HK40090941A - Transmucosal therapeutic system containing agomelatine - Google Patents

Description

Transmucosal therapy system containing agomelatine

This application is a divisional application of Chinese invention patent application (filed on October 2, 2020, application number 202080022400.6, PCT application number PCT/EP2020/077735, entitled "Transmucosal Therapy System Containing Agomelatine").

Invention Technology

This invention relates to a transmucosal therapy system for administering agomelatine via a mucosa into the systemic circulation, as well as its manufacturing method, treatment method, and use.

Background of the Invention

Agomelatine (N-(2-(7-methoxy-1-naphthyl)ethyl)acetamide), the active ingredient, is a melatoninogenic antidepressant developed by Les Laboratoires Servier. Its chemical structure is extremely similar to that of melatonin.

As a melatonergic agonist that stimulates MT1 and MT2 receptors, agomelatine mediates circadian rhythm synchronization, much like melatonin. However, unlike melatonin, agomelatine is also a 5-HT2B/5-HT2C antagonist, and blocking serotonergic 5HT2C receptors leads to enhanced dopamine and norepinephrine release in the prefrontal cortex. An unexpected synergistic effect between MT1/MT2 agonism and 5HT2C antagonism has been observed, and this synergistic effect is presumably explained by the antidepressant activity and unique clinical profile of agomelatine.

Agomelatine is approved in Europe under its brand name and indicated for the treatment of major depressive disorder (MDD). It is currently available in film tablets containing 25 mg, prescribed as an initial dose to be taken at bedtime, with the option to double the dose if no improvement is observed. Agomelatine is the only commercially available antidepressant with the aforementioned mechanism of action.

Orally administered agomelatine undergoes extensive first-pass and systemic metabolism primarily via cytochrome CYP1A2. Despite good oral absorption (>80%), overall bioavailability is extremely low (less than 5%) and exhibits significant inter-individual variability. The time to reach peak plasma concentration and the elimination half-life (t1 _/2) are both approximately 1 to 2 hours, and at steady state, the volume of distribution is 35 liters with 95% plasma protein binding.

Agomelatine appears to have a faster onset of action (usually within 1 week) compared to other antidepressants, and the major known side effects of other antidepressants, such as weight gain, sexual dysfunction, anticholinergic symptoms, and cardiotoxicity, appear to be reduced. However, agomelatine carries the risk of hepatotoxicity with an unexplained mechanism, manifested as increased alanine aminotransferase (ALAT) and/or aspartate aminotransferase (ASAT) levels, and in rare exceptional cases, the consequences are fatal or require liver transplantation. Furthermore, liver damage has been reported to be associated with significantly increased agomelatine exposure, with AUC and _cmax values observed up to 140-fold higher in patients with moderate hepatic impairment compared to healthy subjects.

Servier and Novartis attempted to create a sublingual formulation of agomelatine, presumably to avoid first-pass metabolism and the associated drawbacks outlined above (low oral bioavailability and hepatotoxicity), resulting in placebo-controlled randomized studies using 1 and 2 mg (Servier) or 0.5 and 1 mg agomelatine sublingual tablets (Novartis). No results from the 2008/2009 Servier trial are publicly available. The Novartis study, which began in 2011/2012, was largely unsuccessful because the efficacy of the agomelatine sublingual tablets was inferior to placebo, and because a clear dose-response relationship was not found, although hepatotoxicity was shown to be rare. One reason for the trial's failure appears to have been the significant irritation caused by agomelatine when administered to the oral mucosa. Consequently, the FDA decided not to grant approval for the drug in the United States, despite its advantages over other active ingredients in the treatment of MDD.

Several patent applications from Servier indicate that first methods for providing the aforementioned novel dosage forms (also referred to as “orally dispersed” formulations, such as tablets) involve achieving rapid disintegration within minutes, such as less than three minutes or even less than one minute, presumably to obtain extremely rapid release and to avoid as well as possible the associated drawbacks of enteral delivery and the first-pass effect in the liver. A more recent method involves buccal formulations, such as tablets, intended to dissolve or disintegrate more slowly in the mouth to maintain a sufficiently low concentration of agomelatine in the oral cavity to limit stinging. However, this carries the risk of the tablet being swallowed prematurely by the patient (i.e., before all the active ingredient has been released). Bilayer or multilayer tablets comprising, for example, a placebo core have been proposed so that most of the active ingredient will have been released after a certain time, leaving only the inactive placebo core, to ensure that even if the patient swallows the tablet prematurely, the release of the active ingredient is nearly complete.

However, these orally dispersible formulations do not appear to fully address the patient compliance issues induced by the irritation caused by agomelatine, and premature tablet swallowing has not been prevented, but only mitigated. Incomplete release of the active ingredient remains a risk, depending on the timing of unintentional tablet swallowing. Furthermore, prolonged tablet swallowing means that the patient must maintain the irritating object in the mouth, which is detrimental to patient compliance. Finally, the drug delivery mechanism of these orally dispersible formulations depends on the active ingredient first dissolving in saliva (open system), which is why drug concentration and therefore drug delivery are extremely difficult to control. All these reasons have likely contributed to the fact that currently, no agomelatine formulations are available besides the conventional oral tablets outlined above.

Transmucosal therapeutic systems, or transmucosal delivery systems (also sometimes referred to as buccal patches), consist of one or more thin layers applied to and adhering to the oral mucosa to deliver a drug over a period of time. Dosage forms in film form used for oral application are sometimes also called “oral films” or OTFs; however, OTFs are not necessarily intended to adhere to the mucosa. In a transmucosal therapeutic system, the active ingredient is contained in a soluble layer, and because the film adheres to the mucosa, delivery of the active ingredient is achieved through a combination of direct release of the active ingredient from the transmucosal therapeutic system to the mucosa and indirect delivery of the active ingredient through dissolution in saliva, as in the case of orally dispersed formulations outlined above. To prevent indirect delivery of the active ingredient inherent in open systems, a backing layer may be used to isolate the active ingredient-containing layer from the rest of the oral cavity, particularly from environmental saliva. In any case, OTFs are advantageous when compared to oral dispersible preparations intended to be swallowed, because they do not evoke any negative sensation of having annoying objects in the mouth, because the thin film adhering to the mucosa does not move freely in the oral cavity, and because the film is usually thin enough that it is not perceived by the patient once applied.

However, transmucosal therapy systems are a relatively new form of drug delivery, meaning that knowledge regarding formulation techniques is limited. Formulating dosage forms suitable for transmucosal delivery via OTFs is challenging due to the numerous aspects to consider and the many problems to solve. The main requirements for such transmucosal therapy systems are good adhesion and active ingredient penetration, combined with appropriate disintegration characteristics and time. Equally important is tactile sensation, i.e., a good feel in the mouth, and the stability of the film prior to application (i.e., low fragility). Agomelatine's low solubility makes it a difficult substance to formulate, and as outlined above, a key issue is addressing the irritant sensation caused by the active ingredient in the oral cavity. Furthermore, because agomelatine is primarily used to resynchronize circadian rhythms, the desired drug release profile is a rapid initial increase in drug delivery, followed by only overnight release, and preferably a decreasing release.

To date, no commercially available transmucosal treatment system for agomelatine is available, and no research or investigation into such transmucosal treatment system for agomelatine is known to the applicant.

In summary, there is a strong need for alternative forms of agomelatine administration to overcome the drawbacks of oral and sublingual administration. As outlined above, transmucosal therapy systems can address these shortcomings.

Therefore, there is a need in the art for a transmucosal treatment system for agomelatine.

Invention Objectives and Contents

One objective of this invention is to provide an aminomelatine transmucosal treatment system that overcomes the aforementioned disadvantages of current aminomelatine administration as an alternative form of aminomelatine administration.

Therefore, an object of the present invention is to provide an agomelatine transmucosal treatment system for transmucosal administration of agomelatine, providing a particularly high penetration rate, which is therefore sufficient to achieve a therapeutically effective dose.

Another object of the present invention is to provide an agomelatine transmucosal treatment system for transmucosal administration, providing a drug release profile with rapid initial increase and allowing for overnight administration, such as administration suitable for administration shortly before bedtime.

Furthermore, another objective of the present invention is to provide an oral mucosal treatment system for administering agomelatine via the mucosa without causing irritation at the mucosa or otherwise in the oral cavity.

Another object of the present invention is to provide an oral melatonin transmucosal treatment system for transmucosal administration of agomelatine, providing appropriate adhesion to the mucosa, for example, initially and over time achieving adhesion.

Another object of the present invention is to provide an agomelatine transmucosal treatment system for transmucosal administration that provides appropriate disintegration characteristics, such as in terms of disintegration time and also in terms of the integrity of the transmucosal treatment system (in the presence of multiple layers, the layers do not disintegrate prematurely).

Another objective of the present invention is to provide an agomelatine transmucosal treatment system for transmucosal administration, wherein hepatotoxicity and inter-individual variability are reduced and bioavailability is increased when administered orally.

Furthermore, an objective of the present invention is to provide an oral mucosal treatment system for transmucosal administration of agomelatine, providing a good tactile sensation, i.e., a good feeling in the mouth.

Furthermore, an objective of the present invention is to provide an agomelatine transmucosal treatment system for transmucosal administration that appears to be of a size and thickness suitable for convenient application and handling, provides good patient compliance and/or is easy to manufacture and cost-effective.

These and other objectives are achieved by the present invention, according to one aspect, relating to a transmucosal therapeutic system for transmucosal administration of agomelatine comprising a mucosal adhesion layer structure, said mucosal adhesion layer structure comprising:

A) An agomelatine-containing layer, wherein the agomelatine-containing layer comprises:

i) Agomelatine; and

ii) Soluble film-forming agents.

According to certain embodiments of the present invention, the transmucosal therapy system of the present invention is used in a treatment method, preferably in a method for treating major depressive disorder.

According to other embodiments, the present invention relates to a treatment method, and more particularly to a method for treating major depressive disorder, the treatment method comprising applying the transmucosal treatment system of the present invention to the mucous membranes of a human patient.

According to other embodiments, the present invention relates to the use of the mucosal therapy system of the present invention to manufacture a medicament for treatment, preferably for treating major depressive disorder.

According to another aspect, the present invention relates to a method for manufacturing an agomelatine-containing layer, the method comprising the following steps:

i) Combine at least agomelatine and a soluble film-forming agent in a solvent to obtain a coating composition;

ii) Apply the coating composition to the release liner; and

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

According to certain embodiments, the present invention also relates to a transmucosal treatment system for transmucosal administration of agomelatine, which is available by such a manufacturing method.

According to some embodiments, the present invention also relates to a transmucosal therapeutic system for transmucosal administration of agomelatine, comprising a mucosal adhesion layer structure, said mucosal adhesion layer structure comprising at least:

A) An agomelatine-containing layer, wherein the agomelatine-containing layer comprises:

i) 3 to 10 wt% agomelatine;

ii) Soluble film-forming agents;

iii) 5 to 15 wt% fatty acids;

iv) 0.1 to 2 wt% of one or more sweeteners; and

v) 0.2 to 2.0 wt% of flavoring agent;

in

The soluble polymers are selected from the group consisting of polyvinylpyrrolidone and hydroxypropyl cellulose, and

The area weight of the agomelatine-containing layer is in the range of 100 to 150 g/ ^m² .

Within the meaning of this invention, the term "transmucosal therapy system" or "transmucosal delivery system" refers to a system for administering an active agent (agomelatine) into the systemic circulation via transmucosal delivery by application to the oral mucosa, and is an integral single delivery unit comprising a therapeutically effective amount of agomelatine in a mucosal adhesion layer structure, and optionally including an additional covering layer on top of the agomelatine-containing mucosal adhesion layer structure. The mucosal adhesion layer structure may be located on a release liner (separable protective layer), and therefore, the transmucosal therapy system may also include a release liner. Within the meaning of this invention, the term "transmucosal therapy system" specifically refers to a system that provides passive transmucosal delivery, excluding active transport as in methods including microporousization. Furthermore, unlike certain oral films (sometimes referred to as "rapid rice paper capsules") that may not necessarily have mucosal adhesion and are intended to disintegrate extremely rapidly in saliva, in transmucosal therapy systems, intestinal delivery is entirely unintended.

Within the meaning of this invention, the terms "mucosal adhesion layer structure containing agomelatine" or "mucosal adhesion 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 covering layer adds to the overall size of the transmucosal therapy system, but does not add to the release area. The mucosal adhesion layer structure containing agomelatine comprises at least one agomelatine-containing layer.

Within the meaning of this invention, the term "therapeutic effective amount" refers to the amount of active agent in a transmucosal therapy system that, if administered to a patient via a transmucosal therapy system, is sufficient to provide a similar range (e.g., from about 10% to about 1000%, as measured in AUC) of agomelatine blood levels when compared to blood levels obtained when a single administration of 25 mg of oral agomelatine is given.

Within the meaning of this invention, the terms "active ingredient," "activator," etc., and the term "agomeratine" refer to agomelatine in any pharmaceutically acceptable chemical and morphological form and physical state. These forms include, but are not limited to, agomelatine in its free, dissociated, or any associated form such as hydrates, solvates, etc., as well as agomelatine in particulate form, which may be microparticle-like, crystalline, and particularly one of its polymorphic forms, and/or amorphous; and any mixed form or mixture thereof in any of the above-mentioned forms. When contained in a medium such as a solvent, agomelatine may be dissolved or dispersed, or partially dissolved and partially dispersed.

When agomelatine is mentioned as being used in a specific form in the manufacture of transmucosal therapy systems, this does not preclude the possibility of interactions between this form of agomelatine and other components containing the agomelatine self-adhesive layer structure, such that the active ingredient exists in another form in the final transmucosal therapy system. This means that even if agomelatine is included in a free, dissociable form, it may exist in the final transmucosal therapy system as a hydrate or solvate, or if it is included in one of its polymorphic forms, it may exist in the final transmucosal therapy system in an amorphous form. Unless otherwise indicated, the amount of agomelatine in the self-adhesive layer structure specifically refers to the amount of agomelatine included in the transmucosal therapy system during the manufacture of the transmucosal therapy system, and is calculated based on agomelatine in its free form. That is, when agomelatine is included in an amount of 0.1 mmol, within the meaning of this invention, the amount of agomelatine in the self-adhesive layer structure is considered to be 24.3 mg (the molecular weight of agomelatine is 243 g/mol), whether agomelatine has been included in the transmucosal therapy system during the manufacture in its free form or in any associated form.

Agomelatine starting materials included in a transmucosal therapy system during manufacturing may be in particulate form. Agomelatine may be present, for example, in dispersed particulate and/or dissolved forms within the mucosal adhesion layer structure.

Within the meaning of this invention, the term "particle" refers to a solid particulate material comprising a single particle whose size is negligible relative to the material. Specifically, the particle is a solid, including plastic/deformable solids, including amorphous and crystalline materials.

Within the meaning of this invention, the term "dispersion" refers to a step or combination of steps in which the starting material (e.g., agomelatine) is not completely dissolved. In the context of this invention, depending on the solubility of the starting material (e.g., the solubility of agomelatine in the coating composition), dispersion includes the dissolution of a portion of the starting material (e.g., agomelatine particles).

There are two main types of transmucosal therapy systems: those using a backing layer and those without. As outlined in the introductory background section, the delivery of active ingredient in open-system transmucosal therapy systems without a backing layer will always be a combination of direct delivery from the transmucosal therapy system through the mucosa at the adhesion site and indirect delivery via dissolution of the active ingredient from the transmucosal therapy system into saliva and from saliva through the mucosa. The proportion of different delivery routes depends primarily on factors such as the solubility of the active ingredient and the disintegration time of the transmucosal therapy system. Higher solubility and faster disintegration of the transmucosal therapy system will favor dissolution into saliva compared to direct delivery into the mucosa at the adhesion site. This indirect delivery has the significant advantage of providing a practically several-fold increase in mucosal surface area, thereby enabling systemic release of the active ingredient. On the other hand, dissolution into saliva means that the concentration of the active ingredient and therefore the final delivery amount are difficult to control, and there is a risk of transenteral delivery achieved through unintentional swallowing of saliva. In particular, regarding agomelatine, this also creates the problem of the active ingredient, which has been shown to potentially provide a stimulating sensation, dissolving freely throughout the oral cavity.

Transmucosal therapy systems using a backing layer represent a completely different approach, where the loss of drug release area (limited to the actual size of the patch) is accepted in exchange for limiting the delivery route to more controllable direct transmucosal delivery. Therefore, in the sense of this invention, a "backing layer" is any layer within a transmucosal therapy system capable of preventing the (at least substantial) active ingredient contained within the transmucosal therapy system from dissolving into saliva. This backing layer may be insoluble or dissolving over time. In the latter case, the time required for the backing layer to dissolve is at least as long as the time required for the (substantial) active ingredient to be delivered through the mucosa.

In this context, it also becomes clear that terms such as “dissolved” or “soluble” regarding any layer of a transmucosal therapeutic system (e.g., a backing layer, an active ingredient layer) and, when cast into a film, the film-forming agent, should be understood extremely broadly, rather than in the strict scientific sense of dissolving molecules in a solvent. Any transformation of the solid to liquid state of the involved layer, such as dispersion, formation of a suspension, gelation of the film, and disintegration into smaller gel portions, must be considered “dissolved” in the sense of this invention, provided that the “dissolved” material is free to move in a liquid (e.g., saliva) such that anything existing below the involved layer (i.e., if the mucosal contact layer dissolves, then it is the mucosa, or, for example, if the backing layer dissolves before the active ingredient layer, then it is the active ingredient layer) becomes attainable by a liquid other than the “dissolved” material. In a preferred embodiment, the meaning is limited to the common chemical sense of dissolving molecules in a solvent. It should be noted that the term “dissolved” regarding the substance itself, such as the active agent agomelatine or any excipient, will continue to be used in the common chemical sense of dissolving molecules in a solvent. For example, agomelatine in dissolved form obviously does not include agomelatine in dispersed form. Film-forming agents themselves may be present in the coating composition in a dissolved form in the ordinary chemical sense (e.g., not dispersed, not in the form of small gel portions, etc.) during the manufacture of a transmucosal therapy system, but when the film-forming agent is cast into a film, making such a film “dissolve” also includes the gelation of the film and its disintegration into smaller gel portions.

An active agent-containing layer is, for example, the final cured layer obtained after applying and drying a solvent-containing coating composition. An active agent-containing layer can also be manufactured by laminating two or more cured layers (e.g., dried layers) having the same composition to provide a desired area weight. The active agent-containing layer may have mucosal adhesive properties (in the form of a mucosal adhesive layer), or via a mucosal treatment system, it may include an additional mucosal contact layer with a mucosal adhesive to provide sufficient adhesion. In particular, the active agent-containing layer is a mucosal adhesive layer.

Within the meaning of this invention, the term "mucosal adhesion" refers to a material that adheres specifically to a mucosa, and adheres to the mucosa upon contact with it, but when dry, the material is preferably non-adhesive and can be touched and manipulated, for example, by fingers, such as by applying it into the mouth, without unintentionally adhering to the skin of the fingers. The mucosal adhesion layer has "self-adhesiveness" upon contact with the mucosa, i.e., it provides adhesion to the mucosa such that no further assistance is usually required to achieve fixation. The adhesive strength is preferably strong enough that typical movement in the mouth is insufficient to displace the mucosal adhesion layer adhering to the mucosa. The "mucosal adhesion" layer structure includes a mucosal adhesion layer for mucosal contact, which may be provided in the form of a mucosal adhesion-containing surfactant layer or as an additional layer, namely a mucosal adhesion-mucosal contact layer. A mucosal adhesion overlay layer may still be used to enhance adhesion.

Within the meaning of this invention, the term "mucosal contact layer" refers to a layer included in a transmucosal therapy system for direct contact with the patient's mucosa during application. When a transmucosal therapy system includes a mucosal contact layer, other layers do not contact the mucosa and do not necessarily have mucosal adhesive properties. The release area is provided by the area of the surfactant-containing layer. The mucosal contact layer can be used to enhance adhesion. The dimensions of the additional mucosal contact layer and the surfactant-containing layer are generally mutually extended and correspond to the release area.

Within the meaning of this invention, the term "area weight" refers to the dry weight of a particular layer, such as the surfactant layer, provided in g/ ^m² . Due to manufacturing variability, the area weight value is subject to a tolerance of ±10%, preferably ±7.5%.

Unless otherwise specified, "%" refers to weight%.

Within the meaning of this invention, the term "polymer" refers to any substance composed of so-called repeating units obtained by polymerizing one or more monomers, and includes homopolymers composed of one type of monomers and copolymers composed of two or more types of monomers. Polymers can have any configuration, such as linear polymers, star polymers, comb polymers, brush polymers, and in the case of copolymers, any monomer arrangement, such as alternating, statistical, block copolymers, or graft polymers. Minimum molecular weight varies depending on the type of polymer and is known to those skilled in the art. Polymers can, for example, have molecular weights greater than 2,000, preferably greater than 5,000, and more preferably greater than 10,000 Daltons. Correspondingly, compounds having molecular weights less than 2,000, preferably less than 5,000, or more preferably less than 10,000 Daltons are generally referred to as oligomers.

