Agomelatine film for oral mucosal administration and preparation method thereof

Abstract

The present invention discloses an agomelatine film for oral mucosal administration and a preparation method thereof, and provides a pharmaceutical preparation for administering agomelatine via the oral mucosa. The film is a double-layer film preparation consisting of a drug-containing adhesive layer and a drug-free backing layer. The double-layer film structure ensures good bioavailability and a good mouthfeel of the drug. The drug-containing adhesive layer of the agomelatine film prepared by the present invention comprises 0.1-40% (w / w) of the active ingredient agomelatine or a pharmaceutically acceptable salt thereof, 50-98% (w / w) of one or more film-forming materials, 0.5-20% (w / w) of one or more oil phases, and 0.5-17% (w / w) of one or more surfactants. The backing layer contains 60-100% (w / w) of one or more film-forming materials.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical preparation in the field of medicine, and in particular to a pharmaceutical preparation in the form of a thin film for releasing agomelatine through the oral mucosa and a preparation method thereof. Background Art

[0002] Agomelatine is the world's first melatonin receptor agonist antidepressant. Developed and marketed by Servier in France in 2009, it is another blockbuster antipsychotic. It is a melatonin receptor (MT1 and MT2) agonist and a 5-hydroxytryptamine 2C (5-HT2C) receptor antagonist. Its antidepressant effect is achieved primarily through the synergistic effect of these two agents, which restores the synchronization of disrupted circadian rhythms in patients with depression. Agomelatine has a rapid onset of action and exhibits antidepressant, anxiolytic, sleep rhythm, and circadian rhythm-regulating effects. It can improve nighttime sleep without affecting daytime circadian rhythms. Compared to other antidepressants, agomelatine has fewer adverse reactions, is safer, and has no withdrawal effects, providing a new approach for the clinical treatment of major depressive disorder (MDD).

[0003] Agomelatine is currently available only in the form of 25mg tablets. While clinically effective, agomelatine tablets still have several drawbacks that severely limit their clinical application. First, due to its severe first-pass effect, the bioavailability of agomelatine oral tablets is very low, less than 5%. Furthermore, the coefficient of variation of agomelatine's AUC is approximately 100%-150%, with inter-individual variation (104%) being the primary source, but intra-individual variation (157%) is also significant. Second, agomelatine exhibits significant hepatotoxicity, clinically causing reversible increases in transaminases in some patients, a significant hepatotoxicity that necessitates liver function monitoring during clinical use.

[0004] Agomelatine tablets have low oral bioavailability and large AUC variation (100%-150%), and are also significantly hepatotoxic. All patients should undergo liver function tests at the start of treatment, and regular testing is recommended at 6 weeks (at the end of acute treatment), 12 weeks, and 24 weeks (at the end of maintenance treatment). Existing technical defects have already affected clinical and patient safety.

[0005] Therefore, in view of the existing technical problems, there is a clinical need for a new pharmaceutical composition for delivering agomelatine to improve the bioavailability of agomelatine and reduce hepatotoxicity. Summary of the Invention

[0006] The present invention has discovered a pharmaceutical composition suitable for oral mucosal administration with improved bioavailability. The agomelatine film of the present invention adheres to the buccal or sublingual mucosa and disintegrates or dissolves within minutes. Agomelatine is directly absorbed through the buccal or sublingual mucosa and enters the jugular vein, avoiding gastrointestinal degradation and the first-pass effect in the liver. This results in significantly higher bioavailability than agomelatine oral tablets.

[0007] The epithelial tissue of the oral mucosa (such as the buccal mucosa and sublingual mucosa) is not keratinized and has good permeability. Its abundant blood vessels are directly connected to the jugular vein, providing a foundation for drug absorption. The agomelatine film of the present invention can promote the absorption of agomelatine in the oral mucosa and improve the bioavailability of agomelatine. The agomelatine film of the present invention can achieve the required absorption curve and peak blood concentration of agomelatine and provide good bioavailability. The agomelatine film of the present invention is suitable for delivering agomelatine through the oral mucosa, and its bioavailability can reach 8 to 51 times that of agomelatine oral tablets.

[0008] According to literature reports, oral agomelatine has strong hepatotoxicity, and liver function tests must be strictly monitored during clinical use. Currently, the commercially available agomelatine tablet dosage is 25 mg / day, which is a relatively high oral dose and may cause some damage to the patient's liver function. The present invention provides an agomelatine film for oral mucosal administration. Compared with commercially available oral tablets, it has greatly improved bioavailability, achieving the same therapeutic effect as tablets at a lower dose of agomelatine, reducing the risk of liver damage.

