includes at least one agomelatine-containing layer.

[0033] Within the scope of the meaning of the present invention, the term "therapeutically effective amount" refers to the amount of the active agent in a transmucosal therapeutic system that is sufficient to provide agomelatine blood levels in a similar range (e.g., measured as AUC, about 10% to about 1000%) when compared to the blood levels obtained with a single oral administration of 25 mg of oral agomelatine when administered to a patient by the transmucosal therapeutic system.

[0034] Within the scope of the meaning of the present invention, terms such as "active substance" and "active agent", as well as the term "agomelatine", refer to agomelatine in any pharmaceutically acceptable chemical and morphological forms and physical states. These forms include, but are not limited to, the free, dissociated or any associated forms of agomelatine, such as hydrates, solvates, etc., as well as micronized forms, crystalline forms, and in particular one of its polymorphic forms, and / or the form of particles that can be in an amorphous form, and any hybrid-type forms of agomelatine of any of the foregoing forms or mixtures thereof. Agomelatine can be dissolved or dispersed, or partially dissolved and partially dispersed, when contained in a medium such as a solvent.

[0035] When it is mentioned that agomelatine is used in a specific form in the manufacture of a transmucosal therapeutic system, since this does not exclude the interaction between this form of agomelatine and the other components of the agomelatine-containing self-adhesive layer structure, the active substance is present in another form in the final transmucosal therapeutic system. This means that even if agomelatine is contained in the free, dissociated form, it can be present in the final transmucosal therapeutic system in the form of a hydrate or solvate, or if it is contained in one of its polymorphic forms, it can be present in the final transmucosal therapeutic system in an amorphous form. Unless otherwise indicated, in particular the amount of agomelatine in the mucoadhesive layer structure is related to the amount of agomelatine contained in the transmucosal therapeutic system during the manufacture of the transmucosal therapeutic system and is calculated based on the free form of agomelatine, that is, when agomelatine is contained in an amount of 0.1 mmol, the amount of agomelatine in the self-adhesive layer structure is considered, within the scope of the meaning of the present invention, to be 24.3 mg (the molecular weight of agomelatine is 243 g / mol), regardless of whether agomelatine was contained in its free form or any associated form in the transmucosal therapeutic system during the manufacture.

[0036] During the manufacture of the transmucosal treatment system, the agomelatine starting material contained in the transmucosal treatment system can be in the form of particles. Agomelatine can be present in the mucoadhesive layer structure in the form of particles, for example, dispersed and / or dissolved.

[0037] Within the scope of the present invention, the term "particle" refers to a particulate solid material containing individual particles, the dimensions of which are negligible compared to the material. In particular, the particles are solids including plastics / deformable solids, including amorphous and crystalline materials.

[0038] Within the scope of the present invention, the term "disperse" refers to a step or combination of steps in which the starting material (e.g., agomelatine) is not completely dissolved. Dispersion in the sense of the present invention includes partial dissolution of the starting material (e.g., agomelatine particles), depending on the solubility of the starting material (e.g., the solubility of agomelatine in the coating composition).

[0039] There are mainly two types of transmucosal treatment systems, namely those using a backing layer and those not using a backing layer. As outlined in the background art section of the introduction, the delivery of the active substance in an open-system type of transmucosal treatment system without a backing layer is always a combination of direct delivery from the transmucosal treatment system through the mucosa at the attachment site and indirect delivery through dissolution of the active substance from the transmucosal treatment system into saliva and from saliva through the mucosa. The proportion of the different delivery routes mainly depends on factors such as the solubility of the active substance and the disintegration time of the transmucosal treatment system. The higher the solubility of the transmucosal treatment system and the faster the disintegration, the more favorable the dissolution into saliva will be compared to direct delivery to the mucosa at the attachment site. Such indirect delivery has the advantage of providing an actual increase in the mucosal surface area through which the active substance is released systemically. However, dissolution into saliva means that it is difficult to control the concentration of the active substance and thus the final delivery amount, and the risk of enteral delivery due to unintentional swallowing of saliva is serious. In particular with regard to agomelatine, this also has the problem that the active substance, which has been proven to potentially provide a stimulating sensation, freely dissolves throughout the oral cavity.

[0040] Transmucosal therapeutic systems that use a backing layer have a completely different approach. In such systems, by using a backing layer, the delivery route is substantially restricted to direct transmucosal delivery, which can be much better controlled, reducing the risk of enteral delivery, and most advantageously, by restricting the dissolution of agomelatine in saliva, it is considered that the irritating sensations caused by this active substance can be substantially reduced. The challenge of transmucosal therapeutic systems that use a backing layer is still to provide sufficient transmucosal permeation and delivery of the active substance. Thus, in the context of the present invention, a "backing layer" is any layer within a transmucosal therapeutic system that can prevent the dissolution of (at least a substantial amount of) the active substance contained within the transmucosal therapeutic system into saliva. Such a backing layer can be insoluble or can be soluble over time. In the latter case, the time it takes for the backing layer to dissolve is at least as long as the time it takes for (a substantial amount of) the active substance to be delivered through the mucosa.

[0041] In this context, for any of the layers of the transmucosal treatment system (e.g., backing layer, active substance-containing layer), and for the film former when cast into a film, the terms "dissolve", "solubility", "dissolving", etc. are to be understood very broadly and not in the strict chemical sense of chemically dissolving molecules in a solvent. As long as the "dissolved" material can move freely in a liquid (e.g., saliva), and as a result, what is present under the layer (i.e., the mucosa when the mucosal contact layer dissolves, or the active substance-containing layer when the backing layer dissolves in front of the active substance-containing layer, for example) becomes accessible to the liquid other than the "dissolved" material, the conversion of the solid state of the layer to a liquid state, such as dispersion, formation of a suspension, gelation of the film, and disintegration of the gel into smaller parts, etc., must all be regarded as "dissolving" in the meaning of the present invention. In a preferred embodiment, the meaning is limited to the normal chemical meaning of dissolving molecules in a solvent. It should be noted that the term "dissolving" for substances themselves, such as the active agent agomelatine, or any excipient, etc., continues to be used in the normal chemical meaning of dissolving molecules in a solvent. For example, the dissolved form of agomelatine clearly does not include the dispersed form of agomelatine. The film former itself can be present in the coating composition in a dissolved form in the general chemical sense (e.g., not dispersed, in the form of small parts of a gel, etc.) during the manufacture of the transmucosal treatment system, but when the film former is cast into a film, "dissolving" such a film also includes gelation of the film and disintegration of the gel into smaller parts of the gel.

[0042] The active substance-containing layer is, for example, the final, solidified layer obtained after coating and drying a solvent-containing coating composition. The active substance-containing layer can also be manufactured by laminating two or more such solidified layers (e.g., dried layers) of the same composition to provide the desired areal weight. The active substance-containing layer can be mucoadhesive (in the form of a mucoadhesive layer), or the transmucosal treatment system can include an additional mucosal contact layer that is mucoadhesive to provide sufficient adhesion. In particular, the active substance-containing layer is a mucoadhesive layer.

[0043] Within the scope of the meaning of the present invention, the term "mucoadhesive" refers to a material that adheres particularly to and contacts the mucosa, but is preferably non-tacky when in a dry state, for example, can be touched with a finger, for example, can be manipulated for oral application without inadvertently adhering to the skin of the finger. The mucoadhesive layer is "self-adhesive" when in contact with the mucosa, i.e., provides an adhesive force to the mucosa such that typically no further assistance is required for fixation. The adhesion strength is preferably strong enough that typical movements within the oral cavity are not sufficient to displace the mucoadhesive layer adhered to the mucosa. The "mucoadhesive" layer structure may be provided in the form of a mucoadhesive agent-containing layer or in the form of an additional layer, i.e., a mucoadhesive layer for mucosal contact for mucosal contact. A mucoadhesive overlay may further be employed to improve the adhesive force.

[0044] Within the scope of the meaning of the present invention, the term "mucosal contact layer" refers to a layer contained in a transmucosal therapeutic system that directly contacts the patient's mucosa during administration. When the transmucosal therapeutic system includes a mucosal contact layer, the other layers do not contact the mucosa and do not necessarily have mucoadhesive properties. The release area is provided by the area of the agent-containing layer. The mucosal contact layer can be used to enhance the adhesive force. The sizes of the additional mucosal contact layer and the agent-containing layer usually have the same extent and correspond to the release region.

[0045] Within the scope of the meaning of the present invention, the term "areal weight" refers to the dry weight of a specific layer, for example, the agent-containing layer, provided in g / m 2 units. The areal weight values are subject to a tolerance of ±10%, preferably ±7.5%, due to variations during manufacturing.

[0046] Unless otherwise indicated, "%" refers to weight percent.

[0047] Within the scope of the meaning of the present invention, the term "polymer" refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, including homopolymers consisting of one type of monomer and copolymers consisting of two or more types of monomers. The polymer can have any structure such as a linear polymer, a star polymer, a comb polymer, a brush polymer, etc., and in the case of a copolymer, it can have any monomer arrangement, for example, an alternating, statistical, block copolymer, or a graft polymer. The minimum molecular weight varies depending on the type of polymer and is known to those skilled in the art. The polymer can have a molecular weight of, for example, more than 2,000 Daltons, preferably more than 5,000 Daltons, more preferably more than 10,000 Daltons. Correspondingly, a compound having a molecular weight of less than 2,000 Daltons, preferably less than 5,000 Daltons, or more preferably less than 10,000 Daltons is usually called an oligomer.

[0048] Within the scope of the meaning of the present invention, the term "cross-linking agent" refers to a substance that can cross-link functional groups contained in a polymer.

[0049] Within the scope of the meaning of the present invention, the term "mucoadhesive overlay" refers to a mucoadhesive layer that is located on top of the agomelatine-containing mucoadhesive layer structure, does not contain an active agent, has a larger area than the active agent-containing structure, provides an additional area for adhering to the mucosa, but does not provide an area for releasing the active agent. Thereby, the overall adhesion characteristics of the transmucosal therapeutic system are enhanced.

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

[0051] The in vitro permeation test is carried out using human or animal mucosa, preferably excised stratified porcine mucosa with a thickness of 400 μm and an intact barrier function, using phosphate buffer pH 5.5 or 7.4 as the receiving medium (37 °C), and up to 40% by volume of an organic solvent, such as ethanol, acetonitrile, isopropanol, dipropylene glycol, PEG400, may be added or not added so that the receiving medium may contain, for example, 60% by volume of phosphate buffer (pH 5.5), 30% by volume of dipropylene glycol and 10% by volume of acetonitrile.

[0052] Unless otherwise indicated, the in vitro permeation test is carried out using excised stratified porcine mucosa (esophageal mucosa) with a thickness of 400 μm and an intact barrier function, using phosphate buffer pH 7.4 as the receiving medium (37 °C). The amount of active substance permeated into the receiving medium is determined at regular intervals using HPLC with a UV photometric detector by sampling the sample volume. The measured amount of permeated active substance relates to the amount permeated between the last two sample collection time points and not to the total amount permeated up to that point.

[0053] Thus, within the scope of the meaning of the present invention, the parameter "amount of permeation" is provided in μg / cm 2 units and relates to the amount of active substance permeated at sample intervals over a specific elapsed time per unit area of release. For example, in the in vitro permeation test as described above where the amount of active substance permeated into the receiving medium is measured at time points of, for example, 0, 2, 4, 8, 12, and 24 hours, the "amount of permeation" of the active substance may be provided over the sample interval from the 8-hour time point to the 12-hour time point and corresponds to the measurement result at the 12-hour time point.

[0054] The permeation amount can also be provided as the "cumulative permeation amount" corresponding to the cumulative amount of the active substance permeated at a specific point in time. For example, in the in vitro permeation test as described above where the amount of the active substance permeated into the receiving medium was measured at time points of, for example, 0, 2, 4, 8, 12, and 24 hours, the "cumulative permeation amount" of the active substance at the 12-hour time point corresponds to the sum of the permeation amounts from the 0-hour time point to the 2-hour time point, from the 2-hour time point to the 4-hour time point, from the 4-hour time point to the 8-hour time point, and from the 8-hour time point to the 12-hour time point.

[0055] Within the scope of the present invention, the parameter of "mucosal permeation rate" regarding a specific sample interval at a specific elapsed time is provided in units of μg / (cm 2 h), and is calculated by dividing the permeation amount at the said sample interval measured by the in vitro permeation test as described above in units of μg / cm 2 by the time of the said sample interval. For example, in the in vitro permeation test as described above where the amount of the active substance permeated into the receiving medium was measured at time points of, for example, 0, 2, 4, 8, 12, and 24 hours, the "mucosal permeation rate" at the 12-hour time point is calculated as the permeation amount at the sample interval from the 8-hour time point to the 12-hour time point divided by 4 hours.

[0056] The "cumulative mucosal permeation rate" can be calculated from each cumulative permeation amount by dividing the cumulative permeation amount by the elapsed time. For example, in the in vitro permeation test as described above where the amount of the active substance permeated into the receiving medium was measured at time points of, for example, 0, 2, 4, 8, 12, and 24 hours, the "cumulative mucosal permeation rate" at the 12-hour time point is calculated as the cumulative permeation amount at the 12-hour time point (refer to the above) divided by 12 hours.

[0057] Within the scope of the present invention, the above parameters of permeation amount and mucosal permeation rate (as well as cumulative permeation amount and cumulative mucosal permeation rate) refer to the average value calculated from three in vitro permeation test experiments.

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

[0059] Within the scope of the meaning of the present invention, the term "administration" refers to the application of a dosage form to the oral mucosa of a patient, i.e., a transmucosal therapeutic system, which is then maintained on the mucosa until the agomelatine-containing layer structure dissolves.

[0060] In a typical continuous treatment for MDD, the frequency of drug administration is kept high enough to maintain a therapeutically effective plasma concentration. The interval between two administrations of the dosage form, also called the dosing interval, needs to be adjusted as appropriate. Within the scope of the meaning of the present invention, the term "dosing interval" refers to the period between two consecutive administrations, i.e., the interval between two consecutive time points when the transmucosal therapeutic system is applied to the oral mucosa of the patient. In order to always maintain the plasma concentration at the therapeutic level, the transmucosal therapeutic system must be replaced as soon as, or immediately after, the active agent-containing layer of the previous transmucosal therapeutic system has dissolved, at which point a new therapeutic system is applied. In such a manner (constant plasma level over 24 hours), the dosing interval approximately corresponds to the disintegration time of the active agent-containing layer and can be, for example, 6 hours, 8 hours, or 12 hours. After this period, the active agent-containing layer of the transmucosal therapeutic system dissolves, any residues (e.g., non-dissolvable backing layer) are removed from the oral cavity, and a new transmucosal therapeutic system is applied. Thus, a dosing interval of 12 hours enables a transmucosal therapeutic system replacement pattern of twice a day in a 24-hour treatment.

[0061] However, regarding continuous treatment with agomelatine, the transmucosal therapeutic system is usually administered once a day (24-hour dosing interval), preferably at bedtime, and the disintegration time will preferably be shorter than the dosing interval. The transmucosal therapeutic system can be applied to the mucosa of the patient a little before going to bed (e.g., 5 to 30 minutes) especially in consideration of the delay in the onset of action of the drug. In the case of agomelatine, it seems that maintaining the plasma concentration at the therapeutic level for 24 hours is not necessary, or it may even be contraindicated for the resynchronization of the circadian rhythm. Therefore, 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, for example, the next morning. Thus, the patient does not need to apply the transmucosal therapeutic system, for example, throughout the day thereafter.

[0062] Within the meaning of the present invention, the term "room temperature" refers to the unmodified temperature found in the laboratory where the experiment is conducted, and is usually in the range of 15 to 35 °C, preferably about 18 to 25 °C.

[0063] Within the meaning of the present invention, the term "patient" refers to a subject presenting clinical signs of one or more specific symptoms suggesting the need for treatment, a subject being treated prophylactically or preventively against a pathological condition, or a subject having received a diagnosis of a pathological condition to be treated.

[0064] Within the meaning of the present invention, the term "pharmacokinetic parameter" refers to, for example, plasma curves obtained in clinical studies by single or multiple administrations of an agomelatine transmucosal therapeutic system to healthy human subjects, such as C max , C t and parameters that explain AUC t1-t2 . The pharmacokinetic parameters of individual subjects are summarized using arithmetic and geometric means, such as mean C max , mean AUC t , and mean AUC INF , as well as additional statistical values, such as the respective standard deviation and standard error, minimum value, maximum value, and median (midpoint) when the list of values is ranked. In the context of the present invention, pharmacokinetic parameters, such as C max , C t and AUC t1-t2 refer to arithmetic or geometric mean values, preferably geometric mean values. It is not possible to prevent the absolute mean values obtained for a particular transmucosal therapeutic system in clinical studies from varying to some extent from study to study. To enable comparison of absolute mean values between studies, a reference preparation, for example, any product based on the present invention in the future, can be used as an internal standard. A correction factor can be obtained using the comparison of AUC per release area of each reference preparation in previous and subsequent studies to take into account the differences between studies.

[0065] A clinical study according to the present invention refers to a study conducted in full compliance with the International Conference for Harmonization of Clinical Trials (ICH) as well as the Good Clinical Practices (GCP) and regulations of all applicable regions.

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

[0067] Within the scope of the present invention, the term "subject population" refers to at least 10 individual healthy human subjects.

[0068] Within the scope of the present invention, the term "geometric mean" refers to the mean of the log-transformed data that has been back-transformed to the original scale.

[0069] Within the scope of the present invention, the term "arithmetic mean" refers to the sum of all observations divided by the total number of observations.

[0070] Within the scope of the present invention, the parameter "AUC" corresponds to the area under the plasma concentration-time curve. The AUC value is proportional to the total amount of the active agent absorbed into the blood circulation and is therefore a measure of bioavailability.

[0071] Within the scope of the present invention, "AUC t1-t2 " as a parameter is provided in units of (ng / mL)h and relates to the area under the plasma concentration-time curve from the t1 time point to the t2 time point, and is calculated by the linear trapezoidal method.

[0072] Within the scope of the present invention, the parameter "C max " is provided in units of (ng / mL) and relates to the observed maximum plasma concentration of the active agent.

[0073] Within the scope of the present invention, the parameter "C" t is provided in units of (ng / mL) and relates to the plasma concentration of the active agent observed at time point t.

[0074] Within the scope of the present invention, the parameter "t" max is provided in units of hours and relates to the time point at which the C max value is reached. In other words, t max is the time point of the observed maximum plasma concentration.

[0075] Within the scope of the present invention, the parameter "t" lag is provided in units of hours and relates to the delay between the administration time (in the case of a transmucosal therapeutic system, the time when the transmucosal therapeutic system is first applied to the oral mucosa, i.e., t = 0) and the appearance time of a measurable plasma concentration. t lag can be estimated as the arithmetic mean value of the first time point at which a measurable (i.e., non-zero) plasma concentration of the active agent is obtained, or is represented by the median.

[0076] Within the scope of the present invention, the term "average plasma concentration" is provided in units of (ng / mL) and is the average of the individual plasma concentrations of the active agent, for example agomelatine, at each time point.

[0077] Within the scope of the present invention, the term "coating composition" refers to a composition containing all the components of a drug-containing layer in a solvent that can be coated on a backing layer or a release liner to form an active agent-containing layer upon drying.

[0078] Within the context of the preparation of the coating composition within the scope of the present invention, for example, dissolving the components of the coating composition such as the active agent, the term "dissolving" refers to the process of obtaining a solution that is transparent and contains no particles visible to the naked eye.

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

[0080] Within the scope of the meaning of the present invention, unless otherwise specified, the term "about" refers to an amount that is ±10% of the disclosed amount. In some embodiments, the term "about" refers to an amount that is ±5% of the disclosed amount. In some embodiments, the term "about" refers to an amount that is ±2% of the disclosed amount.

Brief Description of the Drawings

[0081]

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Mode for Carrying Out the Invention

[0082] Structure of the transdermal therapeutic system The present invention relates to a transdermal therapeutic system for the transdermal administration of agomelatine, comprising a mucoadhesive layer structure containing agomelatine.

[0083] The mucoadhesive layer structure contains a therapeutically effective amount of agomelatine and comprises a backing layer and an agomelatine-containing layer containing i) agomelatine and ii) a first soluble film-forming agent.

[0084] Therefore, a transdermal therapeutic system for the transdermal administration of agomelatine comprises a mucoadhesive layer structure containing a therapeutically effective amount of agomelatine, said mucoadhesive layer structure comprising A) a backing layer; and B) i) agomelatine; and ii) an agomelatine-containing layer containing a first soluble film-forming agent.

[0085] The transdermal therapeutic system of the present invention attempts to address, in particular, issues of patient compliance and the potential risk of hepatotoxicity by employing a backing layer. The backing layer protects the active substance from dissolution in saliva and is therefore thought to prevent unintended delivery via the gastrointestinal route and the irritating sensation caused by the active agent agomelatine on the mucosa.

[0086] As outlined above, the backing layer in the context of the present invention is any layer within the transmucosal therapeutic system that can prevent the dissolution of (at least a substantial amount of) the active substance contained within the transmucosal therapeutic system into saliva. Further details regarding the backing layer will be discussed in another chapter below.

[0087] In some specific embodiments, the mucoadhesive layer structure may further comprise C) a mucosa contact layer, and D) one or more additional layers selected from a decorative layer.

[0088] Thus, in certain embodiments, the mucoadhesive layer structure according to the present invention includes an additional mucosa contact layer. In other embodiments, the mucoadhesive layer structure according to the present invention does not include an additional mucosa contact layer. In such embodiments, however, and also in certain other embodiments, the agomelatine-containing layer may be mucoadhesive. The additional mucosa contact layer, if present, is mucoadhesive and provides (improved) adhesion between the mucoadhesive layer structure and the patient's mucosa during administration. The mucosa contact layer is provided immediately below the active agent-containing layer and thus forms an adhesive layer between the mucosa and the agomelatine-containing layer during administration. Considering manufacturing convenience and overall patch size limitations, the size of the agomelatine-containing layer and the size of the mucosa contact layer preferably have the same extent.

[0089] As shown above, the mucoadhesive layer structure may also include a decorative layer. In another embodiment, the mucoadhesive layer structure does not include a decorative layer.

[0090] In contrast to the mucosa contact layer, the decorative layer is located above the agomelatine-containing layer or above the backing layer and is not (necessarily) intended to contact the mucosa.

[0091] As a result, in some specific embodiments, the mucoadhesive layer structure may A) a mucosa contact layer, and B) one or more additional layers selected from a decorative layer, and if different layers are present, the order is as follows. Decoration layer Backing layer Agomelatine-containing layer Mucosal contact layer.