Within the meaning of this invention, the term "crosslinking agent" refers to a substance capable of crosslinking functional groups contained in a polymer.

Within the meaning of this invention, the term "mucosal adhesive overlay" refers to a mucosal adhesive overlay structure located above an agomelatine-containing structure, containing no active agent, having a larger area than the active agent-containing structure, and providing additional area for adhesion to the mucosa, but without any release area of the active agent. This thereby enhances the overall adhesive properties of the transmucosal therapeutic system.

The transmucosal therapy system of the present invention can be characterized by certain parameters, such as those measured in an in vitro permeability test.

In vitro permeability testing is performed using human or animal mucosa, preferably cut-thick porcine mucosa with a thickness of 400 μm and intact barrier function, and using a pH 5.5 or 7.4 phosphate buffer as the receiving medium (37°C). A maximum of 40 vol% organic solvents such as ethanol, acetonitrile, isopropanol, dipropylene glycol, and PEG 400 may or may not be added, so that the receiving medium may contain, for example, 60 vol% pH 5.5 phosphate buffer, 30 vol% dipropylene glycol, and 10 vol% acetonitrile.

Unless otherwise specified, in vitro permeation assays were performed using cut-thick porcine mucosa (esophageal mucosa) obtained with a scalpel, having a thickness of 400 μm and intact barrier function, and using pH 7.4 phosphate buffer as the receiving medium (37°C). The amount of active material permeating into the receiving medium was periodically determined using HPLC with a UV photometric detector, based on a given sample volume. The measurement of permeated active material refers to the amount permeated between two most recent sampling points, not the total amount permeated to date.

Therefore, within the meaning of this invention, the parameter "permeability" is provided in μg/ ^cm² and relates to the amount of active material permeating per unit release area during a sampling interval at a given elapsed time. For example, in the in vitro permeation test described above, in which the amount of active material permeating into the receiving medium has been measured, for example, at 0, 2, 4, 8, 12, and 24 hours, the "permeability" of the active material can be given for sampling intervals, for example, from 8 to 12 hours, and corresponding to the measurement result at 12 hours.

The amount of permeate can also be given in the form of "cumulative permeate," corresponding to the cumulative amount of active material permeated at a certain point in time. For example, in the in vitro permeation test described above, in which the amount of active material permeated into the receiving medium has been measured, for example, at 0, 2, 4, 8, 12, and 24 hours, the "cumulative permeate" of the active material at 12 hours corresponds to the sum of the permeates from 0 hours to 2 hours, 2 hours to 4 hours, 4 hours to 8 hours, and 8 hours to 12 hours.

Within the meaning of this invention, the parameter "mucosal permeation rate" for a given sampling interval at a given elapsed time is provided in μg/(cm² h) and is calculated by dividing the amount of permeation in the sampling interval, as measured in μg/cm² by the in vitro permeation test as described above, by the number of hours in the sampling interval. For example, in the in vitro permeation test as described above, in which the amount of active material permeating into the receiving medium is measured, for example, at 0, 2, 4, 8, 12, and 24 hours, the "mucosal permeation rate" at 12 hours is calculated as the amount of permeation in the sampling interval from 8 to 12 hours divided by 4 hours.

The “cumulative mucosal permeation rate” can be calculated from the corresponding cumulative permeation amount by dividing the cumulative permeation amount by the elapsed time. For example, in the in vitro permeation test described above, in which the amount of active material permeating into the receiving medium is measured, for example, at 0, 2, 4, 8, 12, and 24 hours, the “cumulative mucosal permeation rate” at 12 hours is calculated by dividing the cumulative permeation amount over 12 hours (see above) by 12 hours.

Within the meaning of this invention, the above parameters, permeation volume and mucosal permeation rate (as well as cumulative permeation volume and cumulative mucosal permeation rate), refer to the average value calculated from three in vitro permeation test experiments.

The transmucosal therapy system of the present invention can also be characterized by certain parameters, such as those measured in in vivo clinical studies.

Within the meaning of this invention, the term "application" refers to the application of a dosage form, i.e., a transmucosal treatment system, to the patient's oral mucosa, which is then maintained on the mucosa until the agomelatine-containing layer structure dissolves.

In typical continuous treatment of MDD, the frequency of drug administration is maintained sufficiently high to sustain therapeutically effective plasma concentrations. The interval between two administrations of the same dosage form, also known as the dosing interval, needs to be modified accordingly. Within the meaning of this invention, the term "dosing interval" refers to the period between two consecutive administrations, i.e., the interval between two consecutive time points when a transmucosal treatment system is applied to the patient's oral mucosa. To maintain a constant plasma concentration at therapeutic levels, the transmucosal treatment system must be replaced once the active agent layer of the previous transmucosal treatment system has dissolved or shortly thereafter, at which point a new transmucosal treatment system is applied. In this mode (constant plasma levels throughout the day), the dosing interval roughly corresponds to the disintegration time of the active agent layer and can be, for example, 6 hours, 8 hours, or 12 hours. After this period, the active agent layer of the transmucosal treatment system has dissolved, any residue (e.g., non-soluble backing layer) is removed from the oral cavity, and a new transmucosal treatment system is applied. Thus, in 24-hour treatment, a 12-hour dosing interval allows for a twice-daily (b.i.d.) transmucosal treatment system replacement pattern.

However, for continuous treatment with agomelatine, the transmucosal therapy system will typically be administered once daily (24-hour intervals), preferably at bedtime, and the disintegration time will preferably be shorter than the dosing intervals. The transmucosal therapy system may be applied to the patient's mucosa particularly shortly before bedtime (e.g., 5 to 30 minutes) to account for delayed drug onset. Because maintaining therapeutic plasma concentrations throughout the day for agomelatine does not appear necessary, or may even be contraindicated for resynchronizing circadian rhythms, it is unnecessary to apply another transmucosal therapy system once the active agent layer of the previous transmucosal therapy system has dissolved, for example, by the following morning, so that the patient does not need to hold subsequently applied transmucosal therapy systems, for example, throughout the day.

Within the meaning of this invention, the term "room temperature" refers to the unchanging temperature found in the laboratory where the experiment is conducted, and is generally between 15 and 35°C, preferably between about 18 and 25°C.

Within the meaning of this invention, the term "patient" refers to a subject who presents with one or more specific symptoms indicating a clinical presentation requiring treatment, who is receiving preventative or preventative treatment for a disease, or who has been diagnosed with a disease requiring treatment.

Within the meaning of this invention, the term "pharmacokinetic parameters" refers to parameters describing plasma curves, such as Cmax, _Ct , and AUC _t1-t2 , obtained in clinical studies, for example, by administering a single or multiple doses of agomelatine via a mucosal therapy system to healthy subjects. Pharmacokinetic parameters for a single subject are summarized using arithmetic and geometric means, such as _{mean Cmax} , mean AUC _t , and mean AUC _INF , along with additional statistics such as corresponding standard deviations and standard errors, minimum values, maximum values, and median values when the logarithmic list is graded. In the context of this invention, pharmacokinetic parameters such as _Cmax , _Ct , and AUC _t1-t2 refer to arithmetic or geometric means, and preferably geometric means. It cannot be excluded that the absolute mean obtained for a particular mucosal therapy system in clinical studies may vary to some extent between studies. To allow for comparison of absolute means between studies, a reference formulation, such as any future product based on this invention, may be used as an internal standard. Comparison of the AUC per unit release area of the corresponding reference product in earlier and later studies can be used to obtain a correction factor to account for differences between studies.

The clinical studies of this invention refer to studies conducted in full compliance with the International Council for Harmonisation of Technical Requirements for Clinical Trials (ICH) and all applicable local Good Clinical Practice (GCP) guidelines and regulations.

Within the meaning of this invention, the term "healthy human subject" refers to a male or female subject with a weight in the range of 55 kg to 100 kg and a body mass index (BMI) in the range of 18 to 29, as well as normal physiological parameters such as blood pressure. Healthy human subjects were selected for the purposes of this invention based on and in accordance with the inclusion and exclusion criteria recommended by ICH.

Within the meaning of this invention, the term "subject population" refers to at least ten individual healthy subjects.

Within the meaning of this invention, the term "geometric mean" refers to the average of logarithmically transformed data that has been inversely transformed back to the original scale.

Within the meaning of this invention, the term "arithmetic mean" refers to the sum of all observations divided by the total number of observations.

Within the meaning of this invention, the parameter "AUC" corresponds to the area under the plasma concentration-time curve. The AUC value is proportional to the total amount of active agent absorbed into the bloodstream and is therefore a measure of bioavailability.

Within the meaning of this invention, the parameter “AUC _t1-t2 ” is provided in (ng/ml)h and relates to the area under the plasma concentration-time curve from t1 to t2 hours and is calculated by a linear trapezoidal method.

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

Within the meaning of this invention, the parameter “C _t ” is provided in (ng/ml) and relates to the plasma concentration of the active agent observed at t hours.

Within the meaning of this invention, the parameter "t _max " is provided in h and relates to the time point at which the C _max value is reached. In other words, t _max is the time point at which the maximum observed plasma concentration is reached.

Within the meaning of this invention, the parameter “t- _hysteresis ” is provided as h and relates to the delay between the application time (in the case of a transmucosal treatment system, the time when the transmucosal treatment system is initially applied to the oral mucosa, i.e., t = 0) and the time when a measurable plasma concentration is achieved. t _-hysteresis can be approximately calculated as the arithmetic mean of the first time points when a measurable (i.e., non-zero) active agent plasma concentration is obtained, or expressed by the median.

Within the meaning of this invention, the term "average plasma concentration" is provided in (ng/ml) and is the average value of the individual plasma concentrations of an active agent, such as agomelatine, at each time point.

Within the meaning of this invention, the term "coating composition" refers to a composition containing all components of a drug-containing layer in a solvent, said composition being applied to a backing layer or release liner to form a drug-containing layer upon drying.

Within the meaning of this invention, the term "dissolving" in the preparation of a coating composition, such as dissolving components of the coating composition, such as an active agent, refers to the process of obtaining a clear solution that does not contain any particles visible to the naked eye.

Within the meaning of this invention, the term "solvent" refers to any liquid substance, preferably a volatile organic liquid such as methanol, ethanol, isopropanol, acetone, ethyl acetate, dichloromethane, hexane, n-heptane, heptane, toluene, and mixtures thereof.

Within the meaning of this invention, and unless otherwise specified, the term "about" means an amount that is ±10% of the disclosed amount. In some embodiments, the term "about" means an amount that is ±5% of the disclosed amount. In some embodiments, the term "about" means an amount that is ±2% of the disclosed amount.

Attached Figure Description

Figure 1a depicts the mucosal penetration rate of agomelatine from 0 to 7 hours for the transmucosal treatment system prepared according to Examples 1a to 1f.

Figure 1b depicts the agomelatine utilization rate of the transmucosal treatment system prepared according to Examples 1a to 1f after 7 hours.

Figure 2a depicts the mucosal penetration rate of agomelatine from 0 to 7 hours for the transmucosal treatment system prepared according to Examples 1a, 2 and 3a.

Figure 2b depicts the agomelatine utilization rate of the transmucosal treatment systems prepared according to Examples 1a, 2 and 3a after 7 hours.

Figure 3a depicts the mucosal penetration rate of agomelatine in the transmucosal treatment system prepared according to Examples 3a to 3d over 0 to 6 hours.

Figure 3b depicts the mucosal penetration rate of agomelatine in the transmucosal treatment system prepared according to Examples 3b and 3e to 3h over 0 to 6 hours.

Figure 3c depicts the agomelatine utilization rate of the transmucosal treatment system prepared according to Examples 3a to 3h after 6 hours.

Figure 4a depicts the mucosal penetration rate of agomelatine from 0 to 6 hours for the transmucosal treatment system prepared according to Examples 4a to 4f.

Figure 4b depicts the agomelatine utilization rate of the transmucosal treatment system prepared according to Examples 4a to 4f after 6 hours.

Figure 5a depicts the mucosal penetration rate of agomelatine from 0 to 6 hours for the transmucosal treatment system prepared according to Examples 4b and 5a to 5d.

Figure 5b depicts the agomelatine utilization rate of the transmucosal treatment system prepared according to Examples 4b and 5a to 5d after 6 hours.

Figure 6a depicts the mucosal penetration rate of agomelatine in the transmucosal treatment system prepared according to Examples 6a to 6d over 0 to 6 hours.

Figure 6b depicts the agomelatine utilization rate of the transmucosal treatment system prepared according to Examples 6a to 6d after 6 hours.

Figure 7a depicts the mucosal penetration rate of agomelatine from 0 to 4 hours for the transmucosal therapy systems prepared according to Examples 4b, 6b, 6c, 6d, 7e and 7g.

Figure 7b depicts the mucosal penetration rate of agomelatine from 0 to 4 hours for the transmucosal treatment system prepared according to Examples 4b, 7a to 7d and 7f.

Figure 7c depicts the agomelatine utilization rate of the transmucosal treatment system prepared according to Examples 4b, 6b, 6c, 6d and 7a to 7g after 7 hours.

Figure 8a depicts the agomelatine plasma concentrations obtained from 0 to 8 hours in an in vivo clinical study of the transmucosal therapy system prepared according to Examples 8a to 8c.

Figure 9a depicts the mucosal penetration rate of agomelatine in the transmucosal treatment system prepared according to Examples 4b and 9a to 9f over 0 to 4 hours.

Figure 9b depicts the agomelatine utilization rate of the transmucosal treatment system prepared according to Examples 4b and 9a to 9f after 4 hours.

Figure 9c depicts the total amount of possible degradation substances and agomelatine levels detected in storage stability tests conducted at different time points at 25°C and 60% RH and 40°C and 75% RH for the TTS prepared according to Example 9a.

Figure 9d depicts the total amount of possible degradation substances and agomelatine levels detected in storage stability tests conducted at different time points at 25°C and 60% RH and 40°C and 75% RH for the TTS prepared according to Example 9c.

Detailed Implementation

Structure of transmucosal therapy system

This invention relates to a transmucosal therapy system for transmucosal administration of agomelatine, comprising a mucosal adhesion layer structure containing agomelatine.

The mucosal adhesion layer structure contains a therapeutically effective amount of agomelatine and comprises an agomelatine-containing layer containing i) agomelatine and ii) a soluble film-forming agent.

Therefore, a transmucosal therapy system for transmucosal administration of agomelatine includes a mucosal adhesion layer structure containing a therapeutically effective amount of agomelatine, the mucosal adhesion layer structure comprising:

A) An agomelatine-containing layer, wherein the agomelatine-containing layer comprises:

i) Agomelatine; and

ii) Soluble film-forming agents.

The transmucosal therapeutic system of the present invention seeks to achieve particularly high active ingredient delivery to ensure that the amount of drug delivered is sufficient to achieve a therapeutically effective dose. As detailed in the introductory section, the so-called open system, in which active ingredient delivery is achieved through a combination of direct release of the active ingredient from the transmucosal therapeutic system to the mucosa and indirect delivery of the active ingredient through dissolution in saliva, is particularly advantageous in terms of high active ingredient penetration rate.

Therefore, in some embodiments of the invention, the transmucosal treatment system does not include a backing layer. As outlined above, in the sense of the invention, a backing layer is any layer within the transmucosal treatment system capable of preventing the (at least a large amount) of active ingredients contained within the transmucosal treatment system from dissolving into saliva. Therefore, in certain embodiments, the time required for the backing layer to dissolve is at least as long as the time required for the (large amount) of active ingredients to be delivered through the mucosa, for example, as long as the time required for the active ingredient-containing layer to dissolve. Therefore, in some embodiments, after administration of the transmucosal treatment system to a human patient, the backing layer does not dissolve within less than 15 minutes, less than 10 minutes, or less than 5 minutes. In some embodiments, at 37°C and 150 rpm, the backing layer does not completely dissolve in water, artificial or natural saliva, or any other aqueous medium within less than 30 minutes, less than 15 minutes, or less than 10 minutes.

In some specific embodiments, the mucosal adhesion layer structure may further include one or more other layers selected from the following:

B) Mucosal contact layer, and

C) Decorative layer.

Therefore, in certain embodiments, the mucosal adhesion layer structure of the present invention includes an additional mucosal contact layer. In other embodiments, the mucosal adhesion layer structure of the present invention does not include an additional mucosal contact layer. In this embodiment, but also in certain other embodiments, the agomelatine-containing layer may have mucosal adhesiveness. If present, then the additional mucosal contact layer has mucosal adhesiveness and provides (improved) adhesion between the mucosal adhesion layer structure and the patient's mucosa during application. The mucosal contact layer is provided below the active agent-containing layer, thus forming an adhesive layer between the mucosa and the agomelatine-containing layer during application. For ease of manufacture and to limit the overall patch size, the size of the agomelatine-containing layer and the size of the mucosal contact layer are preferably mutually extended.

As indicated above, the mucosal adhesion layer structure may also include a decorative layer. In another embodiment, the mucosal adhesion layer structure does not include a decorative layer.

Unlike the mucosal contact layer, the decorative layer is located above the agomelatine-containing layer and is not intended to contact the mucosa.

Therefore, in some specific embodiments, the mucosal adhesion layer structure may further include one or more other layers selected from the following:

B) Mucosal contact layer, and

C) Decorative layer,

in

The other layers are adjacent to the agomelatine-containing layer, and

If both are present, then the mucosal contact layer and the decorative layer are adjacent to the agomelatine-containing layer on opposite sides.

The decorative layer may provide decorative features such as coloring or imprinting, or it may simply prevent the patient from touching the agomelatine-containing layer during application of the transmucosal therapy system. For this protective function, it is preferable that the decorative layer completely covers the agomelatine-containing layer. Therefore, in some embodiments, the mucosal adhesion layer structure also includes a decorative layer, and the dimensions of the agomelatine-containing layer and the decorative layer extend together, or the decorative layer is larger in size than the agomelatine-containing layer, thus extending the surface area of the agomelatine-containing layer.

On the other hand, the decorative layer should not be confused with the backing layer. If the decorative layer hinders the release of the active ingredient into saliva, then this is not the function of the decorative layer and would be practically undesirable. Therefore, the decorative layer dissolves rapidly enough not to impede the dissolution of the active ingredient into saliva, and in some embodiments, at 37°C and 150 rpm, the decorative layer dissolves in water, artificial or natural saliva, or any other aqueous medium in less than 3 minutes, less than 1 minute, or less than 30 seconds.

However, in terms of ease of manufacture and simplicity, the most elegant solution for a transmucosal therapy system is when the agomelatine-containing layer is the transmucosal therapy system itself. In other words, in some preferred embodiments, the transmucosal therapy system of the present invention contains neither a mucosal contact layer nor a decorative layer, and in particular, the mucosal adhesion layer structure may consist solely of the agomelatine-containing layer.

Therefore, according to certain embodiments of the invention, the transmucosal treatment system may further include a mucosal adhesive capping layer, or may not include a mucosal adhesive capping layer, and preferably does not include a mucosal adhesive capping layer. This mucosal adhesive capping layer is particularly larger than the agomelatine-containing mucosal adhesive layer structure and adheres to the agomelatine-containing mucosal adhesive layer structure to enhance the overall adhesive properties of the transmucosal treatment system. The area of the mucosal adhesive capping layer adds to the overall size of the transmucosal treatment system, but does not add to the release area. The mucosal adhesive capping layer comprises a mucosal adhesive polymer or a mixture of mucosal adhesive polymers selected from the group consisting of hydroxyethyl cellulose and hydroxypropyl cellulose, which may be the same as or different from any soluble film-forming agent included in the active agent-containing mucosal adhesive layer structure.

As outlined above, a transmucosal treatment system consists of one or more thin layers; therefore, in some embodiments, the transmucosal treatment system is in the form of a film. This film may have a circular, rectangular, or square shape.

The film preferably has a certain thickness because otherwise it would be difficult to incorporate the required amount of active ingredient, and because extremely thin films are not easy to manufacture, especially in terms of providing a uniform thickness. Therefore, in some embodiments, the transmucosal treatment system is in the form of a film having an area weight of at least 25 g/ ^m² , preferably at least 35 g/ ^m² , or more preferably at least 40 g/ ^m² . Alternatively, expressed in terms of thickness, the transmucosal treatment system is in the form of a film having a layer thickness of at least 15 μm, preferably at least 25 μm, and more preferably at least 35 μm. On the other hand, an extremely thick film will be perceived by the patient as an unpleasant object in the oral cavity, and is therefore disadvantageous in terms of patient compliance. Therefore, in some embodiments, the transmucosal treatment system is in the form of a film having an area weight of less than or equal to 300 g/ ^m² , preferably less than or equal to 250 g/ ^m² , or more preferably less than or equal to 200 g/ ^m² . Alternatively, in terms of thickness, the transmucosal treatment system is in the form of a film having a layer thickness of less than 550 μm, preferably less than 400 μm, and more preferably less than 300 μm. In a preferred embodiment, the transmucosal treatment system is in the form of a film having an area weight of 25 to 300 g/m², preferably 35 to 250 g/ ^m² , or more preferably 40 to 200 g/ ^m² , or having a layer thickness of 15 to 550 μm, preferably 25 to 400 μm, and more preferably 35 to 300 μm.