[0009] The present invention provides an agomelatine film, in which the active ingredient, agomelatine, is in an amorphous form to increase the drug's dissolution rate in the oral cavity. The amorphous agomelatine in the film is rapidly released and absorbed after administration, resulting in a more rapid onset of action.

[0010] Agomelatine is highly irritating to the tongue in the oral cavity. During oral mucosal administration, agomelatine diffuses into the oral cavity and irritates the patient's tongue, leading to compliance issues. The agomelatine film of the present invention has a double-layer structure comprising a drug-containing adhesive layer containing agomelatine and a drug-free backing layer. The backing layer effectively prevents drug diffusion into the oral cavity, thereby avoiding tongue irritation and significantly improving patient compliance.

[0011] The agomelatine film of the present invention is applied to the oral mucosa of the subject (such as buccal membrane, sublingual mucosa, etc.), and agomelatine is absorbed into the blood through the oral mucosa. Compared with the agomelatine oral tablet, the time to reach the peak plasma concentration (T maxIn addition, agomelatine of the present invention is absorbed into the blood through the oral mucosa, so administration is not affected by food.

[0012] The agomelatine film of the present invention has a bilayer structure, comprising a drug-containing adhesive layer and a backing layer. The drug-containing adhesive layer comprises 0.1-40% amorphous agomelatine or a pharmaceutically acceptable salt thereof, 50-98% a first film-forming material, 0.5-20% an oil phase, and 0.5-17% a surfactant. Agomelatine is in an amorphous state in the drug-containing adhesive layer.

[0013] As used herein, "pharmaceutically acceptable salts" are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects.

[0014] As used in this application, "about" means ±10% of the recited value.

[0015] Unless otherwise specified, "%" in this application refers to weight percentage (w / w).

[0016] The active ingredient in the pharmaceutical composition is agomelatine or a pharmaceutically acceptable salt thereof, for example, agomelatine iodide salts, such as agomelatine hydroiodide trihydrate, hemi-triiodo agomelatine, hemi-triiodo agomelatine iodine, agomelatine phosphate, agomelatine hydrogen sulfate, agomelatine mesylate, or agomelatine besylate. The amount of agomelatine in the drug-containing adhesive layer is 0.1-10 mg, preferably 0.1-5 mg, 0.3-10 mg, 0.3-5 mg, or 0.5-3 mg. The weight percentage of agomelatine in the drug layer is generally 0.1-40% w / w, preferably 0.5-30% or 0.5-25% w / w.

[0017] The film-forming material selected for the drug-containing adhesive layer is one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl alcohol-polyethylene glycol copolymer (PVA-PEG), polyvinyl alcohol (PVA), povidone (PVP), and polyethylene oxide (PEO). These film-forming materials have good compatibility with agomelatine and provide a sufficiently high drug-loading capacity. The resulting film has good film-forming properties and flexibility, and can maintain agomelatine in an amorphous state in the film for a long time without crystallization. The proportion of the film-forming material in the drug-loading layer is generally 50-98% w / w, preferably 70-95% w / w or 80-95% w / w.

[0018] The oil phase selected for the drug-containing adhesive layer is one or more of propylene glycol dicaprate, glyceryl monolinoleate, glyceryl monooleate, diethylene glycol monoethyl ether, oleoyl polyoxyethylene glycerides, propylene glycol laurate, polyglyceryl-4 oleate, isooctyl palmitate, polyethylene glycol cetearyl ether, and polyglyceryl-3-diisostearate. The proportion of the oil phase in the drug-carrying layer is generally 0.5-25% w / w, preferably 1-20% w / w or 1-15% w / w.

[0019] The surfactant selected for the drug-containing adhesive layer is one or more of lauric acid macrogol glyceride, stearic acid macrogol glyceride, oleic acid macrogol glyceride, linoleic acid macrogol glyceride, sodium lauryl sulfate, mono- and di-caprylic acid macrogol glyceride, polyethylene glycol-32 stearate, caprylic acid macrogol glyceride, and 15-hydroxystearate macrogol glyceride. The proportion of the oil phase in the drug-carrying layer is generally 0.5-17% w / w, preferably 1-15% w / w or 1-10% w / w.

