Ramelteon sublingual film preparation and method for preparing the same

Abstract

This invention provides a sublingual film preparation comprising ramelteon, a film-forming material, and at least one or more of plasticizers, disintegrants, flavoring agents or sweeteners, and stabilizers, wherein the ramelteon is in an amorphous state, and a method for preparing the same. This invention is the first to develop ramelteon as a sublingual film preparation, thereby allowing ramelteon to be administered via the sublingual mucosa. Because the ramelteon of this invention exists in an amorphous state, it is absorbed more easily. The particle size of the ramelteon in the film preparation is dispersed at the molecular level, resulting in even better absorption. Furthermore, the drug does not easily aggregate and recrystallize, resulting in even better stability. However, it has relatively good solubility, so it can be completely dissolved in water within one minute and is rapidly absorbed by the oral mucosa, achieving the objective of rapid onset of action. The absolute bioavailability is significantly higher than tablets and general film preparations in previous studies (>30%), the onset of action is faster, there is no food interaction, the cost is low, and there are few side effects.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, specifically to sublingual films of ramelteon and its preparation method.

Background Art

[0002] Ramelteon was developed by Takeda Pharmaceutical Company Limited in Japan and was launched in July 2005 under the approval of the US Food and Drug Administration as an oral hypnotic drug, being the first melatonin receptor agonist applied in the clinical treatment of insomnia. It is mainly used to treat insomnia of the difficulty falling asleep type, but also has a definite therapeutic effect on chronic insomnia and short-term insomnia.

[0003] Ramelteon is a melatonin receptor agonist and has a rather high affinity for the MT1 receptor and MT2 receptor of melatonin, thus showing a specific full agonistic effect on the MT1 receptor and MT2 receptor, but does not act on the MT3 receptor. Also, it does not bind to neurotransmitter receptors such as the GABA receptor complex and does not interfere with the activity of many enzymes within a certain range, so it can avoid the attentional distraction associated with GABA drugs as well as drug intoxication and drug dependence. The total amount of M-II, the main metabolite of ramelteon, is 20 - 100 times that of the pre-metabolic drug, but its activity is quite low, and the affinity with the MT1 receptor and MT2 receptor is about 1 / 5 and 1 / 10 of the pre-metabolic drug respectively. Compared with the original drug, its pharmacological activity has decreased by about 17 - 27 times. Other metabolites have no activity.

[0004] Currently, the marketed product of ramelteon is a tablet. Clinical data reveals that ramelteon is rapidly absorbed after oral administration, with a median peak time of approximately 0.75 hours (0.5-1.5 hours). While at least 84% can be absorbed after administration, the first-pass effect reduces its absolute bioavailability to just 1.4%. Furthermore, when taken with a high-fat meal, the AUC is 31% higher than when administered on an empty stomach, the Cmax decreases by 22%, and the median Tmax is delayed by 45 minutes. Therefore, developing new administration methods and selecting appropriate dosage forms to avoid the first-pass effect, increase bioavailability, and shorten the peak time by eliminating the influence of food is critically important when developing new ramelteon formulations.

[0005] Chinese Patent Application Publication No. 110996938 discloses a ramelteon composition that is administered via a mucosal transport system (including intranasal or sublingual), avoids the first-pass effect in the liver, contains sulfobutyl ether-β-cyclodextrin in the formulation, and forms inclusions to increase the solubility of ramelteon. This industrial technology employs wet granulation using ethanol as a solvent, but the steps of the industrial technology are cumbersome, the use of organic solvents pollutes the environment and poses an explosion risk, and the prepared granules are relatively hard and have a distinct gravelly feel in the mouth, resulting in poor patient compliance.

[0006] Chinese Patent Application Publication No. 103429223 discloses an oral mucosal absorption formulation of ramelteon, including sublingual or orally administered formulations, which uses large amounts of insoluble additives, microcrystalline cellulose and pregelatinized starch, in the formulation. However, it has a distinct gritty sensation upon administration and lacks a taste masking agent, resulting in poor patient compliance. Furthermore, the industrial technology for preparation involves the use of a fluidized bed, making the process cumbersome and energy-intensive. The median peak time is approximately 0.6 (0.5-0.8) hours, indicating that the onset of effect is still quite slow.