The transmucosal therapy system of the present invention is typically stored in a seam-sealed pouch without any other protective means. However, the mucosal adhesion layer structure may also be located on a removable protective layer (release liner), which is removed from the removable protective layer immediately before application to the mucosa of the patient's mouth. Therefore, the transmucosal therapy system may or may not also include a release liner. The transmucosal therapy system protected by the release liner is also typically stored in a seam-sealed pouch. The packaging may be child-proof and/or age-friendly.

Agomelatine layer

As outlined in more detail above, the transmucosal therapy system of the present invention includes a mucosal adhesion layer structure comprising an agomelatine-containing layer.

In addition, the agomelatine-containing layer includes:

i) Agomelatine; and

ii) Soluble film-forming agents.

The areal weight of the agomelatine-containing layer is a factor determining the amount of active ingredient. A certain thickness is required to obtain a sufficient amount of active ingredient, and it is difficult, especially to apply an extremely thin layer with sufficient accuracy. On the other hand, thick layers can not only cause discomfort in the oral cavity but are also difficult to manufacture and can cause the layer to take too long to dissolve to achieve the desired release profile. In summary, it is preferred that the areal weight of the agomelatine-containing layer is at least 25 g/ ^m² , more preferably at least 35 g/ ^m² , or most preferably at least 40 g/ ^m² , or has an areal weight of less than or equal to 300 g/ ^m² , more preferably less than or equal to 250 g/ ^m² , or most preferably less than or equal to 200 g/ ^m² , or has an areal weight of 25 to 300 g/ ^m² , more preferably 35 to 250 g/ ^m² , or most preferably 40 to 200 g/ ^m² . Regarding the thickness of the agomelatine-containing layer, it is preferred that the agomelatine-containing layer has a thickness of at least 15 μm, preferably at least 25 μm, and more preferably at least 35 μm, or a thickness of less than 550 μm, preferably less than 400 μm, and more preferably less than 300 μm.

In open-system transmucosal therapy systems, which are particularly preferred in this invention (see above), the delivery of the active ingredient is controlled by a combination of direct and indirect delivery as described above. This is why, in the preferred embodiment, the release area, i.e., the surface area containing the agomelatine layer, plays a secondary role in controlling the effective dose. However, a certain minimum size is required to ensure that the patch does not detach from the mucosa prematurely, and also to include sufficient active ingredient without the need for an extremely thick film. On the other hand, if the release area is too large, the transmucosal therapy system will be enormous in size, which is uncomfortable for application and wear, resulting in poor patient compliance. Taking this into consideration, in some embodiments of the invention, the transmucosal therapy system has a release area of at least 0.1 ^cm² , preferably at least 0.2 ^cm² , or more preferably at least 0.5 ^cm² , or a release area of less than or equal to 10 ^cm² , preferably less than or equal to 7 cm², or more preferably less than or equal to 5 cm², or a release area of 0.1 to 10 ^cm² , preferably 0.2 to 7 ^cm² , or more preferably 0.5 to 5 ^cm² .

As outlined above, and without wishing to be bound by theory, it is believed that a sufficient amount of active agent contained in the transmucosal therapy system is necessary to achieve certain advantageous features of the transmucosal therapy system of the present invention, such as good in vitro penetration. On the other hand, if the amount of active agent is too high, this may not only lead to undesirable storage stability problems, such as recrystallization of the active agent when agomelatine is present in dissolved form, but also to potential irritation in the oral cavity due to excessively high drug concentrations. The amount of agomelatine contained in the transmucosal therapy system can be controlled bidirectionally by adjusting the concentration and/or the area weight of the agomelatine-containing layer. Details concerning area weight are outlined above. Regarding concentration, the agomelatine-containing layer contains at least 1 wt% agomelatine, preferably at least 2 wt% agomelatine, and more preferably at least 3 wt% agomelatine; or the agomelatine-containing layer contains less than or equal to 25 wt% agomelatine, preferably less than or equal to 20 wt% agomelatine, and more preferably less than or equal to 10 wt% agomelatine; or the agomelatine-containing layer contains 1 to less than or equal to 25 wt% agomelatine, preferably 2 to less than or equal to 20 wt% agomelatine, and more preferably 3 to less than or equal to 10 wt% agomelatine.

Therefore, in some embodiments of the present invention, the agomelatine-containing layer contains at least 0.1 mg/ ^cm² , preferably at least 0.2 mg/ ^cm² , or more preferably at least 0.4 mg/ ^cm² of agomelatine per unit release area, or wherein the agomelatine-containing layer contains less than or equal to 2.0 mg/ ^cm² , preferably less than or equal to 1.5 mg/ ^cm² , or more preferably less than or equal to 1.2 mg/ ^cm² of agomelatine, or wherein the agomelatine-containing layer contains 0.1 to 2.0 mg/ ^cm² , preferably 0.2 to 1.5 mg/ ^cm² , or more preferably 0.4 to 1.2 mg/ ^cm² of agomelatine.

In terms of the amount of active ingredient, the mucosal adhesion 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 less than or equal to 20 mg, preferably less than or equal to 15 mg, or more preferably less than or equal to 10 mg 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.

As outlined in more detail above, appropriate dissolution properties of the agomelatine-containing layer are extremely important for controlling the delivery route. The faster the disintegration of the transmucosal therapeutic system, the greater the dissolution in saliva compared to direct delivery to the mucosa at the adhesion site. Because one objective of this invention is to achieve particularly high penetration rates, indirect delivery that utilizes the entire mucosa is extremely important and advantageous compared to direct delivery. This means that the transmucosal therapeutic system should disintegrate relatively quickly. Therefore, at 37°C and 150 rpm, the mucosal adhesion layer structure can, for example, dissolve in water, artificial or natural saliva, or any other aqueous medium in less than 5 hours, preferably less than 3 hours, and more preferably less than 2 hours. On the other hand, if dissolution is too rapid, the risk of unintentional ingestion of a large portion of the active ingredient increases. The so-called "rapid rice paper capsule" is a film designed to disintegrate extremely rapidly for intestinal delivery, where swallowing is intentional (and easier, when compared to tablets). Therefore, transmucosal therapy systems differ from rapid rice paper capsules in their delivery mechanism and typically take longer to dissolve compared to rapid rice paper capsules. In the specific case of agomelatine as the active ingredient, high concentrations of the active ingredient are also undesirable due to the risk of irritation, which is another reason why dissolution is preferably not too rapid. Therefore, at 37°C and 150 rpm, the mucosal adhesion layer structure can dissolve in water, artificial or natural saliva, or any other aqueous medium, for example, within greater than 30 seconds, preferably greater than 1 minute, and more preferably greater than 2 minutes. In a preferred embodiment, at 37°C and 150 rpm, the mucosal adhesion layer structure dissolves in water, artificial or natural saliva, or any other aqueous medium within greater than 30 seconds and less than 5 hours, preferably greater than 1 minute and less than 3 hours, and more preferably greater than 2 minutes and less than 2 hours.

Since it is preferred that the agomelatine-containing layer can directly adhere to the mucosa, in some preferred embodiments of the present invention, the agomelatine-containing layer has mucosal adhesiveness.

As will be understood in further detail below, in some embodiments, it is preferred to use ethanol as a solvent instead of water in the coating composition used to prepare the agomelatine-containing layer. Therefore, the agomelatine-containing layer of the present invention can be obtained (and/or obtained) by drying a coated composition comprising agomelatine, a soluble film-forming agent, and ethanol. On the other hand, some soluble film-forming agents have high solubility in water but limited solubility in other solvents. Therefore, using water as a solvent is also advantageous, which is why the agomelatine-containing layer can be obtained (and/or obtained) by drying a coated composition comprising agomelatine, a soluble film-forming agent, and water. A combination of ethanol and water is also possible, i.e., the agomelatine-containing layer can also be obtained (and/or obtained) by drying a coated composition comprising agomelatine, a soluble film-forming agent, ethanol, and water. In terms of the amount of water, an agomelatine-containing layer can be obtained (and/or acquired) by drying a coated composition containing less than 50 wt%, or less than 20 wt%, or less than 10 wt%, or less than 5 wt% water.

When considering the stability of the agomelatine-containing layer in relation to its composition, it is preferable that the agomelatine-containing layer does not contain any volatile components that carry the risk of evaporation and compositional changes after storage. Therefore, in some embodiments, the agomelatine-containing layer is substantially free of volatile solvents. In this sense, volatile solvents may be selected from the group consisting of C1 to C3 straight-chain and branched alcohols, ethyl acetate, hexane, n-heptane, and any mixtures thereof. Considering application via a mucosal treatment system in the oral cavity, volatile solvents particularly include those that should preferably not be digested, such as methanol, ethyl acetate, hexane, n-heptane, and mixtures thereof. Specifically, the agomelatine-containing layer contains less than or equal to 5 wt%, preferably less than or equal to 3 wt%, and more preferably less than or equal to 1 wt% of volatile solvents.

Because agomelatine has low solubility in water, there is a significant risk of recrystallization when the active ingredient is present in a dissolved state due to the presence of a large amount of water in the agomelatine-containing layer. Therefore, in some embodiments, the agomelatine-containing layer is substantially free of water, for example, containing less than or equal to 12 wt%, less than or equal to 8 wt%, less than or equal to 5 wt%, or less than or equal to 4 wt% water.

Agomelatin

According to the present invention, the mucosal adhesion layer structure contains agomelatine in a therapeutically effective amount, and the mucosal adhesion layer structure comprises an agomelatine-containing layer.

Although, according to the present invention, the active agent agomelatine may exist in any form, i.e., in its free dissociated or any associated form such as hydrate, solvate, etc., and in a particulate form, crystalline form, and especially in its polymorphic form, and/or in an amorphous particulate form, and in any mixed form or mixture thereof in any of the above-mentioned forms, and especially in the agomelatine-containing layer, but preferably agomelatine is present in its free dissociated form.

Furthermore, in some embodiments, agomelatine is included 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 mixture of any of the foregoing forms, or a mixture thereof.

In some embodiments, the agomelatine-containing layer can be obtained (and/or acquired) by incorporating agomelatine in a dissolved form, in a dispersed form, in a crystalline form, especially in one of its polymorphic forms, in an amorphous form, as a hydrate, a solvate, a mixture of any of the foregoing forms, or a mixture thereof.

The agomelatine in the agomelatine-containing layer may be (completely) dissolved, or the agomelatine-containing layer may contain agomelatine particles, preferably composed of agomelatine in its free and dissociated form, such that the agomelatine exists in a dispersed form. Needless to say, if the agomelatine exists in a dispersed form, then depending on the solubility of the active ingredient in the agomelatine-containing layer (whether it is, for example, saturated or supersaturated), the agomelatine-containing layer may still contain agomelatine in a dissolved form.

In a preferred embodiment, 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 agomelatine in the layer is present in dissolved form. It is also preferred that the layer containing agomelatine does not contain agomelatine crystals.

As outlined above, it is believed that the amount of agomelatine in a transmucosal therapeutic system is important for the good release of the active ingredient and can be adjusted, for example, by the agomelatine concentration. Therefore, in some embodiments, the concentration of agomelatine in the agomelatine-containing layer is in the range of 1 to 25 wt% agomelatine, preferably 2 to 20 wt% agomelatine, and more preferably 3 to 10 wt% agomelatine, relative to the agomelatine-containing layer.

In some embodiments, as determined by quantitative HPLC, agomelatine has a purity of at least 95%, preferably at least 98%, and more preferably at least 99%. Quantitative HPLC can be performed using reversed-phase HPLC with UV detection. In particular, if HPLC is performed isocratically, the following conditions can be used:

Column: RP eighteen-phase base

XTerra RP18 100 mm x 3.9 mm; 3.5 μm or equivalent mobile phase: 0.06 v/ _{v KH₂PO₄} buffer/acetonitrile (60:40; v:v);

pH 2.5

Gradient: Isocratic flow rate: 1.0 ml

Injection volume: 20 μl

Column temperature: 23℃

Wavelengths: 229 nm and 275 nm

Running time: 5 minutes

In terms of agomelatine content and agomelatine degradation, the transmucosal treatment system of the present invention advantageously exhibits improved stability.

Therefore, in some embodiments, the agomelatine-containing layer initially contains (i.e., shortly after manufacturing, such as within one week) at least 95%, preferably at least 97%, more preferably at least 98%, and even more preferably at least 99% of the theoretical amount of agomelatine included in the agomelatine-containing layer. The theoretical amount of agomelatine is calculated from the amount of agomelatine used in the coating composition and the (actual) area weight of the coated and dried agomelatine-containing layer of the tested transmucosal therapy system.

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

In some other embodiments, the transmucosal therapy systems of the present invention are stable after storage, i.e., they maintain their initial agomelatine content or exhibit low levels of degradation products, as follows:

In one of these embodiments, after being stored at 25°C and 60% relative humidity for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 12 months, the agomelatine-containing layer contains at least 95%, preferably at least 97%, more preferably at least 98%, and even more preferably at least 99% of the theoretical amount of agomelatine included 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, and most preferably at least 12 months, the agomelatine-containing layer may also contain less than 0.5%, preferably less than 0.2%, more preferably less than 0.1%, and even more preferably less than 0.05% of total agomelatine-related degradation substances.

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

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

Preferably, the method for determining agomelatine content and total amount of agomelatine-related degradation products, as well as adhesion and peel strength, is performed as described for Examples 9a and 9c.

Soluble film-forming agent

As summarized above, the transmucosal therapy system of the present invention includes a mucosal adhesion layer structure comprising an agomelatine-containing layer containing a soluble film-forming agent.

This soluble film-forming agent provides sufficient cohesion to the agomelatine-containing layer, provided that the agomelatine-containing layer remains in a dry state. According to some embodiments, once wetted, i.e., when contact with the mucosa has been achieved, the soluble film-forming agent also provides sufficient adhesion to the mucosa. In this embodiment, and more generally, the soluble film-forming agent can be selected from a mucosa-adhesive polymer.

The film-forming agent is the primary control over the solubility of the agomelatine-containing layer. This is why the film-forming agent is described as "soluble." In certain specific embodiments, this means that if cast into a film with an area weight of 30 to 100 g/ ^m² or 50 g/ ^m² , the soluble film-forming agent dissolves in water, artificial or natural saliva, or any other aqueous medium in less than 5 hours, preferably less than 3 hours, more preferably less than 2 hours, and most preferably less than 1 hour at 37°C and 150 rpm. If cast into a film with an area weight of 30 to 100 g/ ^m² or 50 g/ ^m² , the soluble film-forming agent also dissolves in water, artificial or natural saliva, or any other aqueous medium in greater than 5 seconds, preferably greater than 30 seconds, more preferably greater than 1 minute, and most preferably greater than 2 minutes at 37°C and 150 rpm. In particular, if the film is cast into a film having an area weight of 30 to 100 g/ ^m² or 50 g/ ^m² , the soluble film-forming agent can dissolve in greater than 5 seconds and less than 5 hours, preferably in greater than 30 seconds and less than 3 hours, more preferably in greater than 1 minute and less than 2 hours, and most preferably in greater than 2 minutes and less than 1 hour.

Suitable film-forming agents for use as soluble film-forming agents in this invention are selected from the group consisting of polymers such as polyvinylpyrrolidone (available from BASF at 30F), methylcellulose (available from Colorcon), ethylcellulose (available from Colorcon), hydroxyethylcellulose (available from Ashland Industries at 250L), hydroxypropylcellulose (available from Ashland Industries), hydroxypropyl methylcellulose (also known as hydroxypropyl methylcellulose, available from Shin-Etsu), sodium carboxymethylcellulose (the uncrosslinked sodium salt of carboxymethylcellulose, also known as CMC or carboxymethylcellulose, available from Ashland Industries), and polyethylene glycol-polyacetic acid-based... Graft copolymers of vinyl esters and polyvinylcaprolactam (available from BASF), polyvinyl alcohol (available from Kuraray 4-88), polyvinyl alcohol-polyethylene glycol copolymers (available from BASF IR), polyvinylpyrrolidone-polyvinyl acetate copolymers (also known as copovidone and available from BASF, for example, as VA64), polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymers (available from Evonik L100, L12,5, S100 and S12,5), and methacrylic acid-ethyl methacrylate copolymers (available from Evonik L100-55 and L30D55), as well as natural film-forming agents such as shellac, pectin, gelatin, alginate, pullulan, and starch derivatives, and any mixtures thereof.

The soluble film-forming agent should not only provide sufficient cohesion to the agomelatine-containing layer, but preferably also provide a film that is non-sticky in its dry state, allowing the patient to touch and manipulate the agomelatine-containing layer, for example, by applying it to the oral mucosa, without the film adhering to the fingers. Furthermore, since the soluble film-forming agent is a key control for the solubility characteristics of the agomelatine-containing layer, which need to be neither too rapid nor too slow, the soluble film-forming agent is preferably soluble, dispersible, or otherwise disintegrable in an aqueous medium, especially in saliva, or simply in water. On the other hand, film-forming agents soluble in other solvents such as C1-C3 alcohols, particularly ethanol, are also preferred for ease of manufacture and to allow for an anhydrous manufacturing process that is advantageous in avoiding recrystallization of crystals or surfactants. Although it is therefore particularly preferred that the film-forming agent be soluble in both water and ethanol, high solubility can cause the agomelatine-containing layer to dissolve too quickly. Therefore, selecting a film-forming agent is not a simple task.

The inventors have surprisingly discovered that, in view of the above, polymers such as polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, graft copolymers based on polyethylene glycol-polyvinyl acetate and polyvinylcaprolactam, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymers, polyvinylpyrrolidone-polyvinyl acetate copolymers, polyethylene oxide, polyethylene glycol, and any mixtures thereof are preferred for soluble film-forming agents. Particularly preferred are polymers such as polyvinylpyrrolidone, hydroxypropylcellulose, graft copolymers based on polyethylene glycol-polyvinyl acetate and polyvinylcaprolactam, polyvinylpyrrolidone-polyvinyl acetate copolymers, and any mixtures thereof, and most preferably, the soluble film-forming agent is hydroxypropylcellulose or polyvinylpyrrolidone or a mixture thereof.

Hydroxypropyl cellulose is available from Ashland under the trademark Klucel ^™ and is offered in several grades.

The grades differ from each other in molecular weight (MW, as measured by GPC-size exclusion chromatography) and Brookfield viscosity (25°C, LVF, anhydrous), as described below:

The HF grade has a MW of 1,150,000 and a Blockfield viscosity of 1,500-3,000 (1% in water).

The MF grade has a MW of 850,000 and a Blockfield viscosity of 4,000-6,500 (2% in water).

The GF grade has a MW of 370,000 and a Blockfield viscosity of 150-400 (2% in water).

JF grade has a MW of 140,000 and a Blockfield viscosity of 150-400 (5% in water).

The LF grade has a MW of 95,000 and a Blockfield viscosity of 75-150 (5% in water).

EF grade has a MW of 80,000 and a Blockfield viscosity of 300-600 (10% in water).

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

Therefore, in some embodiments, hydroxypropyl cellulose has a molecular weight of 30,000 to 1,500,000 (as measured by GPC size exclusion chromatography), and more preferably, hydroxypropyl cellulose has a molecular weight selected from the following (as measured by GPC size exclusion chromatography):

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

The molecular weight is between 1,100,000 and 1,200,000, particularly 1,150,000. Hydroxypropyl cellulose with a molecular weight (as measured by GPC-size exclusion chromatography) between 75,000 and 85,000, particularly 80,000, is particularly preferred.

Polyvinylpyrrolidone is preferably soluble polyvinylpyrrolidone.

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

Within the meaning of this invention, the term "K value" refers to the value calculated from the relative viscosity of polyvinylpyrrolidone in water, according to the European Pharmacopoeia (Ph.Eur.) and the USP monograph on "povidone".

Therefore, in some embodiments, polyvinylpyrrolidone is selected from polyvinylpyrrolidone having a K value within a range selected from the following groups of components:

9 to 15, and preferably 10.2 to 13.8.

15 to 20, and preferably 15.3 to 18.4.

20 to 27, and preferably 22.5 to 27.0.

27 to 35, and preferably 27.0 to 32.4, and

75 to 110, and preferably 81.0 to 97.2.

or any mixture thereof, and more preferably polyvinylpyrrolidone having a K value in the range of 27.0 to 32.4 or 81.0 to 97.2 and any mixture thereof, and most preferably polyvinylpyrrolidone having a K value in the range of 81.0 to 97.2.