[0020] The drug-containing adhesive layer of the agomelatine film of the present invention contains one or more oil phases and surfactants (emulsifiers), which provide a self-emulsifying drug delivery system. Self-emulsifying drug delivery systems are commonly used to deliver hydrophobic drugs to improve the bioavailability of water-insoluble drugs. In a self-emulsifying drug delivery system, the drug spontaneously forms an emulsion under slight stirring in the aqueous phase. The agomelatine film has good water solubility, and the film can be completely dissolved in water within 5 minutes and self-emulsifies to form an agomelatine microemulsion. The agomelatine film of the present invention has a good absorption curve, blood drug concentration and good bioavailability.

[0021] The rate at which a drug is absorbed by the oral mucosa and the time it remains adhered to the oral mucosa affect its bioavailability. The adhesive in the drug-containing adhesive layer enables the film to adhere to the mucosa until it is completely dissolved. In one embodiment, the agomelatine film further comprises one or more adhesives in the drug-containing adhesive layer. These adhesives should enhance the adhesion of the drug-loaded layer without affecting agomelatine dissolution or reducing agomelatine bioavailability. Suitable adhesives for use in the present invention include one or more materials, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, polyglutamic acid, polycarbophil, carbomer, dextran sulfate, chondroitin sulfate, and sodium carboxymethylcellulose.

[0022] The film-forming material used in the backing layer of the agomelatine film of the present invention is one or more of: hydropropyl methylcellulose (HPMC), hydropropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), hydroxyethyl cellulose (HEC), polyvinyl alcohol (PVA), hydropropyl methylcellulose phthalate (HPMCP), and polyvinyl alcohol phthalate (PVAP). These film-forming materials have a good barrier effect on agomelatine, effectively preventing agomelatine from the drug-containing adhesive layer from diffusing into the oral cavity. The amount of film-forming material in the backing layer is 60-100% w / w, preferably 70-100% w / w or 80-100% w / w, resulting in a backing film with good flexibility.

[0023] When the backing layer thickness is ≥10 μm and ≤60 μm, the drug's irritation is significantly reduced. When the backing layer thickness is <10 μm, the irritation masking effect is poor. When the backing layer thickness is >60 μm, the drug release rate is affected. The preferred thickness of the backing layer is 10-60 μm. A more preferred thickness is 10-40 μm.

[0024] In one embodiment, one or more flavoring agents can be added independently to the drug-containing adhesive layer and / or the backing layer to improve the mouthfeel of the drug. Flavoring agents suitable for the drug-containing adhesive layer and the backing layer include but are not limited to sucrose, glucose, saccharin sodium, fructose, xylitol, stevia, aspartame, sucralose, neotame and acesulfame potassium, peppermint oil, menthol, orange flavor, pineapple flavor, cherry flavor, apple flavor, banana flavor, blueberry flavor, peach flavor, mango flavor, grape flavor. The amount of flavoring agent in the composition is 0.01-5%, preferably about 0.05-2% (w / w) in the drug-containing adhesive layer and 0-5% w / w in the backing layer. The flavoring agent added to the film can improve the taste of the film and provide a good mouthfeel, and can improve patient compliance.

[0025] One or more colorants, such as food, drug, and commercial (FD&C) colors or pharmaceutical (D&C) colors, may be added to the drug-carrying layer and / or the backing layer.

[0026] The present invention provides an agomelatine film with high bioavailability. After dissolving in the oral mucosa, the drug self-emulsifies to form a microemulsion, promoting drug penetration and absorption. The film has a double-layer structure; its backing layer prevents direct drug diffusion into the oral cavity and reduces drug irritation. The agomelatine film of the present invention has a uniform appearance, consistent thickness and color, and good drug stability. Administration through the oral mucosa avoids the drug's first-pass effect, significantly improving agomelatine's bioavailability.

[0027] The agomelatine film of the present invention is absorbed through the oral mucosa and enters the blood, and is absorbed rapidly. In a beagle dog animal test, the agomelatine film was significantly improved compared with the oral tablet (T max :0.75h), shortening the time for blood drug solubility to reach peak (T max : 0.33~0.5h), which can accelerate the onset of effect.