[0092] The decoration layer can provide decorative means such as coloring or printing, or can simply prevent the patient from touching the backing and agomelatine-containing layers during administration of the transmucosal therapeutic system. For such a protective function, it is preferable that the decoration layer completely covers the backing layer and the agomelatine-containing layer. Thus, in certain embodiments, the mucoadhesive layer structure further comprises a decoration layer, and the size of the backing layer and the size of the decoration layer have the same spread, or the decoration layer is larger in size than the backing layer and has an expanded surface area.

[0093] On the other hand, the decoration layer should not be confused with the backing layer. The decoration layer dissolves rapidly, and in certain embodiments, the decoration layer dissolves in water, artificial or natural saliva, or any other aqueous medium at 37 °C and 150 rpm in less than 3 minutes, less than 1 minute, or less than 30 seconds. The overall mucoadhesive layer structure, in certain embodiments, dissolves in water, artificial or natural saliva, or any other aqueous medium at 37 °C and 150 rpm in 10 minutes or more, preferably 15 minutes or more, more preferably 30 minutes or more, or 15 hours or less, preferably 12 hours or less, more preferably 10 hours or less, or between 10 minutes and 15 hours, preferably between 15 minutes and 12 hours, more preferably between 30 minutes and 10 hours.

[0094] From the viewpoint of ease of manufacture and also from the viewpoint of simplicity, in certain preferred embodiments, the transmucosal therapeutic system of the present invention does not include a mucosal contact layer or a decoration layer. Thus, in particular, the mucoadhesive layer structure can simply consist of a backing layer and an agomelatine-containing layer.

[0095] Thus, according to certain embodiments of the present invention, the transmucosal treatment system may further comprise a mucoadhesive overlay or may not comprise a mucoadhesive overlay, preferably does not comprise a mucoadhesive overlay. This mucoadhesive overlay is particularly larger than the agomelatine-containing mucoadhesive layer structure and is adhered thereto to enhance the adhesion characteristics of the entire transmucosal treatment system. The area of the mucoadhesive overlay increases the overall size of the transmucosal treatment system but does not increase the release area.

[0096] As outlined above, the transmucosal treatment system consists of one or more thin layers. Thus, in certain embodiments, the transmucosal treatment system is in the form of a film. Such a film may have a circular, rectangular or square shape.

[0097] The film preferably has a certain thickness. Otherwise, it is difficult to incorporate the required amount of active substance, and very thin films are not easy to manufacture, especially with regard to providing a uniform thickness. Thus, in certain embodiments, the transmucosal treatment system is in the form of a thin film having an area weight of at least 75 g / m 2 , preferably at least 100 g / m 2 , or more preferably at least 130 g / m 2 . Alternatively, when thickened, the transmucosal treatment system is in the form of a thin film having a layer thickness of at least 50 μm, preferably at least 75 μm, more preferably at least 100 μm. On the other hand, very thick films are perceived by the patient as an obstructive object in the oral cavity and are thus disadvantageous in terms of patient compliance. Thus, in certain embodiments, the transmucosal treatment system is 700 g / m 2 or less, preferably 600 g / m 2 or less, or more preferably 500 g / m 2It is in the form of a thin film having the following area weight. Or, with respect to thickness, the transmucosal therapeutic system is in the form of a thin film having a layer thickness of less than 800 μm, preferably less than 700 μm, more preferably less than 550 μm. In a preferred embodiment, the transmucosal therapeutic system is 75 - 700 g / m 2 , preferably 100 - 600 g / m 2 , or more preferably 130 - 500 g / m 2 in area weight, or is in the form of a thin film having a layer thickness of 50 - 800 μm, preferably 75 - 700 μm, more preferably 100 - 550 μm.

[0098] The transmucosal therapeutic system according to the present invention is usually stored in a sealed sachet without further protective means. However, the mucoadhesive layer structure may be located on a removable protective layer (release liner), which is removed immediately before application to the mucosa of the patient's mouth. Thus, the transmucosal therapeutic system may or may not further include a release liner. The transmucosal therapeutic system protected by the release liner is also usually stored in a sealed sachet. This packaging can be safe for children and / or easy to use for the elderly.

[0099] Agomelatine-containing layer As outlined in more detail above, the transmucosal therapeutic system according to the present invention includes a mucoadhesive layer structure including a backing layer and an agomelatine-containing layer.

[0100] Furthermore, the agomelatine-containing layer i) contains agomelatine; and ii) contains a first soluble film-forming agent.

[0101] The areal weight of the agomelatine-containing layer is one of the factors determining the amount of the active substance. To obtain a sufficient amount of the active agent, a certain thickness is required, and it is difficult to coat a very thin layer, especially with sufficient precision. On the other hand, a thick layer can not only cause discomfort in the oral cavity, but also be difficult to manufacture and may result in taking too much time to dissolve for the desired release profile. As a result of consideration, the agomelatine-containing layer has an areal weight of at least 25 g / m 2 and more preferably at least 35 g / m 2 or most preferably at least 40 g / m 2 or has an areal weight of 300 g / m 2 or less, more preferably 250 g / m 2 or less, or most preferably 200 g / m 2 or less, or preferably has an areal weight of 25 - 300 g / m 2 more preferably 35 - 250 g / m 2 or most preferably 40 - 200 g / m 2 With respect to the thickness of the agomelatine-containing layer, the agomelatine-containing layer has a layer thickness of at least 15 μm, preferably at least 25 μm, more preferably at least 35 μm, or preferably has a layer thickness of less than 550 μm, preferably less than 400 μm, more preferably less than 300 μm.

[0102] In a transmucosal therapeutic system comprising a backing layer, the delivery of the active substance is controlled by direct transmucosal delivery as described above, which, in a preferred embodiment, is the reason why the release area, i.e., the surface area of the agomelatine-containing layer, plays a decisive role in the control of the effective dose. To ensure that the patch does not peel off prematurely from the mucosa and to be able to include a sufficient amount of the active substance without the need to use a very thick film, a certain minimum size is required. On the other hand, if the release area is too large, the transmucosal therapeutic system becomes huge in size, the application and wearing become uncomfortable, and the patient compliance decreases. Considering this, in a certain embodiment of the present invention, the transmucosal therapeutic system has at least 0.1 cm2 and preferably at least 0.2 cm 2 or more preferably at least 0.5 cm 2 has a release area of, or 10 cm 2 or less, preferably 7 cm 2 or less, or more preferably 5 cm 2 or less has a release area of, or 0.1 to 10 cm 2 preferably 0.2 to 7 cm 2 or more preferably 0.5 to 5 cm 2 has a release area of.

[0103] As outlined above and without wishing to be bound by theory, a sufficient amount of the active agent included in the transmucosal treatment system is believed to be necessary to achieve certain advantageous features of the transmucosal treatment system according to the present invention, such as good in vitro permeation. On the other hand, if the amount of the active substance is too large, there are not only problems of undesirable storage stability such as recrystallization of the active substance when agomelatine is present in a dissolved form, but also potential irritating sensations in the oral cavity due to too high a drug concentration. The amount of agomelatine contained in the transmucosal treatment system can be controlled in two ways by adjusting the concentration and / or the areal weight of the agomelatine-containing layer. Details regarding the areal weight are as outlined above. Regarding the concentration, the agomelatine-containing layer contains at least 1% by weight of agomelatine, preferably at least 2% by weight of agomelatine, more preferably at least 3% by weight of agomelatine, or the agomelatine-containing layer contains 25% by weight or less of agomelatine, preferably 20% by weight or less of agomelatine, more preferably 10% by weight or less of agomelatine, or the agomelatine-containing layer contains 1 to 25% by weight or less of agomelatine, preferably 2 to 20% by weight or less of agomelatine, more preferably 3 to 10% by weight or less of agomelatine.

[0104] Therefore, in certain embodiments of the present invention, the agomelatine-containing layer has at least 0.1 mg / cm per release area 2 preferably at least 0.2 mg / cm 2or more preferably at least 0.4 mg / cm 2 of agomelatine, or the agomelatine-containing layer contains 2.0 mg / cm 2 or less, preferably 1.5 mg / cm 2 or less, or more preferably 1.2 mg / cm 2 or less of agomelatine, or the agomelatine-containing layer contains 0.1 to 2.0 mg / cm 2 , preferably 0.2 to 1.5 mg / cm 2 , or more preferably 0.4 to 1.2 mg / cm 2 of agomelatine.

[0105] Regarding the amount of the active substance, the mucoadhesive layer structure may contain at least 0.1 mg, preferably at least 0.2 mg, or more preferably at least 0.4 mg of agomelatine, or 20 mg or less, preferably 15 mg or less, or more preferably 10 mg or less of agomelatine, or 0.1 mg to 20 mg, preferably 0.2 mg to 15 mg, or more preferably 0.4 mg to 10 mg of agomelatine.

[0106] As outlined in more detail above, the correct dissolution behavior of the agomelatine-containing layer is very important for controlling the delivery route. The agomelatine-containing layer needs to dissolve / disintegrate sufficiently rapidly to ensure rapid release of the active substance. Thus, the agomelatine-containing layer dissolves in, for example, water, artificial or natural saliva, or 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, most preferably in less than 1 hour. However, if the agomelatine-containing layer dissolves much faster than it actually permeates transmucosally, there is a risk that the dissolved substance leaks into the saliva and that the backing layer peels off. Thus, if dissolution is too fast, the risk of inadvertently swallowing a substantial part of the active substance is high. The so-called "flash wafer" is a film designed to disintegrate very rapidly to achieve enteral delivery, and swallowing is intentional (easier in comparison to tablets). The transmucosal therapeutic system of the present invention, unlike the flash wafer by its delivery mechanism, usually takes longer to dissolve than the flash wafer. In certain circumstances of agomelatine as an active substance, a high concentration of the active substance is not desirable because of the risk of a stinging sensation. This is another reason why dissolution preferably is not too fast. Thus, the agomelatine-containing layer can dissolve in, for example, water, artificial or natural saliva, or any other aqueous medium, at 37 °C and 150 rpm, in more than 5 seconds, preferably in more than 30 seconds, more preferably in more than 1 minute, most preferably in more than 2 minutes. In a preferred embodiment, the agomelatine-containing layer dissolves in water, artificial or natural saliva, or any other aqueous medium, at 37 °C and 150 rpm, 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, most preferably in more than 2 minutes and less than 1 hour.

[0107] Since it is preferred that the agomelatine-containing layer can adhere directly to the mucosa, in certain preferred embodiments of the present invention, the agomelatine-containing layer is mucoadhesive.

[0108] As can be understood in more detail below, in certain embodiments, the coating composition for preparing the agomelatine-containing layer preferably uses ethanol as the solvent and does not use water. Thus, the agomelatine-containing layer according to the invention can be (and / or is) obtained by drying a coated coating composition comprising agomelatine, a soluble film-forming agent, and ethanol. On the other hand, certain soluble film-forming agents have high solubility in water but limited solubility in other solvents. Thus, there are also advantages to using water as the solvent, which is why the agomelatine-containing layer can be (and / or is) obtained by drying a coated coating composition comprising agomelatine, a soluble film-forming agent, and water. A combination of ethanol and water is also possible, i.e., the agomelatine-containing layer can also be (and / or is) obtained by drying a coated coating composition comprising agomelatine, a soluble film-forming agent, ethanol, and water. Regarding the amount of water, the agomelatine-containing layer can be (and / or is) obtained by drying a coated coating composition comprising less than 50% by weight, or less than 20% by weight, or less than 10% by weight, or less than 5% by weight of water.

[0109] Considering the stability of the agomelatine-containing layer with respect to its composition, the agomelatine-containing layer preferably does not contain volatile constituents that risk evaporating and changing the composition during storage. Thus, in certain embodiments, the agomelatine-containing layer is substantially free of volatile solvents. Volatile solvents in this context may be selected from the group consisting of methanol, 1-propanol, 2-propanol, ethyl acetate, hexane, n-heptane, and any mixtures thereof, preferably selected from the group consisting of C1-C3 straight and branched alcohols, ethyl acetate, hexane, n-heptane, and any mixtures thereof. Considering that the transmucosal therapeutic system is applied intraorally, volatile solvents particularly include solvents that should not be digested, such as methanol, ethyl acetate, hexane, n-heptane, and mixtures thereof. In particular, the agomelatine-containing layer contains 5 wt% or less, preferably 3 wt% or less, more preferably 1 wt% or less of volatile solvents.

[0110] Since agomelatine has low solubility in water, a substantial amount of water in the agomelatine-containing layer has a risk of recrystallization when the active substance is present in a dissolved state. Thus, in certain embodiments, the agomelatine-containing layer is substantially free of water, for example, contains 12 wt% or less, 8 wt% or less, 5 wt% or less, or 4 wt% or less of water.

[0111] Backing layer As outlined in more detail above, the transmucosal therapeutic system according to the invention comprises a mucoadhesive layer structure comprising a backing layer. In a preferred embodiment, the backing layer comprises a second film-forming solubility enhancer.

[0112] The backing layer prevents (at least a substantial amount of) the active substance from dissolving in saliva and thus, in certain embodiments, the time it takes for the backing layer to dissolve is at least the same as the time it takes for (at least a substantial amount of) the active substance to be delivered through the mucosa, for example, the same length of time as it takes for the active substance-containing layer to dissolve.

[0113] Thus, in certain embodiments, when the transmucosal treatment system is administered to a human patient, the backing layer dissolves in 5 minutes or more, preferably 10 minutes or more, more preferably 15 minutes or more, or 12 hours or less, preferably 8 hours or less, more preferably 4 hours or less, or between 5 minutes and 12 hours, preferably between 10 minutes and 8 hours, more preferably between 15 minutes and 4 hours.

[0114] The backing layer dissolves in water, artificial or natural saliva, or any other aqueous medium at 37°C and 150 rpm in 10 minutes or more, preferably 15 minutes or more, more preferably 30 minutes or more, or 15 hours or less, preferably 12 hours or less, more preferably 10 hours or less, or between 10 minutes and 15 hours, preferably between 15 minutes and 12 hours, more preferably between 30 minutes and 10 hours.

[0115] With respect to size, the backing layer can in particular be the same size as or larger than the agomelatine-containing layer. Thus, in certain embodiments, the backing layer and the agomelatine-containing layer have the same extent, while in other embodiments, the backing layer is larger than the agomelatine-containing layer and has an expanded surface area. A mucoadhesive layer structure having a backing layer and an agomelatine-containing layer of the same size is easier to manufacture because a two-layer sheet can be die-cut to provide the mucoadhesive layer structure, while a mucoadhesive layer structure in which the backing layer is larger than the agomelatine-containing layer is more difficult to manufacture, but also offers the advantage of less risk of leakage of the active substance because the edges of the active substance-containing layer are also covered by the backing layer.

[0116] The areal weight of the backing layer is important for controlling the dissolution behavior and function of the backing layer to protect the active substance from dissolving in saliva. To provide sufficient protection of the active substance and usually a dissolution time that is long enough, and thus of the same length as the dissolution time of the agomelatine-containing layer, which is necessary for at least the permeation of the active substance, a certain thickness is required. In addition, it is also difficult to coat a very thin layer, especially with sufficient precision. On the other hand, a thick layer can not only cause discomfort in the oral cavity, but also be difficult to manufacture and can result in taking too long to dissolve for a desired (e.g., overnight) application. As a result of the considerations, the backing layer has an areal weight of at least 50 g / m 2 , more preferably at least 75 g / m 2 , or most preferably at least 100 g / m 2 , or has an areal weight of 400 g / m 2 or less, more preferably 350 g / m 2 or less, or most preferably 300 g / m 2 or less, or preferably has an areal weight of 50 - 400 g / m 2 , more preferably 75 - 350 g / m 2 , or most preferably 100 - 300 g / m 2 .

[0117] As outlined above and without wishing to be bound by theory, using a backing layer to prevent the active substance from dissolving in saliva will eliminate or at least substantially reduce the irritating sensations induced by agomelatine in the oral cavity, and thus will lead to an improvement in patient compliance. Therefore, it is of course preferred that the backing layer contains substantially no agomelatine, e.g., less than 1%, preferably less than 0.5%, more preferably less than 0.1%, and most preferably less than 0.05% agomelatine.

[0118] Coating compositions for preparing the backing layer can use various solvents such as ethanol or water. Therefore, the backing layer according to the present invention can be obtained (and / or is obtained) by drying a coated coating composition containing a second soluble film-forming agent and ethanol. On the other hand, certain soluble film-forming agents have high solubility in water but limited solubility in other solvents. Therefore, there are also advantages in using water as the solvent, which is why the backing layer can be obtained (and / or is obtained) by drying a coated coating composition containing a second soluble film-forming agent and water. A combination of ethanol and water is also possible, that is, the backing layer can also be obtained (and / or is obtained) by drying a coated coating composition containing a second soluble film-forming agent, ethanol and water. Regarding the amount of water, the backing layer can be obtained (and / or is obtained) by drying a coated coating composition containing less than 50% by weight, or less than 20% by weight, or less than 10% by weight, or less than 5% by weight of water.

[0119] Considering the stability of the backing layer with respect to its composition, it is preferred that the backing layer does not contain volatile components that have a risk of evaporating and changing the composition during storage. Therefore, in certain embodiments, the backing layer is substantially free of volatile solvents. Volatile solvents in this sense can be selected from the group consisting of methanol, 1-propanol, 2-propanol, ethyl acetate, hexane, n-heptane, and any mixture thereof, preferably selected from the group consisting of C1-C3 linear and branched alcohols, ethyl acetate, hexane, n-heptane, and any mixture thereof. Considering that the transmucosal therapeutic system is applied intraorally, volatile solvents particularly include solvents that should not be digested, such as methanol, ethyl acetate, hexane, n-heptane, and mixtures thereof. In particular, the backing layer contains 5% by weight or less, preferably 3% by weight or less, more preferably 1% by weight or less of volatile solvents.

[0120] As outlined above, since agomelatine has low solubility in water, a substantial amount of water in the agomelatine-containing layer has a risk of recrystallization when the active substance is present in a dissolved state. Since the water present in the backing layer may move to the agomelatine-containing layer, in certain embodiments, the backing layer, particularly in combination with the transmucosal therapeutic system, is substantially free of water, for example, contains 12% by weight or less, 8% by weight or less, 5% by weight or less, or 4% by weight or less of water.

[0121] Agomelatine According to the present invention, the mucoadhesive layer structure contains agomelatine in a therapeutically effective amount, and the mucoadhesive layer structure includes an agomelatine-containing layer.

[0122] According to the present invention, the active agent agomelatine can be present in any form in the transmucosal therapeutic system, particularly in the agomelatine-containing layer, i.e., in its free, dissociated, or any associated form, such as a hydrate, solvate, etc., and in the form of particles that can be in a micronized form, crystalline form, and particularly one of its polymorphic forms, and / or amorphous form, and in the form of any hybrid type form of any of the aforementioned forms or a mixture thereof, but it is preferred that agomelatine is present in its free, dissociated form.

[0123] Furthermore, in certain embodiments, agomelatine is included in the agomelatine-containing layer in a dissolved form, dispersed form, crystalline form, particularly one of its polymorphic forms, amorphous form, as a hydrate, solvate, hybrid type form of any of the aforementioned forms, or a mixture thereof.

[0124] In certain embodiments, the agomelatine-containing layer can be obtained (and / or is obtained) by incorporating agomelatine in a dissolved form, dispersed form, crystalline form, particularly one of its polymorphic forms, amorphous form, as a hydrate, solvate, hybrid type form of any of the aforementioned forms, or a mixture thereof.

[0125] The agomelatine in the agomelatine-containing layer can be (completely) dissolved, or the agomelatine-containing layer may preferably contain agomelatine particles composed of the free and dissociated form of agomelatine, and as a result, the agomelatine exists in a dispersed form. Needless to say, when the agomelatine exists in a dispersed form, the agomelatine-containing layer may still contain agomelatine in a dissolved form depending on the solubility of the active substance in the agomelatine-containing layer (e.g., saturated or supersaturated).

[0126] In a preferred embodiment, the agomelatine is completely dissolved, for example, at least 90 mol%, preferably at least 95 mol%, more preferably at least 98 mol% or most preferably at least 99 mol% of the agomelatine in the agomelatine-containing layer exists in a dissolved form. It is also preferred that the agomelatine-containing layer does not contain agomelatine crystals.

[0127] As outlined above, the amount of agomelatine in the transmucosal therapeutic system is considered important for the good release of the active substance and can be adjusted, for example, by the agomelatine concentration. Thus, in certain embodiments, the concentration of agomelatine in the agomelatine-containing layer ranges from 1 to 25 wt% of agomelatine in the agomelatine-containing layer, preferably 2 to 20 wt% of agomelatine, more preferably 3 to 10 wt% of agomelatine.

[0128] In certain embodiments, the agomelatine has a purity of at least 95%, preferably at least 98%, more preferably at least 99% when determined by quantitative HPLC. The quantitative HPLC can be performed by reverse-phase HPLC using UV detection. Specifically, when the HPLC is performed at a uniform concentration, the following conditions can be used: Column: RP octadecyl phase XTerra RP18 100mm×3.9mm; 3.5μm or equivalent Mobile phase: 0.06 mol KH2PO4 buffer / acetonitrile (60:40; v:v); pH 2.5 Gradient: Uniform concentration Flux: 1.0 ml Injection volume: 20 μL Column temperature: 23 °C Wavelength: 229 nm and 275 nm Run time: 5 minutes

[0129] The transdermal therapeutic system according to the present invention advantageously exhibits improved stability with respect to agomelatine content and agomelatine degradation.

[0130] Thus, in certain embodiments, the agomelatine-containing layer initially (i.e., immediately after manufacture, e.g., within 1 week) contains at least 95%, preferably at least 97%, more preferably at least 98%, even more preferably at least 99% of the theoretical amount of agomelatine contained in the agomelatine-containing layer. The theoretical amount of agomelatine is calculated from the amount of agomelatine used in the coating composition and the (actual) areal weight of the coated and dried agomelatine-containing layer of the transdermal therapeutic system tested.

[0131] The agomelatine-containing layer may also initially contain a total amount of agomelatine-related degradation products of less than 0.5%, preferably less than 0.2%, more preferably less than 0.1%, even more preferably less than 0.05%.

[0132] In certain other embodiments, the transdermal therapeutic systems according to the present invention are stable upon storage, i.e., they can maintain their initial agomelatine content values or present a minor amount of degradation products, which is as follows.

[0133] In one of such embodiments, the agomelatine-containing layer contains at least 95%, preferably at least 97%, more preferably at least 98%, even more preferably at least 99% of the theoretical amount of agomelatine contained in the agomelatine-containing layer after being stored at 25 °C and 60% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, most preferably at least 12 months.

[0134] The agomelatine-containing layer may also contain a total amount of agomelatine-related decomposition substances of less than 0.5%, preferably less than 0.2%, more preferably less than 0.1%, and even more preferably less than 0.05% after being stored at 25 °C and 60% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months.

[0135] In one of such embodiments, the agomelatine-containing layer contains at least 95%, preferably at least 97%, more preferably at least 98%, and even more preferably at least 99% of the theoretical amount of agomelatine contained in the agomelatine-containing layer after being stored at 40 °C / 75% RH for at least 3 months, preferably at least 6 months.