[0007] Chinese Patent Application Publication No. 112190555 discloses ramelteon sublingual tablets and a method for preparing them. However, both ramelteon and the additives require sieving, which easily generates dust, leading to excessive inhalation by laboratory personnel and causing drowsiness, thus creating production safety problems. The industrial technology for powdering ramelteon and mannitol using a ball mill is cumbersome and unsuitable for industrial production. Sublingual tablets are thicker than the sublingual membrane, dissolve slowly, and are easily washed away with saliva.

[0008] In summary, the drawbacks of conventional ramelteon formulations are: (1) a distinct gritty sensation after administration and poor compliance; (2) complex industrial technology, poor safety, long production cycle, and high energy consumption; (3) significant runoff after disintegration, inaccurate dosage, and large individual differences; and (4) the raw material drug is in a crystalline state and has low solubility in saliva. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] Chinese Patent Application Publication No. 110996938 Specification [Patent Document 2] Chinese Patent Application Publication No. 103429223 Specification [Patent Document 3] Chinese Patent Application Publication No. 112190555 Specification [Overview of the Initiative] [Problems that the invention aims to solve]

[0010] To solve the technical problems described above, the present invention provides a sublingual film formulation of ramelteon and a method for preparing the same. [Means for solving the problem]

[0011] The technical solution of the present invention is The sublingual film preparation comprises ramelteon, a film-forming material, and at least one or more of a plasticizer, a disintegrant, a flavoring agent or sweetener, and a stabilizer, wherein the ramelteon is in an amorphous state.

[0012] In the aforementioned sublingual film preparation, the ramelteon particles in the film preparation are dispersed at the molecular level.

[0013] The aforementioned sublingual film preparation contains ramelteon in a weight percentage of 0.1 to 5%.

[0014] The sublingual film preparation has a film thickness of 5 to 1000 μm, preferably 10 to 500 μm, and a weight of 10 to 400 mg, preferably 10 to 100 mg.

[0015] The sublingual film preparation comprises, when calculated by weight, at least 0.1 to 5 parts by weight of ramelteon, 10 to 99 parts by weight of film-forming material, 0.1 to 20 parts by weight of plasticizer, 0.1 to 20 parts by weight of disintegrant, 0.1 to 10 parts by weight of flavoring or sweetening agent, and 0.0 to 10 parts by weight of stabilizer.

[0016] The sublingual film preparation is characterized in that the film-forming material is selected from one or more of vinylpyrrolidone copolymer, Soluplus®, polyvinylpyrrolidone, hypromellose, polyvinyl alcohol, polyoxyethylene, polyethylene glycol, hydroxypropyl cellulose, and hydroxyethyl cellulose. Preferably, the film-forming material is selected from at least one of vinylpyrrolidone copolymer, polyoxyethylene, and Soluplus. More preferably, the film-forming material is selected from vinylpyrrolidone copolymer and polyoxyethylene.

[0017] The sublingual film agent has a weight ratio of the vinylpyrrolidone copolymer to the polyoxyethylene of 1:(0.25~4), preferably 1:(0.5~2).

[0018] In the sublingual film agent, the plasticizer is selected from one or more of polyethylene glycol, glycerin, propylene glycol, triacetin, triethyl citrate, sorbitol, mannitol, and dibutyl phthalate.

[0019] In the sublingual film agent, the disintegrant is selected from one or more of low-substituted hypromellose, low-substituted hydroxypropyl cellulose, starch, methyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, potassium polyacrylate, and microcrystalline cellulose.

[0020] In the sublingual film agent, the sweetening agent is selected from one or more of aspartame, mannitol, glycerin, fructose, xylitol, sucralose, sorbitol, saccharin, sodium saccharin, stevioside, sucrose, acesulfame potassium, maltitol, sodium cyclamate, alitame, and lactitol.

[0021] In the sublingual film agent, the flavoring agent is selected from one or more of menthol, sodium citrate, trehalose, citric anhydride, essence, ethyl propionate, and diethyl malonate.