[0028] The present invention also provides a method for preparing an agomelatine double-layer film, which comprises the following steps: (a) preparing a drug-containing adhesive layer: dissolving agomelatine or an acceptable salt thereof, one or more first film-forming materials, one or more oil phases, and one or more surfactants in a first solvent to prepare a drug-containing film-forming liquid; (b) uniformly coating the drug-containing film-forming liquid and drying it to form a film to obtain a drug-containing adhesive layer; (c) preparing a backing layer: dissolving one or more second film-forming materials in a second solvent; (d) uniformly coating the backing layer film-forming liquid on the prepared drug-containing adhesive layer and drying it to obtain a double-layer film; and (e) peeling the dried double-layer film from the substrate to obtain an agomelatine film.

[0029] Agomelatine is poorly soluble in water. To promote the dissolution of the raw material and improve the uniformity of the drug content, (a) the concentration of the first aqueous solution containing an organic solvent is selected to be 40.0%-100.0%.

[0030] In the above preparation steps (a) and (c), flavoring agents and coloring agents may be added to the solution to improve taste and recognition.

[0031] The drying temperature used in the above preparation steps (b) and (d) is 40 to 100°C, preferably 60 to 90°C.

[0032] Through the preparation method of the present invention, agomelatine exists in an amorphous form in the drug-containing adhesive layer, so that the film can produce a faster dissolution rate, thereby improving the bioavailability of agomelatine.

[0033] The substrate materials used in the film coating and drying process are polyethylene terephthalate (PET), polypropylene resin (PP), polymethylpentene resin (TPX), etc.

[0034] After step (e), the double-layer film may be cut into suitable sizes and shapes before further packaging.

[0035] The agomelatine film of the present invention has a length of about 1-4 cm and a width of about 1-4 cm; preferably, a length of about 1-3 cm and a width of about 1-3 cm.

[0036] The present invention provides a method for administering agomelatine via the buccal mucosa or sublingual mucosa, which is used for treating mental illnesses such as depression and insomnia.

[0037] The oral mucosal administration preparation prepared by the present invention is used for mammals, such as humans, horses, dogs and cats, with human treatment being the most preferred. DETAILED DESCRIPTION

[0038] The present invention will be further described in detail below with reference to the examples. It should be noted that the following description is merely an illustration of the technical solutions claimed in the present invention and does not constitute any limitation on these technical solutions. The scope of protection of the present invention shall be subject to the contents of the appended claims.

[0039] Example 1: Agomelatine film (crystalline film)

[0040] This example tests an agomelatine crystalline film, and the formulation and preparation method are as follows:

[0041] prescription:

[0042]

[0043] Preparation process:

[0044] Dissolve / disperse agomelatine in the solvent under continuous stirring;

[0045] Add other excipients and continue stirring until a homogeneous mixture is formed;

[0046] Vacuum / stand still to defoam;

[0047] Apply the defoamed film-forming liquid evenly on the substrate;

[0048] Drying at a temperature of about 60°C to 90°C to form a film;

[0049] After film formation, cut the film into suitable size and shape and put it into small bags or suitable packaging containers.

[0050] The agomelatine film prepared according to the above formulation and preparation method exhibited excellent film-forming properties and was easily removed from the substrate film. It had a smooth appearance and uniform color. Crystalline powder particles of the active ingredient, agomelatine, were evenly dispersed throughout the film. X-ray powder diffraction analysis revealed that the agomelatine was in a crystalline state. In dissolution testing, the drug particles released after the film dissolved and became suspended in the dissolution medium, resulting in slow and incomplete dissolution.

[0051] Table 1 Dissolution results of Example 1 (Agomelatine in crystalline state)

[0052]

[0053] The agomelatine film prepared in Example 1 was compared with agomelatine tablets, and a pharmacokinetic test was conducted on beagle dogs. The results showed that the bioavailability of the agomelatine film was 2.2 times that of the tablets. The specific experimental results are shown in Example 10.

[0054] At the same time, different concentrations of ethanol solutions (0-30%) and isopropanol solutions (0-30%) were tested as solvents instead of water. The agomelatine in the prepared films was in a crystalline state and dissolved slowly.

[0055] Example 2: Agomelatine film (amorphous film)

[0056] In this example, the preparation method described in Example 1 was followed, except that the solvent in the formulation was changed from purified water to a 50% ethanol solution. The agomelatine used in the formulation was in the same crystalline state as in Example 1. An agomelatine film was prepared according to the following formulation. Agomelatine was in an amorphous state in the final film.