[0136] The agomelatine-containing layer may also contain a total amount of agomelatine-related decomposition substances of less than 0.5%, preferably less than 0.2%, more preferably less than 0.1%, and even more preferably less than 0.05% after being stored at 40 °C / 75% RH for at least 3 months, preferably at least 6 months.

[0137] The method for determining the agomelatine content, the total amount of agomelatine-related decomposition substances, as well as the adhesive force and the peel-off force is preferably carried out as described for Examples 9a and 9c.

[0138] The first and second soluble film formers As outlined above, the transmucosal therapeutic system according to the invention comprises a backing layer and a mucoadhesive layer structure comprising an agomelatine-containing layer containing i) agomelatine and ii) a first soluble film former, and the backing layer preferably contains a second soluble film former.

[0139] The first and (if present) second soluble film formers provide sufficient adhesion of the agomelatine-containing layer and the backing layer as long as the transmucosal therapeutic system is kept in a dry state. According to certain embodiments, the first soluble film former may also provide sufficient adhesion to the mucosa once wetted, i.e. when in contact with the mucosa. In such embodiments, however also generally, the first soluble film former may be selected from mucoadhesive polymers. The second soluble film former may or may not be selected from mucoadhesive polymers.

[0140] The film former is the main control over the dissolution behavior of the agomelatine-containing layer and the backing layer. This is why the film former is “soluble”.

[0141] In certain specific embodiments, when the first soluble film former is cast onto a film having an areal weight of 30 to 100 g / m 2 or 50 g / m 2 , it dissolves in water, artificial or natural saliva, or 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, most preferably in even less time. The first soluble film former also, when cast onto a film having an areal weight of 30 to 100 g / m 2 or 50 g / m 2 , may dissolve in water, artificial or natural saliva, or 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, most preferably more than 2 minutes. Notably, the first soluble film former also, when cast onto a film having an areal weight of 30 to 100 g / m 2 or 50 g / m 2 , may dissolve in more than 5 seconds and less than 5 hours, preferably more than 30 seconds and less than 3 hours, more preferably more than 1 minute and less than 2 hours, most preferably more than 2 minutes and less than 1 hour.

[0142] Film-forming agents suitable as the first and / or second soluble film-forming agents according to the present invention include, for example, polymers such as polyvinylpyrrolidone (commercially available from BASF as Kollidon® 30F), methylcellulose (commercially available from Colorcon as Methocel®), ethylcellulose (commercially available from Colorcon as Ethocel®), hydroxyethylcellulose (commercially available from Ashland Industries as Natrosol® 250L), hydroxypropylcellulose (commercially available from Ashland Industries as Klucel®), hydroxypropylmethylcellulose (also known as hypromellose, commercially available from Shin-Etsu as Pharmacoat®), sodium carboxymethylcellulose (the non-crosslinked sodium salt of carboxymethylcellulose, also called CMC or carmellose, commercially available from Ashland Industries as Blanose®), polyethylene glycol-polyvinyl acetate- and polyvinyl caprolactam-based graft copolymers (commercially available from BASF as Soluplus®), polyvinyl alcohol (commercially available from Kuraray as Mowiol® 4-88), polyvinyl alcohol-polyethylene glycol copolymers (commercially available from BASF as Kollicoat® IR), polyvinylpyrrolidone-polyvinyl acetate copolymers (also called copovidone, commercially available from BASF as Kollidon® VA64), polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymers (from Evonik, Eudragit® L100, Eudragit® L12,5, Eudragit® S100 and Eudragit® S12,(commercially available as 5), and methacrylic acid-ethyl methacrylate copolymers (commercially available from Evonik as Eudragit® L100-55 and Eudragit® L30D55), and natural film formers such as shellac, pectin, gelatin, alginates, pullulan and starch derivatives, and any mixtures thereof.

[0143] The first and second soluble film formers should not only be able to provide sufficient adhesion to the agomelatine-containing layer and the backing layer, but preferably also provide a film that is not sticky in the dry state so that the patient can touch and manipulate the transmucosal therapeutic system containing these layers, for example, apply it to the oral mucosa without it adhering to the finger. In addition, the first and second soluble film formers are the main control over the dissolution behavior of the agomelatine-containing layer and the backing layer, which should not be too fast or too slow. Therefore, the first and / or second soluble film formers are preferably soluble, dispersible or otherwise disintegratable in an aqueous medium, specifically saliva, or simply water. On the other hand, for ease of manufacture and to enable a water-free manufacturing process (which is advantageous in terms of avoiding crystallization or recrystallization of the crystals or the active agent), film formers that are soluble in other solvents such as C1-C3 alcohols, especially ethanol, are also preferred. Therefore, it is particularly preferred that the film former (first or second) is soluble in both water and ethanol, but a high solubility may cause the dissolution of the agomelatine-containing layer to be too rapid. Therefore, the selection of the film former is not an easy task.

[0144] The inventors have surprisingly found that, in view of the above, polymers such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol - polyvinyl acetate - and polyvinylcaprolactam - based graft copolymers, polyvinyl alcohol - polyethylene glycol copolymers, polyvinylpyrrolidone - polyvinyl acetate copolymers, polyethylene oxide, polyethylene glycol, methacrylic acid - methyl methacrylate copolymers, and methacrylic acid - ethyl methacrylate copolymers, and any mixtures thereof are preferred as the first soluble film - forming agent. The first soluble film - forming agent is particularly preferably hydroxypropylcellulose or a mixture of one or more polymers selected from hydroxypropylcellulose and ethylcellulose. On the other hand, the second soluble film - forming agent is preferably a mixture of hydroxyethylcellulose and hydroxypropylcellulose.

[0145] Hydroxypropylcellulose is commercially available under the brand name Klucel(™) from Ashland and is offered in several grades.

[0146] The grades differ by molecular weight MW (measured by GPC size - exclusion chromatography) and Brookfield viscosity (25 °C, LVF, moisture - free) and are as follows. The HF grade has an MW of 1,150,000 and a Brookfield viscosity of 1500 - 3000 (1% in water), The MF grade has an MW of 850,000 and a Brookfield viscosity of 4000 - 6500 (2% in water), The GF grade has an MW of 370,000 and a Brookfield viscosity of 150 - 400 (2% in water), The JF grade has an MW of 140,000 and a Brookfield viscosity of 150 - 400 (5% in water). The LF grade has an MW of 95,000 and a Brookfield viscosity of 75 - 150 (5% in water), The EF grade has an MW of 80,000 and a Brookfield viscosity of 300 - 600 (10% in water), The ELF grade has an MW of 40,000 and a Brookfield viscosity of 150 - 300 (10% in water).

[0147] Therefore, in certain embodiments, hydroxypropyl cellulose has a molecular weight (measured by GPC size exclusion chromatography) of 30,000 - 1,500,000, and in particular, hydroxypropyl cellulose is between 35,000 and 45,000, especially 40,000 between 75,000 and 85,000, especially 80,000 between 90,000 and 100,000, especially 95,000 between 130,000 and 150,000, especially 140,000 between 350,000 and 400,000, especially 370,000, between 800,000 and 900,000, especially 850,000, and has a molecular weight (measured by GPC size exclusion chromatography) selected from between 1,100,000 and 1,200,000, especially 1,150,000.

[0148] In view of the above, in certain preferred embodiments, the first soluble film - forming agent is hydroxypropyl cellulose, or a mixture of one or more polymers selected from hydroxypropyl cellulose having a molecular weight of 50,000 - 1,500,000 and ethyl cellulose, and more preferably, the first soluble film - forming agent is hydroxypropyl cellulose, or between 75,000 and 85,000, especially 80,000 between 90,000 and 100,000, especially 95,000 between 350,000 and 400,000, especially 370,000, and It is a mixture of one or more polymers selected from hydroxypropyl cellulose having a molecular weight between 1,100,000 and 1,200,000, particularly selected from 1,150,000, and ethyl cellulose. Most preferably, the first soluble film-forming agent is hydroxypropyl cellulose having a molecular weight between 90,000 and 100,000, particularly 95,000, or hydroxypropyl cellulose having a molecular weight between 75,000 and 85,000, particularly 80,000, hydroxypropyl cellulose having a molecular weight between 350,000 and 400,000, particularly 370,000, and a mixture of one or more polymers selected from ethyl cellulose, particularly a mixture of hydroxypropyl cellulose having a molecular weight between 75,000 and 85,000, particularly 80,000, and hydroxypropyl cellulose having a molecular weight between 350,000 and 400,000, particularly 370,000, or a mixture of hydroxypropyl cellulose having a molecular weight between 75,000 and 85,000, particularly 80,000, and ethyl cellulose.

[0149] Also in a preferred specific embodiment, the second soluble film-forming agent is a mixture of hydroxyethyl cellulose and a molecular weight of 50,000 to 1,500,000, particularly, between 75,000 and 85,000, particularly 80,000 between 90,000 and 100,000, particularly 95,000 between 350,000 and 400,000, particularly 370,000, and a mixture of hydroxypropyl cellulose having a molecular weight selected from between 1,100,000 and 1,200,000, particularly 1,150,000. More preferably, the second soluble film-forming agent is a mixture of hydroxyethyl cellulose and hydroxypropyl cellulose having a molecular weight between 75,000 and 85,000, particularly 80,000. In the present specification, the ratio of hydroxyethyl cellulose and hydroxypropyl cellulose having a molecular weight between 75,000 and 85,000, particularly 80,000, is preferably 1:2 to 8:1, more preferably 1:1 to 4:1, and most preferably 2:1.

[0150] Polyvinylpyrrolidone is preferably soluble polyvinylpyrrolidone.

[0151] The term "soluble polyvinylpyrrolidone" refers to polyvinylpyrrolidone, also known as povidone, which is soluble at more than 10% in at least ethanol, preferably in water, diethylene glycol, methanol, n-propanol, 2-propanol, n-butanol, chloroform, methylene chloride, 2-pyrrolidone, macrogol 400, 1,2 propylene glycol, 1,4 butanediol, glycerol, triethanolamine, propionic acid and acetic acid. Examples of commercially available polyvinylpyrrolidones include Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® 25, Kollidon® 30, and Kollidon® 90 F provided by BASF, or povidone K90F. Different grades of Kollidon® are defined in terms of the K value, which reflects the average molecular weight of the polyvinylpyrrolidone grade. 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, and Kollidon® 30 is characterized by a K value range of 27.0 to 32.4 corresponding to a nominal K value of 30. Kollidon® 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, the amount of peroxide is preferably within a certain restricted range. In particular, the amount of peroxide is 500 ppm or less, more preferably 150 ppm or less, and most preferably 100 ppm or less.

[0152] Within the meaning of the present invention, the term "K value" refers to a value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the European Pharmacopoeia (Ph.Eur.) and USP monographs for "povidone".

[0153] Thus, in certain embodiments, the polyvinylpyrrolidone is selected from polyvinylpyrrolidone having a K value within a range selected from the group of ranges consisting of 9 to 15, preferably 10.2 to 13.8, 15 to 20, preferably 15.3 to 18.4, 20 to 27, preferably 22.5 to 27.0, 27 to 35, preferably 27.0 to 32.4, and 75 to 110, preferably 81.0 to 97.2, more preferably polyvinylpyrrolidone having a K value within the range of 27.0 to 32.4 or 81.0 to 97.2 and any mixtures thereof, and most preferably polyvinylpyrrolidone having a K value within the range of 81.0 to 97.2.

[0154] In order to provide sufficient adhesion to the agomelatine-containing layer and the backing layer, a certain amount of the first and second soluble film formers should be included. Thus, in certain preferred embodiments, the amount of the first soluble film former is at least 65% by weight, more preferably at least 70% by weight, and most preferably at least 75% by weight of the agomelatine-containing layer. On the other hand, the amount of the first soluble film former can also be 98% by weight or less, 94% by weight or less, or 90% by weight or less of the agomelatine-containing layer. In certain embodiments, the amount of the first soluble film former ranges from 65 to 98% by weight, 70 to 94% by weight, or 75 to 90% by weight of the agomelatine-containing layer. In certain preferred embodiments, the amount of the second soluble film former is at least 65% by weight, more preferably at least 75% by weight, and most preferably at least 85% by weight of the backing layer. In certain embodiments, the amount of the second soluble film former ranges from 65 to 100% by weight, 75 to 100% by weight, or 85 to 100% by weight of the backing layer.

[0155] Such a film former may be present as the first and / or second soluble film former in the agomelatine-containing layer and / or the backing layer, but may also be contained in any overlay.

[0156] Further additives The agomelatine-containing layer and the backing layer of the transmucosal therapeutic system according to the invention may each contain further excipients or additives selected from the group consisting of fatty acids, sweeteners, flavoring agents, coloring agents, permeation enhancers, solubilizers, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffering reagents and further film formers.

[0157] Such additives may be present in the agomelatine-containing layer in an amount of 0.001 to 15% by weight of the agomelatine-containing layer per additive. In certain embodiments, the total amount of all additives is 0.001 to 25% by weight of the agomelatine-containing layer. Hereinafter, when ranges of amounts of specific additives are provided, such ranges refer to the amounts per individual additive.

[0158] In pharmaceutical preparations, it should be noted that formulation ingredients are categorized according to their physicochemical and physiological properties and according to their functions. This means, in particular, that a substance or compound classified in a certain category of formulation ingredients is not excluded from classification into another category. For example, a particular polymer can be a crystallization inhibitor but can also be a tackifier. Some substances can, for example, be typical plasticizers and at the same time act as permeation enhancers. A person skilled in the art can, based on their general knowledge, determine to which category(ies) of formulation ingredients a particular substance or compound belongs. Details of excipients and additives are provided below, but these should not be understood as being exclusive. Other substances not explicitly listed herein can also be used according to the present invention, and substances and / or compounds explicitly listed in one category of formulation ingredients are not excluded from use as another formulation ingredient in the context of the present invention.

[0159] Considering the potential stinging or irritating effects of agomelatine, substances that can mask or modify the taste, or substances that may reduce the effects of agomelatine, are particularly preferred. For example, researchers have shown that certain fatty acids can reduce capsaicin-induced effects such as pain / itching.

[0160] 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. The backing layer also preferably comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, and flavoring agents.

[0161] Fatty acids can in particular be saturated or unsaturated, linear or branched carboxylic acids containing from 4 to 24 carbon atoms, and in particular can be selected from the group consisting of caprylic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linolenic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid. Particular preference is given to oleic acid or linoleic acid.

[0162] With regard to the amount, the agomelatine-containing layer and / or the backing layer preferably contain one or more fatty acids in an amount of at least 1% by weight, more preferably at least 3% by weight, even more preferably at least 4% by weight. The agomelatine-containing layer and / or the backing layer can also contain one or more fatty acids in an amount of 15% by weight or less, preferably 12% by weight or less, more preferably 10% by weight or less. Finally, the agomelatine-containing layer and / or the backing layer can also contain one or more fatty acids in an amount of 1 to 15% by weight, preferably 3 to 12% by weight, more preferably 4 to 10% by weight.

[0163] In certain preferred embodiments, the agomelatine-containing layer and / or the backing layer contain one or more natural or artificial sweeteners selected from the group consisting of sucrose, glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidin, neotame, steviol glycosides, thaumatin and sodium saccharin. Particularly preferably, the agomelatine-containing layer contains one or more natural or artificial sweeteners selected from the group consisting of sucrose, sucralose and sodium saccharin. In such particularly preferred embodiments, i.e., when the agomelatine-containing layer contains one or more natural or artificial sweeteners selected from the group consisting of sucralose, sucrose and sodium saccharin, the amount of sweetener is, respectively, at least 0.05% by weight, preferably at least 0.1% by weight, more preferably at least 0.3% by weight, and / or 2.0% by weight or less, preferably 1.5% by weight or less, more preferably 1.0% by weight or less, and / or 0.05 to 2.0% by weight, preferably 0.1 to 1.5% by weight, more preferably 0.3 to 1.0% by weight.

[0164] Also, in a preferred embodiment, the agomelatine-containing layer and / or the backing layer contain one or more natural or artificial flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetyl propionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethyl vanillin and eucalyptol, and flavoring compositions such as peppermint flavor. Vanillin, methyl salicylate, menthol, peppermint flavor and eucalyptol are particularly preferred. In such a particularly preferred embodiment, i.e., when the agomelatine-containing layer and / or the backing layer contain 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, respectively, at least 0.1% by weight, preferably at least 0.3% by weight, more preferably at least 0.4% by weight, and / or 10% by weight or less, preferably 6% by weight or less, more preferably 4% by weight or less, and / or 0.1 to 10% by weight, preferably 0.3 to 6% by weight, more preferably 0.4 to 4% by weight, or the amounts are, in total, at least 0.1% by weight, preferably at least 0.5% by weight, more preferably at least 0.7% by weight, and / or 15% by weight or less, preferably 10% by weight or less, more preferably 8% by weight or less, and / or 0.1 to 15% by weight, preferably 0.5 to 10% by weight, more preferably 0.7 to 8% by weight. Suitable flavoring agents are also commercially available from Mane, and any of those distinguishable by the notes such as apple, caramel, chocolate, lemon, mint, etc. can be used as the flavoring agent in the present invention.

[0165] In certain embodiments, the agomelatine-containing layer and / or the backing layer contain one or more colorants. Any colorant suitable for use in pharmaceutical / food applications can be included, particularly colorants approved for use by the US FDA or the European agencies EFSA / EMA. Such colorants can be, for example, titanium dioxide, brilliant blue FCF, indigo carmine, fast green FCF, erythrosine, allura red AC, tartrazine and sunset yellow FCF, curcumin, riboflavin, riboflavin-5'-phosphate, quinoline yellow, orange yellow S, cochineal, carminic acid, azorubine, carmoisine, amaranth, ponceau 4R, cochineal red A, patent blue V, indigotin, chlorophyll, chlorophyllin, copper complexes of chlorophyll and chlorophyllin, green S, plain caramel, caustic sulfite caramel, ammonia caramel, sulfite ammonia caramel, brilliant black BN, black PN, vegetable carbon, brown HT, carotene, annatto, bixin, norbixin, paprika extract, capsanthin, capsorubin, lycopene, beta-apo-8'-carotenal, lutein, canthaxanthin, beetroot red, betanin, anthocyanin, calcium carbonate, iron oxides and hydroxides, aluminum, silver, gold and lithol rubine BK, and can be selected from the group consisting of these.

[0166] The agomelatine-containing layer and / or the backing layer may contain one or more additional film formers in addition to those disclosed for the above-mentioned soluble film formers. Such additional film formers are different from those previously disclosed for the soluble film formers. Thus, in certain embodiments, the agomelatine-containing layer and / or the backing layer contain one or more additional film formers in addition to those disclosed for the above-mentioned first and second soluble film formers. Such additional film formers are different from those previously disclosed for the soluble film formers. The one or more additional film formers may be included in the agomelatine-containing layer and / or the backing layer, each, in an amount of at least 2% by weight, preferably at least 5% by weight, more preferably at least 10% by weight, and / or 40% by weight or less, preferably 30% by weight or less, more preferably 25% by weight or less, and / or in an amount of 2 to 40% by weight, preferably 5 to 30% by weight, more preferably 10 to 25% by weight, and / or in total, in an amount of at least 5% by weight, preferably at least 15% by weight, more preferably at least 20% by weight, or 40% by weight or less, preferably 30% by weight or less, more preferably 25% by weight or less, and / or in an amount of 5 to 40% by weight, preferably 15 to 30% by weight, more preferably 20 to 25% by weight.

[0167] In certain embodiments, the agomelatine-containing layer and / or the backing layer contain one or more solubilizing agents. Suitable solubilizing agents can be selected, for example, from the group consisting of ethoxylated sorbitan esterified with a fatty acid, 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 polyethoxylated castor oil. Such solubilizing agents can be contained in the agomelatine-containing layer and / or the backing layer, respectively, in an amount of at least 1% by weight, preferably at least 3% by weight, more preferably at least 5% by weight, and / or in an amount of 25% by weight or less, preferably 20% by weight or less, more preferably 15% by weight or less, and / or in an amount of 1-25% by weight, preferably 3-20% by weight, more preferably 5-15% by weight.

[0168] The agomelatine-containing layer and / or the backing layer may also contain one or more emulsifying agents. Such emulsifying agents can be selected, for example, from the group consisting of soy lecithin, sodium phosphate, monoglycerides and diglycerides of fatty acids, sodium stearoyl lactate, diacetyl tartaric acid esters of monoglycerides and diglycerides, and polyethoxylated hydrogenated castor oil (commercially available from BASF as Chremophor RH 40). The emulsifying agent can be contained, for example, in the agomelatine-containing layer and / or the backing layer, respectively, in an amount of at least 1% by weight, preferably at least 3% by weight, more preferably at least 5% by weight, and / or in an amount of 25% by weight or less, preferably 20% by weight or less, more preferably 15% by weight or less, and / or in an amount of 1-25% by weight, preferably 3-20% by weight, more preferably 5-15% by weight.

[0169] In certain embodiments, the agomelatine-containing layer and / or the backing layer comprise one or more plasticizers. The one or more plasticizers may be selected from the group consisting of monosaccharides, disaccharides, oligosaccharides and polysaccharides, and derivatives thereof, such as sorbitol (commercially available from Cargill as Sorbidex™), polyethylene glycol, triacetin, triethyl citrate, propylene glycol, glycerol and medium-chain triglycerides. The agomelatine-containing layer and / or the backing layer may each comprise one or more plasticizers in an amount of at least 0.5 wt%, preferably at least 1 wt%, more preferably at least 5 wt%, and / or 25 wt% or less, preferably 20 wt% or less, more preferably 15 wt% or less, and / or in an amount of 0.5 - 25 wt%, preferably 1 - 20 wt%, more preferably 5 - 15 wt%.

[0170] The agomelatine-containing layer may also comprise a penetration enhancer. In one embodiment, the agomelatine-containing layer comprises a penetration enhancer selected from the group consisting of diethylene glycol monoethyl ether (transcutol), dipropylene glycol, levulinic acid, lauryl lactate, lactic acid, dimethylethyleneurea, N,N'-dimethylpropyleneurea DMPU and N,N-diethyl-meta-toluamide (DEET), 2-(2-ethoxyethoxy)ethanol, 2,5-dimethylisosorbide (dothieol), propylene glycol monocaprylate, 2-methoxy-4-(prop-2-en-1-yl)phenol and laurocapram. Such penetration enhancers may each be included in the agomelatine-containing layer in an amount of at least 1 wt%, preferably at least 2 wt%, more preferably at least 5 wt%, and / or 20 wt% or less, preferably 15 wt% or less, more preferably 10 wt% or less, and / or in an amount of 1 - 20 wt%, preferably 2 - 15 wt%, more preferably 5 - 10 wt%.