To provide sufficient cohesion to the agomelatine-containing layer, a certain amount of soluble film-forming agent should be included. Therefore, in some preferred embodiments, the amount of soluble film-forming agent is at least 65 wt%, more preferably at least 75 wt%, and most preferably at least 85 wt%. On the other hand, the amount of soluble film-forming agent may also be less than or equal to 98 wt%, less than or equal to 94 wt%, or less than or equal to 90 wt%. In some embodiments, the amount of soluble film-forming agent relative to the agomelatine-containing layer is in the range of 65 to 98 wt%, 75 to 94 wt%, or 80 to 90 wt%.

This film-forming agent can be present as a soluble film-forming agent in the agomelatine-containing layer, but may also be contained in an optional capping layer.

Other additives

The agomelatine-containing layer of the transmucosal therapy system of the present invention may contain other excipients or additives selected from the group consisting of: fatty acids, sweeteners, flavoring agents, coloring agents, penetration enhancers, solubilizers, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffering agents and other film-forming agents.

The additives may be present in the agomelatine-containing layer in an amount of 0.001 to 15 wt% of each additive. In one embodiment, the total amount of all additives is 0.001 to 25 wt% relative to the agomelatine-containing layer. Hereinafter, when a range of amounts for a particular additive is given, such range refers to the amount of each individual additive.

It should be noted that in pharmaceutical formulations, formulation components are classified according to their physicochemical and physiological properties and according to their functions. This specifically means that a substance or compound belonging to one class may not be excluded from another formulation component class. For example, a polymer may be a crystallization inhibitor but also a thickener. Some substances may be, for example, typical softeners but also act as penetration enhancers. A skilled person can determine, based on his common sense, which one or more formulation component classes a substance or compound belongs to. Details regarding excipients and additives are provided below; however, these details should not be construed as exclusive. Other substances not expressly listed in this description may also be used according to the invention, and for the purposes of this invention, substances and/or compounds expressly listed for one formulation component class may not be excluded from being used as another formulation component.

Given the potential stinging or irritating effects of agomelatine, substances that can mask or improve the taste or mitigate its effects are particularly preferred. For example, researchers have shown that certain fatty acids can reduce capsaicin-induced effects such as pain/itching.

Therefore, in some preferred embodiments, the agomelatine layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, and flavoring agents.

The fatty acids may particularly be saturated or unsaturated straight-chain or branched carboxylic acids containing 4 to 24 carbon atoms, and are particularly selected from the group consisting of: caprylic acid, myristone acid, palmitoleic acid, juglans regia, oleic acid, trans-oleic acid, isoleic acid, linoleic acid, trans-linoleic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid. Oleic acid or linoleic acid is particularly preferred.

In terms of quantity, the agomelatine-containing layer preferably contains at least 1 wt%, more preferably at least 3 wt%, and even more preferably at least 4 wt% of one or more fatty acids. The agomelatine-containing layer may also contain less than or equal to 15 wt%, preferably less than or equal to 12 wt%, and even more preferably less than or equal to 10 wt% of one or more fatty acids. Finally, the agomelatine-containing layer may also contain 1 to 15 wt%, preferably 3 to 12 wt%, and even more preferably 4 to 10 wt% of one or more fatty acids.

In some preferred embodiments, the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of: sucrose, glucose, fructose, sorbitol, mannitol, isomaltitol, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclohexylsulfamic acid, neohesperidine, neotame, steviol glycoside, thaumatin, and sodium saccharin. Particularly preferably, the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of sucrose, sucralose, and sodium saccharin. In this particularly preferred embodiment, the agomelatine layer comprises one or more natural or artificial sweeteners selected from the group consisting of sucralose, sucrose, and sodium saccharin, each sweetener being at least 0.05 wt%, preferably at least 0.1 wt%, and more preferably at least 0.3 wt%, and/or less than or equal to 2.0 wt%, preferably less than or equal to 1.5 wt%, and more preferably less than or equal to 1.0 wt%, and/or from 0.05 to 2.0 wt%, preferably from 0.1 to 1.5 wt%, and more preferably from 0.3 to 1.0 wt%.

In a preferred embodiment, the agomelatine layer comprises one or more natural or artificial flavorings selected from the group consisting of: vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetoyl propionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl sebadienoate, allyl hexanoate, ethyl maltol, 2,4-dimethylthiomethane, ethyl vanillin, and eucalyptol, as well as flavoring compositions such as peppermint flavoring. Vanillin, methyl salicylate, menthol, peppermint flavoring, and eucalyptol are particularly preferred. In this particularly preferred embodiment, the agomelatine layer comprises one or more flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, peppermint flavoring agent, and eucalyptol, each flavoring agent being at least 0.1 wt%, preferably at least 0.3 wt%, and more preferably at least 0.4 wt%, and/or less than or equal to 10 wt%, preferably less than or equal to 6 wt%, and more preferably less than or equal to 4 wt%, and/or 0.1 to 10 wt%, preferably 0.3 to 6 wt%, and more preferably 0.4 to 4 wt%, or the total being at least 0.1 wt%, preferably at least 0.5 wt%, and more preferably at least 0.7 wt%, and/or less than or equal to 15 wt%, preferably less than or equal to 10 wt%, and more preferably less than or equal to 8 wt%, and/or 0.1 to 15 wt%, preferably 0.5 to 10 wt%, and more preferably 0.7 to 8 wt%. Suitable flavoring agents are also available commercially from Mane, and any of those flavoring agents labeled by their flavor profile, such as apple, caramel, chocolate, lemon, mint, etc., can be used as flavoring agents in this invention.

In some embodiments, the agomelatine-containing layer comprises one or more colorants. Any colorant suitable for pharmaceutical/food applications may be included, particularly those permitted for use by the US FDA or by the European agency EFSA/EMA. The colorant may, for example, be selected from the group consisting of: titanium dioxide, brilliant blue FCF, indigo carmine, fast green FCF, erythrosine, allura red AC, tartrazine and sunset yellow FCF, curcumin, riboflavin, riboflavin-5'-phosphate, quinoline yellow, orange yellow S, carmine, carmine acid, azorubine, pale red, amaranth, poinsettia 4R, carmine A, patent blue V, indigo, chlorophyll, chlorophyll acid, copper complexes of chlorophyll and chlorophyll acid, green... S, regular caramel, caustic sulfite caramel, ammonia caramel, ammonium sulfite caramel, Brilliant Black BN, Black PN, vegetable carbon black, Brown HT, carotene, annatto, annattoin, norostatin, capsicum extract, capsicum red, capsicum rubigin, lycopene, β-apo-8'-carotene, lutein, canthaxanthin, betaine, betaine, anthocyanins, calcium carbonate, iron oxides and hydroxides, aluminum, silver, gold, and Lithorubigin BK.

In addition to the film-forming agents disclosed above for soluble film-forming agents, the agomelatine-containing layer may also contain one or more other film-forming agents. These other film-forming agents differ from those previously disclosed for soluble film-forming agents. Each of the one or more other film-forming agents may be included in the agomelatine-containing layer in an amount of at least 2 wt%, preferably at least 5 wt%, and more preferably at least 10 wt%, and/or in an amount of less than or equal to 40 wt%, preferably less than or equal to 30 wt%, and more preferably less than or equal to 25 wt%, and/or in an amount of 2 to 40 wt%, preferably 5 to 30 wt%, and more preferably 10 to 25 wt%, and/or in a total amount of at least 5 wt%, preferably at least 15 wt%, and more preferably at least 20 wt%, or in an amount of less than or equal to 40 wt%, preferably less than or equal to 30 wt%, and more preferably less than or equal to 25 wt%, and/or in an amount of 5 to 40 wt%, preferably 15 to 30 wt%, and more preferably 20 to 25 wt%.

In some embodiments, the agomelatine-containing layer comprises one or more solubilizers. Suitable solubilizers may be selected, for example, from the group consisting of: ethoxylated dehydrated sorbitols esterified with fatty acids, such as polyoxyethylene dehydrated sorbitol monolaurate, polyoxyethylene dehydrated sorbitol monopalmitate, polyoxyethylene dehydrated sorbitol monostearate, and polyoxyethylene dehydrated sorbitol monooleate (commercially available from Tween 80 or polysorbate 80), safflower oil, propylene glycol, and polyethoxylated castor oil. The solubilizers may each be included in the agomelatine-containing layer in an amount of at least 0.3 wt%, preferably at least 0.5 wt%, and more preferably at least 1.0 wt%, and/or in an amount of less than or equal to 5 wt%, preferably less than or equal to 4 wt%, and more preferably less than or equal to 3 wt%, and/or in an amount of 0.3 to 5 wt%, preferably 0.5 to 4 wt%, and more preferably 1.0 to 3 wt%.

The agomelatine-containing layer may also contain one or more emulsifiers. The emulsifiers may, for example, be selected from the group consisting of: soybean lecithin, sodium phosphate, monoglycerides and diglycerides of fatty acids, sodium stearoyl lactylate, diacetyl tartrate of monoglycerides and diglycerides, and polyethoxylated hydrogenated castor oil (available commercially from BASF at Chremophor RH 40). Each emulsifier may be included in the agomelatine-containing layer, for example, in an amount of at least 1 wt%, preferably at least 3 wt%, and more preferably at least 5 wt%, and/or in an amount of less than or equal to 25 wt%, preferably less than or equal to 20 wt%, and more preferably less than or equal to 15 wt%, and/or in an amount of 1 to 25 wt%, preferably 3 to 20 wt%, and more preferably 5 to 15 wt%.

In a particular embodiment, the agomelatine-containing layer comprises one or more plasticizers. The one or more plasticizers may be selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides and derivatives such as sorbitol (commercially available from Cargill via Sorbidex ^™ ), polyethylene glycol, triacetin, triethyl citrate, propylene glycol, glycerol, and medium-chain triglycerides. The agomelatine-containing layer may contain one or more plasticizers in an amount of at least 0.5 wt%, preferably at least 1 wt%, and more preferably at least 5 wt%, and/or in an amount of less than or equal to 25 wt%, preferably less than or equal to 20 wt%, or more preferably less than or equal to 15 wt%, and/or in an amount of 0.5 to 25 wt%, preferably 1 to 20 wt%, and more preferably 5 to 15 wt%.

The agomelatine-containing layer may also include a penetration enhancer. In one embodiment, the agomelatine-containing layer comprises a penetration enhancer selected from the group consisting of: transcutol, dipropylene glycol, levulinic acid, 2,5-dimethylisosorbate (dottisol), lauryl lactate, lactic acid, dimethyl ethyl urea, N,N-diethyl-m-toluamide (DEET), propylene glycol monooctanoate, 2-methoxy-4-(prop-2-en-1-yl)phenol, and laurocapram. The penetration enhancer may be included in the agomelatine-containing layer in an amount of at least 1 wt%, preferably at least 2 wt%, and more preferably at least 5 wt%, and/or in an amount of less than or equal to 20 wt%, preferably less than or equal to 15 wt%, and more preferably less than or equal to 10 wt%, and/or in an amount of 1 to 20 wt%, preferably 2 to 15 wt%, and more preferably 5 to 10 wt%.

On the other hand, certain compounds that can be considered as penetration enhancers are not preferred. Therefore, in some embodiments, the agomelatine layer contains a penetration enhancer selected from the group consisting of no more than 5 wt%, preferably no more than 1 wt%, more preferably no more than 0.2 wt%, and most preferably no more than 0.1 wt% of the following: bile acids, bile salts, bile acid derivatives, acylcarnitine, sodium lauryl sulfate, dimethyl sulfoxide, sodium lauryl sulfate, terpenes, cyclodextrins, cyclodextrin derivatives, saponins, saponin derivatives, chitosan, EDTA, citric acid, and salicylates.

The agomelatine-containing layer of the present invention may include a pH adjuster. Preferably, the pH adjuster is selected from monobasic and polybasic acids, monobasic, dibasic and tribasic acids, buffer solutions of mixtures of weak acids and their conjugate bases, amine derivatives, inorganic base derivatives, and polymers having basic and acidic functional groups, respectively.

Release

The transmucosal therapy system of the present invention is designed to administer a specific amount of agomelatine transmucosally into the systemic circulation, particularly during nighttime hours.

The application of the mucosal treatment system of the present invention generally and preferably consists of: applying a mucosal adhesion layer structure to the oral mucosa of a human patient (after removal of the final dissipation liner), and maintaining the mucosal adhesion layer structure on the mucosa until it dissolves. The application site may be the buccal, sublingual, gingival, or palate; that is, in a preferred embodiment, the application of the mucosal treatment system consists of: applying a mucosal adhesion layer structure to the buccal, sublingual, gingival, or palatal mucosa of a human patient, and preferably to the buccal mucosa, and maintaining the mucosal adhesion layer structure on the mucosa until it dissolves.

In a particular embodiment of the invention, as measured with porcine esophageal mucosa, the transmucosal treatment system of the invention, as described above, provides an agomelatine mucosal penetration rate of 10 μg/cm² ^- hr to 150 μg/cm² ^- hr after 1 hour.

In some embodiments, such as those measured with porcine esophageal mucosa, over an 8-hour period, the transmucosal treatment system of the present invention provides a cumulative release of agomelatine of at least 0.02 mg/ ^cm² , preferably at least 0.05 mg/ ^cm² , and more preferably at least 0.1 mg/ ^cm² , and/or less than or equal to 0.5 ^mg / ^cm² , preferably less than or equal to 0.4 mg/ ^cm² , and more preferably less than or equal to 0.3 mg/ ^cm² , and/or from 0.02 mg/ ^cm² to 0.5 mg/ ^cm² , preferably from 0.05 mg/ ^cm² to 0.4 mg/cm², and more preferably from 0.1 mg/ ^cm² to 0.3 mg/ ^cm² .

Treatment methods/medical uses

According to one aspect of the invention, the transmucosal therapeutic system of the invention is used in a treatment method, and particularly in a method of treating a human patient. According to another aspect, the invention relates to a treatment method in which the transmucosal therapeutic system of the invention is administered to a human patient. In yet another aspect, the invention relates to the use of the transmucosal therapeutic system of the invention in the manufacture of a medicament for performing treatment, preferably for treating a human patient.

Most patients with classic mood disorders (major depression, the depressive phase of bipolar disorder, or generalized anxiety disorder), that is, more than 80%, show disruption of their sleep-wake cycle and sleep structure. Characteristically, difficulty falling asleep (increased sleep latency) followed by intermittent sleep leads to significant daytime sleepiness, which further impairs their ability to function properly in daily life, creating a vicious cycle. Regarding depression, although there are no specific treatment guidelines, the available options are generally based on the premise that depression and sleep disturbances share a bidirectional relationship; therefore, successfully treating one condition will reciprocally benefit the other.

In recent years, it has become increasingly clear that disruption of the circadian rhythm—the dysregulation and dysfunction of the “body clock,” which locks in core physiological functions such as body temperature and blood pressure, and also in the extremely complex neurotransmitter responses to the time of day—is a major factor that justifies treatment focus in major depressive disorder. Dysfunction of the link between the suprachiasmatic nucleus, the pineal gland, and the neurohormone it produces—melatonin—has been shown to be a primary cause of these phenomena. Melatonin has been widely promoted (and marketed) as a “non-photodynamic circadian rhythm resynchronizer” for the treatment of jet lag and shift work-related insomnia, and numerous studies have been published on its antidepressant and anti-anxiety effects. Due to the low oral bioavailability of melatonin, synthetic melatonin receptor agonists have been explored; the most well-known of these is agomelatine.

Although agomelatine is approved for the treatment of depression, it has been proposed for other indications, such as bipolar disorder, generalized anxiety disorder, Smith-Magenis syndrome, periventricular leukomalacia, and OCD.

Therefore, in some embodiments, the transmucosal therapy system of the present invention is preferably used in a method for treating major depressive disorder. Similarly, in some other embodiments, the present invention relates to a method for treating major depressive disorder, wherein the transmucosal therapy system of the present invention is administered to a human patient. In other embodiments, the present invention relates to the use of the transmucosal therapy system of the present invention in the manufacture of a medicament for treating major depressive disorder.

Treatment for depression, also known as major depressive disorder (MDD), may include addressing various conditions in patients with depression/MDD, such as major depressive episodes, anxiety symptoms, sleep-wake cycle disturbances, daytime sleepiness, and insomnia (most MDD patients, more than 80%, suffer from depression combined with insomnia). In other implementations, treatment may also involve addressing bipolar disorder, generalized anxiety disorder, Smith-Magilli syndrome, periventricular leukomalacia, or OCD.

As outlined above, transmucosal delivery avoids the first-pass effect; therefore, unlike oral agomelatine formulations, the transmucosal treatment system of the present invention carries a lower risk of hepatotoxicity. Therefore, there are no limitations regarding the patient group to be treated. Treatment includes treating patients with or without hepatic impairment, including those with at least mild or at least moderate hepatic impairment.

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

In any treatment outlined for the foregoing aspects and embodiments, the transmucosal treatment system is preferably applied by: applying a mucosal adhesive layer structure to the oral mucosa of a human patient, and maintaining it on the mucosa until it dissolves. In a preferred embodiment, the transmucosal treatment system is applied by: applying a mucosal adhesive layer structure to the buccal, sublingual, gingival, or palatal mucosa of a human patient, and maintaining it on the mucosa until it dissolves. In a preferred embodiment, the transmucosal treatment system is applied in the evening or at night before bedtime.

In another embodiment, the transmucosal treatment system of the present invention can also be used in a method of reducing at least one agomelatine-related side effects in a patient relative to an equivalent oral dose of agomelatine.

The present invention also relates to a method for reducing at least one agomelatine-related side effects in patients treated with oral agomelatine therapy, the method comprising:

a) Discontinue oral agomelatine therapy; and

b) Applying the transmucosal treatment system of the present invention to the oral mucosa of a human patient, wherein the transmucosal treatment system provides a reduction of at least one agomelatine-related side effect relative to an equivalent oral dose of agomelatine.

In this method, a transmucosal treatment system can deliver an amount of agomelatine equivalent to the amount initially delivered by oral agomelatine therapy.

Manufacturing method

The present invention also relates to a method for manufacturing an agomelatine-containing layer for use in a transmucosal therapy system, a corresponding mucosal adhesion layer structure comprising the agomelatine-containing layer, and a corresponding transmucosal therapy system.

According to the present invention, a method for manufacturing an agomelatine-containing layer includes the following steps:

i) Combine at least agomelatine and a soluble film-forming agent in a solvent to obtain a coating composition;

ii) Apply the coating composition to the release liner; and

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

In this method, the suitable soluble film-forming agent is the same as those previously mentioned. Therefore, in some embodiments, if cast into a film having an area weight of 50 g/ ^m² , the soluble film-forming agent, at 37°C and 150 rpm, dissolves in water, artificial or natural saliva, or any other aqueous medium within less than 5 hours, preferably less than 3 hours, more preferably less than 2 hours, and most preferably less than 1 hour, and/or within more than 5 seconds, preferably more than 30 seconds, more preferably more than 1 minute, and most preferably more than 2 minutes, and/or within more than 5 seconds and less than 5 hours, preferably more than 30 seconds and less than 3 hours, more preferably more than 1 minute and less than 2 hours, and most preferably more than 2 minutes and less than 1 hour.

The soluble film-forming agent may also be selected from the group consisting of polymers such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, graft copolymers based on polyethylene glycol-polyvinyl acetate and polyvinylcaprolactam, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl methacrylate copolymer, natural film-forming agents such as shellac, pectin, gelatin, alginate, pullulan and starch derivatives, and any mixture thereof. The soluble film-forming agent is preferably selected from the group consisting of polymers such as polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, graft copolymers based on polyethylene glycol-polyvinyl acetate and polyvinylcaprolactam, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyethylene oxide, polyethylene glycol, and any mixture thereof, and more preferably selected from the group consisting of polymers such as polyvinylpyrrolidone, hydroxypropylcellulose, graft copolymers based on polyethylene glycol-polyvinyl acetate and polyvinylcaprolactam, polyvinylpyrrolidone-polyvinyl acetate copolymer, and any mixture thereof.

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

In other specific embodiments, the soluble film-forming agent is polyvinylpyrrolidone, preferably selected from soluble polyvinylpyrrolidone, and particularly selected from polyvinylpyrrolidone having a K value within a range selected from the group consisting of:

9 to 15, and preferably 10.2 to 13.8.

15 to 20, and preferably 15.3 to 18.4.

20 to 27, and preferably 22.5 to 27.0.

27 to 35, and preferably 27.0 to 32.4, and

75 to 110, with 81.0 to 97.2 being preferred.

In this manufacturing method, in step i), agomelatine is soluble or dispersible to obtain a coating composition.