[0057] prescription:

[0058]

[0059] The agomelatine film prepared according to the above formulation and preparation method exhibited a smooth appearance and uniform color, with no visible crystalline particles on the film. X-ray powder diffraction analysis of the prepared agomelatine film revealed that the agomelatine was in an amorphous state. Dissolution experiments also revealed that the drug dissolved with the film, reaching a solubility of 95% within 10 minutes. However, this solubility subsequently dropped to 76% due to precipitation of the supersaturated portion. Therefore, the amorphous agomelatine film prepared in this example outperformed the crystalline film described in Example 1 in terms of drug dispersion uniformity and dissolution rate. However, due to agomelatine's low solubility, it was prone to reprecipitation.

[0060] Table 2: Dissolution results of Example 2 (Agomelatine is in an amorphous state)

[0061]

[0062] The agomelatine film of Example 2 was subjected to animal experiments, and the bioavailability was 8.9 times that of the oral tablet, which was significantly improved compared to the crystalline film of Example 1. The specific experimental results are shown in Example 10.

[0063] Example 3: Agomelatine film (amorphous film + surfactant)

[0064] In this example, the preparation method described in Example 1 was followed, and Tween 80, a surfactant, was added to the formulation of Example 2. Agomelatine film was prepared according to the following formulation. Agomelatine was also in an amorphous state in the final film.

[0065] prescription:

[0066]

[0067] The agomelatine film prepared according to the above formulation and preparation method exhibited a smooth appearance and uniform color, with no visible crystalline particles on the film. X-ray powder diffraction analysis of the prepared agomelatine film revealed that the agomelatine was in an amorphous state. Dissolution experiments also revealed that the drug dissolved with the film, reaching a dissolution rate of 98% within 10 minutes and maintaining complete dissolution thereafter. Therefore, the amorphous agomelatine film containing a surfactant (Example 3) avoids the problem of drug recrystallization after dissolution, and is superior to the amorphous film described in Example 2.

[0068] Table 3: Dissolution results of Example 3 (Agomelatine is in amorphous state)

[0069]

[0070] The agomelatine film of Example 3 was subjected to animal experiments. The bioavailability was 12.3 times that of the oral tablet, which was significantly improved compared to the amorphous film without surfactant added in Example 2. The specific experimental results are shown in Example 10.

[0071] At the same time, experiments were conducted with 40-100% ethanol aqueous solution, 40-100% isopropanol aqueous solution, 40-100% dichloromethane aqueous solution, 40-100% acetone aqueous solution, 40-100% tert-butanol aqueous solution, and different types and proportions of film-forming materials including hydroxypropyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer, polyvinyl alcohol, copovidone, and polyethylene oxide. The agomelatine in the prepared films was in an amorphous state, with a uniform appearance, rapid dissolution, and no recrystallization or precipitation after dissolution.

[0072] Example 4: Agomelatine film (amorphous film + surfactant + oil phase)

[0073] This example follows the preparation method described in Example 1, and adds oil phase medium chain triglyceride (Labrafac TM lipophile WL 1349, Gattefossé), and agomelatine film was prepared according to the following formula. Agomelatine was also in an amorphous state in the final film.

[0074] prescription:

[0075]

[0076] Dissolution testing of the agomelatine film prepared according to the above formulation and preparation method showed that the drug dissolved with the film, but did not successfully form an emulsified state. The dissolution rate reached 97% after 10 minutes and remained completely dissolved thereafter. Animal experiments with the agomelatine film of Example 4 showed a bioavailability 11.7 times that of the oral tablet, with no significant difference compared to the amorphous film of Example 3. Detailed experimental results are shown in Example 10.

[0077] Example 5: Agomelatine film (amorphous film + surfactant + oil phase, self-emulsifiable)

[0078] In this example, the preparation method described in Example 1 was followed, except that the surfactant was replaced with polyethylene glycol laurate and the oil phase was replaced with diethylene glycol monoethyl ether in the formulation of Example 3. An agomelatine film was prepared according to the following formulation. Agomelatine was also in an amorphous state in the final film.

[0079] prescription:

[0080]

[0081] Dissolution testing of the agomelatine film prepared according to the above formulation and preparation method showed that the drug dissolved with the film, disintegrating into a slightly milky, self-emulsified state. The solubility reached 94% within 10 minutes, and the film remained completely dissolved thereafter. Animal experiments with the agomelatine film of Example 5 demonstrated a bioavailability 46.7 times that of the oral tablet, significantly improving the bioavailability compared to the surfactant-containing amorphous film of Example 3. Specific experimental results are shown in Example 10.