[0171] On the other hand, certain compounds that can be regarded as permeation enhancers are not preferred. Thus, in some embodiments, the agomelatine-containing layer does not contain a permeation enhancer selected from the group consisting of bile acids, bile salts, bile acid derivatives, acyl carnitines, sodium dodecyl sulfate, dimethyl sulfoxide, sodium lauryl sulfate, terpenes, cyclodextrins, cyclodextrin derivatives, saponins, saponin derivatives, chitosan, EDTA, citric acid, and salicylates, in an amount of more than 5% by weight, preferably more than 1% by weight, more preferably more than 0.2% by weight, and most preferably more than 0.1% by weight.

[0172] The agomelatine-containing layer according to the invention may contain a pH regulator. Preferably, the pH regulator is selected from monotropic and polytropic acids, monobasic, dibasic and tribasic acids, buffers containing mixtures of weak bases and their conjugate bases, amine derivatives, inorganic alkali derivatives, and polymers having basic and acidic functionalities, respectively.

[0173] Release characteristics The transmucosal therapeutic system according to the invention is designed to administer a specific amount of agomelatine transmucosally into the systemic circulation, especially at night.

[0174] Administration of the transmucosal therapeutic system of the invention generally and preferably consists of applying the mucoadhesive layer structure to the mucosa of the oral cavity of a human patient (after removal of the release liner that is ultimately present), and maintaining it on the mucosa until it dissolves. The application site can be buccal, sublingual, gingival or palatal, i.e., in a preferred embodiment, administration of the transmucosal therapeutic system consists of applying the mucoadhesive layer structure to the buccal, sublingual, gingival or palatal mucosa, preferably the buccal mucosa of the oral cavity of a human patient, and maintaining it on the mucosa until it dissolves.

[0175] In certain embodiments of the invention, as described above, the transmucosal therapeutic system according to the invention, when measured using porcine esophageal mucosa, has a value of 10 μg / cm 2 -hr to 150 μg / cm 2Provide the mucosal permeation rate of agomelatine for -hr.

[0176] In certain embodiments, the transmucosal therapeutic system according to the present invention, when measured using porcine esophageal mucosa, provides a cumulative release of agomelatine of at least 0.02 mg / cm 2 , preferably at least 0.05 mg / cm 2 , more preferably at least 0.1 mg / cm 2 , and / or 0.5 mg / cm 2 or less, preferably 0.4 mg / cm 2 or less, more preferably 0.3 mg / cm 2 or less, and / or 0.02 mg / cm 2 to 0.5 mg / cm 2 , preferably 0.05 mg / cm 2 to 0.4 mg / cm 2 , more preferably 0.1 mg / cm 2 to 0.3 mg / cm 2 over 8 hours.

[0177] Treatment method / Medical use According to certain aspects of the present invention, the transmucosal therapeutic system according to the present invention is for use in a method of treatment, particularly in a method of treating a human patient. According to another aspect, the present invention relates to a method of treatment, wherein the transmucosal therapeutic system according to the present invention is administered to a human patient. In yet another aspect, the present invention relates to the use of the transmucosal therapeutic system of the present invention for the manufacture of a medicament for treatment, preferably for the treatment of a human patient.

[0178] The majority of patients, that is, more than 80% of patients suffering from classical mood disorders (major depressive disorder, the depressive phase of bipolar disorder, or generalized anxiety disorder), show disturbances in the sleep-wake cycle and sleep architecture. Characteristically, difficulty falling asleep (increased sleep latency) followed by fragmented sleep results in marked daytime sleepiness, further impairing the ability to function properly in daily life and establishing a vicious cycle. With regard to depression, although there are no specific treatment guidelines, the available options generally are based on the premise that depression and sleep disorders share a bidirectional relationship, so that successful treatment of one condition will benefit the other mutually.

[0179] In recent years, it has become clear that circadian rhythm disruption, that is, not only disturbances in core physiological functions such as body temperature and blood pressure, but also adaptation disorders and dysfunction of the "body clock" that fixes the responses of very complex neurotransmitters to the time of day, are major factors in major depressive disorders that require therapeutic attention. Dysfunction of the connection between the suprachiasmatic nucleus, the pineal gland, and the neurohormone (melatonin) it produces has been suggested as the main cause of these phenomena. Melatonin has been strongly advocated (and marketed) as a "non-photic circadian resynchronizer" for treating jet lag and insomnia associated with shift work, and much has been published about its antidepressant and anxiolytic effects. Because of the low oral bioavailability of melatonin, synthetic melatonin receptor agonists have been investigated. The most prominent among them is agomelatine.

[0180] Agomelatine is approved for the treatment of depression, but has been proposed for the treatment of other indications such as bipolar disorder, generalized anxiety disorder, Smith-Magenis syndrome, periventricular leukomalacia, and OCD.

[0181] Thus, in certain embodiments, a transmucosal treatment system according to the present invention is preferably for use in a method of treating major depressive disorder. Similarly, in certain other embodiments, the present invention relates to a method of treating major depressive disorder, and a transmucosal treatment system according to the present invention is administered to a human patient. In still other embodiments, the present invention relates to the use of a transmucosal treatment system of the present invention for the manufacture of a medicament for treating major depressive disorder.

[0182] Treatment of depression, or major depressive disorder, also known as major depressive disorder, may include treatment of conditions in patients with depression / MDD, such as major depressive episodes, anxiety symptoms, sleep-wake cycle disorders, daytime sleepiness and insomnia (the majority of MDD patients, i.e., more than 80% suffer from depression combined with insomnia). In other embodiments, treatment may generally also refer to the treatment of bipolar disorder, generalized anxiety disorder, Smith-Magenis syndrome, periventricular leukomalacia, or OCD.

[0183] As outlined above, transmucosal delivery avoids the first-pass effect and thus a transmucosal treatment system according to the present invention has a lower risk of hepatotoxicity than oral agomelatine formulations. Thus, there are no restrictions regarding the patient population to be treated. Treatment includes the treatment of human patients, with or without liver dysfunction, including patients with at least mild or at least moderate liver dysfunction.

[0184] Also, in certain embodiments, treatment with the transmucosal treatment system of the present invention provides a reduction in at least one agomelatine-related side effect as compared to an equivalent oral dose of agomelatine. As outlined above, in certain specific embodiments, such agomelatine-related side effects are hepatotoxicity. The comparison with an equivalent oral dose of agomelatine should be understood as a comparison of the incidence and intensity of side effects in a clinical study when using transmucosal and oral agomelatine at doses that result in substantially the same plasma exposure of agomelatine. As compared to an equivalent oral dose of agomelatine, the incidence of at least one agomelatine-related side effect can be reduced by at least about 30%, preferably at least about 40%, more preferably at least about 70%, most preferably at least about 80%, and / or the intensity of at least one agomelatine-related side effect can be reduced as compared to an equivalent oral dose of agomelatine. The intensity of the side effect can be determined, for example, by classifying the side effect on a scale indicating the intensity of "mild", "moderate" or "severe", and the reduction in intensity can be quantified by comparing the median intensity.

[0185] In any of the treatments outlined for the above aspects and embodiments, the transmucosal treatment system is preferably administered by applying a mucoadhesive layer structure to the oral mucosa of a human patient and maintained on the mucosa until dissolution. In a preferred embodiment, the transmucosal treatment system is administered by applying a mucoadhesive layer structure to the buccal, sublingual, gingival or palatal mucosa of the oral cavity of a human patient and maintained on the mucosa until dissolution. In a more preferred embodiment, the transmucosal treatment system is administered in the evening or at night before bedtime.

[0186] In another embodiment, the transmucosal treatment system according to the present invention can also be for use in a method of reducing at least one agomelatine-related side effect in a patient as compared to an equivalent oral dose of agomelatine.

[0187] The present invention also relates to a method of reducing at least one agomelatine-related side effect in a patient being treated with oral agomelatine therapy, the method comprising a) discontinuing oral agomelatine therapy; and b) administering a transmucosal therapeutic system according to the invention to the mucosa of the oral cavity of a human patient, the transmucosal therapeutic system providing a reduction in at least one agomelatine-related side effect as compared to an equivalent oral dose of agomelatine.

[0188] In such a method, the transmucosal therapeutic system can deliver an amount of agomelatine equivalent to the amount of agomelatine inherently provided by oral agomelatine therapy.

[0189] Manufacturing process The invention further relates to an agomelatine-containing layer for use in a transmucosal therapeutic system, and a corresponding mucoadhesive layer structure comprising the agomelatine-containing layer, and a manufacturing process for the corresponding transmucosal therapeutic system.

[0190] According to the invention, the manufacturing process of the agomelatine-containing layer comprises i) combining at least agomelatine and a first soluble film-forming agent in a solvent to obtain a first coating composition; ii) coating the coating composition onto a release liner; and iii) drying the coated coating composition to form an agomelatine-containing layer.

[0191] In such a process, a suitable first soluble film-forming agent is the same as those described above.

[0192] In this manufacturing process, in step i), agomelatine can dissolve or disperse to obtain a coating composition.

[0193] Agomelatine has poor solubility in water and thus there is a risk of recrystallization, so it is preferable not to use water. Thus, in a preferred embodiment, the solvent does not contain water in an amount of more than 5% by weight, preferably more than 2% by weight, more preferably more than 1% by weight, and most preferably more than 0.5% by weight. On the other hand, depending on the solubility of the soluble film-forming agent used in different solvents, it may be advantageous to use water. Thus, in some embodiments, the solvent contains water.

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

[0195] The preference for the first soluble film-forming agent and other constituents of the agomelatine-containing layer is as outlined above. Thus, in one embodiment, step i) consists of combining at least agomelatine, the first soluble 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), agomelatine can be combined in a dissolved form, a dispersed form, a crystalline form, particularly one of its polymorphic forms, an amorphous form, as a hydrate, a solvate, a hybrid form of any of the foregoing forms or a mixture thereof.

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

[0197] Next, the agomelatine-containing layer produced as outlined above is further supplemented with at least a backing layer to provide the transmucosal therapeutic system of the present invention.

[0198] Thus, in one first aspect, the present invention also relates to a process for manufacturing a transmucosal therapeutic system, which process A) manufacturing the agomelatine-containing layer as outlined above; B) manufacturing the backing layer by a process comprising: i) dissolving at least a second film-forming agent soluble in a solvent to obtain a second coating composition; ii) coating the second coating composition onto a release liner; and iii) drying the second coated coating composition to form the backing layer; and C) laminating the obtained agomelatine-containing layer and the backing layer.

[0199] In another second aspect, the present invention relates to a process for manufacturing a transmucosal therapeutic system, the process comprising: A) manufacturing the agomelatine-containing layer as outlined above; B) preparing a transmucosal therapeutic system comprising a mucoadhesive layer structure comprising a backing layer and an agomelatine-containing layer by a process comprising: i) dissolving at least a second film-forming agent soluble in a solvent to obtain a second coating composition; ii) coating the second coating composition obtained in A) onto the agomelatine-containing layer; and iii) drying the second coated coating composition to form a backing layer coated on the agomelatine-containing layer.

[0200] In such a process according to the second aspect, step ii) of coating the second coating composition onto the agomelatine-containing layer is preferably carried out at least once, in particular 2 or 3 times.

[0201] In both the first and second aspects, in B) of the process, the solvent comprises one or more of alcoholic solvents such as methanol, ethanol and isopropanol, and water, preferably the solvent comprises ethanol or consists of ethanol, and / or the solvent comprises water.

[0202] In such a process according to the first or second aspect, drying is preferably carried out in one or more cycles at room temperature and / or at 40 to 90 °C, more preferably at 60 to 80 °C, and more preferably, drying is carried out at a temperature of 40 to 90 °C, or 60 to 80 °C.

[0203] The mucoadhesive layer structure containing an agomelatine-containing layer and the corresponding trans-mucosal therapeutic system can be produced using the process outlined above, for example, by sealing in a pouch of primary packaging material and using further manufacturing steps such as punching out individual trans-mucosal therapeutic systems and packaging, as known to the person skilled in the art. Such further steps preferably result in a mucoadhesive layer structure or a trans-mucosal therapeutic system as described in the previous chapter.

[0204] The present invention relates in particular to an agomelatine-containing layer obtainable (and / or obtained) by the above process, as well as to a mucoadhesive layer structure and a trans-mucosal therapeutic system.

Examples

[0205] The present invention will now be described more fully with reference to the accompanying examples. However, it should be understood that the following description is illustrative only and should in no way be construed as limiting the present invention. The numerical values provided in the examples regarding the amounts of components or areal weights in the compositions may vary slightly due to fluctuations during production.

[0206] Examples 1A to 1F Coating composition The formulations of the agomelatine-containing coating compositions of Examples 1a to 1f are summarized in Table 1.1 below. As also shown in Table 1.1, the formulations are based on weight percentages.

[0207]

Table 1-1

Table 1-2

[0208] Preparation of the first coating composition (agomelatine-containing layer) For Examples 1a to 1f, a beaker was filled with agomelatine. Approximately one-third of ethanol, eucalyptol, menthol, methyl salicylate, novaminto fresh peppermint, coliphor RH 40, FD&C Red No. 40, and sucralose were added and then stirred. Polyvinylpyrrolidone was added under stirring. A second beaker was filled with distilled water. Polysorbate 80 was added and then the mixture was stirred. The remaining ethanol was added under stirring. The contents of the two beakers were mixed under stirring to obtain a slightly red solution with visible crystalline precipitation.

[0209] Preparation of the second coating composition (backing layer) For Examples 1b to 1f, ethanol was placed in a beaker and then stirred. Ethylcellulose and castor oil were added under stirring to obtain a slightly opaque mixture.

[0210] The resulting backing composition was coated onto a polyester film (polyethylene terephthalate film, single-sided silicon-treated, thickness 75 μm, which can function as a release liner) and dried at room temperature for approximately 10 minutes and at 70 °C for 20 minutes. The coating thickness resulted in an area weight of 20.9 g / m 2 (Examples 1b, 1e and 1f) and 20.8 g / m 2 (Examples 1c and 1d).

[0211] After removing the release liner, it was applied to the agomelatine-containing coating on the backing layer.

[0212] Coating of the first coating composition The resulting agomelatine-containing first coating composition of Example 1a was coated onto a polyester film (a polyethylene terephthalate film, single-sided silicon-treated, 75 μm thick, which can function as a release liner) and dried at room temperature for approximately 5 minutes and at 50 °C for 10 minutes (Example 1a). For Example 1a, the dried film is the final agomelatine-containing mucoadhesive layer structure.

[0213] The coating thickness resulted in an area weight of 57.9 g / m 2 (Example 1a).

[0214] The resulting agomelatine-containing first coating compositions of Examples 1b - 1f were coated onto the dried backing layer and dried at room temperature for approximately 5 minutes, at 50 °C for 10 minutes, and at 90 °C for 4 minutes (Examples 1b and 1f), at room temperature for approximately 5 minutes and at 50 °C for 10 minutes (Example 1c), at room temperature for approximately 6 minutes, at 50 °C for 12 minutes, and at 90 °C for 4 minutes (Example 1d), and at room temperature for approximately 5 minutes, at 50 °C for 10 minutes, and at 90 °C for 2 minutes (Example 1e), respectively.

[0215] The coating thickness resulted in an area weight of 57.9 g / m 2 (Example 1a), 53.9 g / m 2 (Example 1b), 34.9 g / m 2 (Example 1c), 72.1 g / m 2 (Example 1d), 50.5 g / m 2 (Example 1e), and 53.4 g / m 2 (Example 1f), respectively.

[0216] Preparation of the transdermal therapeutic system (for all examples) Next, the individual transmucosal treatment systems were punched out from the agomelatine-containing mucoadhesive layer structure. This is advantageous when the OTF does not adhere sufficiently to the mucosa based only on its physical properties and / or when the agomelatine-containing layer has prominent corners (square or rectangular shape) for the purpose of avoiding waste. Next, the transmucosal treatment systems were punched out and sealed in a pouch of primary packaging material under a protective atmosphere, for example, by flowing nitrogen gas, as is customary in the art.

[0217] Measurement of the mucosal permeation rate The permeation amount and the corresponding mucosal permeation rate of the transmucosal treatment systems prepared according to Examples 1a to 1f were determined by in vitro experiments according to the OECD guidelines (adopted on April 13, 2004) using porcine mucosa (esophageal mucosa). For all transmucosal treatment systems, a 400-μm-thick mucosa with an intact barrier function was prepared using a dermatome. A die cut with an area of 0.798 cm 2 was punched out from the transmucosal treatment system, applied to the mucosa, and the upper surface of the mucosa with the transmucosal treatment system was immersed in artificial saliva (the lower surface was in contact with the receiving medium, and the upper surface was compartmentalized into a mucosal area of 1.145 cm 2 . The agomelatine permeation amount in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37 ± 1 °C was measured, and the corresponding mucosal permeation rate was calculated. The results are shown in Table 1.2 and Figure 1a.

[0218]

Table 2

[0219] Utilization rate of agomelatine The utilization rate of agomelatine at the 7-hour time point was calculated based on the cumulative permeation amount and the initial agomelatine content at the 7-hour time point. The results are shown in Table 1.3 and Figure 1b.

[0220]

Table 3

[0221] In vitro experiments show good mucosal permeation rate and good utilization rate. In particular, Example 1a without a backing layer shows a fast release of the active substance. However, Examples 1b - 1d show that good permeation can still be obtained even when using a backing layer. Also, as the area weight increases (and thus the amount of the active substance increases), the permeation rate increases. Similarly, increasing the amount of the active substance by changing the concentration of the active substance also leads to an increase in the permeation rate (Examples 1e and 1f).

[0222] Example 2 Preparation of permeation samples In Example 2, the mucosal permeation rate of pure agomelatine in natural saliva was determined for the trans - mucosal therapeutic systems of Examples 1a and 3a. Therefore, in Example 2, instead of the trans - mucosal therapeutic system, an agomelatine - containing solution was prepared from 0.877 mg of agomelatine in 300 μl of natural saliva.

[0223] Measurement of mucosal permeation rate The permeation amount and the corresponding mucosal permeation rate of the trans - mucosal therapeutic systems prepared according to Example 1a (containing some crystalline substances), 3a (crystal - free), and the above - mentioned agomelatine solution (Example 2) were determined by in vitro experiments using porcine mucosa (esophageal mucosa) according to the OECD guidelines (adopted on April 13, 2004). For all trans - mucosal therapeutic systems, a 400 - μm - thick mucosa with an intact barrier function was prepared using a dermatome. For Examples 1a and 3a, a die - cut of an area of 0.798 cm 2 was punched out and applied to the mucosa. The upper surface of the mucosa with the trans - mucosal therapeutic system was immersed in 300 μl of natural saliva (the lower surface was in contact with the receiving medium, and the upper surface was compartmentalized into a mucosal area of 1.595 cm 2 ). For Example 2, instead of applying the trans - mucosal therapeutic system and adding natural saliva, the above - mentioned permeation sample was directly applied to the mucosa (this was also 1.595 cm 2(having an area of), the API content per mucosal area was set to about 0.55 mg / cm 2 The agomelatine permeation amount in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37 ± 1°C was measured, and the corresponding mucosal permeation rate was calculated. The results are shown in Table 2.1 and Figure 2a.

[0224]

Table 4

[0225] Utilization rate of agomelatine The utilization rate of agomelatine at the 7-hour time point was calculated based on the cumulative permeation amount and the initial agomelatine content at the 7-hour time point. The results are shown in Table 2.2 and Figure 2b.

[0226]

Table 5

[0227] The in vitro experiment shows a good mucosal permeation rate and sufficient utilization rate.

[0228] Examples 3A to 3H Coating composition The formulations of the agomelatine-containing coating compositions of Examples 3a to 3h are summarized in Tables 3.1 and 3.2 below. As also shown in Tables 3.1 and 3.2, the formulations are based on weight percentages.

[0229]

Table 6-1

Table 6-2

[0230]

Table 7-1

Table 7-2

[0231] Preparation of the First Coating Composition (Agomelatine-Containing Layer) For Example 3a, a beaker was filled with agomelatine. Ethanol, eucalyptol, menthol, methyl salicylate, novamint fresh peppermint, kolliphor RH 40, FD&C Red No. 40, sucralose, and polysorbate 80 were added, and then the mixture was stirred. Polyvinylpyrrolidone was added under stirring, and after stirring for about 2.5 hours, a clear, red solution was obtained.

[0232] For Examples 3b to 3h, the same coating composition was used for the agomelatine-containing layer, which was prepared as follows: A beaker was filled with agomelatine. Ethanol, menthol, eucalyptol, methyl salicylate, kolliphor RH 40, FD&C Red No. 40, sucralose, and polysorbate 80 were added, and then the mixture was stirred. A clear solution was obtained. Polyvinylpyrrolidone was added and stirred overnight, and then novamint fresh peppermint was added dropwise under stirring to obtain a clear, red solution.

[0233] Preparation of the Second Coating Composition (Backing Layer) For Example 3c, a beaker was filled with ethylcellulose. Ethanol was added, and then the mixture was stirred. Castor oil was added under stirring to obtain a slightly opaque mixture.

[0234] For Examples 3e to 3h, a beaker was filled with ethanol. Purified water and Kollidon were added, and then the mixture was stirred to obtain a solution. Eudragit and glycerol were added under stirring to obtain a clear mixture. For Examples 3f and 3g, a sodium hydroxide solution was added to bring the pH as shown in Table 3.2 above.

[0235] The resulting second coating compositions of Examples 3c and 3e - 3h were coated onto a polyester film (polyethylene terephthalate film, single - sided silicon - treated, 75 μm thick, which can function as a release liner) and dried at room temperature for approximately 10 minutes and at 70 °C for 20 minutes (Example 3c), and at room temperature for approximately 5 minutes, at 35 °C for 10 minutes, and at 80 °C for 2 minutes (Examples 3e - 3h), respectively. The coating thicknesses resulted in areal weights of 12.3 g / m 2 (Example 3c), 26.8 g / m 2 (Example 3e), 26.0 g / m 2 (Example 3f), 20.5 g / m 2 (Example 3g) and 22.9 g / m 2 (Example 3h), respectively. For Example 3d, a commercially available 15 - μm - thick polyethylene terephthalate film was used as the backing layer.

[0236] Coating of the first coating composition The resulting agomelatine - containing first coating compositions of Examples 3a and 3b were coated onto a polyester film (polyethylene terephthalate film, single - sided silicon - treated, 75 μm thick, which can function as a release liner) and dried at room temperature for approximately 15 minutes and at 70 °C for 5 minutes (Example 3a), or at room temperature for approximately 5 minutes, at 50 °C for 10 minutes, and at 90 °C for 2 minutes (Example 3b), respectively. For Examples 3a and 3b, the dried film is the final agomelatine - containing mucoadhesive layer structure.

[0237] The resulting agomelatine - containing first coating compositions of Examples 3c and 3e - 3h were coated onto the dried backing layer and dried at room temperature for approximately 5 minutes, at 50 °C for 10 minutes, and at 90 °C for 2 minutes (Examples 3c and 3e - 3h).