Because agomelatine is poorly soluble in water, there is a risk of recrystallization, so it is preferable not to use water. Therefore, in a preferred embodiment, the solvent contains water in an amount not greater than 5 wt%, preferably not greater than 2 wt%, more preferably not greater than 1 wt%, and most preferably not greater than 0.5 wt%. On the other hand, depending on the solubility of the soluble film-forming agent in different solvents, the use of water may be advantageous. Therefore, in some embodiments, the solvent contains water.

Therefore, in the methods described above, the solvent preferably comprises an alcohol solvent selected from methanol, ethanol, isopropanol and mixtures thereof, and more preferably, the solvent comprises ethanol or is composed of ethanol.

Preferred ingredients for the soluble film-forming agent and other components containing the agomelatine layer are as outlined above. Therefore, in one embodiment, step i) comprises combining at least agomelatine, the 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. Furthermore, in step i), agomelatine can be combined in soluble form, dispersed form, crystalline form, particularly one of its polymorphs, amorphous form, as a hydrate, solvate, a mixture of any of the foregoing forms, or a mixture thereof.

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

Mucosal adhesion layer structures containing agomelatine layers and corresponding transmucosal therapy systems can be manufactured using the methods outlined above, employing other manufacturing steps known to those skilled in the art, such as stamping out individual transmucosal therapy systems and packaging, for example, by sealing them in pouches made from primary packaging materials. These other steps preferably produce mucosal adhesion layer structures or transmucosal therapy systems as described in the preceding chapters.

The present invention also relates in particular to agomelatine-containing layers and mucosal adhesion layer structures and transmucosal therapy systems that can be obtained (and/or acquired) by the methods described above.

Example

The present invention will now be described more fully with reference to the accompanying embodiments. However, it should be understood that the following description is illustrative only and should not be construed as limiting the invention in any way. The numerical values regarding the amount or area weight of components in the compositions provided in the embodiments may vary slightly due to manufacturing variability.

Examples 1A–1F

Coating composition

The formulations of the agomelatine-containing coating compositions of Examples 1a to 1f are summarized in Table 1.1 below. The formulations are based on weight percentages, as also indicated in Table 1.1.

Table 1.1

Preparation of the first coating composition (containing an agomelatine layer)

For Examples 1a to 1f, a first beaker was loaded with agomelatine. Approximately one-third of the ethanol, eucalyptol, menthol, methyl salicylate, Novamint Fresh Peppermint, Kolliphor RH 40, FD&C Red #40, and sucralose were added, and the mixture was stirred. Polyvinylpyrrolidone was added while stirring. A second beaker was loaded with distilled water. Polysorbate 80 was added, and the mixture was stirred. The remaining ethanol was added while stirring. The contents of both beakers were mixed while stirring to obtain a slightly reddish solution with visible crystalline precipitate.

Preparation of the second coating composition (backing layer)

For Examples 1b to 1f, beakers were filled with ethanol and then stirred. Ethyl cellulose and castor oil were added while stirring to obtain a slightly opaque mixture.

The resulting backing composition was coated onto a polyester film (polyethylene terephthalate film, one side siliconized, 75 μm thick, which can serve as a release liner) and dried at room temperature for about 10 minutes and at 70°C for about 20 minutes. The coating thicknesses given are area weights of 20.9 g/ ^m² (Examples 1b, 1e, and 1f) and 20.8 g/ ^m² (Examples 1c and 1d).

Remove the release liner before applying the agomelatine-containing coating to the backing layer.

Application of the first coating composition

The first coating composition containing agomelatine obtained in Example 1a was applied to a polyester film (polyethylene terephthalate film, one side siliconized, 75 μm thick, which can serve as a release liner) and dried at room temperature for about 5 minutes and at 50°C for about 10 minutes (Example 1a). For Example 1a, the dried film is the final adhesive layer structure containing agomelatine.

The coating thickness yielded an area weight of 57.9 g/m² (Example 1a).

The first coating compositions containing agomelatine obtained in Examples 1b to 1f were applied onto a dried backing layer and dried for approximately 5 minutes at room temperature, approximately 10 minutes at 50°C, and approximately 4 minutes at 90°C (Examples 1b and 1f), approximately 5 minutes at room temperature, and approximately 10 minutes at 50°C (Example 1c), approximately 6 minutes at room temperature, approximately 12 minutes at 50°C, and approximately 4 minutes at 90°C (Example 1d), and approximately 5 minutes at room temperature, approximately 10 minutes at 50°C, and approximately 2 minutes at 90°C (Example 1e).

For the agomelatine-containing layer, the coating thicknesses were given as area weights of 57.9 g/ ^m² (Example 1a), 53.9 g/ ^m² (Example 1b), 34.9 g/ ^m² (Example 1c), 72.1 g/ ^m² (Example 1d), 50.5 g/ ^m² (Example 1e), and 53.4 g/ ^m² (Example 1f).

Preparation of a transmucosal therapy system (all embodiments)

Next, individual transmucosal treatment systems are stamped from the agomelatine-containing mucosal adhesion layer structure. This is advantageous when the OTF does not adhere sufficiently to the mucosa based on its individual physical properties, and/or when the agomelatine-containing layer has distinct corners (square or rectangular shape) for the purpose of avoiding waste. The transmucosal treatment system is then stamped and, as is customary in the art, sealed into a pouch made of primary packaging material, for example, under a protective atmosphere achieved by rinsing with nitrogen.

Measuring mucosal permeation rate

Using porcine mucosa (esophageal mucosa), the permeation volume and corresponding mucosal permeation rate of the transmucosal therapy systems prepared according to Examples 1a to 1f were determined by in vitro experiments according to OECD guidelines (officially adopted on April 13, 2004). For all transmucosal therapy systems, the mucosa was prepared to a thickness of 400 μm with complete barrier function using a dermabrasion tool. A die-cut with an area of 0.798 ^cm² was punched from the transmucosal therapy system, applied to the mucosa, and the mucosa with the transmucosal therapy system was immersed in artificial saliva on the upper part (the lower part was in contact with the receiving medium, and the upper part was divided to a mucosal area of 1.145 ^cm² ). The permeation volume of agomelatine in the receiving medium (phosphate buffer solution at pH 7.4) was measured at a temperature of 37 ± 1 °C, and the corresponding mucosal permeation rate was calculated. The results are shown in Table 1.2 and Figure 1a.

Table 1.2

*: As in all other embodiments, the standard deviation in this embodiment is calculated based on the n method.

Agomelatine utilization

The utilization rate of agomelatine at 7 hours was calculated based on the cumulative permeate and the initial agomelatine content. The results are shown in Table 1.3 and Figure 1b.

Table 1.3

In vitro experiments showed good mucosal penetration rate and good utilization. In particular, this showed that Example 1a without a backing layer had advantageous rapid release of the active ingredient compared to those examples with a backing layer. Examples 1b to 1d showed that the penetration rate increased with increasing areal weight (and therefore the amount of active ingredient). Similarly, increasing the amount of active ingredient by changing the concentration of the active ingredient also resulted in an increase in the penetration rate (Examples 1e and 1f).

Example 2

Preparation of permeation samples

In Example 2, the mucosal penetration rate of pure agomelatine in natural saliva was determined relative to the transmucosal therapy system used in Examples 1a and 3a. Therefore, for Example 2, instead of the transmucosal therapy system, an agomelatine-containing solution was prepared from 0.877 mg of agomelatine in 300 μl of natural saliva.

Measuring mucosal permeation rate

Using porcine mucosa (esophageal mucosa), the permeation volume and corresponding mucosal permeation rate of the transmucosal therapy systems prepared according to Examples 1a (containing a certain amount of crystalline material) and 3a (without crystals), as well as the above-mentioned agomelatine solution (Example 2), were determined by in vitro experiments according to OECD guidelines (officially adopted on April 13, 2004). For all transmucosal therapy systems, the mucosa was prepared to a thickness of 400 μm with complete barrier function using a dermabrasion tool. For Examples 1a and 3a, a die-cut material with an area of 0.798 ^cm² was punched from the transmucosal therapy system and applied to the mucosa. The mucosa with the transmucosal therapy system was immersed in 300 μl of natural saliva on the upper part (the lower part was in contact with the receiving medium, and the upper part was divided into mucosal areas of 1.595 ^cm² ). For Example 2, instead of applying via a transmucosal treatment system and adding natural saliva, the above-described permeation sample was applied directly to a mucosa (also with an area of 1.595 ^cm² ) to achieve an API content of approximately 0.55 mg/ ^cm² per mucosal area. Agomelatine permeation in the receiving medium (phosphate buffer solution at pH 7.4) was measured at 37 ± 1 °C, and the corresponding mucosal permeation rate was calculated. The results are shown in Table 2.1 and Figure 2a.

Table 2.1

*: As in all other embodiments, the standard deviation in this embodiment is calculated based on the n method.

Agomelatine utilization

The utilization rate of agomelatine at 7 hours was calculated based on the cumulative permeate and the initial agomelatine content. The results are shown in Table 2.2 and Figure 2b.

Table 2.2

In vitro experiments showed good mucosal penetration rate and satisfactory utilization.

Examples 3A-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. The formulations are based on weight percentages, as also indicated in Tables 3.1 and 3.2.

Table 3.1

Table 3.2

Preparation of the first coating composition (containing an agomelatine layer)

For Example 3a, a beaker was loaded with agomelatine. Ethanol, eucalyptol, menthol, methyl salicylate, Novamint peppermint, Kolliphor RH 40, FD&C Red #40, sucralose, and polysorbate 80 were added, and the mixture was stirred. Polyvinylpyrrolidone was added while stirring to obtain a clear red solution after approximately 2.5 hours of stirring.

For Examples 3b to 3h, the same coating composition was used for the agomelatine-containing layer, which was prepared as follows: A beaker was loaded with agomelatine. Ethanol, menthol, eucalyptol, methyl salicylate, Kolliphor RH40, FD&C Red #40, sucralose, and polysorbate 80 were added, and the mixture was stirred. A clear solution was obtained. Polyvinylpyrrolidone was added, and after stirring overnight, Novamint Fresh Peppermint was added dropwise with stirring to obtain a clear red solution.

Preparation of the second coating composition (backing layer)

For Example 3c, a beaker was loaded with ethyl cellulose. Ethanol was added, and the mixture was stirred. Castor oil was added while stirring to obtain a slightly opaque mixture.

For Examples 3e to 3h, a beaker was filled with ethanol. Purified water and Kollidon were added, and the mixture was stirred to obtain a solution. Eudragit and glycerol were added with stirring to obtain a clear mixture. For Examples 3f and 3g, sodium hydroxide solution was added to produce the pH indicated in Table 3.2 above.

The second coating compositions obtained in Examples 3c and 3e to 3h were applied to a polyester film (polyethylene terephthalate film, one side siliconized, 75 μm thick, which can serve as a release liner) and dried at room temperature for about 10 minutes, at 70°C for about 20 minutes (Example 3c), at room temperature for about 5 minutes, at 35°C for about 10 minutes, and at 80°C for about 2 minutes (Examples 3e to 3h), respectively. The coating thicknesses were given as area weights of 12.3 g/ ^m² (Example 3c), 26.8 g/ ^m² (Example 3e), 26.0 g/ ^m² (Example 3f), 20.5 g/ ^m² (Example 3g), and 22.9 g/ ^m² (Example 3h), respectively. For Example 3d, a commercially available polyethylene terephthalate film with a thickness of 15 μm was used as a backing layer.

Application of the first coating composition

The agomelatine-containing first coating compositions obtained in Examples 3a and 3b were applied to a polyester film (polyethylene terephthalate film, one side siliconized, 75 μm thick, which can serve as a release liner) and dried, respectively, at room temperature for about 15 minutes and at 70°C for about 5 minutes (Example 3a), or at room temperature for about 5 minutes, at 50°C for about 10 minutes, and at 90°C for about 2 minutes (Example 3b). For Examples 3a and 3b, the dried film is the final agomelatine-containing adhesive film structure.

The first coating composition containing agomelatine obtained in Examples 3c and 3e to 3h was applied onto the dried backing layer and dried at room temperature for about 5 minutes, at 50°C for about 10 minutes, and at 90°C for about 2 minutes (Examples 3c and 3e to 3h).

The coating thicknesses are given as area-weight values of 55.4 g/ ^m² (Example 3a) and 50.0 g/ ^m² (Examples 3b, 3c, and 3e to 3h), respectively. The coating method for 3d is the same as that for Examples 3b, 3c, and 3e to 3h, except that the coating composition is applied to a 15 μm thick polyethylene terephthalate film, thereby producing a transmucosal therapeutic system with a backing layer (made of polyethylene terephthalate film).

Preparation of transmucosal therapy system

Examples 3b, 3c, and 3e to 3h of the transmucosal therapy system are prepared by laminating a backing layer onto an agomelatine-containing layer. The release liner is removed prior to lamination.

Other steps (such as stamping out individual devices) are performed as in Example 1.

Measuring mucosal permeation rate

Using porcine mucosa (esophageal mucosa), the permeation volume and corresponding mucosal permeation rate of the transmucosal therapy systems prepared according to Examples 3a to 3h were determined by in vitro experiments according to OECD guidelines (officially adopted on April 13, 2004). For all transmucosal therapy systems, the mucosa was prepared to a thickness of 400 μm with complete barrier function using a dermabrasion tool. A die-cut with an area of 0.522 ^cm² was punched from the transmucosal therapy system, applied to the mucosa, and the mucosa with the transmucosal therapy system was immersed in artificial saliva on the upper part (the lower part was in contact with the receiving medium, and the upper part was divided to a mucosal area of 1.145 ^cm² ). The amount of agomelatine permeation in the receiving medium (phosphate buffer solution at pH 7.4) was measured at a temperature of 37 ± 1 °C, and the corresponding mucosal permeation rate was calculated. The results are shown in Tables 3.3 and 3.4 and Figures 3a and 3b.

Table 3.3

*: As in all other embodiments, the standard deviation in this embodiment is calculated based on the N method.

Table 3.4

*: As in all other embodiments, the standard deviation in this embodiment is calculated based on the N method.

Agomelatine utilization

The utilization rate of agomelatine at 6 hours was calculated based on the cumulative permeate and the initial agomelatine content. The results are shown in Table 3.5 and Figure 3c.

Table 3.5

In vitro experiments showed good mucosal penetration rate and good utilization rate.

Examples 4A-4F

Coating composition

The formulations of the agomelatine-containing coating compositions of Examples 4a to 4f are summarized in Tables 4.1 and 4.2 below. The formulations are based on weight percentages, as also indicated in Tables 4.1 and 4.2.

Table 4.1

Table 4.2

Preparation of the first coating composition (containing an agomelatine layer)

For Example 4a, a beaker was loaded with agomelatine. Ethanol, menthol, eucalyptol, methyl salicylate, Kolliphor RH 49, FD&C Red #40, sucralose, and polysorbate 80 were added, and the mixture was stirred. Polyvinylpyrrolidone and Novamint peppermint were added while stirring to obtain a viscous mixture.

For Example 4b, a beaker was filled with ethanol. Eucalyptol, menthol, methyl salicylate, Kolliphor RH 49, FD&C Red #40, sucralose, and polysorbate 80 were added, and the mixture was stirred. Hydroxypropyl cellulose, Novamint peppermint, and agomelatine were added while stirring to obtain a viscous mixture.

For Example 4c, a beaker was filled with ethanol. Eucalyptol, menthol, methyl salicylate, Novamint Fresh Peppermint, Kolliphor RH 49, FD&C Red #40, sucralose, and polysorbate 80 were added, and the mixture was stirred. Soluplus, Miglyol 812, and agomelatine were added while stirring to obtain a mixture with low viscosity.

For Examples 4d, 4e, and 4f, beakers were loaded with agomelatine. Ethanol, eucalyptol, menthol, methyl salicylate, Novamint Fresh Peppermint, Kolliphor RH49, FD&C Red #40, sucralose, and polysorbate 80 were added, and the mixture was stirred. Polyvinylpyrrolidone was added while stirring to obtain a viscous mixture.

Preparation of the second coating composition (backing layer)

For Examples 4e and 4f, beakers were filled with ethanol. Purified water and FD&C Blue 1 were added, and the mixture was stirred. Kollidon, Eudragit, and glycerol were added while stirring to obtain the final mixture.

The second coating compositions obtained in Examples 4e and 4f were applied to a polyester film (polyethylene terephthalate film, one side siliconized, 75 μm thick, which can serve as a release liner) and dried at room temperature for about 5 minutes, at 35°C for about 10 minutes, and at 80°C for about 2 minutes. The coating thickness yielded an area weight of 47.4 g/ ^m² .

Preparation of adhesive compositions

For Example 4e, a beaker was filled with ethanol. Purified water and menthol were added, and the mixture was stirred. Hydroxyethyl cellulose, castor oil, and polysorbate 80 were added while stirring to obtain an opaque mixture.

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

The adhesive compositions obtained in Examples 4e and 4f were applied onto the aforementioned backing layer and dried at room temperature for about 5 minutes, at 50°C for about 10 minutes, and at 90°C for about 2 minutes. The coating thicknesses were given as area weights of 25.2 g/ ^m² (Example 4e) and 23.5 g/ ^m² (Example 4f), respectively. Die-cut pieces with dimensions of 1.1 ^cm² were stamped from the adhesive backing layer.

Application of the first coating composition

The agomelatine-containing coating compositions obtained in Examples 4a to 4f were applied to polyester films (polyethylene terephthalate films, one side siliconized, 75 μm thick, which can serve as release liner) and dried, respectively, at room temperature for about 5 minutes, at 50°C for about 10 minutes, and at 90°C for about 2 minutes (Examples 4a to 4c), and at room temperature for about 5 minutes, at 50°C for about 15 minutes, and at 90°C for about 2 minutes (Examples 4d to 4f). The coating thicknesses were given as area-weight values of 49.5 g/ ^m² (Example 4a), 48.6 g/ ^m² (Example 4b), 58.5 g/ ^m² (Example 4c), and 115.4 g/ ^m² (Examples 4d, 4e, and 4f).

For Examples 4a to 4d, the dried film is the final agomelatine-containing mucosal adhesive layer structure. For Examples 4e and 4f, die-cut pieces with a size of 0.28 cm² are punched from the dried film and laminated together with the above-described adhesive backing layer in such a manner that the backing layer extends uniformly to all sides of the agomelatine-containing layer to provide an agomelatine-containing mucosal adhesive layer structure.

Preparation of transmucosal therapy system

See Example 1.

Measuring mucosal permeation rate

Using porcine mucosa (esophageal mucosa), the permeation volume and corresponding mucosal permeation rate of the transmucosal therapy systems prepared according to Examples 4a to 4e were determined by in vitro experiments according to OECD guidelines (officially adopted on April 13, 2004). For all transmucosal therapy systems, the mucosa was prepared to a thickness of 400 μm with complete barrier function using a skin knife. Die-cut materials with an area of 0.522 ^cm² of the transmucosal therapy systems from Examples 4a to 4d and the above-described agomelatine-containing mucosal adhesion layer structures of Examples 4e and 4f were applied to the mucosa, and the mucosa with the transmucosal therapy system was immersed in artificial saliva on the upper part (the lower part was in contact with the receiving medium, and the upper part was divided to a mucosal area of 1.145 ^cm² ). The permeation volume of agomelatine in the receiving medium (phosphate buffer solution at pH 7.4) was measured at a temperature of 37 ± 1 °C, and the corresponding mucosal permeation rate was calculated. The results are shown in Table 4.3 and Figure 4a.

Table 4.3

*: As in all other embodiments, the standard deviation in this embodiment is calculated based on the n method.

Agomelatine utilization

The utilization rate of agomelatine at 6 hours was calculated based on the cumulative permeate and initial agomelatine content. The results are shown in Table 4.4 and Figure 4b.

Table 4.4

In vitro experiments showed good mucosal penetration rate and satisfactory utilization. In particular, the mucosal penetration was surprisingly high compared to the same formulation equipped with a backing layer (Example 4d compared to Examples 4e and 4f). This also shows that hydroxypropyl cellulose has similar properties to polyvinylpyrrolidone (see Examples 4a and 4b), which is even better than systems equipped with a backing layer with more than twice the amount of active ingredient (Examples 4a and 4b compared to 4e and 4f).

Examples 5A-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. The formulations are based on weight percentages, as also indicated in Tables 4.1 and 5.1.

Table 5.1

Preparation of the first coating composition (containing an agomelatine layer)

For Examples 5a and 5b, beakers were loaded with agomelatine. Vanilla flavoring, ethanol, sucralose, sodium saccharin, oleic acid, FD&C Yellow #5, and hydroxypropyl cellulose were added, and the mixture was stirred to obtain a clear mixture.

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

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 40 and hydroxypropyl cellulose were added with stirring to obtain an opaque mixture.

For Example 5d, a beaker was filled with ethanol. Purified water and FD&C Blue 1 were added, and the mixture was stirred. Kollidon, Eudragit, and glycerol were added while stirring to obtain a final mixture.