[0022] In the sublingual film agent, the stabilizer is selected from one or more of butyl hydroxyanisole, citric acid, dibutyl hydroxytoluene, sodium ascorbate, vitamins, sodium sulfite, and fumaric acid.

[0023] The method for preparing the sublingual film agent is as follows. (1) After weighing the weights of ramelteon, film-forming material, plasticizer, disintegrant, flavoring agent or sweetening agent, and stabilizer, put them into a mixer and mix them. (2) Place it into the equipment that heats and melt-extrudes the mixture at a speed of 0.01 to 100 kg / h, and after extrusion, use a film stretching machine to stretch it into a film. Adjust the rotation speed of the film stretching machine to obtain films with various thicknesses and widths, and (3) The step of cutting the prepared film into film agents with various sizes and shapes by a film cutting machine at least includes.

Advantages of the Invention

[0024] The present invention has the following beneficial effects.

[0025] The present invention first develops lamotrigine as a sublingual film agent, whereby lamotrigine can be administered through the sublingual mucosa. The lamotrigine of the present invention exists in an amorphous state, so it is more easily absorbed. Since the particle size in the film agent of lamotrigine is in a molecular-level dispersion state, the absorption is better, and the drug does not easily aggregate and recrystallize, and has better stability. However, due to its relatively good solubility, it can be completely dissolved in water within 1 minute, and is rapidly absorbed by the oral mucosa to achieve the purpose of rapid onset of effect. The absolute bioavailability is clearly higher than >30% compared with the tablets and general film agents of prior studies, the onset of effect is faster, there is no effect of food, the cost is low, and the side effects are small.

[0026] The drug composition of the present invention is such that by sticking the above-mentioned preparation under the tongue of a subject, the drug is absorbed through the oral mucosa and enters the blood. The absorption is rapid, and compared with the tablets of prior studies (Tmax about 45 minutes), the peak time of the blood drug concentration is significantly shortened (Tmax about 7 minutes) and becomes similar to an injection. In addition, the drug preparation of the present invention is not affected by food, has no gritty feeling, and there is no need to drink water, so the compliance of patients taking the drug is greatly improved.

[0027] The novel industrial technology for film manufacturing employed in this invention enables continuous production, shortens the production cycle, increases yield, reduces energy consumption, reduces production space, lowers costs, and is more environmentally friendly and safe because it does not use organic solvents. Furthermore, compared to solvent-based film agents that cannot form a molecular state distribution, the amorphous film agent of this patent has a faster dissolution rate, resulting in faster absorption in the sublingual mucosa, faster onset of effect, better stability, and less prone to crystal precipitation. [Modes for carrying out the invention]

[0028] Ratio 1 As shown in the table below, the prescription specifies a ramelteon dosage of 0.8 mg, a single dose of 1 ml, and a lot of 1000 vials. The percentage of the total weight of each component used (in grams) is as follows:

[0029] [Table 1]

[0030] Preparation method Approximately 900 ml of water for injection was taken, sodium chloride was added and stirred to dissolve it, then ramelteon was added and stirred until completely dissolved, and the volume was adjusted to 1000 ml using water for injection, and this was divided into 1000 bottles of 1 ml each.

[0031] Ratio Proportionality 2 When preparing a blank film agent to use as a crystalline control sample, the amount of each component used (in grams) is as follows:

[0032] [Table 2]

[0033] process According to the formula, vinylpyrrolidone copolymer, polyoxyethylene, crosslinked polyvinylpyrrolidone, sucralose, sorbitol, and dibutylhydroxytoluene were placed in a mixer and mixed at 12 rpm for 5 minutes. The mixture was then placed in the feeder of a heated melt extruder, with the barrel temperature set to 80°C, 100°C, 130°C, 140°C, 140°C, 140°C, 140°C, 140°C, the opening module temperature to 140°C, the film stretching speed to 2, and the screw rotation speed to 50 rpm. After film formation, the film was cut to the appropriate size and shape and packaged.