[0238] The coating thicknesses were 55.4 g / m 2 (Example 3a) and 50.0 g / m 2(3b, 3c, and 3e - 3h) resulted in the areal weight. The coating process of 3d was the same as that of Examples 3b, 3c, and 3e - 3h, except that the coating composition was coated on a 15 - μm - thick polyethylene terephthalate film. Thus, a trans - mucosal therapeutic system with a backing layer (polyethylene terephthalate film) was obtained.

[0239] Preparation of Trans - mucosal Therapeutic System The trans - mucosal therapeutic systems of Examples 3b, 3c, and 3e - 3h were prepared by laminating a backing layer onto an agomelatine - containing layer. Lamination was carried out after removing the release liner.

[0240] Further steps (e.g., punching out individual devices) were carried out as in Example 1.

[0241] Measurement of Mucosal Permeation Rate The permeation amount and the corresponding mucosal permeation rate of the trans - mucosal therapeutic systems prepared according to Examples 3a - 3h were determined by in vitro experiments using porcine mucosa (esophageal mucosa) in accordance with the OECD guidelines (adopted on April 13, 2004). For all trans - mucosal therapeutic systems, a 400 - μm - thick mucosa with an intact barrier function was prepared using a dermatome. A die - cut of 0.522 cm 2 in area was punched out from the trans - mucosal therapeutic system, applied to the mucosa, and the upper surface of the mucosa with the trans - mucosal therapeutic system was immersed in artificial saliva (the lower surface was in contact with the receiving medium, and the upper surface was compartmentalized into a mucosal area of 1.145 cm 2 . The agomelatine permeation amount in the receiving medium (phosphate - buffered saline pH 7.4) at a temperature of 37 ± 1 °C was measured, and the corresponding mucosal permeation rate was calculated. The results are shown in Tables 3.3 and 3.4 and Figures 3a and 3b.

[0242]

Table 8

[0243]

Table 9

[0244] Utilization rate of agomelatine The utilization rate of agomelatine at the 6-hour time point was calculated based on the cumulative permeation amount and the initial agomelatine content at the 6-hour time point. The results are shown in Table 3.5 and Figure 3c.

[0245]

Table 10

[0246] In vitro experiments show good mucosal permeation rate and good utilization rate. Examples 3c - 3h show that even when using a backing layer, compared with Examples 3a and 3b, the permeation is low but still good permeation can be achieved.

[0247] Examples 4A - 4F Coating composition The formulations of the agomelatine-containing coating compositions of Examples 4a - 4f are summarized in Tables 4.1 and 4.2 below. As also shown in Tables 4.1 and 4.2, the formulations are based on weight percentages.

[0248]

Table 11

[0249]

Table 12 - 1

Table 12 - 2

[0250] Preparation of the first coating composition (agomelatine-containing layer) For Example 4a, a beaker was filled with agomelatine. Ethanol, menthol, eucalyptol, methyl salicylate, Kollicoat RH 49, FD&C Red No. 40, sucralose, and polysorbate 80 were added, and then the mixture was stirred. Polyvinylpyrrolidone and Novaminto Fresh Peppermint were added with stirring to obtain a viscous mixture.

[0251] For Example 4b, a beaker was filled with ethanol. Eucalyptol, menthol, methyl salicylate, Kollicoat RH 49, FD&C Red No. 40, sucralose, and polysorbate 80 were added, and then the mixture was stirred. Hydroxypropylcellulose, Novaminto Fresh Peppermint, and agomelatine were added with stirring to obtain a viscous mixture.

[0252] For Example 4c, a beaker was filled with ethanol. Eucalyptol, menthol, methyl salicylate, Novaminto Fresh Peppermint, Kollicoat RH 49, FD&C Red No. 40, sucralose, and polysorbate 80 were added, and then the mixture was stirred. Soluplus, Miglyol 812, and agomelatine were added with stirring to obtain a low-viscosity mixture.

[0253] For Examples 4d, 4e, and 4f, a beaker was filled with agomelatine. Ethanol, eucalyptol, menthol, methyl salicylate, Novaminto Fresh Peppermint, Kollicoat RH 49, FD&C Red No. 40, sucralose, and polysorbate 80 were added, and then the mixture was stirred. Polyvinylpyrrolidone was added with stirring to obtain a viscous mixture.

[0254] Preparation of the Second Coating Composition (Backing Layer) For Examples 4e and 4f, a beaker was filled with ethanol. Purified water and FD&C Blue No. 1 were added, and then the mixture was stirred. Kollidon, Eudragit, and glycerol were added with stirring to obtain a mixture.

[0255] The resulting second coating compositions of Examples 4e and 4f were coated onto a polyester film (a polyethylene terephthalate film, single-sided silicon-treated, 75 μm thick, which can function as a release liner) and dried at room temperature for approximately 5 minutes, at 35 °C for 10 minutes, and at 80 °C for 2 minutes. The coating thickness resulted in an areal weight of 47.4 g / m 2 .

[0256] Preparation of the Adhesive Composition For Example 4e, a beaker was filled with ethanol. Purified water and menthol were added, and then the mixture was stirred. Hydroxyethyl cellulose, castor oil, and polysorbate 80 were added under stirring to obtain an opaque mixture.

[0257] For Example 4f, a beaker was filled with ethanol. Menthol was added, and then the mixture was stirred. Hydroxypropyl cellulose and castor oil were added under stirring to obtain a viscous mixture.

[0258] The resulting adhesive compositions of Examples 4e and 4f were coated onto the above backing layer and dried at room temperature for approximately 5 minutes, at 50 °C for 10 minutes, and at 90 °C for 2 minutes. The coating thicknesses resulted in areal weights of 25.2 g / m 2 (Example 4e) and 23.5 g / m 2 (Example 4f), respectively. A die cut of 1.1 cm 2 in size was punched out from the adhesive backing layer.

[0259] Coating of the First Coating Composition The resulting agomelatine-containing coating compositions of Examples 4a to 4f were coated on a polyester film (polyethylene terephthalate film, single-sided silicon-treated, 75 μm thick, which can function as a release liner) and dried at room temperature for approximately 5 minutes, at 50 °C for 10 minutes, and at 90 °C for 2 minutes (Examples 4a to 4c) and at room temperature for approximately 5 minutes, at 50 °C for 15 minutes, and at 90 °C for 2 minutes (Examples 4d to 4f), respectively. The coating thicknesses resulted in areal weights of 49.5 g / m 2 (Example 4a), 48.6 g / m 2 (Example 4b), 58.5 g / m 2 (Example 4c), and 115.4 g / m 2 (Examples 4d, 4e, and 4f), respectively.

[0260] For Examples 4a to 4d, the dry film is the final agomelatine-containing mucoadhesive layer structure. For Examples 4e and 4f, a die cut of 0.28 cm 2 in size was punched out from the dry film and laminated with the above die cut of the adhesive backing layer such that the backing layer extends uniformly on all sides of the agomelatine-containing layer to obtain an agomelatine-containing mucoadhesive layer structure.

[0261] Preparation of the transdermal therapeutic system See Example 1.

[0262] Measurement of the mucosal permeation rate The permeation amount and the corresponding mucosal permeation rate of the transdermal therapeutic systems prepared according to Examples 4a to 4e were determined by in vitro experiments according to the OECD guidelines (adopted on April 13, 2004) using porcine mucosa (esophageal mucosa). For all transdermal therapeutic systems, a mucosa with a thickness of 400 μm with an intact barrier function was prepared using a dermatome. 0.522 cm punched out from the transdermal therapeutic systems of Examples 4a to 4d 2The area was cut, and the above-mentioned agomelatine-containing mucoadhesive layer structures of Examples 4e and 4f were applied to the mucosa. The upper surface of the mucosa with the transmucosal treatment system was immersed in artificial saliva (the lower surface was in contact with the receiving medium, and the upper surface was compartmentalized into a mucosal area of 1.145 cm 2 ). The amount of agomelatine permeated in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37 ± 1 °C was measured, and the corresponding mucosal permeation rate was calculated. The results are shown in Table 4.3 and Figure 4a.

[0263]

Table 13

[0264] Utilization rate of agomelatine The utilization rate of agomelatine at the 6-hour time point was calculated based on the cumulative permeation amount and the initial agomelatine content at the 6-hour time point. The results are shown in Table 4.4 and Figure 4b.

[0265]

Table 14

[0266] In vitro experiments show good mucosal permeation rates and sufficient utilization rates. Examples 4e and 4f compared with Example 4d show that even when a backing layer is used, low but still good permeation can be achieved. It also shows that hydroxypropyl cellulose has performance similar to that of polyvinylpyrrolidone (see Examples 4a and 4b).

[0267] Examples 5A to 5D Coating composition The formulations of the agomelatine-containing coating compositions of Examples 4b and 5a to 5d are summarized in Table 4.1 above and Table 5.1 below. As also shown in Tables 4.1 and 5.1, the formulations are based on weight percentages.

[0268]

Table 15-1

Table 15-2

[0269] Preparation of the First Coating Composition (Agomelatine-Containing Layer) For Examples 5a and 5b, a beaker was filled with agomelatine. Vanillin flavor, ethanol, sucralose, saccharin Na, oleic acid, FD&C Yellow No. 5, and hydroxypropylcellulose were added, and then the mixture was stirred to obtain a transparent mixture.

[0270] For Example 5c, a beaker was filled with agomelatine. Polyvinyl alcohol was added, and the mixture was stirred to obtain a white mixture.

[0271] Preparation of the Second Coating Composition (Backing Layer) For Examples 5b and 5c, beakers were filled with purified water or ethanol, respectively. FD&C Red No. 40 and hydroxypropylcellulose were added with stirring to obtain an opaque mixture.

[0272] For Example 5d, a beaker was filled with ethanol. Purified water and FD&C Blue No. 1 were added, and then the mixture was stirred. Kollidon, Eudragit, and glycerol were added with stirring to obtain a mixture.

[0273] The resulting second coating compositions of Examples 5b, 5c, and 5d were coated onto a polyester film (polyethylene terephthalate film, single-sided silicon-treated, 75 μm thick, which can function as a release liner) and dried at approximately 40 °C for 15 minutes and 70 °C for 15 minutes (Example 5b), and at approximately room temperature for 10 minutes, 40 °C for 15 minutes, and 70 °C for 10 minutes (Example 5c), and at approximately room temperature for 5 minutes, 35 °C for 10 minutes, and 80 °C for 2 minutes (Example 5d). The coating thicknesses were 105.1 g / m 2 (Example 5b), 99.6 g / m 2(Example 5c) and 78.3 g / m 2 (Example 5d) resulted in the areal weight. For Example 5c, a die cut of 0.8 cm 2 in size was punched out.

[0274] Preparation of the Adhesive Composition For Example 5d, a beaker was filled with ethanol. Purified water and methanol were added and then the mixture was stirred. Hydroxyethyl cellulose, castor oil, and polysorbate 80 were added under stirring to obtain a homogeneous mixture.

[0275] The resulting adhesive composition of Example 5d was coated onto the upper backing layer and dried at room temperature for approximately 5 minutes, at 50 °C for 10 minutes, and at 90 °C for 2 minutes. The coating thickness resulted in an areal weight of 95.6 g / m 2 (Example 5d).

[0276] A die cut of 0.8 cm 2 in size was punched out from the adhesive backing layer.

[0277] Coating of the First Coating Composition The resulting agomelatine-containing coating compositions of Examples 5a, 5c, and 5d were coated onto a polyester film (a polyethylene terephthalate film, single-sided silicon-treated, 75 μm thick, which can function as a release liner) and dried at room temperature for approximately 10 minutes, at 40 °C for 15 minutes, and at 70 °C for 10 minutes (Example 5a) as well as at 70 °C for 5 minutes (Example 5c), and at room temperature for approximately 5 minutes, at 50 °C for 15 minutes, and at 90 °C for 2 minutes (Example 5d). For Example 5a, the dried film is the final agomelatine-containing mucoadhesive layer structure. For Examples 5c and 5d, a die cut of 0.28 cm 2 in size was punched out from the dried film and laminated with the above-mentioned die cut of the backing layer or the adhesive backing layer so that the backing layer extends uniformly on all sides of the agomelatine-containing layer to obtain an agomelatine-containing mucoadhesive layer structure.

[0278] The resulting agomelatine-containing first coating composition of Example 5b was coated onto the dried backing layer and dried at room temperature for approximately 10 minutes, at 40 °C for 15 minutes, and at 70 °C for 10 minutes.

[0279] The coating thicknesses resulted in areal weights of 95.7 g / m 2 (Example 5a), 95.9 g / m 2 (Example 5b), 82.9 g / m 2 (Example 5c), and 115.4 g / m 2 (Example 5d), respectively.

[0280] Preparation of the transmucosal therapeutic system See Example 1.

[0281] Measurement of the mucosal permeation rate The permeation amounts and the corresponding mucosal permeation rates of the transmucosal therapeutic systems prepared according to Example 4b and Examples 5a - 5d were determined by in vitro experiments according to the OECD guidelines (adopted on 13 April 2004) using porcine mucosa (esophageal mucosa). For all transmucosal therapeutic systems, a mucosa with a thickness of 400 μm and an intact barrier function was prepared using a dermatome. Die cuts with an area of 0.28 cm 2 (Example 4b) and 0.8 cm 2 (Examples 5a and 5b), as well as the above-mentioned agomelatine-containing mucoadhesive layer structure of Examples 5c and 5d, were applied to the mucosa and the upper surface of the mucosa with the transmucosal therapeutic system was immersed in artificial saliva (the lower surface was in contact with the receiving medium and the upper surface was compartmentalized into a mucosal area of 1.145 cm 2 ). The agomelatine permeation amount in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37 ± 1 °C was measured and the corresponding mucosal permeation rate was calculated. The results are shown in Table 5.2 and Figure 5a.

[0282] [Table 16]

[0283] Utilization rate of agomelatine The utilization rate of agomelatine at the 6-hour time point was calculated based on the cumulative permeation amount at the 8-hour time point and the initial agomelatine content. The results are shown in Table 5.3 and Figure 5b.

[0284]

Table 17

[0285] In vitro experiments show good mucosal permeation rate and sufficient utilization rate. All formulations show good permeation behavior, but Example 4b (release area 0.28 cm 2 , mucosal area 1.145 cm 2 ) was compared with Examples 5a and 5b (release area 0.8 cm 2 , mucosal area 1.145 cm 2 ) to demonstrate the important role of the total mucosal area available for permeation in the open system. Therefore, Example 5b, which has an agomelatine-containing layer similar to that of Example 5a but is provided with a backing layer, shows permeation as good as that of Example 5a.

[0286] Examples 6A - 6D Coating composition The formulations of the agomelatine-containing coating compositions of Examples 6a - 6d are summarized in Table 6.1 below. As also shown in Table 6.1, the formulations are based on weight percentages.

[0287]

Table 18

[0288] Preparation of coating composition For Examples 6a - 6c, beakers were filled with agomelatine. Vanilla flavor, ethanol, sucralose, saccharin Na, and oleic acid (Examples 6b and 6c) were added, and then the mixture was stirred. Hydroxypropyl cellulose was added with stirring to obtain a clear solution.

[0289] For Example 6d, a beaker was filled with agomelatine. Vanillin flavor, ethanol, sucralose, saccharin Na, and oleic acid were added, and then the mixture was stirred. Titanium dioxide and hydroxypropyl cellulose were added with stirring to obtain a white mixture.

[0290] Coating of the coating composition The resulting agomelatine-containing coating compositions of Examples 6a to 6d were coated onto a polyester film (one-sided silicon-treated, 75 μm thick, which can function as a release liner) and dried at room temperature for approximately 10 minutes, at 40 °C for 15 minutes, and at 70 °C for 10 minutes. The coating thicknesses were 93.8 g / m 2 (Example 6a), 93.6 g / m 2 (Example 6b), 94.3 g / m 2 (Example 6c), and 98.3 g / m 2 (Example 6d) resulting in areal weights. The dried films were not further laminated with an additional backing layer and are thus the final agomelatine-containing mucoadhesive layer structure.

[0291] Preparation of the transdermal therapeutic system See Example 1.

[0292] Measurement of the mucosal permeation rate The permeation amounts and the corresponding mucosal permeation rates of the transdermal therapeutic systems prepared according to Examples 6a to 6d were determined by in vitro experiments according to the OECD guidelines (adopted on April 13, 2004) using porcine mucosa (esophageal mucosa). For all transdermal therapeutic systems, a 400-μm-thick mucosa with an intact barrier function was prepared using a dermatome. A die-cut of 0.524 cm 2 in area was punched out from the transdermal therapeutic system, applied to the mucosa, and the upper surface of the mucosa with the transdermal therapeutic system was immersed in artificial saliva (the lower surface was in contact with the receiving medium, and the upper surface was 1.145 cm 2(which is compartmentalized into the mucosal area). The amount of agomelatine permeated in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37 ± 1°C was measured, and the corresponding mucosal permeation rate was calculated. The results are shown in Table 6.2 and Figure 6a.

[0293] [Table 19]

[0294] Utilization rate of agomelatine The utilization rate of agomelatine at the 6-hour time point was calculated based on the cumulative permeation amount and the initial agomelatine content at the 6-hour time point. The results are shown in Table 6.3 and Figure 6b.

[0295] [Table 20]

[0296] The in vitro experiments show good mucosal permeation rates and sufficient utilization rates. These examples show that sufficient permeation behavior can be obtained even at low agomelatine concentrations, and that the performance of hydroxypropyl cellulose is comparable to that of polyvinylpyrrolidone. They also show that a certain amount of fatty acid also seems to increase the permeation rate (see Example 6b compared to Examples 6a and 6c).

[0297] Examples 7A - 7G Coating composition The formulations of the agomelatine-containing coating compositions of Examples 4b and 6b - 6d are summarized in Tables 4.1 and 6.1 above. The formulations of the agomelatine-containing coating compositions of Examples 7a - 7g are summarized in Tables 7.1 and 7.2 below. As also shown in these tables, the formulations are based on weight percentages.

[0298] [Table 21-1] [Table 21-2]

[0299]

Table 22-1

Table 22-2

[0300] Preparation of the First Coating Composition (Agomelatine-Containing Layer) The first coating composition of Example 7g was prepared in the same manner as that of Example 4b.

[0301] For Examples 7a to 7c, beakers were filled with agomelatine. Ethanol was added, and then the mixture was stirred. Polyvidone K90 and polyvidone K30 (Example 7a), hydroxypropyl cellulose (Example 7b), and polyvidone K90 (Example 7c) were added under stirring, respectively, to obtain a viscous mixture.

[0302] For Example 7d, a beaker was filled with agomelatine. Polyvinyl alcohol was added, and the mixture was stirred to obtain a white mixture.

[0303] For Example 7e, a beaker was filled with polyvinyl alcohol. Purified water was added, and then the mixture was stirred and heated to 95°C. Vanilla flavor, sucralose, saccharin Na, oleic acid, and agomelatine were added under stirring to obtain a viscous mixture.

[0304] For Example 7f, a beaker was filled with agomelatine. Ethanol, vanilla flavor, sucralose, saccharin Na, oleic acid, and FD&C Yellow No. 5 were added, and then the mixture was stirred. Hydroxypropyl cellulose was added under stirring to obtain a viscous mixture.

[0305] Coating of the First Coating Composition The resulting agomelatine-containing coating compositions of Examples 7a to 7f were coated onto a polyester film (one-sided silicon-treated, 75 μm thick, which can function as a release liner) and dried at room temperature for approximately 10 minutes, at 40 °C for 15 minutes, and at 70 °C for 10 minutes (Examples 7a to 7c and 7f), at 70 °C for 5 minutes (Example 7d), and at 70 °C for 15 minutes (Example 7e). The coating thickness was 104.4 g / m 2 (Example 7a), 103.2 g / m 2 (Example 7b), 100.7 g / m 2 (Example 7c), 82.9 g / m 2 (Example 7d), 98.4 g / m 2 (Example 7e), and 95.7 g / m 2 (Example 7f), resulting in the areal weights indicated above.

[0306] The resulting agomelatine-containing coating composition of Example 7g was coated onto a polyester film (one-sided silicon-treated, 75 μm thick, which can function as a release liner) and dried at room temperature for approximately 5 minutes, at 50 °C for 15 minutes, and at 90 °C for 2 minutes. The coating thickness was 115.4 g / m 2 resulting in the areal weight indicated above.

[0307] Die cuts of 0.28 cm 2 in size were punched out from the dried agomelatine-containing layer.

[0308] Preparation of the second coating composition (backing layer) For Examples 7a to 7d and 7g (same backing layer), and for Examples 7e and 7f (same backing layer), beakers were filled with vanilla flavor. Sucralose, saccharin, oleic acid, ethanol, purified water, FD&C Red, and polyethylene glycol (Examples 7a to 7d and 7g) and glycerol (Examples 7e and 7f) were added respectively, and then the mixture was stirred. Kollidon and Eudragit were added with stirring to obtain a clear solution.

[0309] The resulting second coating composition was coated onto a polyester film (a polyethylene terephthalate film, single-sided silicon-treated, 75 μm thick, which can function as a release liner) and dried at room temperature for approximately 10 minutes, at 40 °C for 15 minutes, and at 70 °C for 5 minutes. The coating thicknesses resulted in areal weights of 92.2 g / m 2 (7a to 7d and 7g) and 81.2 g / m 2 (Examples 7e and 7f), respectively.

[0310] Die cuts of 0.8 cm in size were punched out from the dried backing layer. 2

[0311] Preparation of the transmucosal therapeutic system For Examples 7a to 7d and 7g, die cuts of the agomelatine-containing layer were adhered to the die cuts of the respective backing layers using a small amount of 23.5% ethanolic PVP90 solution such that the backing layer extended uniformly on all sides of the agomelatine-containing layer, and then laminated to obtain an agomelatine-containing mucoadhesive layer structure. For Examples 7e and 7f, the dried film was also laminated to the respective backing layers such that the backing layer extended uniformly on all sides of the agomelatine-containing layer to obtain an agomelatine-containing mucoadhesive layer structure.

[0312] Further steps (e.g., punching out individual devices) were carried out as in Example 1.

[0313] Measurement of the mucosal permeation rate The permeation amount and the corresponding mucosal permeation rate of the transdermal therapeutic system prepared according to Examples 4b, 6b to 6d, and 7a to 7g were determined by in vitro experiments according to the OECD guidelines (adopted on April 13, 2004) using porcine mucosa (esophageal mucosa). For all transdermal therapeutic systems, a 400-μm-thick mucosa with an intact barrier function was prepared using a dermatome. The above-mentioned agomelatine-containing mucoadhesive layer structure was applied to the mucosa, and the upper surface of the mucosa with the transdermal therapeutic system was immersed in artificial saliva (the lower surface was in contact with the receiving medium, and the upper surface was compartmentalized into a mucosal area of 1.145 cm 2 ). The agomelatine permeation amount in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37 ± 1 °C was measured, and the corresponding mucosal permeation rate was calculated. The results are shown in Tables 7.3 and 7.4 and Figures 7a and 7b.