[0082] Example 6: Agomelatine film (amorphous film + surfactant + oil phase)

[0083] In this example, the preparation method described in Example 1 was followed, and different oil-phase formulas were tested on the formulation of Example 5. Agomelatine film was prepared according to the following formulation. Agomelatine was also in an amorphous state in the final film.

[0084] prescription:

[0085]

[0086] Dissolution experiments of agomelatine films prepared according to the above prescription and preparation method showed that the drug dissolved along with the dissolution of the films of Examples 6-1 and 6-2, and an emulsified state was not successfully formed. However, the drug dissolved along with the dissolution of the films of Examples 6-3 and 6-4, and a slightly milky white emulsion was formed after disintegration.

[0087] In the agomelatine films prepared in Examples 6-1 to 6-4, agomelatine was in an amorphous state.

[0088] This example also tests medium-chain triglycerides, Span 80, polyoxyethylene 35 castor oil, monoolein, diethylene glycol monoethyl ether, oleoyl polyoxyethylene glyceride and other oil phases. Among them, the agomelatine film prepared using medium-chain triglycerides, Span 80, and polyoxyethylene 35 castor oil as the oil phase cannot achieve self-emulsification, while the agomelatine film prepared using monoolein, diethylene glycol monoethyl ether, and oleoyl polyoxyethylene glyceride as the oil phase can achieve self-emulsification.

[0089] At the same time, different proportions of oil phase, such as 1%, 5%, 10%, 15%, 20%, and 30%, were also tested. When the oil phase accounted for 1-20%, agomelatine films with good appearance could be obtained after coating and drying, and self-emulsification could be achieved. When the oil phase accounted for 30%, the film after coating and drying was soft and easy to stick due to the high proportion of the oil phase. The most preferred oil phase ratio is 1-15%.

[0090] Example 7: Agomelatine film (amorphous film + surfactant + oil phase)

[0091] In this example, the preparation method described in Example 1 was followed, and different surfactant (emulsifier) ​​formulations were tested on the formulation of Example 5. Agomelatine films were prepared according to the following formulations. Agomelatine was in an amorphous state in the final films.

[0092] prescription:

[0093]

[0094] Dissolution experiments of agomelatine films prepared according to the above prescription and preparation method showed that the drug dissolved along with the dissolution of the films of Examples 7-1 and 7-2, and an emulsified state was not successfully formed. However, the drug dissolved along with the dissolution of the films of Examples 7-3 and 7-4, and a slightly milky white emulsion was formed after disintegration.

[0095] This example also tests Tween 20, stearic acid, glyceryl monostearate, oleic acid macrogol glyceride, linoleic acid macrogol glyceride, and sodium lauryl sulfate as surfactants (emulsifiers). The agomelatine film prepared using Tween 20, stearic acid, and glyceryl monostearate cannot achieve self-emulsification, while the agomelatine film prepared using oleic acid macrogol glyceride, linoleic acid macrogol glyceride, and sodium lauryl sulfate as surfactants (emulsifiers) can achieve self-emulsification.

[0096] At the same time, different proportions of surfactant usage, such as 1%, 5%, 10%, 15%, and 20%, were also tested. When the proportion was 1-15%, agomelatine films with good appearance could be obtained after coating and drying, and self-emulsification could be achieved. When the surfactant proportion was 20%, self-emulsification could not be formed due to the high proportion of surfactant. The most preferred surfactant (emulsifier) ​​proportion is 1-10%.

[0097] Example 8: Agomelatine film (single-layer film mouthfeel)

[0098] In this example, the sample obtained in Example 5 (single-layer self-emulsifying film) was subjected to a taste test on multiple volunteers. When the film attached to the oral mucosa began to dissolve and the drug was released, the volunteers found that the drug was significantly irritating to the tongue and had a poor taste.

[0099] The experiment also tested a variety of flavoring agents (menthol, orange flavor, cherry flavor, apple flavor, etc.), different combinations of sweeteners (sucrose, glucose, saccharin sodium, fructose, xylitol, stevia, aspartame, sucralose, etc.) using a single-layer film. Different combinations of sweeteners and flavoring agents were also used for taste masking (such as sucralose and menthol, xylitol and menthol, etc.). Various proportions of sweeteners and flavoring agents were tested, but none of them significantly improved the irritation of agomelatine on the tongue.

[0100] Example 9: Agomelatine film (double-layer film)

[0101] In this embodiment, a backing layer was added on the basis of the above embodiment 5, and an agomelatine double-layer film was prepared according to the following prescription.