The second coating compositions obtained in Examples 5b, 5c, and 5d were applied to a polyester film (polyethylene terephthalate film, one side siliconized, 75 μm thick, which can serve as a release liner) and dried at approximately 40°C for about 15 minutes, approximately 70°C for about 15 minutes (Example 5b), approximately 10 minutes at room temperature, approximately 40°C for about 15 minutes, approximately 70°C for about 10 minutes (Example 5c), approximately 5 minutes at room temperature, approximately 10 minutes at 35°C, and approximately 2 minutes at 80°C (Example 5d). The coating thicknesses were given as area-weights of 105.1 g/ ^m² (Example 5b), 99.6 g/ ^m² (Example 5c), and 78.3 g/ ^m² (Example 5d), respectively. For Example 5c, a die-cut with a dimension of 0.8 ^cm² was punched from the dried backing layer.

Preparation of adhesive compositions

For Example 5d, a beaker was filled with ethanol. Purified water and methanol were added, and the mixture was stirred. Hydroxyethyl cellulose, castor oil, and polysorbate 80 were added while stirring to obtain a homogeneous mixture.

The adhesive composition obtained in Example 5d was applied onto the above backing layer and dried at room temperature for about 5 minutes, at 50°C for about 10 minutes, and at 90°C for about 2 minutes. The coating thickness was given as an area weight of 95.6 g/ ^m² (Example 5d).

Die-cut material with a size of 0.8 cm² is stamped from an adhesive backing layer.

Application of the first coating composition

The agomelatine-containing coating compositions obtained in Examples 5a, 5c, and 5d were applied to polyester films (polyethylene terephthalate films, one side siliconized, 75 μm thick, which can serve as release liner) and dried, respectively, at room temperature for about 10 minutes, at 40°C for about 15 minutes, and at 70°C for about 10 minutes (Example 5a), at 70°C for about 5 minutes (Example 5c), at room temperature for about 5 minutes, at 50°C for about 15 minutes, and at 90°C for about 2 minutes (Example 5d). For Example 5a, the dried film was the final agomelatine-containing adhesive film structure. For Examples 5c and 5d, die-cut pieces having a size of 0.28 ^cm² are punched from a dry film and laminated together with the die-cut pieces of the above-described backing layer or adhesive backing layer in such a manner that the backing layer extends uniformly to all sides of the agomelatine-containing layer to provide an adhesive membrane structure containing agomelatine.

The first coating composition containing agomelatine obtained in Example 5b was applied onto a dry backing layer and dried at room temperature for about 10 minutes, at 40°C for about 15 minutes, and at 70°C for about 10 minutes.

The coating thicknesses are given as area weights of 95.7 g/ ^m² (Example 5a), 95.9 g/ ^m² (Example 5b), 82.9 g/ ^m² (Example 5c) and 115.4 g/ ^m² (5d), respectively.

Preparation of transmucosal therapy system

See Example 1.

Measuring mucosal permeation rate

Using porcine mucosa (esophageal mucosa), the permeation volume and corresponding mucosal permeation rate of the transmucosal therapy systems prepared according to Examples 4b and 5a to 5d were determined by in vitro experiments according to OECD guidelines (officially adopted on April 13, 2004). For all transmucosal therapy systems, the mucosa was prepared to a thickness of 400 μm with complete barrier function using a skin knife. Die-cut materials with areas of 0.28 ^cm² (Example 4b) and 0.8 ^cm² (Examples 5a and 5b) stamped from the transmucosal therapy system and the above-described ago agomelatine-containing mucosal adhesion layer structures of Examples 5c and 5d were applied to the mucosa, and the mucosa with the transmucosal therapy system was immersed in artificial saliva on the upper part (the lower part was in contact with the receiving medium, and the upper part was divided into mucosal areas of 1.145 ^cm² ). Agomelatine permeation in the receiving medium (phosphate buffer solution at pH 7.4) was measured at 37 ± 1 °C, and the corresponding mucosal permeation rate was calculated. The results are shown in Table 5.2 and Figure 5a.

Table 5.2

*: As in all other embodiments, the standard deviation in this embodiment is calculated based on the n method.

Agomelatine utilization

The utilization rate of agomelatine at 6 hours was calculated based on the cumulative permeate at 8 hours and the initial agomelatine content. The results are shown in Table 5.3 and Figure 5b.

Table 5.3

In vitro experiments showed good mucosal penetration rate and satisfactory utilization. Although all formulations showed good penetration properties, a comparison of Example 4b (release area 0.28 cm², mucosal area 1.145 ^cm² ) with Examples 5a and 5b (release area 0.8 ^cm² , mucosal area 1.145 cm²) demonstrated the important role of the total mucosal area available for penetration in the case of an open system.

Examples 6A-6D

Coating composition

The formulations of the agomelatine-containing coating compositions of Examples 6a to 6d are summarized in Table 6.1 below. The formulations are based on weight percentages, as also indicated in Table 6.1.

Table 6.1

Preparation of coating composition

For Examples 6a to 6c, beakers were loaded with agomelatine. Vanilla flavoring, ethanol, sucralose, sodium saccharin, and oleic acid (Examples 6b and 6c) were added, and the mixture was stirred. Hydroxypropyl cellulose was added while stirring to obtain a clear solution.

For Example 6d, a beaker was loaded with agomelatine. Vanilla flavoring, ethanol, sucralose, sodium saccharin, and oleic acid were added, and the mixture was stirred. Titanium dioxide and hydroxypropyl cellulose were added while stirring to obtain a white mixture.

Coating composition application

The agomelatine-containing coating compositions obtained in Examples 6a to 6d were applied onto a polyester film (silicified on one side, 75 μm thick, which could serve as a release liner) and dried at room temperature for about 10 minutes, at 40°C for about 15 minutes, and at 70°C for about 10 minutes. The coating thicknesses were given as area-weights of 93.8 g/ ^m² (Example 6a), 93.6 g/ ^m² (Example 6b), 94.3 g/ ^m² (Example 6c), and 98.3 g/ ^m² (Example 6d), respectively. The dried film was not further laminated with an additional backing layer and thus constituted the final agomelatine-containing adhesive film structure.

Preparation of transmucosal therapy system

See Example 1.

Measuring mucosal permeation rate

Using porcine mucosa (esophageal mucosa), the permeation volume and corresponding mucosal permeation rate of the transmucosal therapy systems prepared according to Examples 6a to 6d were determined by in vitro experiments according to OECD guidelines (officially adopted on April 13, 2004). For all transmucosal therapy systems, the mucosa was prepared to a thickness of 400 μm with complete barrier function using a dermabrasion tool. A die-cut with an area of 0.524 ^cm² was punched from the transmucosal therapy system, applied to the mucosa, and the mucosa with the transmucosal therapy system was immersed in artificial saliva on the upper part (the lower part was in contact with the receiving medium, and the upper part was divided to a mucosal area of 1.145 ^cm² ). The amount of agomelatine permeation in the receiving medium (phosphate buffer solution at pH 7.4) was measured at a temperature of 37 ± 1 °C, and the corresponding mucosal permeation rate was calculated. The results are shown in Table 6.2 and Figure 6a.

Table 6.2

*: As in all other embodiments, the standard deviation in this embodiment is calculated based on the n method.

Agomelatine utilization

The utilization rate of agomelatine at 6 hours was calculated based on the cumulative permeate and initial agomelatine content. The results are shown in Table 6.3 and Figure 6b.

Table 6.3

In vitro experiments showed good mucosal penetration rates and satisfactory utilization. These examples demonstrate that satisfactory permeation characteristics are achieved even at lower agomelatine concentrations, and that the performance of hydroxypropyl cellulose is similar to that of polyvinylpyrrolidone. It is also shown that a certain amount of fatty acid appears to increase the permeation rate (see comparison of Example 6b with Examples 6a and 6c).

Examples 7A-7G

Coating composition

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

Table 7.1

Table 7.2

Preparation of the first coating composition (containing an agomelatine layer)

The first coating composition of Example 7g was prepared in a manner similar to that of the first coating composition of Example 4b.

For Examples 7a to 7c, beakers were loaded with agomelatine. Ethanol was added, and the mixture was stirred. Povidone K90 and Povidone K30 (Example 7a), hydroxypropyl cellulose (Example 7b), and Povidone K90 (Example 7c) were added under stirring to obtain a viscous mixture.

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

For Example 7e, a beaker was filled with polyvinyl alcohol. Purified water was added, and the mixture was stirred and heated to 95°C. Vanilla flavoring, sucralose, sodium saccharin, oleic acid, and agomelatine were added while stirring to obtain a viscous mixture.

For Example 7f, a beaker was loaded with agomelatine. Ethanol, vanilla flavoring, sucralose, sodium saccharin, oleic acid, and FD&C Yellow 5 were added, and the mixture was stirred. Hydroxypropyl cellulose was added while stirring to obtain a viscous mixture.

Application of the first coating composition

The agomelatine-containing coating compositions obtained in Examples 7a to 7f were applied to polyester films (silicified on one side, 75 μm thick, which could serve as release liner) and dried at room temperature for about 10 minutes, at 40°C for about 15 minutes, and at 70°C for about 10 minutes (Examples 7a to 7c and 7f), at 70°C for about 5 minutes (Example 7d), and at 70°C for about 15 minutes (Example 7e). The coating thicknesses were given as area weights of 104.4 g/ ^m² (Example 7a), 103.2 g/ ^m² (Example 7b), 100.7 g/ ^m² (Example 7c), 82.9 g/ ^m² (Example 7d), 98.4 g/ ^m² (Example 7e), and 95.7 g/ ^m² (Example 7f).

The agomelatine-containing coating composition obtained in Example 7g was applied onto a polyester film (silicified on one side, 75 μm thick, which can serve as a release liner) and dried at room temperature for about 5 minutes, at 50°C for about 15 minutes, and at 90°C for about 2 minutes. The coating thickness yielded an area weight of 115.4 g/ ^m² .

Die-cut material with a size of 0.28 ^cm² is stamped from a dried agomelatine-containing layer.

Preparation of the second coating composition (backing layer)

For Examples 7a to 7d and 7g (same backing), and for Examples 7e and 7f (same backing), beakers were filled with vanilla flavoring. 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 the mixture was stirred. Kollidon and Eudragit were added while stirring to obtain a clear solution.

The resulting second coating composition was applied to a polyester film (polyethylene terephthalate film, one side siliconized, 75 μm thick, which can serve as a release liner) and dried at room temperature for about 10 minutes, at 40°C for about 15 minutes, and at 70°C for about 5 minutes. The coating thicknesses were given as area weights of 92.2 g/ ^m² (7a to 7d and 7g) and 81.2 g/ ^m² (Examples 7e and 7f), respectively.

Die-cut pieces with a size of 0.8 ^cm² are stamped from the dry backing layer.

Preparation of transmucosal therapy system

For Examples 7a to 7d and 7g, a small amount of 23.5% PVP90 ethanol solution was used to attach the die-cut material containing the agomelatine layer to the die-cut material containing the corresponding backing layer, so that the backing layer extends uniformly to all sides of the agomelatine-containing layer, and then lamination was performed to provide an adhesive layer structure containing agomelatine. For Examples 7e and 7f, a dried film was laminated together with the corresponding backing layer, further extending the backing layer uniformly to all sides of the agomelatine-containing layer, to provide an adhesive layer structure containing agomelatine.

Other steps (such as stamping out individual devices) are performed as in Example 1.

Measuring mucosal permeation rate

Using porcine mucosa (esophageal mucosa), the permeation volume and corresponding mucosal permeation rate of the transmucosal therapy systems prepared according to Examples 4b, 6b to 6d, and 7a to 7g were determined by in vitro experiments according to OECD guidelines (officially adopted on April 13, 2004). For all transmucosal therapy systems, the mucosa was prepared to a thickness of 400 μm with complete barrier function using a dermabrasion. The above-described agomelatine-containing mucosal adhesion layer structure was applied to the mucosa, and the mucosa with the transmucosal therapy system was immersed in artificial saliva on the upper part (the lower part was in contact with the receiving medium, and the upper part was divided into mucosal areas of 1.145 cm²). The permeation volume of agomelatine in the receiving medium (phosphate buffer solution at pH 7.4) was measured at 37 ± 1 °C, and the corresponding mucosal permeation rate was calculated. The results are shown in Tables 7.3 and 7.4 and Figures 7a and 7b.

Table 7.3

*: As in all other embodiments, the standard deviation in this embodiment is calculated based on the n method.

Table 7.4

*: As in all other embodiments, the standard deviation in this embodiment is calculated based on the n method.

Agomelatine utilization

The utilization rate of agomelatine at 4 hours was calculated based on the cumulative permeate and the initial agomelatine content. The results are shown in Table 7.5 and Figure 7c.

Table 7.5

In vitro experiments showed good mucosal penetration rates and satisfactory utilization. These examples demonstrate satisfactory permeation characteristics even at lower agomelatine concentrations, and that the properties of hydroxypropyl cellulose and polyvinyl alcohol are similar to those of polyvinylpyrrolidone (see Examples 7b, 7c, and 7d).

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. The formulations are based on weight percentages, as also indicated in Tables 4.1 and 8.1.

Table 8.1

Preparation of the first coating composition (containing an agomelatine layer)

For Examples 8a to 8c, beakers were loaded with agomelatine. Ethanol, eucalyptol, menthol, methyl salicylate, Novamint peppermint, Kolliphor RH40, sucralose, FD&C Red #40, and polysorbate 80 were added, and the mixture was stirred. Povidone was added while stirring to obtain a viscous mixture.

Application of the first coating composition

The agomelatine-containing coating compositions obtained in Examples 8a to 8c were applied to a polyester film (polyethylene terephthalate film, one side siliconized, 75 μm thick, which can serve as a release liner) and dried at room temperature for about 10 minutes, at 50°C for about 15 minutes, and at 90°C for about 2 minutes. The coating thickness yielded an area weight of 109.7 g/ ^m² .

For Example 8a, the dried film is the final adhesive layer structure containing agomelatine. For Examples 8b and 8c, die-cut pieces with a size of 1.6 ^cm² are punched from the dried agomelatine-containing layer.

Preparation of the second coating composition (backing layer)

For Example 8b, a beaker was filled with ethanol. FD&C Green 3 was added, and the mixture was stirred. Ethyl cellulose N50F, castor oil, and glycerin were added while stirring to obtain a final mixture.

The second coating composition of Example 8c was prepared in a manner similar to that of Example 5d above.

The resulting second coating composition was applied to a polyester film (polyethylene terephthalate film, one side siliconized, 75 μm thick, which can serve as a release liner) and dried at room temperature for about 10 minutes, at 70°C for about 20 minutes (Example 8b), at room temperature for about 5 minutes, at 35°C for about 10 minutes, and at 80°C for about 2 minutes (Example 8c). The coating thicknesses were given as area weights of 19.2 g/ ^m² (Example 8b) and 78.3 g/ ^m² (Example 8c), respectively.

Preparation of adhesive compositions

Fill a beaker with ethanol. Add purified water and menthol, then stir the mixture. While stirring, add hydroxyethyl cellulose, castor oil, and polysorbate 80 to obtain a homogeneous mixture.

The obtained adhesive composition was applied onto a dry backing layer and dried at room temperature for about 5 minutes, at 50°C for about 10 minutes, and at 90°C for about 2 minutes. The coating thicknesses were given as area weights of 42.9 g/ ^m² (Example 8b) and 95.7 g/ ^m² (Example 8c), respectively. Die-cut pieces with dimensions of 5.5 ^cm² were stamped from the dried adhesive backing layer.

Preparation of transmucosal therapy system

For Examples 8b and 8c, the dried film is laminated together with the corresponding adhesive backing layer to provide an agomelatine-containing adhesive layer structure.

Other steps (such as stamping out individual devices) are performed as in Example 1.

In vivo studies using Göttingen minipig

To evaluate agomelatine delivery, in vivo experiments were conducted using Göttingen miniature pigs (female, approximately 6 to 7 months old, weighing 13.8–14.3 kg at the start of the study). Four miniature pigs were used. For Examples 8a and 8b, one animal was administered the transmucosal treatment system of Examples 8a, 8b, and 8c, prepared as described above, to the buccal mucosa of two animals (one system per animal) for Example 8c. The total wearing time of the transmucosal treatment system was 4 hours (after which the application area was cleaned to remove any potential residue of the transmucosal treatment system). No residue was observed for Example 8a, and a small amount of residue was observed for Examples 8b and 8c, which had backings.

Miniature pigs were kept under sedation during the study.

Blood samples were collected at eight time points following application of the transmucosal treatment system. Samples were collected at 0 (before processing), 0.5, 1, 1.5, 2, 4 (immediately before removal of the test item), 5, and 8 hours. Plasma samples were analyzed in accordance with the principles of OECD Good Laboratory Practices (as revised in 1997). These principles are consistent with other international GLP regulations.

Agomelatine concentrations in miniature pig plasma were determined sequentially using validated liquid-liquid extraction and LC-MS/MS. All samples collected prior to the start of treatment were measured below the limit of quantitation (0.100 ng/mL).

The measured agomelatine plasma concentrations are summarized in Table 8.2 and illustrated in Figure 8a.

In addition, the mucosal condition was macroscopically assessed immediately after OTF removal 4 hours after application and cleaning of the OTF application site, and a Draize score was obtained based on the following scoring procedure, which is in accordance with OECD Guideline No. 404 on Chemical Testing, formally adopted on July 28, 2015: "Acute Dermal Irritation/Corrosion".

None of the formulations showed any irritation after removal of the transmucosal therapy system at 4 hours (see Table 8.2).

Table 8.2

*: According to the Dresden method, the scoring procedure for assessing potential mucosal irritation at 4 hours is as follows: 0 = no erythema, no edema, 1 = very mild erythema (faintly discernible), very mild edema (faintly discernible), 2 = well-defined erythema, mild edema, 3 = moderate to severe erythema, moderate edema, 4 = severe erythema, severe edema.

Maximum plasma concentrations were measured 2–4 hours after the start of treatment and were in the range of 9.0 to 11.8 ng/mL for the backed OTF according to Examples 8b and 8c, and 57.2 ng/mL for the unbacked OTF according to Example 8a. The extremely high PK data achievable with the unbacked transmucosal treatment system according to Example 8a can be explained by the fact that the open system allows API delivery through the entire oral mucosa. The high delivery rate remains highly advantageous because the patch size and/or active ingredient concentration can be reduced compared to systems containing a backing layer. After 4 hours, the backed transmucosal treatment system showed low, but still high, permeability, although limiting the penetration area to 1.6 ^cm² . Because agomelatine can be quantified with high PK data 4 hours after removal of the transmucosal treatment system, potential residual agomelatine may remain within the mucosa.

Examples 9A-9F

Coating composition

The formulations of the agomelatine-containing coating compositions of Examples 4b and 9a to 9f are summarized in Table 4.1 above and Table 9.1 below. The formulations are based on weight percentages, as also indicated in Tables 4.1 and 9.1.

Table 9.1

Preparation of the first coating composition (containing an agomelatine layer)

For the _TiO₂ solution, load a beaker with 2.80 g of _TiO₂ . Add oleic acid and then stir the mixture to obtain the _TiO₂ solution.

For Examples 9b, 9c, and 9d, beakers were filled with vanilla flavoring. Sucralose, sodium saccharin, ethanol, hydroxypropyl cellulose GF, hydroxypropyl cellulose EF, carbomer solution, and agomelatine were added, and the mixture was stirred. _TiO2 solution was added while stirring to obtain a viscous mixture.

For Example 9a, a beaker was filled with vanilla flavoring. Sucralose, sodium saccharin, agomelatine, and ethanol were added, and the mixture was stirred. A _TiO₂ solution and hydroxypropyl cellulose were added while stirring to obtain a viscous mixture.

For Examples 9e and 9f, beakers were filled with vanilla flavoring. Sucralose, sodium saccharin, and ethanol were added, and the mixture was stirred. While stirring, a carboplatin solution, ethyl cellulose, hydroxypropyl cellulose, agomelatine, and _TiO2 solution were added to obtain a viscous mixture.

Application of the first coating composition

The resulting agomelatine-containing coating composition was applied to a polyester film (polyethylene terephthalate film, one side siliconized, 75 μm thick, which can serve as a release liner) and dried at room temperature for about 10 minutes, at 40°C for about 15 minutes, and at 70°C for about 10 minutes. The coating thicknesses were given as area-weight values of 117.0 g/ ^m² (Examples 9a to 9d), 123.5 g/ ^m² (Example 9e), and 117.5 g/ ^m² (Example 9f), respectively.

For Examples 9a and 9b, the dried film is the final adhesive layer structure containing agomelatine. For Example 9d, a die-cut with a size of 0.28 ^cm² is punched from the dried agomelatine-containing layer.

Preparation of the second coating composition (backing layer)

For Examples 9c to 9f, a beaker is filled with vanilla flavoring. Sucralose, sodium saccharin, oleic acid, FD&C Red 40, ethanol, and purified water are added, and the mixture is stirred. Hydroxypropyl cellulose and hydroxyethyl cellulose are added while stirring to obtain a viscous mixture.