[0314]

Table 23

[0315]

Table 24

[0316] Utilization rate of agomelatine The utilization rate of agomelatine at the 4-hour time point was calculated based on the cumulative permeation amount and the initial agomelatine content at the 4-hour time point. The results are shown in Table 7.5 and Figure 7c.

[0317]

Table 25

[0318] The in vitro experiments show a good mucosal permeation rate and sufficient utilization rate. These examples show that sufficient permeation behavior can be obtained even at low agomelatine concentrations, and that the performance of hydroxypropyl cellulose and polyvinyl alcohol is comparable to that of polyvinyl pyrrolidone (see Examples 7b, 7c, and 7d).

[0319] Examples 8A - 8C Coating composition The formulations of the agomelatine - containing coating compositions of Examples 4b, 8a, and 8b are summarized in Table 4.1 above and Table 8.1 below. As also shown in Tables 4.1 and 8.1, the formulations are based on weight percentages.

[0320]

Table 26 - 1

Table 26 - 2

[0321] Preparation of the first coating composition (agomelatine - containing layer) For Examples 8a - 8c, beakers were filled with agomelatine. Ethanol, eucalyptol, menthol, methyl salicylate, novamint fresh pepper mint, coliphor RH 40, sucralose, FD&C Red No. 40, and polysorbate 80 were added, and then the mixture was stirred. Povidone was added with stirring to obtain a viscous mixture.

[0322] Coating of the first coating composition The resulting agomelatine - containing coating compositions of Examples 8a - 8c were coated onto a polyester film (polyethylene terephthalate film, single - sided silicon - treated, 75 μm thick, which can function as a release liner) and dried at room temperature for approximately 10 minutes, at 50 °C for 15 minutes, and at 90 °C for 2 minutes. The coating thickness resulted in an area weight of 109.7 g / m 2

[0323] For Example 8a, the dried film is the final agomelatine - containing mucoadhesive layer structure. For Examples 8b and 8c, die - cuts of 1.6 cm 2 in size were punched out from the dried agomelatine - containing layer.

[0324] ​Preparation of the Second Coating Composition (Backing Layer) For Example 8b, a beaker was filled with ethanol. FD&C Green No. 3 was added, and then the mixture was stirred. Ethyl cellulose N50F, castor oil, and glycerol were added under stirring to obtain a mixture.

[0325] The second coating composition of Example 8c was prepared in the same manner as Example 5d above.

[0326] The resulting second coating composition was coated onto a polyester film (polyethylene terephthalate film, single-sided silicon-treated, thickness 75 μm, which can function as a release liner) and dried at room temperature for approximately 10 minutes and at 70 °C for 20 minutes (Example 8b), and at room temperature for approximately 5 minutes, at 35 °C for 10 minutes, and at 80 °C for 2 minutes. The coating thicknesses resulted in areal weights of 19.2 g / m 2 (Example 8b) and 78.3 g / m 2 (Example 8c), respectively.

[0327] Preparation of the Adhesive Composition A beaker was filled with ethanol. Purified water and menthol were added, and then the mixture was stirred. Hydroxyethyl cellulose, castor oil, and polysorbate 80 were added under stirring to obtain a homogeneous mixture.

[0328] The resulting adhesive composition was coated onto the dried backing layer and dried at room temperature for approximately 5 minutes, at 50 °C for 10 minutes, and at 90 °C for 2 minutes. The coating thicknesses resulted in areal weights of 42.9 g / m 2 (Example 8b) and 95.7 g / m 2 (Example 8c), respectively. Die cuts of 5.5 cm 2 in size were punched out from the dried adhesive backing layer.

[0329] Preparation of the Transmucosal Therapeutic System For Examples 8b and 8c, the dry films were laminated with their respective adhesive backing layers to obtain agomelatine-containing mucoadhesive layer structures.

[0330] Further steps (e.g., punching out individual devices) were carried out as in Example 1.

[0331] In vivo study using Göttingen minipigs To evaluate the delivery of agomelatine, in vivo experiments were carried out using Göttingen minipigs (female, about 6 - 7 months old, body weight at the start of the study was 13.8 - 14.3 kg). Four minipigs were used. The transmucosal therapeutic systems of Examples 8a, 8b and 8c prepared as described above were administered to the buccal mucosa of one animal each for Examples 8a and 8b, and two animals for Example 8c (1 system / animal). The total wearing time of the transmucosal therapeutic system was 4 hours (after 4 hours, the application area was washed to remove potential residues of the transmucosal therapeutic system). No residues were observed in Example 8a, and slight residues were observed in Examples 8b and 8c with backing.

[0332] During the study, the minipigs were kept under sedation.

[0333] After application of the transmucosal therapeutic system, blood samples were taken at eight time points. Samples were taken at 0 (before treatment), 0.5, 1, 1.5, 2, 4 (immediately before removal of the test item), 5 and 8 hours. Analysis of plasma samples was carried out in accordance with the principles of the OECD Principles of Good Laboratory Practice (revised 1997). These principles are adhered to by other international GLP regulations.

[0334] The concentration of agomelatine in minipig plasma was determined using validated liquid - liquid extraction followed by LC - MS / MS. All samples taken before the start of treatment were measured to be below the limit of quantification (0.100 ng / mL).

[0335] The measured agomelatine plasma concentrations are summarized in Table 8.2 and shown in Figure 8a.

[0336] In addition, immediately after the removal of the OTF, the state of the mucosa was visually measured 4 hours after application and after washing on the OTF application side, and a Draize score was obtained based on the following scoring scheme according to OECD Guideline No. 404: "Acute Dermal Irritation / Corrosion" for the testing of chemicals adopted on July 28, 2015.

[0337] Four hours after removing the transmucosal treatment system, none of the formulations showed irritation (see Table 8.2).

[0338]

Table 27

[0339] The maximum plasma concentration was measured 2 - 4 hours after the start of treatment and was in the range of 9.0 - 11.8 ng / mL for the OTFs according to Examples 8b and 8c with backing and 57.2 ng / mL for the OTF according to Example 8a without backing. Very high PK data for the transmucosal treatment system according to Example 8a without backing could be achieved. This can be explained by the release system that enables the delivery of the API through the mucosa of the entire oral cavity. The high delivery rate is still highly advantageous as the patch size and / or the concentration of the active substance can be decreased compared to the system containing the backing layer. The transmucosal treatment system with the backing layer has a limited permeation area of 1.6 cm 2 but shows a lower but still high permeability over 4 hours. Agomelatine could be quantified 4 hours after the removal of the transmucosal treatment system with higher PK data, so potential residual agomelatine may be present within the mucosa.

[0340] Examples 9A - 9F Coating composition The formulations of the agomelatine-containing coating compositions of Examples 4b and 9a - 9f are summarized in Table 4.1 above and Table 9.1 below. As also shown in Tables 4.1 and 9.1, the formulations are based on weight percentages.

[0341]

Table 28-1

Table 28-2

Table 28-3

[0342] Preparation of the first coating composition (agomelatine-containing layer) Regarding the TiO2 solution, a beaker was filled with 2.80 g of TiO2. Oleic acid was added and then the mixture was stirred to obtain the TiO2 solution.

[0343] For Examples 9b, 9c and 9d, a beaker was filled with vanilla flavor. Sucralose, saccharin Na, ethanol, hydroxypropyl cellulose GF, hydroxypropyl cellulose EF, carbopol solution, and agomelatine were added and then the mixture was stirred. The TiO2 solution was added with stirring to obtain the viscose mixture.

[0344] For Example 9a, a beaker was filled with vanilla flavor. Sucralose, saccharin Na, agomelatine, and ethanol were added and then the mixture was stirred. The TiO2 solution and hydroxypropyl cellulose were added with stirring to obtain the viscose mixture.

[0345] For Examples 9e and 9f, a beaker was filled with vanilla flavor. Sucralose, saccharin Na, and ethanol were added and then the mixture was stirred. The carbopol solution, ethyl cellulose, hydroxypropyl cellulose, agomelatine, and TiO2 solution were added with stirring to obtain the viscose mixture.

[0346] Coating of the first coating composition The resulting agomelatine-containing coating composition was coated onto a polyester film (a polyethylene terephthalate film, silicon-treated on one side, 75 μm thick, which can function as a release liner), and dried at room temperature for approximately 10 minutes, at 40 °C for 15 minutes, and at 70 °C for 10 minutes. The coating thicknesses resulted in areal weights of 117.0 g / m 2 (Examples 9a - 9d), 123.5 g / m 2 (Example 9e), and 117.5 g / m 2 (Example 9f) respectively.

[0347] For Examples 9a and 9b, the dried film is the final agomelatine-containing mucoadhesive layer structure. For Example 9d, a die-cut of 0.28 cm 2 in size was punched out from the dried agomelatine-containing layer.

[0348] Preparation of the second coating composition (backing layer) For Examples 9c - 9f, beakers were filled with vanilla flavor. Sucralose, saccharin Na, oleic acid, FD&C Red No. 40, ethanol, and purified water were then added to the mixture and stirred. Hydroxypropyl cellulose and hydroxyethyl cellulose were added under stirring to obtain a viscous mixture.

[0349] The resulting backing composition was coated twice onto the dried agomelatine-containing layer (in the case of Examples 9c, 9e, and 9f) or onto a polyester film (a polyethylene terephthalate film, silicon-treated on one side, 75 μm thick, which can function as a release liner), and dried at room temperature for approximately 10 minutes, at 50 °C for 15 minutes, and at 80 °C for 10 minutes. The coating thicknesses resulted in total areal weights (agomelatine-containing layer and backing layer) of 382 g / cm 2 (Example 9c), 272.2 g / m 2 (Example 9d) or 388.1 g / m 2 (Examples 9e and 9f) respectively.

[0350] For Examples 9c, 9e and 9f, a die cut of 0.28 cm in size was punched out from the dried layer to obtain an agomelatine-containing mucoadhesive layer structure. 2

[0351] For Example 9d, a die cut of 0.28 cm in size was punched out from the backing layer and adhered to each agomelatine-containing layer via a small amount of a second coating composition so that the backing layer extended uniformly on all sides of the agomelatine-containing layer, to obtain an agomelatine-containing mucoadhesive layer structure. 2

[0352] Preparation of the transdermal therapeutic system Please refer to Example 1.

[0353] Measurement of the mucosal permeation rate The permeation amount and the corresponding mucosal permeation rate of the transdermal therapeutic systems prepared according to Example 4b and Examples 9a to 9f were determined by in vitro experiments according to the OECD guidelines (adopted on April 13, 2004) using porcine mucosa (esophageal mucosa). For all transdermal therapeutic systems, a 400-μm thick mucosa with an intact barrier function was prepared using a dermatome. A die cut of 0.28 cm in area punched out from the transdermal therapeutic systems of Examples 9a and 9b, as well as the above-mentioned agomelatine-containing mucoadhesive layer structure, were applied to the mucosa, and the upper surface of the mucosa with the transdermal therapeutic system was immersed in artificial saliva (the lower surface was in contact with the receiving medium, and the upper surface was compartmentalized into a mucosal area of 1.145 cm). The agomelatine permeation amount in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37 ± 1 °C was measured, and the corresponding mucosal permeation rate was calculated. The results are shown in Tables 9.2 and 9.3 and Figure 9a. 2 2

[0354]

Table 29

[0355]

Table 30

[0356] Utilization rate of agomelatine The utilization rate of agomelatine at the 4-hour time point was calculated based on the cumulative permeation amount and the initial agomelatine content at the 4-hour time point. The results are shown in Table 9.4 and Figure 9c.

[0357]

Table 31

[0358] In vitro experiments show good mucosal permeation rate and good utilization rate. These examples again show that the transdermal therapeutic system with a backing layer provides lower but still good active substance delivery when compared with those without a backing layer.

[0359] Measurement of storage stability Long-term storage stability tests were carried out for Examples 9a to 9c under different test conditions, namely storage at 25 °C and 60% relative humidity (RH), and at 40 °C and 75% RH. Samples were taken from the transdermal therapeutic system 3, 6, 9, and 12 months after storage at 25 °C and 60% RH, and 3 and 6 months after storage at 40 °C and 75% RH. The ethanol and water contents were determined, and the amount of agomelatine and various potential degradation substances were determined by a specific quantitative HPLC method based on the agomelatine content calculated from the (actual) areal weight of the transdermal therapeutic system tested. The results are shown in Tables 9.5 to 9.8 and Figures 9c and 9d.

[0360]

Table 32

[0361]

Table 33

[0362]

Table 34

[0363]

Table 35

[0364] The stability data indicate that for Examples 9a and 89c, the initial and storage stabilities are excellent with respect to both the amount of agomelatine (especially the amount of agomelatine remaining after storage) and the total of potential degradation substances.

[0365] Dissolution experiment 10 As outlined in more detail above, the soluble film-forming agent is preferably soluble, dispersible, or otherwise disintegrating in an aqueous medium such as water, while film-forming agents that are soluble in, for example, ethanol are also preferred.

[0366] To observe the dissolution behavior of potential film-forming agents, 10 wt% (+ / - 0.1 percentage points) mixtures of the polymer in water, ethanol, or a 1:1 water / ethanol mixture were prepared and the dissolution behavior was recorded. Viscosity as well as other observations were recorded. The results are summarized in Table 10.1 below.

[0367]

Table 36-1

Table 36-2

Table 36-3

[0368] Examples 11A to 11I Coating composition The formulations of the agomelatine-containing coating compositions of Examples 11a to 11i are summarized in Tables 11.1 and 11.2 below. As also shown in Tables 11.1 and 11.2, the formulations are based on weight percentages.

[0369]

Table 37-1

Table 37-2

[0370]

Table 38-1

Table 38-2

[0371] Preparation of the first coating composition (agomelatine-containing layer) For the TiO2 solution, a beaker was filled with 2.80 g of TiO2. Oleic acid was added and then the mixture was stirred to obtain the TiO2 solution.

[0372] For Examples 11a, 11f and 11g, a beaker was filled with vanilla flavor. Sucralose, saccharin Na, and ethanol were added and then the mixture was stirred. The carbopol solution, hydroxypropyl cellulose, agomelatine, and TiO2 solution were added with stirring to obtain a viscose mixture.

[0373] For Examples 11b and 11i, a beaker was filled with vanilla flavor. Sucralose, saccharin Na, and purified water were added and then the mixture was stirred. The carbopol solution, polyvinyl alcohol, agomelatine, and TiO2 solution were added with stirring to obtain a viscose mixture.

[0374] Regarding Examples 11c and 11h, a beaker was filled with vanilla flavor. Sucralose, saccharin Na, ethanol, and Carbopol solution were added, and then the mixture was stirred. Povidone, agomelatine, and TiO2 solution were added with stirring to obtain a viscous mixture.

[0375] Regarding Example 11d, a beaker was filled with vanilla flavor. Sucralose, saccharin Na, ethanol, hydroxypropyl cellulose GF, hydroxypropyl cellulose EF, Carbopol solution, and agomelatine were added, and then the mixture was stirred. TiO2 solution was added with stirring to obtain a viscous mixture.

[0376] Regarding Example 11e, a beaker was filled with vanilla flavor. Sucralose, saccharin Na, and ethanol were added, and then the mixture was stirred. Carbopol solution, ethyl cellulose, hydroxypropyl cellulose, agomelatine, and TiO2 solution were added with stirring to obtain a viscous mixture.

[0377] Coating of the first coating composition The resulting agomelatine-containing coating composition was coated on a polyester film (polyethylene terephthalate film, single-sided silicon-treated, 75 μm thick, which can function as a release liner) and dried at room temperature for approximately 10 minutes, at 40 °C for 15 minutes, and at 70 °C for 10 minutes (Examples 11a and 11c - 11h) and at 80 °C for 10 minutes (Examples 11b and 11i), respectively. The coating thickness was 119.8 g / m 2 (Examples 11a and 11g), 160.5 g / m 2 (Example 11b), 126.3 g / m 2 (Example 11c), 126.0 g / m 2 (Example 11d), 120.6 g / m 2 (Example 11e), 116.5 g / m 2 (Example 11f), 125.2 g / m 2 (Example 11h), and 149.9 g / m 2resulted in the areal weight of (Example 11i).

[0378] Preparation of the second coating composition (backing layer) For Examples 11a to 11c, a beaker was filled with vanilla flavor. Sucralose, saccharin Na, oleic acid, FD&C Red No. 40, ethanol, purified water, and hydroxypropyl cellulose were added, and then the mixture was stirred. Hydroxyethyl cellulose was added with stirring to obtain a mixture.

[0379] For Examples 11d to 11i, a beaker was filled with vanilla flavor. Sucralose, saccharin Na, oleic acid, glycerol, FD&C Red No. 40, ethanol, and purified water were added, and then the mixture was stirred. Hydroxypropyl cellulose and Eudragit L100-55 were added with stirring to obtain a red mixture.

[0380] The resulting backing composition was coated twice onto the dried agomelatine-containing layer and dried at about 50 °C for about 15 minutes and at 80 °C for 10 minutes (for Examples 11a to 11c), or coated once onto the dried agomelatine-containing layer and dried at about 40 °C for about 15 minutes and at 70 °C for 10 minutes (for Examples 11d to 11i).

[0381] The coating thickness was, respectively, 390.6 g / m 2 (Example 11a), 446.6 g / m 2 (Example 11b), 404.3 g / m 2 (Example 11c), 239.0 g / m 2 (Example 11d), 237.2 g / m 2 (Example 11e), 237.0 g / m 2 (Example 11f), 237.9 g / m 2 (Example 11g), 256.7 g / m 2 (Example 11h), and 259.4 g / m 2 resulted in the total areal weight (agomelatine-containing layer and backing layer) of (Example 11i).

[0382] A 0.8 cm 2 diameter die cut was punched out from the dried layer to obtain the agomelatine-containing mucoadhesive layer structure.

[0383] Preparation of the transmucosal therapeutic system Refer to Example 1.

[0384] Mucoadhesion experiment 12 As outlined in more detail above, the agomelatine-containing layer needs to exhibit appropriate dissolution behavior and also provide sufficient adhesion to the mucosa. When present, the backing layer in combination with the agomelatine-containing layer should not peel off from the agomelatine-containing layer and preferably should not dissolve faster than the agomelatine-containing layer.

[0385] To observe the dissolution behavior and mucoadhesion of certain combinations of the agomelatine-containing layer and the backing layer, a mucoadhesion experiment using porcine mucosa (esophageal mucosa) was carried out using the transmucosal therapeutic systems of Examples 9c, 9e, 9f and 11a - 11i.

[0386] Experimental setup For all transmucosal therapeutic systems, a 400 μm thick mucosa with an intact barrier function was prepared using a dermatome, and a 0.8 cm 2 area die cut prepared as outlined above for Examples 9c, 9e, 9f and 11a - 11i was applied to the mucosa. Two samples were prepared for each example (n = 2). The upper surface of the mucosa with the transmucosal therapeutic system was immersed in 300 μl of artificial saliva (the lower surface was in contact with 250 μm of artificial saliva and the upper surface was compartmentalized in 50 μl of artificial saliva over a 4 cm 2 mucosal area). The dissolution behavior and mucoadhesive properties of the transmucosal therapeutic system were determined visually initially (2 minutes after application) and periodically at certain time points after application and also using the tip of a plastic syringe plunger upside down.

[0387] Results All samples showed very good initial mucosal adhesion, i.e., the samples could not be displaced.

[0388] Regarding Example 9c, two samples completely dissolved after 4 hours and 6 hours, respectively. During this time, none of the samples could be displaced.

[0389] In the samples of Example 9e, after 2 hours and 15 minutes, the patches of the transmucosal therapeutic system began to disintegrate at the edges. The detached parts could be displaced. The first sample completely dissolved after 4.5 hours. The second sample was almost completely dissolved after 6 hours, and the remaining part could be displaced.

[0390] Both samples of Example 9f had only a small residual part left after 6 hours, which showed good adhesion to the mucosa and could not be displaced.

[0391] The first sample of Example 11a was almost completely dissolved and displaced (deviated from the center) when visually inspected after 5 hours and completely dissolved after 5 hours and 20 minutes. In the second sample of Example 11a, a small residual part remained after 6 hours, which showed good adhesion to the mucosa and could not be displaced.

[0392] Both samples of Example 11b rolled up approximately 1 minute after application and did not adhere to the mucosa any further. After 3 minutes, the samples unrolled by themselves and adhered again. The backing layer completely dissolved after 1.5 hours, and at that time the agomelatine-containing layer was still present. The agomelatine-containing layer began to dissolve after 2.5 hours and completely dissolved after 5 hours in the first sample. In the second sample, some residual fragments of the agomelatine-containing layer were still floating on the mucosa after 5.5 hours.

[0393] Regarding Example 11c, the agomelatine-containing layer dissolved after 1.5 hours, and at that time the backing layer was still present. After 6 hours, a gelatinous residue remained, which could be displaced. Both samples showed similar behavior.

[0394] The samples of Example 11d could both be displaced after about 1 hour.

[0395] The samples of Example 11e could be displaced after about 3 / 4 hour and about 1 hour, respectively.

[0396] The samples of Example 11f could both be displaced with a little force applied after about 3 / 4 hour and could be easily displaced after about 1 hour.

[0397] The first sample of Example 11g could be displaced after about 1 / 2 hour. The second sample of Example 11g could be displaced after 6 minutes but adhered firmly after another 4 minutes. After about 1 / 2 hour in total, the second sample could be displaced again.

[0398] The samples of Example 11h could both be displaced after about 1 / 2 hour.

[0399] The samples of Example 11i both rolled up immediately when immersed in artificial saliva and remained coiled. The rolled-up samples could be displaced after about 1 / 2 hour.

[0400] These results are summarized in Table 12.1 below. When the two samples showed different results, both results are shown separated by a comma.

[0401] The abbreviations used in Table 12.1 are as follows. HPC: Hydroxypropyl cellulose EC: Ethyl cellulose PVA: Polyvinyl alcohol System: Transmucosal therapeutic system AL: Agomelatine-containing layer BL: Backing layer

[0402] [Table 39-1] [Table 39-2]

[0403] Water Absorption Experiment 13 A certain specific soluble film - forming agent exhibits hygroscopic behavior. To evaluate the water absorption over time, different coating compositions were prepared, the coating compositions were coated, and films were obtained by drying the coated layers. The films were stored at room temperature for 7 days, either open or packaged in a sealed - seam pouch. The detailed composition of the coated films, drying conditions, and the results obtained are shown in Table 13.1 below.

[0404]

Table 40

[0405] The present invention particularly relates to the following further items.