[0102] prescription:

[0103]

[0104] Drug-containing adhesive layer: Completely dissolve agomelatine in the solvent, then add the other ingredients in the formulation and stir until completely dissolved. Let it stand or vacuum to eliminate bubbles. Evenly transfer the film-forming solution to a conveyor belt and dry it at 60-90°C. The solvent evaporates during the drying process. Once the film is formed, remove it.

[0105] Backing layer: Add all other components in the formulation, except titanium dioxide (which should be evenly dispersed in the film-forming solution), to the solvent in the formulation and stir until completely dissolved. Then add the titanium dioxide and stir to evenly disperse it. Allow to stand or vacuum to eliminate bubbles. Evenly apply the film-forming solution to the dried drug-containing adhesive layer and dry at 60-90°C. The solvent will evaporate during the drying process. After the film is formed, cut it into suitable sizes and shapes and package it to obtain the agomelatine film.

[0106] The agomelatine film prepared according to the above prescription has good film-forming properties, a smooth appearance, and a uniform color. The backing layer is white and the drug-containing adhesive layer is orange.

[0107] The sample obtained in this example was subjected to taste testing on multiple volunteers. The volunteers reported a significantly improved taste compared to the single-layer film formulation of Example 8, with no tongue irritation noted throughout the entire process. The agomelatine film formulation of Example 9 was subjected to pharmacokinetic testing, demonstrating a bioavailability of 51.7 times that of the oral tablet formulation, significantly higher than that of the oral tablet formulation. Detailed experimental results are shown in Example 10.

[0108] In addition, other different types of backing layer film-forming materials, including polyvinyl alcohol (PVP), polyvinyl alcohol polyethylene glycol copolymer (PVA-PEG), hydroxypropyl cellulose (HPC), polyethylene oxide (PEO), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), cellulose acetate phthalate (CAP), hydroxyethyl cellulose (HEC), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose phthalate (HPMCP), and polyvinyl phthalate (PVAP), were tested with different usage amounts (50-100% (w / w)) and different backing layer thicknesses (5 μm to 100 μm). Among them, the formulations using polyvinyl alcohol (PVP), polyvinyl alcohol polyethylene glycol copolymer (PVA-PEG), hydroxypropyl cellulose (HPC), and polyethylene oxide (PEO) did not improve the palatability of the formulation. The use of 80-100% (w / w) of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), cellulose acetate phthalate (CAP), hydroxyethyl cellulose (HEC), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl alcohol phthalate (PVAP), or a combination thereof can significantly improve the mouthfeel of the prescription. When the backing layer thickness is ≥10 μm and ≤60 μm, the irritation of the drug is significantly reduced. When the backing layer thickness is less than 10 μm, the irritation masking effect is poor. When the backing layer thickness is greater than 60 μm, the release rate of the drug is significantly affected. Therefore, the preferred backing layer thickness is 10-60 μm, and the more preferred thickness is 10-40 μm.

[0109] At the same time, sweeteners and flavorings can be added to the backing layer formulation to further improve the taste of the formulation, such as sucralose, aspartame, saccharin sodium, neotame, acesulfame potassium, menthol, peppermint oil, orange flavor, pineapple flavor, cherry flavor, blueberry flavor and grape flavor, with the content ranging from 0.01% to 5% w / w. The results show that all the tested sweeteners and flavorings can further improve the taste of the formulation.

[0110] Example 10: Bioavailability of agomelatine film

[0111] In this example, pharmacokinetic studies were conducted on beagle dogs using agomelatine oral tablets (Weixin), Example 1, Example 2, Example 3, Example 4, Example 5, and Example 9. (i) 1 mg agomelatine film groups (Examples 1, 2, 3, 4, 5, and 9) were administered and applied to the oral mucosa; and (ii) 25 mg agomelatine tablets were administered orally. Blood was collected before each administration (0 min) and at 0.17 h, 0.33 h, 0.5 h, 0.75 h, 1.0 h, 1.5 h, 2.0 h, 3.0 h, 4.0 h, 5.0 h, and 6.0 h after administration. The agomelatine concentration in plasma was determined by LC-MS / MS. The relative bioavailability of the prepared films and tablets was calculated. The results are shown in the table below. The relative bioavailability of the oral films prepared in Examples 1 to 5 and 9 were 221%, 892%, 1233%, 1167%, 4674% and 5167% of that of the oral tablets, respectively. max The T values ​​were 0.75h, 0.5h, 0.5h, 0.5h, 0.33h and 0.39h, respectively, which were significantly shorter than the T values ​​of oral tablets. max 0.75h, indicating that the prepared film, when administered through the oral mucosa, has a significantly faster absorption rate than oral tablets and a significantly higher bioavailability than oral tablets. In Examples 1 and 2, the bioavailability of the amorphous film was higher than that of the crystalline film, indicating that preparing agomelatine as an amorphous film in the formulation can improve bioavailability. Compared with Example 2 and Example 3, adding a surfactant to the amorphous formulation can improve bioavailability. Compared with Example 3 and Example 4, there was no significant difference in bioavailability when an oil phase was added to the formulation of Example 3 but no self-emulsification was formed. Compared with Example 4 and Example 5, the bioavailability of Example 5, which can form a self-emulsification, was significantly higher than that of the non-self-emulsification formulation. There was no significant difference in bioavailability between Example 5 and Example 9, but the double-layer film showed a significant improvement in mouthfeel.