The resulting backing composition was applied twice over a dried agomelatine-containing layer (for Examples 9c, 9e, and 9f) or over a polyester film (polyethylene terephthalate film, one side siliconized, 75 μm thick, which can serve as a release liner) (for Example 9d), and dried at room temperature for about 10 minutes, at 50°C for about 15 minutes, and at 80°C for about 10 minutes. The coating thicknesses were given as a total area weight (including the agomelatine layer and the backing layer) of 382 g/ ^cm² (Example 9c), 272.2 g/ ^m² (Example 9d), or 388.1 g/ ^m² (Examples 9e and 9f).

For Examples 9c, 9e, and 9f, die-cut pieces with a size of 0.28 ^cm² are stamped from the dried layer to provide an agomelatine-containing mucosal adhesive layer structure.

For Example 9d, a die-cut with a size of 0.28 ^cm² is stamped from the backing layer, and a small amount of the second coating composition is applied to the corresponding agomelatine-containing layer in such a way that the backing layer extends uniformly to all sides of the agomelatine-containing layer to provide an agomelatine-containing mucosal adhesive layer structure.

Preparation of transmucosal therapy system

See Example 1.

Measuring mucosal permeation rate

Using porcine mucosa (esophageal mucosa), the permeation volume and corresponding mucosal permeation rate of the transmucosal therapy systems prepared according to Examples 4b and 9a to 9f were determined by in vitro experiments according to OECD guidelines (officially adopted on April 13, 2004). For all transmucosal therapy systems, the mucosa was prepared to a thickness of 400 μm with complete barrier function using a skin knife. A die-cut material with an area of 0.28 ^cm² from the transmucosal therapy systems of Examples 9a and 9b, along with the above-described agomelatine-containing mucosal adhesion layer structure, was applied to the mucosa, and the mucosa with the transmucosal therapy system was immersed in artificial saliva on the upper part (the lower part was in contact with the receiving medium, and the upper part was divided to a mucosal area of 1.145 ^cm² ). The permeation volume of agomelatine in the receiving medium (phosphate buffer solution at pH 7.4) was measured at a temperature of 37 ± 1 °C, and the corresponding mucosal permeation rate was calculated. The results are shown in Tables 9.2 and 9.3 and Figure 9a.

Table 9.2

*: As in all other embodiments, the standard deviation in this embodiment is calculated based on the n method.

Table 9.3

*: As in all other embodiments, the standard deviation in this embodiment is calculated based on the n method.

Agomelatine utilization

The utilization rate of agomelatine at 4 hours was calculated based on the cumulative permeate and the initial agomelatine content. The results are shown in Table 9.4 and Figure 9c.

Table 9.4

In vitro experiments showed good mucosal penetration rates and good utilization. These examples further demonstrate that open systems without backing layers provide increased active ingredient delivery compared to those systems with backing layers.

Storage stability measurement

Long-term storage stability tests were conducted on Examples 9a and 9c under different test conditions: storage at 25°C and 60% relative humidity (RH) and at 40°C and 75% RH. Samples were taken from transmucosal therapy systems after storage at 25°C and 60% RH for 3, 6, 9, and 12 months, and after storage at 40°C and 75% RH for 3 and 6 months. Ethanol and water contents were determined, and the amounts of agomelatine and various possible degradation products were determined by a specific quantitative HPLC method based on the agomelatine content calculated from the (actual) area weight of the tested transmucosal therapy system. The results are shown in Tables 9.5 to 9.8 and Figures 9c and 9d.

Table 9.5

*n.d. = Not detected, LOQ = Limit of Quantitation (0.05%)

Table 9.6

*n.d. = Not detected, LOQ = Limit of Quantitation (0.05%)

Table 9.7

*n.d. = Not detected, LOQ = Limit of Quantitation (0.05%), N/A = No data

Table 9.8

*n.d. = Not detected, LOQ = Limit of Quantitation (0.05%), N/A = No data

Stability data show that Examples 9a and 89c exhibit excellent initial and storage stability in terms of both the amount of agomelatine (particularly the amount of agomelatine remaining after storage) and the sum of possible degradation substances.

Dissolution Experiment 10

As outlined in more detail above, soluble film-forming agents are preferably soluble, dispersible, or otherwise disintegratable in aqueous media such as water, and on the other hand, film-forming agents soluble in, for example, ethanol are also preferred.

To observe the solubility properties of potential film-forming agents, mixtures of the polymer at 10 wt% (+/- 0.1% point) in water, ethanol, or a 1:1 water/ethanol mixture were prepared, and the solubility properties were recorded. Viscosities and other observations were also recorded. The results are summarized in Table 10.1 below.

Table 10.1

Water absorption test 11

Some soluble film-forming agents exhibit hygroscopic properties. To evaluate the water absorption over time, different coating compositions were prepared, and films were obtained by coating with the compositions and allowing the coated layers to dry. The films were stored at room temperature for 7 days, either open or in seam-sealed pouches. The detailed composition, drying conditions, and results of the coated films are given in Table 11.1 below.

Table 11.1

Drying conditions A: 10 minutes at 50°C and 15 minutes at 70°C.

Drying condition B: 10 minutes at 40°C and 15 minutes at 60°C.

Drying condition B: 15 minutes at 40°C and 10 minutes at 70°C.

This invention particularly relates to the following other items:

1. A transmucosal therapeutic system for transmucosal administration of agomelatine, comprising a mucosal adhesion layer structure, wherein the mucosal adhesion layer structure comprises

A) Agomelatine-containing layer, the agomelatine-containing layer comprising

i) Agomelatine; and

ii) Soluble film-forming agents.

2. The transmucosal therapy system as described in item 1,

in

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

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

in

The soluble film-forming agent is selected from the group consisting of polymers such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, graft copolymers based on polyethylene glycol-polyvinyl acetate and polycaprolactam, 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.

4. The transmucosal therapy system as described in item 3,

in

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

5. The transmucosal therapy system as described in item 4,

in

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

6. The transmucosal therapy system as described in item 5,

The soluble film-forming agent is hydroxypropyl cellulose.

7. The transmucosal therapy system as described in item 6,

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

8. The transmucosal therapy system as described in item 7,

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

9. The transmucosal therapy system as described in item 5,

The soluble film-forming agent is polyvinylpyrrolidone.

10. The transmucosal therapy system according to item 9,

The polyvinylpyrrolidone mentioned therein is selected from soluble polyvinylpyrrolidone.

11. The transmucosal therapy system as described in item 9,

The polyvinylpyrrolidone mentioned above is selected from polyvinylpyrrolidones having a K value within a range selected from the following groups:

9 to 15, and preferably 10.2 to 13.8.

15 to 20, and preferably 15.3 to 18.4.

20 to 27, and preferably 22.5 to 27.0.

27 to 35, and preferably 27.0 to 32.4, and

75 to 110, with 81.0 to 97.2 being preferred.

12. The transmucosal therapy system according to any one of items 1 to 11,

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

13. The transmucosal therapy system according to any one of items 1 to 12,

The agomelatine-containing layer contains at least 1 wt% agomelatine, at least 2 wt% agomelatine, or at least 3 wt% agomelatine.

14. The transmucosal therapy system according to any one of items 1 to 13,

The agomelatine-containing layer contains less than or equal to 25 wt% agomelatine, less than or equal to 20 wt% agomelatine, or less than or equal to 10 wt% agomelatine.

15. The transmucosal therapy system according to any one of items 1 to 14,

The agomelatine-containing layer comprises 1 to less than or equal to 25 wt% agomelatine, 2 to less than or equal to 20 wt% agomelatine, or 3 to less than or equal to 10 wt% agomelatine.

16. The transmucosal therapy system according to any one of items 1 to 15,

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

17. The transmucosal therapy system according to item 16,

The agomelatine-containing layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, and flavoring agents.

18. The transmucosal therapy system as described in item 17,

The fatty acid described therein is a saturated or unsaturated straight-chain or branched carboxylic acid containing 4 to 24 carbon atoms, and is particularly selected from the group consisting of: caprylic acid, myristone acid, palmitoleic acid, fuscisic acid, oleic acid, trans oleic acid, isoleic acid, linoleic acid, trans linoleic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid.

19. The transmucosal therapy system as described in item 18,

The fatty acid mentioned therein is oleic acid or linoleic acid.

20. The transmucosal therapy system according to any one of entries 16 to 19,

The agomelatine layer contains one or more fatty acids in an amount of at least 1 wt%, at least 3 wt%, or at least 4 wt%, or in an amount of less than or equal to 15 wt%, less than or equal to 12 wt%, or less than or equal to 10 wt%, or in an amount of 1 to 15 wt%, 3 to 12 wt%, or 4 to 10 wt%.

21. The transmucosal therapy system as described in item 16,

The agomelatine-containing layer contains one or more natural or artificial sweeteners selected from the group consisting of: sucrose, glucose, fructose, sorbitol, mannitol, isomaltitol, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclohexylsulfamic acid, neohesperidin, neotame, steviol glycosides, sematrandole, and sodium saccharin.

22. The transmucosal therapy system as described in item 21,

The agomelatine-containing layer contains one or more natural or artificial sweeteners selected from the group consisting of sucrose, sucralose, and sodium saccharin.

23. The transmucosal therapy system as described in item 22,

The agomelatine layer contains one or more natural or artificial sweeteners selected from the group consisting of sucralose, sucrose, and sodium saccharin in an amount of at least 0.05 wt%, at least 0.1 wt%, or at least 0.3 wt%, or less than or equal to 2.0 wt%, less than or equal to 1.5 wt%, or less than or equal to 1.0 wt%, or in an amount of 0.05 to 2.0 wt%, 0.1 to 1.5 wt%, or 0.3 to 1.0 wt%.

24. The transmucosal therapy system as described in item 16,

The agomelatine-containing layer comprises one or more natural or artificial flavorings selected from the group consisting of: vanillin, methyl salicylate, menthol, chamomile, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl sebadienoate, allyl hexanoate, ethyl maltol, 2,4-dimethylthiomethane, ethyl vanillin, and eucalyptol, as well as flavoring compositions such as peppermint flavorings.

25. The transmucosal therapy system as described in item 24,

The aforementioned agomelatine layer comprises one or more flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, peppermint flavoring agent, and eucalyptol, in an amount of at least 0.1 wt%, at least 0.3 wt%, or at least 0.4 wt%, or less than or equal to 10 wt%, at least 6 wt%, or less than or equal to 4 wt%, or in an amount of 0.1 to 10 wt%, 0.3 to 6 wt%, or 0.4 to 4 wt%, or in a total amount of at least 0.1 wt%, at least 0.5 wt%, or at least 0.7 wt%, or less than or equal to 15 wt%, at least 10 wt%, or less than or equal to 8 wt%, or in an amount of 0.1 to 15 wt%, 0.5 to 10 wt%, or 0.7 to 8 wt%.

26. The transmucosal therapy system as described in item 16,

The agomelatine-containing layer comprises one or more colorants selected from the group consisting of: titanium dioxide, brilliant blue FCF, indigo carmine, fast green FCF, erythrosine, allura red AC, tartrazine and sunset yellow FCF, curcumin, riboflavin, riboflavin-5'-phosphate, quinoline yellow, orange yellow S, carmine, carmine acid, azorubine, pale red, amaranth, poinsettia 4R, carmine A, patent blue V, indigo, chlorophyll, chlorophyll and chlorophyll. Copper complexes, green S, ordinary caramel, caustic sulfite caramel, ammonia caramel, ammonium sulfite caramel, Brilliant Black BN, Black PN, vegetable carbon black, brown HT, carotene, annatto, annattoin, norothyrin, capsicum extract, capsicum red, capsicum rubigin, lycopene, β-apo-8'-carotene, lutein, canthaxanthin, betaine, betaine, anthocyanins, calcium carbonate, iron oxides and hydroxides, aluminum, silver, gold, and lithorubigin BK.

27. The transmucosal therapy system as described in item 16,

The agomelatine-containing layer contains one or more other film-forming agents, wherein the other film-forming agents are different from the soluble film-forming agent.

28. The transmucosal therapy system as described in item 27,

The agomelatine-containing layer comprises one or more other film-forming agents in an amount of at least 2 wt%, at least 5 wt%, or at least 10 wt%, or in an amount of less than or equal to 40 wt%, less than or equal to 30 wt%, or less than or equal to 25 wt%, or in an amount of 2 to 40 wt%, 5 to 30 wt%, or 10 to 25 wt%, or in an amount of at least 5 wt%, at least 15 wt%, or at least 20 wt%, or in an amount of less than or equal to 40 wt%, less than or equal to 30 wt%, or less than or equal to 25 wt%, or in an amount of 5 to 40 wt%, 15 to 30 wt%, or 20 to 25 wt%.

29. The transmucosal therapy system as described in item 16,

The agomelatine-containing layer comprises one or more solubilizers selected from the group consisting of: fatty acid-esterified ethoxylated sorbitols such as polyoxyethylene sorbitol monolaurate, polyoxyethylene sorbitol monopalmitate, polyoxyethylene sorbitol monostearate, and polyoxyethylene sorbitol monooleate, safflower oil, propylene glycol, and polyethoxylated castor oil.

30. The transmucosal therapy system as described in item 29,

The agomelatine-containing layer contains one or more solubilizers in an amount of at least 0.3 wt%, at least 0.5 wt%, or at least 1.0 wt%, or in an amount of less than or equal to 5 wt%, less than or equal to 4 wt%, or less than or equal to 3 wt%, or in an amount of 0.3 to 5 wt%, 0.5 to 4 wt%, or 1.0 to 3 wt%.

31. The transmucosal therapy system as described in item 16,

The agomelatine-containing layer comprises one or more emulsifiers selected from the group consisting of: soybean lecithin, sodium phosphate, monoglycerides and diglycerides of fatty acids, sodium stearoyl lactylate, diacetyl tartrate of monoglycerides and diglycerides, and polyethoxylated hydrogenated castor oil.

32. The transmucosal therapy system according to item 31,

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%, or in an amount of less than or equal to 25 wt%, less than or equal to 20 wt%, or less than or equal to 15 wt%, or in an amount of 1 to 25 wt%, 3 to 20 wt%, or 5 to 15 wt%.

33. The transmucosal therapy system as described in item 16,

The agomelatine-containing layer contains one or more plasticizers selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides and derivatives such as sorbitol, polyethylene glycol, triacetin, triethyl citrate, propylene glycol, glycerol, and medium-chain triglycerides.

34. The transmucosal therapy system as described in item 33,

The agomelatine layer contains one or more plasticizers in an amount of at least 0.5 wt%, at least 1 wt%, or at least 5 wt%, or in an amount of less than or equal to 25 wt%, less than or equal to 20 wt%, or less than or equal to 15 wt%, or in an amount of 0.5 to 25 wt%, 1 to 20 wt%, or 5 to 15 wt%.

35. The transmucosal therapy system according to any one of items 1 to 34,

The agomelatine-containing layer does not contain, in amounts greater than 0.1 wt%, greater than 0.2 wt%, greater than 1 wt%, or greater than 5 wt%, a permeation enhancer selected from the group consisting of: bile acids, bile salts, bile acid derivatives, acylcarnitine, sodium lauryl sulfate, dimethyl sulfoxide, sodium lauryl sulfate, terpenes, cyclodextrins, cyclodextrin derivatives, saponins, saponin derivatives, chitosan, EDTA, citric acid, and salicylates.

36. The transmucosal therapy system according to any one of items 1 to 35,

The agomelatine-containing layer comprises a penetration enhancer selected from the group consisting of: diethylene glycol monoethyl ether, dipropylene glycol, levulinic acid, 2,5-dimethyl isosorbide ether, lauryl lactate, dimethyl ethyl urea, N,N-diethyl-m-toluamide, propylene glycol monooctanoate, 2-methoxy-4-(prop-2-en-1-yl)phenol, lactic acid, and lauryl ketone.

37. The transmucosal therapy system according to any of entries 16 to 36,

The agomelatine-containing layer contains a penetration enhancer in an amount of at least 1 wt%, at least 2 wt%, or at least 5 wt%, or in an amount of less than or equal to 20 wt%, less than or equal to 15 wt%, or less than or equal to 10 wt%, or in an amount of 1 to 20 wt%, 2 to 15 wt%, or 5 to 10 wt%.

38. The transmucosal therapy system according to any one of items 1 to 37,

The agomelatine-containing layer therein is substantially free of water.

39. The transmucosal therapy system as described in item 38,

The agomelatine-containing layer contains less than or equal to 12 wt%, less than or equal to 8 wt%, less than or equal to 5 wt%, or less than or equal to 4 wt% water.

40. The transmucosal therapy system according to any one of entries 1 to 39,

The agomelatine-containing layer therein does not contain volatile solvents.

The volatile solvent is selected from the group consisting of C1 to C3 straight-chain and branched alcohols, ethyl acetate, hexane, n-heptane, and any mixture thereof.

41. The transmucosal therapy system according to item 40,

The agomelatine-containing layer contains less than or equal to 5 wt%, less than or equal to 3 wt%, or less than or equal to 1 wt% of volatile solvent.

42. The transmucosal therapy system according to any one of items 1 to 41,

The agomelatine-containing layer is obtained by drying the coated composition comprising the agomelatine, the soluble film-forming agent, and ethanol.

43. The transmucosal therapy system according to any one of items 1 to 42,

The agomelatine-containing layer is obtained by drying the coated composition containing the agomelatine, the soluble film-forming agent, and water.

44. The transmucosal therapy system as described in item 42 or 43,

The agomelatine-containing layer is obtained by drying a coated composition comprising the agomelatine, the soluble film-forming agent, ethanol, and water.

45. The transmucosal therapy system according to any one of entries 42 to 44,

The agomelatine-containing layer is obtained by drying a coated composition containing less than 50 wt%, or less than 20 wt%, or less than 10 wt%, or less than 5 wt% water.

46. The transmucosal therapy system according to any one of items 1 to 45,

The agomelatine-containing layer has an area weight of at least 25 g/ ^m² , at least 35 g/ ^m² , or at least 40 g/ ^m² , or an area weight of less than or equal to 300 g/ ^m² , less than or equal to 250 g/ ^m² , or less than or equal to 200 g/ ^m² , or an area weight of 25 to 300 g/ ^m² , 35 to 250 g/ ^m² , or 40 to 200 g/ ^m² .

47. The transmucosal therapy system according to any one of entries 1 to 46,

The agomelatine-containing layer contains at least 0.1 mg/ ^cm² , at least 0.2 mg/ ^cm² , or at least 0.4 mg/ ^cm² of agomelatine; or the agomelatine-containing layer contains less than or equal to 2.0 mg/ ^cm² , less than or equal to 1.5 mg/ ^cm² , or less than or equal to 1.2 mg/ ^cm² of agomelatine; or the agomelatine-containing layer contains 0.1 to 2.0 mg/ ^cm² , 0.2 to 1.5 mg/ ^cm² , or 0.4 to 1.2 mg/ ^cm² of agomelatine.

48. The transmucosal therapy system according to any one of entries 1 to 47,

The agomelatine is included in the agomelatine-containing layer in a dissolved form, a dispersed form, a crystalline form, especially in one of its polymorphic forms, an amorphous form, as a hydrate, a solvate, a mixture of any of the foregoing forms, or a mixture thereof.

49. The transmucosal therapy system according to any one of entries 1 to 48,

The agomelatine-containing layer can be obtained by incorporating agomelatine in a dissolved form, a dispersed form, a crystalline form, especially in one of its polymorphic forms, an amorphous form, as a hydrate, a solvate, a mixture of any of the foregoing forms, or a mixture thereof.

50. The transmucosal therapy system according to any one of entries 1 to 49,

The agomelatine in the aforementioned agomelatine-containing layer is either dissolved or present in a dispersed form.

51. The transmucosal therapy system according to item 50,

The agomelatine in the aforementioned agomelatine-containing layer exists in a dispersed form.

52. The transmucosal therapy system as described in item 50,

The agomelatine in the agomelatine-containing layer is dissolved.

53. The transmucosal therapy system according to any one of items 1 to 52,

The agomelatine-containing layer contains at least 90 mol%, preferably at least 95 mol%, more preferably at least 98 mol%, and most preferably at least 99 mol% of the agomelatine in a dissolved form.

54. The transmucosal therapy system according to any one of items 1 to 53,

The agomelatine-containing layer does not contain agomelatine crystals.

55. The transmucosal therapy system according to any one of entries 1 to 54,

The agomelatine, as determined by quantitative HPLC, has a purity of at least 95%, preferably at least 98%, and more preferably at least 99%.

56. The transmucosal therapeutic system according to any one of items 1 to 55, wherein the mucosal adhesion layer structure further comprises one or more other layers selected from:

B) Mucosal contact layer, and

C) Decorative layer,

in

The other layers are adjacent to the agomelatine-containing layer, and

If both are present, then the mucosal contact layer and the decorative layer are adjacent to the agomelatine-containing layer on opposite sides.