[0406] 1. A trans - mucosal therapeutic system for the trans - mucosal administration of agomelatine comprising a muco - adhesive layer structure, wherein the muco - adhesive layer structure comprises A) a backing layer; and B) i) agomelatine; and ii) an agomelatine - containing layer comprising a first soluble film - forming agent, said trans - mucosal therapeutic system.

[0407] 2. When the first soluble film - forming agent is cast onto a film having an area weight of 30 - 100 g / m 2 , or 50 g / m 2 , it dissolves in water, artificial or natural saliva, or 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 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, more than 30 seconds and less than 3 hours, more than 1 minute and less than 2 hours, or more than 2 minutes and less than 1 hour. The trans - mucosal therapeutic system according to item 1.

[0408] 3. The transmucosal therapeutic system according to item 1 or 2, wherein the first soluble film-forming agent is selected from the group consisting of polymers such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol-polyvinyl acetate- and polyvinylcaprolactam-based graft copolymers, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymer, and methacrylic acid-ethyl methacrylate copolymer, and natural film-forming agents such as shellac, pectin, gelatin, alginate, pullulan and starch derivatives, and any mixtures thereof.

[0409] 4. The transmucosal therapeutic system according to item 3, wherein the first soluble film-forming agent is selected from the group consisting of polymers such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol-polyvinyl acetate- and polyvinylcaprolactam-based graft copolymers, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymer, and methacrylic acid-ethyl methacrylate copolymer, and any mixtures thereof.

[0410] 5. The transmucosal therapeutic system according to item 4, wherein the first soluble film-forming agent is hydroxypropylcellulose or a mixture of one or more polymers selected from hydroxypropylcellulose and ethylcellulose.

[0411] 6. The transmucosal therapeutic system according to item 5, wherein the first soluble film-forming agent is hydroxypropyl cellulose, or a mixture of one or more polymers selected from hydroxypropyl cellulose having a molecular weight of 50,000 to 1,500,000 and ethyl cellulose.

[0412] 7. The first soluble film-forming agent is hydroxypropyl cellulose, or between 75,000 and 85,000, particularly 80,000 between 90,000 and 100,000, particularly 95,000 between 350,000 and 400,000, particularly 370,000, and between 1,100,000 and 1,200,000, particularly 1,150,000, The transmucosal therapeutic system according to item 6, which is a mixture of one or more polymers selected from hydroxypropyl cellulose having a molecular weight selected therefrom and ethyl cellulose.

[0413] 8. The first soluble film-forming agent is hydroxypropyl cellulose having a molecular weight between 90,000 and 100,000, particularly 95,000, or a mixture of one or more polymers selected from hydroxypropyl cellulose having a molecular weight between 75,000 and 85,000, particularly 80,000, hydroxypropyl cellulose having a molecular weight between 350,000 and 400,000, particularly 370,000, and ethyl cellulose, particularly a mixture of hydroxypropyl cellulose having a molecular weight between 75,000 and 85,000, particularly 80,000, and hydroxypropyl cellulose having a molecular weight between 350,000 and 400,000, particularly 370,000, or a mixture of hydroxypropyl cellulose having a molecular weight between 75,000 and 85,000, particularly 80,000, and ethyl cellulose. The transmucosal therapeutic system according to item 7.

[0414] 9. The amount of the first soluble film-forming agent is at least 65 wt%, at least 70 wt% or at least 75 wt% of the agomelatine-containing layer, or the amount of the first soluble film-forming agent is 98 wt% or less, 94 wt% or less or 90 wt% or less, or the amount of the first soluble film-forming agent is in the range of 65 - 98 wt%, 70 - 94 wt% or 75 - 90 wt%. The transmucosal therapeutic system according to any one of items 1 - 8.

[0415] 10. When the transmucosal therapeutic system is administered to a human patient, the backing layer dissolves in 5 minutes or more, 10 minutes or more or 15 minutes or more, or 12 hours or less, 8 hours or less or 4 hours or less, or between 5 minutes and 12 hours, between 10 minutes and 8 hours, or between 15 minutes and 4 hours. The transmucosal therapeutic system according to any one of items 1 - 9.

[0416] 11. The backing layer dissolves in water, artificial or natural saliva, or any other aqueous medium at 37 °C and 150 rpm in 10 minutes or more, 15 minutes or more or 30 minutes or more, or 15 hours or less, 12 hours or less or 10 hours or less, or between 10 minutes and 15 hours, between 15 minutes and 12 hours, or between 30 minutes and 10 hours. The transmucosal therapeutic system according to any one of items 1 - 10.

[0417] 12. The backing layer contains a second soluble film-forming agent. The transmucosal therapeutic system according to any one of items 1 - 11.

[0418] 13. The transmucosal therapeutic system according to item 12, wherein the second soluble film-forming agent is selected from the group consisting of polymers such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol-polyvinyl acetate- and polyvinylcaprolactam-based graft copolymers, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymers, polyvinylpyrrolidone-polyvinyl acetate copolymers, polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymers, and methacrylic acid-ethyl methacrylate copolymers, and natural film-forming agents such as shellac, pectin, gelatin, alginates, pullulan and starch derivatives, and any mixtures thereof.

[0419] 14. The transmucosal therapeutic system according to item 13, wherein the second soluble film-forming agent is a mixture of hydroxyethylcellulose and hydroxypropylcellulose.

[0420] 15. The second soluble film-forming agent is a mixture of hydroxyethylcellulose and hydroxypropylcellulose having a molecular weight of 50,000 to 1,500,000, particularly between 75,000 and 85,000, particularly 80,000 between 90,000 and 100,000, particularly 95,000 between 350,000 and 400,000, particularly 370,000, and The transmucosal therapeutic system according to item 14, which is a mixture of hydroxyethylcellulose and hydroxypropylcellulose having a molecular weight selected from between 1,100,000 and 1,200,000, particularly 1,150,000.

[0421] 16. The transmucosal therapeutic system according to item 15, wherein the second soluble film-forming agent is a mixture of hydroxyethylcellulose and hydroxypropylcellulose having a molecular weight between 75,000 and 85,000, particularly 80,000.

[0422] 17. The ratio of hydroxyethyl cellulose and hydroxypropyl cellulose having a molecular weight between 75,000 and 85,000, particularly 80,000, is 1:2 to 8:1, or 1:1 to 4:1, or 2:1, and the transmucosal therapeutic system according to item 16.

[0423] 18. The amount of the second soluble film-forming agent is at least 65% by weight, at least 75% by weight or at least 85% by weight of the backing layer, or the amount of the second soluble film-forming agent is in the range of 65 to 100% by weight, 75 to 100% by weight, or 80 to 100% by weight, and the transmucosal therapeutic system according to any one of items 1 to 17.

[0424] 19. The sizes of the backing layer and the agomelatine-containing layer have the same spread, and the transmucosal therapeutic system according to any one of items 1 to 18.

[0425] 20. The backing layer is larger in size than the agomelatine-containing layer, and the surface area is expanded, and the transmucosal therapeutic system according to any one of items 1 to 18.

[0426] 21. The agomelatine-containing layer contains at least 1% by weight of agomelatine, at least 2% by weight of agomelatine, or at least 3% by weight of agomelatine, and the transmucosal therapeutic system according to any one of items 1 to 20.

[0427] 22. The agomelatine-containing layer contains 25% by weight or less of agomelatine, 20% by weight or less of agomelatine, or 10% by weight or less of agomelatine, and the transmucosal therapeutic system according to any one of items 1 to 21.

[0428] 23. The agomelatine-containing layer contains 1 to 25% by weight or less of agomelatine, 2 to 20% by weight or less of agomelatine, or 3 to 10% by weight or less of agomelatine, and the transmucosal therapeutic system according to any one of items 1 to 22.

[0429] 24. The transmucosal therapeutic system according to any one of items 1 to 23, wherein the agomelatine-containing layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, flavoring agents, coloring agents, permeation enhancers, solubilizing agents, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffer reagents, and further film-forming agents.

[0430] 25. The transmucosal therapeutic system according to item 24, wherein the agomelatine-containing layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, and flavoring agents.

[0431] 26. The fatty acid is a saturated or unsaturated, linear or branched carboxylic acid containing 8 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, linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid. The transmucosal therapeutic system according to item 25.

[0432] 27. The fatty acid is oleic acid or linoleic acid. The transmucosal therapeutic system according to item 26.

[0433] 28. The agomelatine-containing layer contains one or more fatty acids in an amount of at least 1% by weight, at least 3% by weight, or at least 4% by weight, or in an amount of 15% by weight or less, 12% by weight or less, or 10% by weight or less, or in an amount of 1 to 15% by weight, 3 to 12% by weight, or 4 to 10% by weight. The transmucosal therapeutic system according to any one of items 24 to 27.

[0434] 29. The transmucosal therapeutic system according to item 24, wherein the agomelatine-containing layer contains one or more natural or artificial sweeteners selected from the group consisting of sucrose, glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidin, neotame, steviol glycoside, thaumatin, and sodium saccharin.

[0435] 30. The transmucosal therapeutic system according to item 29, wherein the agomelatine-containing layer contains one or more natural or artificial sweeteners selected from the group consisting of sucrose, sucralose, and sodium saccharin.

[0436] 31. The transmucosal therapeutic system according to item 30, wherein the agomelatine-containing layer contains one or more natural or artificial sweeteners selected from the group consisting of sucralose, sucrose, and sodium saccharin, each in an amount of at least 0.05% by weight, at least 0.1% by weight, or at least 0.3% by weight, or in an amount of 2.0% by weight or less, 1.5% by weight or less, or 1.0% by weight or less, or in an amount of 0.05 - 2.0% by weight, 0.1 - 1.5% by weight, or 0.3 - 1.0% by weight.

[0437] 32. The transmucosal therapeutic system according to item 24, wherein the agomelatine-containing layer contains one or more natural or artificial flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetyl propionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethyl vanillin, and eucalyptol, and a flavoring composition, such as a peppermint flavor.

[0438] 33. The agomelatine-containing layer contains one or more flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, peppermint flavor, and eucalyptol, each in an amount of at least 0.1% by weight, at least 0.3% by weight, or at least 0.4% by weight, or in an amount of 10% by weight or less, 6% by weight or less, or 4% by weight or less, or in an amount of 0.1 to 10% by weight, 0.3 to 6% by weight, or 0.4 to 4% by weight, or in total, in an amount of at least 0.1% by weight, at least 0.5% by weight, or at least 0.7% by weight, or in an amount of 15% by weight or less, 10% by weight or less, or 8% by weight or less, or in an amount of 0.1 to 15% by weight, 0.5 to 10% by weight, or 0.7 to 8% by weight, the transmucosal therapeutic system according to item 32.

[0439] 34. The agomelatine-containing layer contains 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, sunset yellow FCF, curcumin, riboflavin, riboflavin-5'-phosphate, quinoline yellow, orange yellow S, cochineal, carminic acid, azorbic, carmoisine, amaranth, ponceau 4R, cochineal red A, patent blue V, indigotin, chlorophyll, chlorophyllin, copper complexes of chlorophyll and chlorophyllin, green S, plain caramel, caustic sulfite caramel, ammonia caramel, sulfite ammonia caramel, brilliant black BN, black PN, vegetable carbon, brown HT, carotene, annatto, bixin, norbixin, paprika extract, capsanthin, capsorubin, lycopene, beta-apo-8'-carotenal, lutein, zeaxanthin, beetroot red, betanin, anthocyanin, calcium carbonate, iron oxide and iron hydroxide, aluminum, silver, gold, and lysol rubin BK, the transmucosal therapeutic system according to item 24.

[0440] 35. The transmucosal therapeutic system according to item 24, wherein the agomelatine-containing layer contains one or more additional film formers, and the additional film formers are different from the first soluble film former.

[0441] 36. The agomelatine-containing layer contains one or more additional film formers, each in an amount of at least 2% by weight, at least 5% by weight or at least 10% by weight, or 40% by weight or less, 30% by weight or less, or 25% by weight or less, or in an amount of 2 to 40% by weight, 5 to 30% by weight, or 10 to 25% by weight, or in total, in an amount of at least 5% by weight, at least 15% by weight or at least 20% by weight, or 40% by weight or less, 30% by weight or less, or 25% by weight or less, or in an amount of 5 to 40% by weight, 15 to 30% by weight, or 20 to 25% by weight, as described in item 35 of the transmucosal therapeutic system.

[0442] 37. The transmucosal therapeutic system according to item 24, wherein the agomelatine-containing layer contains 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 oleosome, propanediol and polyethoxylated castor oil.

[0443] 38. The transmucosal therapeutic system according to item 37, wherein the agomelatine-containing layer contains one or more solubilizers, each in an amount of at least 1% by weight, at least 3% by weight or at least 5% by weight, or 25% by weight or less, 20% by weight or less, or 15% by weight or less, or in an amount of 1 to 25% by weight, 3 to 20% by weight, or 5 to 15% by weight.

[0444] 39. The transmucosal therapeutic system according to item 24, wherein the agomelatine-containing layer contains one or more emulsifiers selected from the group consisting of soy lecithin, sodium phosphate, monoglycerides and diglycerides of fatty acids, sodium stearoyl lactylate, diacetyl tartaric acid esters of monoglycerides and diglycerides, and polyethoxylated hydrogenated castor oil.

[0445] 40. The transmucosal therapeutic system according to item 39, wherein the agomelatine-containing layer contains one or more emulsifiers in an amount of at least 1 wt%, at least 3 wt% or at least 5 wt% each, or in an amount of 25 wt% or less, 20 wt% or less, or 15 wt% or less, or in an amount of 1-25 wt%, 3-20 wt%, or 5-15 wt%.

[0446] 41. The transmucosal therapeutic system according to item 24, wherein the agomelatine-containing layer contains one or more plasticizers selected from the group consisting of monosaccharides, disaccharides, oligosaccharides and polysaccharides, and derivatives thereof, such as sorbitol, polyethylene glycol, triacetin, triethyl citrate, propylene glycol, glycerol and medium-chain triglycerides.

[0447] 42. The transmucosal therapeutic system according to item 41, wherein the agomelatine-containing layer contains one or more plasticizers in an amount of at least 0.5 wt%, at least 1 wt% or at least 5 wt% each, or in an amount of 25 wt% or less, 20 wt% or less, or 15 wt% or less, or in an amount of 0.5-25 wt%, 1-20 wt%, or 5-15 wt%.

[0448] 43. The transmucosal therapeutic system according to any one of items 1 to 42, wherein the agomelatine-containing layer does not contain a permeation enhancer selected from the group consisting of bile acids, bile salts, bile acid derivatives, acylcarnitine, sodium dodecyl sulfate, dimethyl sulfoxide, sodium lauryl sulfate, terpenes, cyclodextrins, cyclodextrin derivatives, saponins, saponin derivatives, chitosan, EDTA, citric acid, and salicylates in an amount exceeding 0.1% by weight, exceeding 0.2% by weight, exceeding 1% by weight, or exceeding 5% by weight.

[0449] 44. The transmucosal therapeutic system according to any one of items 1 to 43, wherein the agomelatine-containing layer contains a permeation enhancer selected from the group consisting of diethylene glycol monoethyl ether, dipropylene glycol, levulinic acid, lauryl lactate, lactic acid, dimethylethyleneurea, N,N'-dimethylpropyleneurea DMPU, and N,N-diethyl-meta-toluamide (DEET), 2-(2-ethoxyethoxy)ethanol, 2,5-dimethylisosorbide, propylene glycol monocaprylate, 2-methoxy-4-(prop-2-en-1-yl)phenol, and laurocapram.

[0450] 45. The transmucosal therapeutic system according to any one of items 24 to 44, wherein the agomelatine-containing layer contains a permeation enhancer in an amount of at least 1% by weight, at least 2% by weight, or at least 5% by weight, or in an amount of 20% by weight or less, 15% by weight or less, or 10% by weight or less, or in an amount of 1 to 20% by weight, 2 to 15% by weight, or 5 to 10% by weight.

[0451] 46. The transmucosal therapeutic system according to any one of items 1 to 45, wherein the agomelatine-containing layer is substantially free of water.

[0452] 47. The transmucosal therapeutic system according to item 46, wherein the agomelatine-containing layer contains 12% by weight or less, 8% by weight or less, 5% by weight or less, or 4% by weight or less of water.

[0453] 48. The transmucosal therapeutic system according to any one of items 1 to 47, wherein the agomelatine-containing layer substantially does not contain a volatile solvent, and the volatile solvent is selected from the group consisting of methanol, 1-propanol, 2-propanol, ethyl acetate, hexane, n-heptane, and any mixture thereof, and in particular is selected from the group consisting of C1-C3 linear and branched alcohols, ethyl acetate, hexane, n-heptane, and any mixture thereof.

[0454] 49. The transmucosal therapeutic system according to item 48, wherein the agomelatine-containing layer contains 5% by weight or less, 3% by weight or less, or 1% by weight or less of a volatile solvent.

[0455] 50. The transmucosal therapeutic system according to any one of items 1 to 49, wherein the agomelatine-containing layer can be obtained by drying a coated coating composition containing the agomelatine, the first soluble film-forming agent, and ethanol.

[0456] 51. The transmucosal therapeutic system according to any one of items 1 to 50, wherein the agomelatine-containing layer can be obtained by drying a coated coating composition containing the agomelatine, the first soluble film-forming agent, and water.

[0457] 52. The transmucosal therapeutic system according to item 50 or 51, wherein the agomelatine-containing layer can be obtained by drying a coated coating composition containing the agomelatine, the first soluble film-forming agent, ethanol, and water.

[0458] 53. The transmucosal therapeutic system according to any one of items 50 to 52, wherein the agomelatine-containing layer can be obtained by drying a coated coating composition containing less than 50% by weight, or less than 20% by weight, or less than 10% by weight, or less than 5% by weight of water.

[0459] 54. The agomelatine-containing layer is at least 25 g / m 2, having an area weight of at least 35 g / m 2 or having an area weight of at least 40 g / m 2 or having an area weight of 300 g / m 2 or less, 250 g / m 2 or less, or having an area weight of 200 g / m 2 or less, or having an area weight of 25 - 300 g / m 2 , 35 - 250 g / m 2 or 40 - 200 g / m 2 The transmucosal treatment system according to any one of Items 1 to 53, having an area weight as described above.

[0460] 55. The agomelatine-containing layer contains at least 0.1 mg / cm 2 , at least 0.2 mg / cm 2 or at least 0.4 mg / cm 2 of agomelatine, or the agomelatine-containing layer contains 2.0 mg / cm 2 or less, 1.5 mg / cm 2 or less, or 1.2 mg / cm 2 or less of agomelatine, or the agomelatine-containing layer contains 0.1 - 2.0 mg / cm 2 , 0.2 - 1.5 mg / cm 2 or 0.4 - 1.2 mg / cm 2 of agomelatine. The transmucosal treatment system according to any one of Items 1 to 54, containing agomelatine as described above.

[0461] 56. The agomelatine is contained in the agomelatine-containing layer in a dissolved form, a dispersed form, a crystalline form, particularly one of its polymorphic forms, an amorphous form, as a hydrate, a solvate, a hybrid form of any of the aforementioned forms, or a mixture thereof. The transmucosal treatment system according to any one of Items 1 to 55, containing agomelatine as described above.

[0462] 57. The transmucosal therapeutic system according to any one of items 1 to 56, wherein the agomelatine-containing layer can be obtained by incorporating the agomelatine in a dissolved form, a dispersed form, a crystalline form, in particular one of its polymorphic forms, an amorphous form, as a hydrate, a solvate, a hybrid form of any of the foregoing forms or a mixture thereof.

[0463] 58. The transmucosal therapeutic system according to any one of items 1 to 57, wherein the agomelatine in the agomelatine-containing layer is dissolved or present in a dispersed form.

[0464] 59. The transmucosal therapeutic system according to item 58, wherein the agomelatine in the agomelatine-containing layer is present in a dispersed form.

[0465] 60. The transmucosal therapeutic system according to item 58, wherein the agomelatine in the agomelatine-containing layer is dissolved.

[0466] 61. The transmucosal therapeutic system according to any one of items 1 to 60, wherein at least 90 mol%, preferably at least 95 mol%, more preferably at least 98 mol%, most preferably at least 99 mol% of the agomelatine in the agomelatine-containing layer is present in a dissolved form.

[0467] 62. The transmucosal therapeutic system according to any one of items 1 to 61, wherein the agomelatine-containing layer does not contain agomelatine crystals.

[0468] 63. The transmucosal therapeutic system according to any one of items 1 to 62, wherein the agomelatine has a purity of at least 95%, preferably at least 98%, more preferably at least 99% as determined by quantitative HPLC.

[0469] 64. The transmucosal therapeutic system according to any one of items 1 to 63, wherein the backing layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, flavoring agents, coloring agents, permeation enhancers, solubilizing agents, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffer reagents, and further film-forming agents.

[0470] 65. The transmucosal therapeutic system according to item 64, wherein the backing layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, and flavoring agents.

[0471] 66. The fatty acid is a saturated or unsaturated, linear or branched carboxylic acid containing 8 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, linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid. The transmucosal therapeutic system according to item 65.

[0472] 67. The transmucosal therapeutic system according to item 64, wherein the backing layer contains one or more natural or artificial sweeteners selected from the group consisting of sucrose, glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidin, neotame, steviol glycoside, thaumatin, and sodium saccharin.

[0473] 68. The transmucosal therapeutic system according to item 64, wherein the backing layer comprises one or more natural or artificial flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetyl propionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethyl vanillin, and eucalyptol, and a flavoring composition, such as a peppermint flavor.

[0474] 69. The transmucosal therapeutic system according to item 64, wherein the backing 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, sunset yellow FCF, curcumin, riboflavin, riboflavin-5'-phosphate, quinoline yellow, orange yellow S, cochineal, carminic acid, azorubine, carmoisine, amaranth, ponceau 4R, cochineal red A, patent blue V, indigotin, chlorophyll, chlorophyllin, chlorophyll and copper complexes of chlorophyll, green S, plain caramel, caustic sulfite caramel, ammonia caramel, sulfite ammonia caramel, brilliant black BN, black PN, vegetable carbon, brown HT, carotene, annatto, bixin, norbixin, paprika extract, capsanthin, capsorubin, lycopene, beta-apo-8'-carotenal, lutein, canthaxanthin, beetroot red, betanin, anthocyanin, calcium carbonate, iron oxide and iron hydroxide, aluminum, silver, gold, and lysol rubin BK.

[0475] 70. The transmucosal therapeutic system according to item 64, wherein the backing layer comprises one or more additional film formers, and the additional film formers are different from the second soluble film formers.

[0476] 71. The transmucosal therapeutic system according to item 64, wherein the backing layer contains one or more solubilizing agents 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 oleosome, propanediol, and polyethoxylated castor oil.

[0477] 72. The transmucosal therapeutic system according to item 64, wherein the backing layer contains one or more emulsifying agents selected from the group consisting of soy lecithin, sodium phosphate, monoglycerides and diglycerides of fatty acids, sodium stearoyl lactate, diacetyl tartaric acid esters of monoglycerides and diglycerides, and polyethoxylated hydrogenated castor oil.