[0112] Bioavailability test results of different examples of prescriptions

[0113]

[0114] Note*:

[0115] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the present invention. Anyone skilled in the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by one of ordinary skill in the art without departing from the spirit and technical principles disclosed herein are intended to be covered by the claims of the present invention.

Claims

1. An agomelatine film for oral mucosal administration, comprising: (A) a drug-containing adhesive layer: comprising 0.1-40 parts by weight of amorphous agomelatine, 50-98 parts by weight of a first film-forming material, 0.5-20 parts by weight of an oil phase, 0.5-17 parts by weight of a surfactant; (b) a soluble backing layer comprising 60-100 parts by weight of a second film-forming material; The first film-forming material is one or more of hypromellose, hydroxypropyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer, polyvinyl alcohol, povidone, and polyethylene oxide; The second film-forming material is one or more of hydroxypropyl methylcellulose acetate succinate, hypromellose, cellulose acetate phthalate, hydroxyethyl cellulose, polyvinyl alcohol, hypromellose phthalate, and polyvinyl phthalate; The oil phase is one or more of propylene glycol dicaprate, monolinolein glyceryl, monoolein glyceryl, diethylene glycol monoethyl ether, and oleoyl polyoxyethylene glyceride; The surfactant is one or more of lauric acid macrogol glyceride, stearic acid macrogol glyceride, oleic acid macrogol glyceride, linoleic acid macrogol glyceride, and sodium lauryl sulfate.

2. The agomelatine film according to claim 1, characterized in that The backing layer has a thickness of 10 μm to 60 μm.

3. The agomelatine film according to claim 1, characterized in that: The drug-containing adhesive layer contains 0.5%-25% by weight of agomelatine.

4. The agomelatine film according to claim 1, characterized in that: The drug-containing adhesive layer also contains one or more flavoring agents.

5. The agomelatine film according to claim 1, characterized in that: The backing layer also contains one or more flavoring agents.

6. The agomelatine film according to claim 1, characterized in that: The drug-containing adhesive layer comprises 0.5%-25% by weight of agomelatine, 70-95% by weight of a first film-forming material, 1-20% by weight of an oil phase, and 1-15% by weight of a surfactant.

7. The agomelatine film according to claim 6, characterized in that: The drug-containing adhesive layer contains 0.1-10 mg of amorphous agomelatine.

8. The agomelatine film according to claim 1, characterized in that: The drug-containing adhesive layer further comprises an adhesive for improving the adhesion of the film in the oral mucosa.

9. The method for preparing the agomelatine film according to claim 1 is: (a) adding agomelatine, a first film-forming material, an oil phase and a surfactant into a first aqueous solution containing an organic solvent to prepare a drug-containing film-forming solution; (b) uniformly coating the drug-containing film-forming liquid and drying it to form a film to obtain a drug-containing adhesive layer; (c) adding a second film-forming material to water or a second aqueous solution containing an organic solvent to prepare a backing layer film-forming solution; (d) The backing layer film-forming liquid is evenly coated on the prepared drug-containing adhesive layer and dried to form a film, thereby obtaining a double-layer membrane comprising the backing layer and the drug-containing adhesive layer.

10. The method for preparing agomelatine film according to claim 9, characterized in that: The concentration of the organic solvent in the first aqueous solution containing an organic solvent in (a) is 40%-100% w / w; the organic solvent is one or more of ethanol, isopropanol, acetone, tert-butanol, and dichloromethane.

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