[0034] Example 1 Please refer to the table below for the prescription. The standard dose of ramelteon is 2 mg, the weight of one piece is 40 mg, and the lot is 1000 pieces. The percentage of the total weight of each component used (in grams) is as follows:

[0035] [Table 3]

[0036] process According to the formula, ramelteon, Soluplus, polyoxyethylene, microcrystalline cellulose, and sodium saccharin were placed in a mixer and mixed at 12 rpm for 5 minutes. The mixture was then placed in the feeder of a heated melt extruder, and glycerin was slowly added to the barrel using a peristaltic pump. The barrel temperature was set to 80°C, 100°C, 120°C, 130°C, 130°C, 130°C, 130°C, 130°C, the opening module temperature to 130°C, the film stretching speed to 3, and the screw rotation speed to 20 rpm. After film formation, the film was cut to the appropriate size and shape and packaged.

[0037] result The ramelteon orally soluble film prepared by the above-described formulation and process exhibited good film-forming properties, a smooth surface, uniform color and gloss, a rapid disintegration rate, good mechanical properties, and the presence of the drug in an amorphous state.

[0038] Disintegration time: Measured using the disintegration time testing method described in Appendix 0921 of the 2020 edition of the "Chinese Pharmacopoeia".

[0039] [Table 4]

[0040] Tensile test data

[0041] [Table 5]

[0042] Example 2 Please refer to the table below for the prescription. The standard dose of ramelteon is 2 mg, the weight of one piece is 40 mg, and the lot is 1000 pieces. The percentage of the total weight of each component used (in grams) is as follows:

[0043] [Table 6]

[0044] process According to the formula, ramelteon, hypromellose, and aspartame were placed in a mixer and mixed at 12 rpm for 5 minutes. Then the mixture was placed in the feeder of a heated melt extruder, and propylene glycol was slowly added to the barrel using a peristaltic pump. The barrel temperature was set to 100°C, 150°C, 170°C, 170°C, 170°C, 170°C, 170°C, 170°C, the opening module temperature to 170°C, the film stretching speed to 2, and the screw rotation speed to 20 rpm. After film formation, the film was cut to the appropriate size and shape and packaged.

[0045] result The ramelteon film preparation prepared by the above-described formulation and process exhibited good film-forming properties, a smooth surface, uniform color and gloss, a rapid disintegration rate, good mechanical properties, and the presence of the drug in an amorphous state.

[0046] Disintegration time: Measured using the disintegration time testing method described in Appendix 0921 of the 2020 edition of the "Chinese Pharmacopoeia".

[0047] [Table 7]

[0048] Tensile test data

[0049] [Table 8]

[0050] Example 3 Please refer to the table below for the prescription. The standard dose of ramelteon is 2 mg, the weight of one piece is 40 mg, and the lot is 1000 pieces. The percentage of the total weight of each component used (in grams) is as follows:

[0051] [Table 9]

[0052] process According to the formula, ramelteon, Soluplus, sorbitol, cross-linked carboxymethylcellulose sodium, and sucralose were placed in a mixer and mixed at 12 rpm for 5 minutes. The mixture was then placed in the feeder of a heated melt extruder, with the barrel temperature set to 50°C, 70°C, 90°C, 100°C, 100°C, 100°C, 100°C, 100°C, the opening module temperature to 100°C, the film stretching speed to 1.5, and the screw rotation speed to 20 rpm. After film formation, the film was cut to the appropriate size and shape and packaged.

[0053] result The ramelteon film preparation prepared by the above-described formulation and process exhibited good film-forming properties and a rapid disintegration rate, but granules were present on the surface and the drug existed in crystalline form.

[0054] Disintegration time: Measured using the disintegration time testing method described in Appendix 0921 of the 2020 edition of the "Chinese Pharmacopoeia".