57. The transmucosal therapy system as described in item 56,

The mucosal adhesion layer structure described herein does not include a mucosal contact layer.

58. The transmucosal therapy system as described in item 56,

The mucosal adhesion layer structure further includes a mucosal contact layer, and the mucosal contact layer has mucosal adhesive properties.

59. The transmucosal therapy system as described in Items 56 or 58,

The mucosal adhesion layer structure further includes a mucosal contact layer.

The dimensions of the agomelatine-containing layer and the dimensions of the mucosal contact layer are mutually extended.

60. The transmucosal therapy system according to any of entries 56 to 59,

The adhesive layer structure described herein does not include a decorative layer.

61. The transmucosal therapy system according to any of entries 56 to 59,

The adhesive layer structure further includes a decorative layer.

The decorative layer prevents the patient from touching the agomelatine-containing layer during the application of the transmucosal treatment system.

62. The transmucosal therapy system as described in any of entries 56 to 59 and 61,

The adhesive layer structure further includes a decorative layer.

The dimensions of the agomelatine-containing layer and the decorative layer are mutually extended, or the decorative layer is larger in size than the agomelatine-containing layer, thereby extending the surface area of the agomelatine-containing layer.

63. The transmucosal therapy system as described in any of entries 56 to 59, 61, and 62,

The decorative layer dissolves in water, artificial or natural saliva, or any other aqueous medium in less than 3 minutes, less than 1 minute, or less than 30 seconds at 37°C and 150 rpm.

64. The transmucosal therapy system according to any one of items 1 to 55,

The mucosal adhesion layer structure is composed of the agomelatine-containing layer.

65. The transmucosal therapy system according to any one of entries 1 to 64,

The agomelatine-containing layer has mucosal adhesion.

66. The transmucosal therapy system according to any one of items 1 to 65,

The mucosal adhesion layer structure contains agomelatine in a therapeutically effective amount.

67. The transmucosal therapy system according to any one of items 1 to 66,

The mucosal adhesion layer structure 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 less than or equal to 20 mg, less than or equal to 15 mg, or less than or equal to 10 mg of agomelatine, or the agomelatine-containing layer contains 0.1 mg to 20 mg, 0.2 mg to 15 mg, or 0.4 mg to 10 mg of agomelatine.

68. The transmucosal therapy system according to any one of items 1 to 67,

in

At 37°C and 150 rpm, the mucosal adhesion layer structure dissolves in water, artificial or natural saliva, or any other aqueous medium within 30 seconds and less than 5 hours, or within 1 minute and less than 4 hours, or within 2 minutes and less than 3 hours, or within 4 minutes and less than 2 hours.

69. The transmucosal therapy system according to any one of entries 1 to 68,

The transmucosal therapy system has a release area of at least 0.1 ^cm² , at least 0.2 ^cm² , or at least 0.5 ^cm² , or a release area of less than or equal to 10 ^cm² , less than or equal to 7 ^cm² , or less than or equal to 5 ^cm² , or a release area of 0.1 to 10 ^cm² , 0.2 to 7 ^cm² , or 0.5 to 5 ^cm² .

70. The transmucosal therapy system according to any one of entries 1 to 69,

The transmucosal treatment system described herein does not include a backing layer.

When the transmucosal treatment system is applied to a human patient, the backing layer does not dissolve within 15 minutes, 10 minutes, or 5 minutes.

71. The transmucosal therapy system according to any one of items 1 to 70,

The transmucosal treatment system described herein does not include a backing layer.

The backing layer is not completely dissolved in water, artificial or natural saliva, or any other aqueous medium within less than 30 minutes, less than 15 minutes, or less than 10 minutes at 37°C and 150 rpm.

72. The transmucosal therapy system according to any one of items 1 to 71,

The transmucosal treatment system described herein does not include a backing layer.

73. The transmucosal therapy system according to any one of items 1 to 72,

The transmucosal treatment system also includes a peeling pad.

74. The transmucosal therapy system according to any one of items 1 to 65,

The transmucosal treatment system described herein does not include a peeling liner.

75. The transmucosal therapy system according to any one of entries 1 to 74,

The transmucosal treatment system described herein is in the form of a thin film.

76. The transmucosal therapy system as described in item 75,

The transmucosal treatment system is in the form of a film having an area weight of at least 25 g/ ^m² , at least 35 g/ ^m² , or at least 40 g/ ^m² , or less than or equal to 300 g/ ^m² , less ^than or equal to 250 g/m², or less than or equal to 200 g/ ^m² , or an area weight of 25 to 300 g/ ^m² , 35 to 250 g/ ^m² , or 40 to 200 g/ ^m² .

77. The transmucosal therapy system according to any one of items 1 to 76,

The transmucosal treatment system is in the form of a thin film with a circular, rectangular, or square shape.

78. The transmucosal therapy system according to any one of items 1 to 77,

The application of the transmucosal treatment system comprises: applying the mucosal adhesion layer structure to the mucosa of a human patient's oral cavity, and maintaining the mucosal adhesion layer structure on the mucosa until it dissolves.

79. The transmucosal therapy system as described in item 78,

The application of the transmucosal treatment system consists of: applying the mucosal adhesion layer structure to the buccal, sublingual, gingival, or palatal mucosa of a human patient, and maintaining the mucosal adhesion layer structure on the mucosa until it dissolves.

80. The transmucosal therapy system according to any one of entries 1 to 79,

As measured using porcine esophageal mucosa, the transmucosal treatment system provides an agomelatine mucosal penetration rate of 10 μg/cm²-hr to 150 μg/cm²-hr after 1 hour.

81. The transmucosal therapy system according to any one of items 1 to 80,

As measured using porcine esophageal mucosa, over an 8-hour period, the transmucosal treatment system provides a cumulative release of agomelatine of at least 0.02 mg/ ^cm² , at least 0.05 mg/ ^cm² , or at least 0.1 mg/ ^cm² , or less than ^or equal to 0.5 mg/ ^cm² , less than or equal to 0.4 mg/ ^cm² , or less than or equal to 0.3 ^mg / ^cm² , or 0.02 mg/cm² to 0.5 mg/cm², 0.05 mg/ ^cm² to 0.4 mg/ ^cm² , or 0.1 mg/ ^cm² to 0.3 mg/ ^cm² .

82. The transmucosal therapy system according to any one of items 1 to 81,

The method of using the transmucosal treatment system to treat human patients.

83. The transmucosal therapy system as described in item 82,

The method of using the transmucosal therapy system for treating major depressive disorder.

84. The transmucosal therapy system as described in item 82 or 83,

The transmucosal therapy system is used in the treatment method.

The transmucosal treatment system is applied by applying the mucosal adhesion layer structure to the mucosa of a human patient's oral cavity and maintaining it on the mucosa until it dissolves.

85. The transmucosal therapy system as described in item 84,

The transmucosal therapy system is used in the treatment method.

The transmucosal treatment system is applied by applying the mucosal adhesion layer structure to the buccal, sublingual, gingival, or palatal mucosa of a human patient and maintaining it on the mucosa until it dissolves.

86. The transmucosal therapy system according to any one of entries 82 to 85,

The transmucosal therapy system is used in the treatment method.

The transmucosal treatment system is applied at night or before bedtime.

87. A treatment method,

The application of the transmucosal treatment system as described in any of entries 1 to 81 to a human patient.

88. The method of treating major depressive disorder as described in entry 88,

The application of the transmucosal treatment system as described in any of entries 1 to 81 to a human patient.

89. The treatment method described in item 88 or 89,

The transmucosal treatment system according to any of entries 1 to 81 is applied by: applying the mucosal adhesion layer structure to the mucosa of a human patient's oral cavity, and maintaining it on the mucosa until it dissolves.

90. The treatment method described in item 89,

The transmucosal treatment system described in any of entries 1 to 82 is applied by: applying the mucosal adhesion layer structure to the mucosa of a human patient, particularly to the buccal, sublingual, gingival, or palatal mucosa, and maintaining it on the mucosa until it dissolves.

91. The treatment method described in any of entries 87 to 90,

The transmucosal treatment system is applied at night or before bedtime.

92. A method for manufacturing an agomelatine layer, the method comprising the following steps:

i) Combine at least agomelatine and a soluble film-forming agent in a solvent to obtain a coating composition;

ii) Apply the coating composition to the release liner; and

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

93. The method described in accordance with entry 92,

In step i), the agomelatine is dissolved.

94. The method described in accordance with entry 92,

In step i), the agomelatine is dispersed.

95. The method described according to any of entries 92 to 94,

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

96. The method described in accordance with entry 95,

The solvent mentioned above contains ethanol, or is composed of ethanol.

97. The method described according to any of entries 92 to 95,

The solvent mentioned above contains water.

98. The method described according to any of entries 92 to 96,

The solvent does not contain water in amounts greater than 5 wt%, greater than 2 wt%, greater than 1 wt%, or greater than 0.5 wt%.

99. The method described according to any of entries 92 to 98,

The drying process is carried out at temperatures of 40 to 90°C or 60 to 80°C.

100. The method described according to any of entries 92 to 99,

Step i) consists of a coating composition obtained by combining at least agomelatine, a soluble film-forming agent, and one or more excipients selected from the group consisting of fatty acids, sweeteners, and flavoring agents in a solvent.

101. The method described according to any of entries 92 to 100,

If cast into a film with an area weight of 50 g/ ^m² , then at 37°C and 150 rpm, the soluble film-forming agent dissolves in water, artificial or natural saliva, or any other aqueous medium in less than 5 hours, less than 3 hours, less than 2 hours, or less than 1 hour, or in greater than 5 seconds, greater than 30 seconds, greater than 1 minute, or greater than 2 minutes, or greater than 5 seconds and less than 5 hours, greater than 30 seconds and less than 3 hours, greater than 1 minute and less than 2 hours, or greater than 2 minutes and less than 1 hour.

102. The method described according to any of entries 92 to 101,

The soluble film-forming agent is selected from the group consisting of polymers such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, graft copolymers based on polyethylene glycol-polyvinyl acetate and polycaprolactam, 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, natural film-forming agents such as shellac, pectin, gelatin, alginate, pullulan, and starch derivatives, and any mixtures thereof.

103. The method described according to item 102,

in

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

104. The method described according to item 103,

in

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

105. The method described according to item 104,

The soluble film-forming agent is hydroxypropyl cellulose.

106. The method described in accordance with entry 105,

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

107. The method described according to item 106,

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

108. The method described according to item 104,

The soluble film-forming agent is polyvinylpyrrolidone.

109. The method described in accordance with entry 108,

The polyvinylpyrrolidone mentioned therein is selected from soluble polyvinylpyrrolidone.

110. The method described according to entries 108 or 109,

The polyvinylpyrrolidone mentioned above is selected from polyvinylpyrrolidones having a K value within a range selected from the following groups:

9 to 15, and preferably 10.2 to 13.8.

15 to 20, and preferably 15.3 to 18.4.

20 to 27, and preferably 22.5 to 27.0.

27 to 35, and preferably 27.0 to 32.4, and

75 to 110, with 81.0 to 97.2 being preferred.

111. The method described according to any of entries 92 to 110,

In step 1), agomelatine is combined in a dissolved form, a dispersed form, a crystalline form, especially in one of its polymorphic forms, an amorphous form, as a eutectic, as a hydrate, a solvate, a mixture of any of the foregoing forms, or a mixture thereof.

112. A transmucosal treatment system for transmucosal administration of agomelatine, said transmucosal treatment system being obtainable by the manufacturing method described in any of entries 92 to 111.

113. A transmucosal therapeutic system for transmucosal administration of agomelatine, comprising a mucosal adhesion layer structure, wherein the mucosal adhesion layer structure comprises at least...

A) Agomelatine-containing layer, the agomelatine-containing layer comprising

i) 3 to 10 wt% agomelatine;

ii) Soluble film-forming agents, and

iii) 5 to 15 wt% fatty acids,

iv) 0.1 to 2 wt% of one or more sweeteners, and

(v) 0.2 to 2.0 wt% flavoring

in

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

The area weight of the agomelatine-containing layer is in the range of 100 to 150 g/ ^m² .

Claims (17)

1. A transmucosal therapeutic system for transmucosal administration of agomelatine, comprising a mucosal adhesion layer structure, wherein the mucosal adhesion layer structure comprises A) Agomelatine-containing layer, the agomelatine-containing layer comprising i) Agomelatine; and ii) Soluble film-forming agents. 2. The transmucosal therapy system according to claim 1, in If cast into a film having an area weight of 30 to 100 g/m² or 50 g/m², then at 37°C and 150 rpm, the soluble film-forming agent dissolves in water, artificial or natural saliva, or any other aqueous medium in less than 5 hours, less than 3 hours, less than 2 hours, or less than 1 hour, or in greater than 5 seconds, greater than 30 seconds, greater than 1 minute, or greater than 2 minutes, or greater than 5 seconds and less than 5 hours, greater than 30 seconds and less than 3 hours, greater than 1 minute and less than 2 hours, or greater than 2 minutes and less than 1 hour. 3. The transmucosal therapy system according to claim 1 or 2, in The soluble film-forming agent is selected from the group consisting of polymers such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, graft copolymers based on polyethylene glycol-polyvinyl acetate and polyvinylcaprolactam, 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, and/or The amount of the soluble film-forming agent relative to the agomelatine-containing layer is at least 65 wt%, at least 75 wt%, or at least 85 wt%, or the amount of the soluble film-forming agent is less than or equal to 98 wt%, less than or equal to 94 wt%, or less than or equal to 90 wt%, or the amount of the soluble film-forming agent is in the range of 65 to 98 wt%, 75 to 94 wt%, or 80 to 90 wt%. 4. The transmucosal therapy system according to any one of claims 1 to 3, The agomelatine-containing layer comprises at least 1 wt% agomelatine, at least 2 wt% agomelatine, or at least 3 wt% agomelatine, and/or The agomelatine-containing layer contains less than or equal to 25 wt% agomelatine, less than or equal to 20 wt% agomelatine, or less than or equal to 10 wt% agomelatine, and/or The agomelatine-containing layer comprises 1 to less than or equal to 25 wt% agomelatine, 2 to less than or equal to 20 wt% agomelatine, or 3 to less than or equal to 10 wt% agomelatine, and/or The agomelatine in the aforementioned agomelatine-containing layer is dissolved or exists in a dispersed form, and/or The agomelatine-containing layer does not contain agomelatine crystals. 5. The transmucosal therapy system according to any one of claims 1 to 4, The agomelatine-containing layer further comprises one or more excipients selected from the group consisting of: fatty acids, sweeteners, flavoring agents, colorants, penetration enhancers, solubilizers, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffering agents, and other film-forming agents. Specifically, the fatty acid is a saturated or unsaturated straight-chain or branched carboxylic acid containing 4 to 24 carbon atoms, and is particularly selected from the group consisting of: caprylic acid, myristone acid, palmitoleic acid, juglans regia, oleic acid, trans-oleic acid, isoleic acid, linoleic acid, trans-linoleic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid, and/or Specifically, the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of: sucrose, glucose, fructose, sorbitol, mannitol, isomaltitol, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclohexylsulfamic acid, neohesperidin, neotame, steviol glycosides, sematrandole, and sodium saccharin, and/or Specifically, the agomelatine-containing layer comprises one or more natural or artificial flavorings selected from the group consisting of: vanillin, methyl salicylate, menthol, chamomile, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl sebadienoate, allyl hexanoate, ethyl maltol, 2,4-dimethylthiomethane, ethyl vanillin, and eucalyptol, as well as flavoring compositions such as peppermint flavorings. 6. The transmucosal therapy system according to any one of claims 1 to 5, The agomelatine-containing layer therein is substantially free of water, and/or The agomelatine-containing layer contains less than or equal to 12 wt%, less than or equal to 8 wt%, less than or equal to 5 wt%, or less than or equal to 4 wt% water. 7. The transmucosal therapy system according to any one of claims 1 to 6, The agomelatine-containing layer is obtained by drying the coated composition, the coated composition comprising... The agomelatine, the soluble film-forming agent, and ethanol, or The agomelatine, the soluble film-forming agent, and water, and/or The agomelatine, the soluble film-forming agent, ethanol and water, and/or The agomelatine-containing layer is obtained by drying a coated composition containing less than 50 wt%, or less than 20 wt%, or less than 10 wt%, or less than 5 wt% water. 8. The transmucosal therapy system according to any one of claims 1 to 7, The agomelatine-containing layer has an area weight of at least 25 g/ ^m² , at least 35 g/ ^m² , or at least 40 g/ ^m² , or an area weight of less than or equal to 300 g/ ^m² , less than or equal to 250 g/m², or less than or equal to 200 g/m², or an area weight of 25 to 300 g/m², 35 to 250 g/ ^m² , or 40 to 200 g/ ^m² . 9. The transmucosal therapy system according to claim 8, The mucosal adhesion layer structure may or may not include a mucosal contact layer, and/or The adhesive layer structure may or may not include a decorative layer, and/or The transmucosal treatment system described therein does not include a backing layer, and in particular, the backing layer does not dissolve within less than 15 minutes, less than 10 minutes, or less than 5 minutes after the transmucosal treatment system is applied to a human patient. 10. The transmucosal therapy system according to any one of claims 1 to 9, in At 37°C and 150 rpm, the mucosal adhesion layer structure dissolves in water, artificial or natural saliva, or any other aqueous medium within a timeframe of more than 30 seconds and less than 5 hours, or more than 1 minute and less than 4 hours, or more than 2 minutes and less than 3 hours, or more than 4 minutes and less than 2 hours. 11. The transmucosal therapy system according to any one of claims 1 to 10, As measured using porcine esophageal mucosa, the transmucosal treatment system provides an agomelatine mucosal penetration rate of 10 μg/cm²-hr to 150 μg/cm²-hr after 1 hour, and/or As measured using porcine esophageal mucosa, over an 8-hour period, the transmucosal treatment system provides a cumulative release of agomelatine of at least 0.02 mg/ ^cm² , at least 0.05 mg/ ^cm² , or at least 0.1 mg/ ^cm² , or less than ^or equal to 0.5 mg/ ^cm² , less than or equal to 0.4 mg/ ^cm² , or less than or equal to 0.3 ^mg / ^cm² , or 0.02 mg/cm² to 0.5 mg/cm², 0.05 mg/ ^cm² to 0.4 mg/ ^cm² , or 0.1 mg/ ^cm² to 0.3 mg/ ^cm² . 12. The transmucosal therapy system according to any one of claims 1 to 11, The method of using the transmucosal treatment system to treat human patients. 13. A treatment method, The transmucosal treatment system according to any one of claims 1 to 11 is administered to a human patient. 14. The transmucosal therapy system according to claim 12 or the treatment method according to claim 13, The treatment methods described are methods for treating major depressive disorder, and/or The transmucosal treatment system is applied by: applying the mucosal adhesion layer structure to the mucosa of a human patient's oral cavity, and particularly to the buccal, sublingual, gingival, or palatal mucosa, and maintaining it on the mucosa until it dissolves, and/or The transmucosal treatment system is applied at night or before bedtime. 15. A method for manufacturing an agomelatine-containing layer, the method comprising the following steps: i) Combine at least agomelatine and a soluble film-forming agent in a solvent to obtain a coating composition; ii) Apply the coating composition to the release liner; and iii) Dry the applied coating composition to form the agomelatine-containing layer. 16. A transmucosal therapeutic system for transmucosal administration of agomelatine comprising a mucosal adhesion layer structure, wherein the mucosal adhesion layer structure comprises at least A) Agomelatine-containing layer, the agomelatine-containing layer comprising i) 3 to 10 wt% agomelatine; ii) Soluble film-forming agents, and iii) 5 to 15 wt% fatty acids, iv) 0.1 to 2 wt% of one or more sweeteners, and (v) 0.2 to 2.0 wt% flavoring in The soluble film-forming agent is selected from the group consisting of polyvinylpyrrolidone and hydroxypropyl cellulose, and The area weight of the agomelatine-containing layer is in the range of 100 to 150 g/ ^m² . 17. A method for determining the permeation volume and corresponding mucosal permeation rate of agomelatine transmucosal therapy system using porcine esophageal mucosa, comprising the following steps: a. The mucosa was prepared to a thickness of 400 μm using a dermabrasion tool, thus maintaining its complete barrier function; b. A die-cut material with an area of 0.798 ^cm² is punched from a transmucosal treatment system, applied to the mucosa, and the upper part of the mucosa with the transmucosal treatment system is immersed in artificial saliva, the lower part is in contact with the receiving medium, and the upper part is divided to 1.145 cm². Mucosal area per ^cm² ; c. Measure the amount of agomelatine permeate in the receiving medium at a temperature of 37±1℃ and calculate the corresponding mucosal permeation rate, wherein the receiving medium is a phosphate buffer solution with pH 7.4.