[0478] 73. The transmucosal therapeutic system according to item 64, wherein the backing layer contains one or more plasticizers selected from the group consisting of monosaccharides, disaccharides, oligosaccharides and polysaccharides, and derivatives thereof, such as sorbitol, polyethylene glycol, triacetin, triethyl citrate, propylene glycol, glycerol and medium-chain triglycerides.

[0479] 74. The transmucosal therapeutic system according to any one of items 1 to 73, wherein the transmucosal therapeutic system is substantially free of water.

[0480] 75. The transmucosal therapeutic system according to item 74, wherein the transmucosal therapeutic system contains 10% by weight or less, 5% by weight or less, or 3% by weight or less of water.

[0481] 76. The transmucosal therapeutic system according to any one of items 1 to 75, wherein the backing layer substantially does not contain a volatile solvent, and the volatile solvent is selected from the group consisting of methanol, 1-propanol, 2-propanol, ethyl acetate, hexane, n-heptane, and any mixture thereof, particularly selected from the group consisting of C1-C3 linear and branched alcohols, ethyl acetate, hexane, n-heptane, and any mixture thereof.

[0482] 77. The transmucosal therapeutic system according to item 76, wherein the backing layer contains 5% by weight or less, 3% by weight or less, or 1% by weight or less of a volatile solvent.

[0483] 78. The transmucosal therapeutic system according to any one of items 1 to 77, wherein the backing layer can be obtained by drying a coated coating composition containing the second soluble film-forming agent and ethanol.

[0484] 79. The transmucosal therapeutic system according to any one of items 1 to 78, wherein the backing layer can be obtained by drying a coated coating composition containing the second soluble film-forming agent and water.

[0485] 80. The transmucosal therapeutic system according to item 78 or 79, wherein the backing layer can be obtained by drying a coated coating composition containing the second soluble film-forming agent, ethanol, and water.

[0486] 81. The transmucosal therapeutic system according to any one of items 78 to 80, wherein the backing layer can be obtained by drying a coated coating composition containing less than 50% by weight, less than 20% by weight, less than 10% by weight, or less than 5% by weight of water.

[0487] 82. The backing layer is at least 50 g / m 2 at least 75 g / m 2 or at least 100 g / m2 has an areal weight of, or 400 g / m 2 or less, 350 g / m 2 or less, or 300 g / m 2 or less, or has an areal weight of 50 - 400 g / m 2 , 75 - 350 g / m 2 , or 100 - 300 g / m 2 and is a transmucosal therapeutic system according to any one of items 1 to 81.

[0488] 83. The mucoadhesive layer structure further includes C) a mucosa contact layer, and D) one or more additional layers selected from a decorative layer, and when the different layers are present, their order is decorative layer backing layer agomelatine-containing layer mucosa contact layer, and is a transmucosal therapeutic system according to any one of items 1 to 82.

[0489] 84. The mucoadhesive layer structure further includes a mucosa contact layer or does not include it, and is a transmucosal therapeutic system according to item 83.

[0490] 85. The mucoadhesive layer structure further includes a mucosa contact layer, and the mucosa contact layer is mucoadhesive, and is a transmucosal therapeutic system according to item 84.

[0491] 86. The mucoadhesive layer structure further includes a mucosa contact layer, and the size of the agomelatine-containing layer and the size of the mucosa contact layer have the same spread, and is a transmucosal therapeutic system according to any one of items 83 to 85.

[0492] 87. The mucoadhesive layer structure further includes a decorative layer or does not include it, and is a transmucosal therapeutic system according to any one of items 83 to 86.

[0493] 88. The transmucosal treatment system according to any one of items 83 to 87, wherein the mucoadhesive layer structure further includes a decorative layer, and the size of the backing layer and the size of the decorative layer have the same spread.

[0494] 89. The transmucosal treatment system according to any one of items 83 to 88, wherein the decorative layer dissolves in water, artificial or natural saliva, or any other aqueous medium at 37 ° C and 150 rpm in less than 3 minutes, less than 1 minute, or less than 30 seconds.

[0495] 90. The transmucosal treatment system according to any one of items 1 to 89, wherein the mucoadhesive layer structure consists of the backing layer and the agomelatine-containing layer.

[0496] 91. The transmucosal treatment system according to any one of items 1 to 90, wherein the agomelatine-containing layer is mucoadhesive.

[0497] 92. The transmucosal treatment system according to any one of items 1 to 91, wherein the mucoadhesive layer structure contains agomelatine in a therapeutically effective amount.

[0498] 93. The transmucosal treatment system according to any one of items 1 to 92, wherein the agomelatine-containing layer contains at least 0.1 mg, at least 0.2 mg, or at least 0.4 mg of agomelatine, or the agomelatine-containing layer contains 20 mg or less, 15 mg or less, or 10 mg or less of agomelatine, or the agomelatine-containing layer contains 0.1 mg to 20 mg, 0.2 mg to 15 mg, or 0.4 mg to 10 mg of agomelatine.

[0499] 94. The transmucosal treatment system according to any one of items 1 to 93, wherein the mucoadhesive layer structure dissolves in water, artificial or natural saliva, or any other aqueous medium at 37 ° C and 150 rpm in 10 minutes or more, 15 minutes or more, or 30 minutes or more, or in 15 hours or less, 12 hours or less, or 10 hours or less, or between 10 minutes and 15 hours, between 15 minutes and 12 hours, or between 30 minutes and 10 hours.

[0500] 95. The transmucosal treatment system has a release area of at least 0.1 cm 2 , at least 0.2 cm 2 , or at least 0.5 cm 2 , or has a release area of 10 cm 2 or less, 7 cm 2 or less, or 5 cm 2 or less, or has a release area of 0.1 - 10 cm 2 , 0.2 - 7 cm 2 , or 0.5 - 5 cm 2 , and is the transmucosal treatment system according to any one of items 1 - 94.

[0501] 96. The transmucosal treatment system according to any one of items 1 - 95, further comprising a release liner.

[0502] 97. The transmucosal treatment system according to any one of items 1 - 95, wherein the transmucosal treatment system does not include a release liner.

[0503] 98. The transmucosal treatment system according to any one of items 1 - 97, wherein the transmucosal treatment system is in the form of a film.

[0504] 99. The transmucosal treatment system according to item 98, which is in the form of a thin film and has an area weight of at least 75 g / m 2 , at least 100 g / m 2 , or at least 130 g / m 2 , or has an area weight of 700 g / m 2 or less, 600 g / m 2 or less, or 500 g / m 2 or less, or has an area weight of 75 - 700 g / m 2 , 100 - 600 g / m 2 , or 130 - 500 g / m 2 .

[0505] 100. The transmucosal therapeutic system according to any one of items 1 to 99, which is in the form of a film having a circular, rectangular, or square shape.

[0506] 101. The transmucosal therapeutic system according to any one of items 1 to 100, wherein the administration of the transmucosal therapeutic system comprises applying the mucoadhesive layer structure to the mucosa of the oral cavity of a human patient and maintaining it on the mucosa until it dissolves.

[0507] 102. The transmucosal therapeutic system according to item 101, wherein the administration of the transmucosal therapeutic system comprises applying the mucoadhesive layer structure to the buccal, sublingual, gingival, or palatal mucosa of the oral cavity of a human patient and maintaining it on the mucosa until it dissolves.

[0508] 103. The transmucosal therapeutic system according to any one of items 1 to 102, which provides a mucosal permeation rate of agomelatine of 10 μg / cm 2 -hr to 150 μg / cm 2 -hr when measured on porcine esophageal mucosa.

[0509] 104. The transmucosal therapeutic system according to any one of items 1 to 103, which provides a cumulative release of agomelatine of at least 0.02 mg / cm 2 , at least 0.05 mg / cm 2 or at least 0.1 mg / cm 2 , or 0.5 mg / cm 2 or less, 0.4 mg / cm 2 or less, or 0.3 mg / cm 2 or less, or 0.02 mg / cm 2 to 0.5 mg / cm 2 , 0.05 mg / cm 2 to 0.4 mg / cm 2 , or 0.1 mg / cm 2 to 0.3 mg / cm 2 when measured using porcine esophageal mucosa.

[0510] 105. A transmucosal treatment system according to any one of items 1 to 104 for use in a method of treating a human patient.

[0511] 106. A transmucosal treatment system according to item 105 for use in a method of treating major depression.

[0512] 107. For use in a treatment method, wherein the transmucosal treatment system is administered by applying the mucoadhesive layer structure to the mucosa of the oral cavity of a human patient and is maintained on the mucosa until it dissolves. The transmucosal treatment system according to item 105 or 106.

[0513] 108. For use in a treatment method, wherein the transmucosal treatment system is administered by applying the mucoadhesive layer structure to the buccal, sublingual, gingival or palatal mucosa of the oral cavity of a human patient and is maintained on the mucosa until it dissolves. The transmucosal treatment system according to item 107.

[0514] 109. For use in a treatment method, wherein the transmucosal treatment system is administered in the evening or at night before bedtime. The transmucosal treatment system according to any one of items 105 to 108.

[0515] 110. A treatment method, wherein a transmucosal treatment system according to any one of items 1 to 104 is administered to a human patient.

[0516] 111. A method of treating major depression according to item 110, wherein a transmucosal treatment system according to any one of items 1 to 104 is administered to a human patient.

[0517] 112. A treatment method according to item 110 or 111, wherein a transmucosal treatment system according to any one of items 1 to 105 is administered by applying the mucoadhesive layer structure to the mucosa of the oral cavity of a human patient and is maintained on the mucosa until it dissolves. 113. The transmucosal treatment system according to any one of items 1 to 105 is administered by applying the mucoadhesive layer structure to the mucosa of the oral cavity of a human patient, in particular, the buccal, sublingual, gingival or palatal mucosa, and is maintained on the mucosa until it dissolves. The treatment method according to item 112.

[0518] 114. The treatment method according to any one of items 110 to 113, wherein the transmucosal treatment system is administered in the evening or at night before bedtime.

[0519] 115. A process for producing an agomelatine-containing layer, i) combining at least agomelatine and a first soluble film-forming agent in a solvent to obtain a first coating composition; ii) coating the first coating composition on a release liner; and iii) drying the first coated coating composition to form the agomelatine-containing layer. The manufacturing process.

[0520] 116. The process according to item 115, wherein in step i), the agomelatine is dissolved.

[0521] 117. The process according to item 115, wherein in step i), the agomelatine is dispersed.

[0522] 118. The process according to any one of items 115 to 117, wherein the solvent comprises an alcoholic solvent selected from methanol, ethanol, isopropanol and mixtures thereof.

[0523] 119. The process according to item 118, wherein the solvent comprises ethanol or consists of ethanol.

[0524] 120. The process according to any one of items 115 to 119, wherein the solvent comprises water.

[0525] 121. The process according to any one of items 115 to 119, wherein the solvent does not contain water in an amount exceeding 5 wt%, 2 wt%, 1 wt% or 0.5 wt%.

[0526] 122. The process according to any one of items 115 to 121, wherein drying is carried out at a temperature of 40 to 90 °C, or 60 to 80 °C.

[0527] 123. The process according to any one of items 115 to 122, wherein step i) comprises combining at least agomelatine, a first soluble 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.

[0528] 124. The process according to any one of items 115 to 123, wherein in step i), the agomelatine is combined in dissolved form, dispersed form, crystalline form, in particular one of its polymorphic forms, amorphous form, as a hydrate, solvate, hybrid form of any of the aforementioned forms, or a mixture thereof.

[0529] 125. A manufacturing process for a transmucosal therapeutic system, A) manufacturing an agomelatine-containing layer according to items 115 to 124; B) manufacturing a backing layer by a process comprising: i) dissolving at least a second soluble film-forming agent in a solvent to obtain a second coating composition; ii) coating the second coating composition onto a release liner; and iii) drying the second coated coating composition to form the backing layer; and C) laminating the obtained agomelatine-containing layer and the backing layer.

[0530] 126. A manufacturing process for a transmucosal therapeutic system, A) manufacturing an agomelatine-containing layer according to items 115 to 124; B) a transmucosal therapeutic system comprising a mucoadhesive layer structure comprising a backing layer and an agomelatine-containing layer, i) dissolving at least a second soluble film-forming agent in a solvent to obtain a second coating composition; ii) coating the second coating composition onto the agomelatine-containing layer obtained in A); and iii) drying the second coated coating composition to form the backing layer coated on the agomelatine-containing layer, the manufacturing process comprising the steps.

[0531] 127. The process according to item 126, wherein step ii) is carried out at least once, in particular 2 or 3 times.

[0532] 128. In B), the process according to any one of items 125 to 127, wherein the solvent comprises one or more of an alcoholic solvent such as methanol, ethanol and isopropanol, and water.

[0533] 129. The process according to any one of items 125 to 128, wherein the solvent comprises ethanol or consists of ethanol.

[0534] 130. The process according to any one of items 125 to 129, wherein the solvent comprises water.

[0535] 131. The process according to any one of items 125 to 130, wherein drying is carried out at a temperature of 40 to 90 °C or 60 to 80 °C.

[0536] 132. A transmucosal therapeutic system for the transmucosal administration of agomelatine, obtainable by the manufacturing process according to any one of items 126 to 131.

[0537] 133. A transmucosal therapeutic system for the transmucosal administration of agomelatine comprising a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least A) a backing layer; and B) i) 3 to 7% by weight of agomelatine; ii) a first soluble film-forming agent, and iii) 5 to 15% by weight of a fatty acid, iv) 0.1 to 2.0% by weight of one or more sweeteners, and v) 0.2 to 2.0% by weight of a flavoring agent, comprising an agomelatine-containing layer, wherein said first soluble polymer is hydroxypropyl cellulose, or a mixture of one or more polymers selected from hydroxypropyl cellulose and ethyl cellulose, wherein the areal weight of said agomelatine-containing layer ranges from 100 to 150 g / m 2 and wherein said backing layer comprises 5 to 15% by weight of a fatty acid, 0.1 to 2.0% by weight of one or more sweeteners, 0.2 to 2.0% by weight of a flavoring agent, and a second soluble film-forming agent, said second soluble film-forming agent being a mixture of hydroxyethyl cellulose and hydroxypropyl cellulose, wherein the areal weight of said backing layer ranges from 100 to 300 g / m 2 said transmucosal therapeutic system.

Claims

1. A transmucosal therapeutic system for the transmucosal administration of agomelatine comprising a mucoadhesive layer structure, wherein the mucoadhesive layer structure is A) a backing layer; and B) i) agomelatine; and ii) an agomelatine-containing layer comprising a first soluble film-forming agent, wherein the first soluble film-forming agent is hydroxypropyl cellulose or a mixture of polymers selected from hydroxypropyl cellulose and ethyl cellulose, and the backing layer comprises a second soluble film-forming agent which is a mixture of hydroxyethyl cellulose and hydroxypropyl cellulose, said transmucosal therapeutic system.

2. When the first soluble film-forming agent is cast onto a film having an area weight of 30 to 100 g / m 2 or 50 g / m 2 it dissolves in water, artificial or natural saliva, or 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 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, more than 30 seconds and less than 3 hours, more than 1 minute and less than 2 hours, or more than 2 minutes and less than 1 hour. The transmucosal therapeutic system according to claim 1.

3. The amount of the first soluble film-forming agent is at least 65 wt%, at least 70 wt% or at least 75 wt% of the agomelatine-containing layer, or the amount of the first soluble film-forming agent is 98 wt% or less, 94 wt% or less or 90 wt% or less, or the amount of the first soluble film-forming agent is in the range of 65 - 98 wt%, 70 - 94 wt%, or 75 - 90 wt%. The transmucosal therapeutic system according to claim 1 or 2.

4. When the transmucosal therapeutic system is administered to a human patient, the backing layer dissolves within 5 minutes or more, 10 minutes or more, or 15 minutes or more, or within 12 hours or less, 8 hours or less, or 4 hours or less, or between 5 minutes and 12 hours, between 10 minutes and 8 hours, or between 15 minutes and 4 hours. The transmucosal therapeutic system according to any one of claims 1 to 3.

5. Optionally, the amount of the second soluble film-forming agent is at least 65 wt%, at least 75 wt% or at least 85 wt% of the backing layer, or the amount of the second soluble film-forming agent is in the range of 65 - 100 wt%, 75 - 100 wt%, or 80 - 100 wt%. The transmucosal therapeutic system according to claim 4.

6. The size of the backing layer and the size of the agomelatine-containing layer have the same spread, or the backing layer is larger in size than the agomelatine-containing layer and has an expanded surface area. The transmucosal therapeutic system according to claim 4 or 5.

7. The agomelatine-containing layer contains at least 1% by weight of agomelatine, at least 2% by weight of agomelatine, or at least 3% by weight of agomelatine, and / or The agomelatine-containing layer contains 25% by weight or less of agomelatine, 20% by weight or less of agomelatine, or 10% by weight or less of agomelatine, and / or The agomelatine-containing layer contains 1 to 25% by weight or less of agomelatine, 2 to 20% by weight or less of agomelatine, or 3 to 10% by weight or less of agomelatine, and / or The agomelatine in the agomelatine-containing layer is dissolved or present in a dispersed form, and / or The transmucosal therapeutic system according to any one of claims 1 to 6, wherein the agomelatine-containing layer does not contain agomelatine crystals.

8. The transmucosal therapeutic system according to any one of claims 1 to 7, wherein the agomelatine-containing layer and / or the backing layer further contains one or more excipients selected from the group consisting of fatty acids, sweeteners, flavoring agents, coloring agents, permeation enhancers, solubilizing agents, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffer reagents, and additional film-forming agents.

9. The agomelatine-containing layer has an area weight of at least 25 g / m 2 , at least 35 g / m 2 , or at least 40 g / m 2 , or has an area weight of 300 g / m 2 or less, 250 g / m 2 or less, or 200 g / m 2 or less, or has an area weight of 25 to 300 g / m 2 , 35 to 250 g / m 2 , or 40 to 200 g / m 2 , and / or The backing layer has an areal weight of at least 50 g / m 2 , at least 75 g / m 2 , or at least 100 g / m 2 , or has an areal weight of 400 g / m 2 or less, 350 g / m 2 or less, or 300 g / m 2 or less, or has an areal weight of 50 to 400 g / m 2 , 75 to 350 g / m 2 , or 100 to 300 g / m 2 , and / or The transmucosal treatment system has an area weight of at least 75 g / m 2 , at least 100 g / m 2 , or at least 130 g / m 2 ; or an area weight of 700 g / m 2 or less, 600 g / m 2 or less, or 500 g / m 2 or less; or an area weight of 75 to 700 g / m 2 , 100 to 600 g / m 2 , or 130 to 500 g / m 2 and is in the form of a thin film, the transmucosal treatment system according to any one of claims 1 to 8.

10. The mucosal adhesive layer structure consists of the backing layer and the agomelatine-containing layer, and / or The transmucosal therapeutic system according to any one of claims 1 to 9, wherein the mucosal adhesive layer structure dissolves in water, artificial or natural saliva, or any other aqueous medium at 37°C and 150 rpm for 10 minutes or more, 15 minutes or more, or 30 minutes or more, or for 15 hours or less, 12 hours or less, or 10 hours or less, or between 10 minutes and 15 hours, between 15 minutes and 12 hours, or between 30 minutes and 10 hours.

11. When measured in the porcine esophageal mucosa, the transmucosal treatment system provides a mucosal permeation rate of agomelatine of 10 μg / cm 2 -hr to 150 μg / cm 2 -hr after 1 hour, and / or When measured using porcine esophageal mucosa, the transmucosal treatment system provides a cumulative release of agomelatine of at least 0.02 mg / cm 2 , at least 0.05 mg / cm 2 or at least 0.1 mg / cm 2 , or 0.5 mg / cm 2 or less, 0.4 mg / cm 2 or less, or 0.3 mg / cm 2 or less, or 0.02 mg / cm 2 to 0.5 mg / cm 2 , 0.05 mg / cm 2 to 0.4 mg / cm 2 or 0.1 mg / cm 2 to 0.3 mg / cm 2 The transmucosal treatment system according to any one of claims 1 to 10.

12. The transmucosal therapeutic system according to any one of claims 1 to 11, for use in a method of treating a human patient.

13. The method of treatment is a method of treating major depressive disorder, and / or The transmucosal therapeutic system is administered by applying the mucosal adhesive layer structure to the mucosa of the oral cavity of a human patient and is maintained on the mucosa until it dissolves, and / or The transmucosal therapeutic system according to claim 12, wherein the transmucosal therapeutic system is administered in the evening or at night before bedtime.

14. A manufacturing process of a transmucosal therapeutic system, A) The agomelatine-containing layer is i) combining at least agomelatine and a first soluble film-forming agent in a solvent to obtain a first coating composition; ii) coating the first coating composition onto a release liner; and iii) drying the first coated coating composition to form the agomelatine-containing layer, wherein the first soluble film-forming agent is hydroxypropyl cellulose or a mixture of polymers selected from hydroxypropyl cellulose and ethyl cellulose, and B) a backing layer, i) dissolving at least a second soluble film-forming agent in a solvent to obtain a second coating composition; ii) coating the second coating composition onto a release liner; and iii) drying the second coated coating composition to form the backing layer, C) laminating the obtained agomelatine-containing layer and the backing layer, or B) a transmucosal therapeutic system comprising a mucoadhesive layer structure comprising a backing layer and an agomelatine-containing layer, i) dissolving at least a second soluble film-forming agent in a solvent to obtain a second coating composition; ii) coating the second coating composition onto the agomelatine-containing layer obtained in A); and iii) drying the second coated coating composition to form the backing layer coated on the agomelatine-containing layer, wherein the second soluble film-forming agent is a mixture of hydroxyethyl cellulose and hydroxypropyl cellulose, said manufacturing process.

15. A transmucosal therapeutic system for the transmucosal administration of agomelatine comprising a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least A) a backing layer; and B) i) 3 to 7% by weight of agomelatine; ii) a first soluble film-forming agent, and iii) 5 to 15% by weight of a fatty acid, iv) 0.1 to 2.0% by weight of one or more sweeteners, and v) 0.2 to 2.0% by weight of a flavoring agent, The first soluble polymer is one or a mixture of polymers selected from hydroxypropyl cellulose, or hydroxypropyl cellulose and ethyl cellulose, The areal weight of the agomelatine-containing layer is in the range of 100 to 150 g / m 2 2, and The backing layer contains 5 to 15% by weight of a fatty acid, 0.1 to 2.0% by weight of one or more sweeteners, 0.2 to 2.0% by weight of a flavoring agent, and a second soluble film-forming agent, and the second soluble film-forming agent is a mixture of hydroxyethyl cellulose and hydroxypropyl cellulose, The areal weight of the backing layer is in the range of 100 to 300 g / m 2 of the transmucosal treatment system.

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