[0055] Melting curve

[0056] [Table 10]

[0057] [Table 11]

[0058] Tensile test data

[0059] [Table 12]

[0060] Example 4 Film preparations of various thicknesses were prepared. The differences in mechanical performance, elution time, and disintegration time of these films of different thicknesses were compared, calculated based on a lot size of 1000 pieces. The amount of each component used (in grams) is as follows:

[0061] [Table 13]

[0062] process According to the formula, ramelteon, vinylpyrrolidone copolymer, polyoxyethylene, cross-linked polyvinylpyrrolidone, sucralose, sorbitol, and dibutylhydroxytoluene were placed in a mixer and mixed at 12 rpm for 5 minutes. The mixture was then placed in the feeder of a heated melt extruder, with the barrel temperature set to 80°C, 100°C, 130°C, 140°C, 140°C, 140°C, 140°C, and the opening module temperature set to 140°C. The screw rotation speed was set to 50 rpm, and the film stretching speed was adjusted within the range of 1 to 5 to obtain films of various thicknesses. After film formation, the films were cut to appropriate sizes and shapes and packaged.

[0063] result The ramelteon film preparations of various thicknesses prepared by the above-described formulation and process exhibited good film-forming properties, a smooth surface, and uniform color and gloss.

[0064] Melting curve

[0065] [Table 14]

[0066] Disintegration time: Measured using the disintegration time testing method described in Appendix 0921 of the 2020 edition of the "Chinese Pharmacopoeia".

[0067] [Table 15]

[0068] Tensile test data

[0069] [Table 16]

[0070] Film formulations ranging in thickness from 10 to 500 μm can all form films and exhibit good film-forming properties. However, even a 10 μm film is relatively flexible, and its mechanical properties are considerably lower. Further reductions in thickness may affect the transport and administration of the film. Due to its greater thickness, the 500 μm film has a disintegration time approaching 5 minutes (according to the 2020 edition of the "Chinese Pharmacopoeia").

[0071] Example 5 Film formulations of various sizes were prepared, and the effect of the proportion of various raw materials in the total amount on the properties of the film was compared, along with the absorption status in the bodies of animals. Please refer to the table below for the percentages (in units: %) of each component in the formulation.

[0072] Formulation 1: Standard amount 0.1 mg, weight per piece 100 mg, raw material content 0.1%, lot quantity 1000 pieces Formulation 2: Standard amount 0.3mg, weight per piece 30mg, raw material content 1.0%, lot quantity 1000 pieces Formulation 3: Standard amount 0.8mg, weight per piece 20mg, raw material content 4.0%, lot quantity 1000 pieces Formulation 4: Standard dose 2.0 mg, weight per piece 40 mg, raw material content 5.0%, lot quantity 1000 pieces Formulation 5: Standard amount 8.0 mg, weight per piece 80 mg, raw material content 10.0%, lot quantity 1000 pieces

[0073] [Table 17]

[0074] process According to the formula, ramelteon, vinylpyrrolidone copolymer, polyoxyethylene, cross-linked polyvinylpyrrolidone, sucralose, sorbitol, and dibutylhydroxytoluene were placed in a mixer and mixed at 12 rpm for 5 minutes. The mixture was then placed in the feeder of a heated melt extruder, with the barrel temperature set to 80°C, 100°C, 130°C, 140°C, 140°C, 140°C, 140°C, 140°C, the opening module temperature to 140°C, the film stretching speed to 2.5, and the screw rotation speed to 50 rpm. After film formation, the film was cut to the appropriate size and shape and packaged.

[0075] result The ramelteon film preparation prepared by the above-described formulation and process exhibits good film-forming properties, a smooth surface, uniform color and gloss, and a rapid disintegration rate.

[0076] Melting curve

[0077] [Table 18]

[0078] Disintegration time: Measured using the disintegration time testing method described in Appendix 0921 of the 2020 edition of the "Chinese Pharmacopoeia".

[0079] [Table 19]

[0080] Tensile test data

[0081] [Table 20]

[0082] Stability Measurement: After packaging, the products were left at 60°C / 75% relative humidity and the relevant substances were measured after 1 week and 2 weeks, respectively. Please refer to the following for various results.

[0083] [Table 21]

[0084] In light of the results of Example 5, the differences in disintegration times among formulations with various drug concentrations were not significant (the differences were mainly due to thickness), and all formulations disintegrated and dispersed rapidly, as well as dissolved rapidly. Rapid stability experiments showed that all five formulations were stable, and no significant degradation occurred.

[0085] Example 6 Film preparations were made with various ratios of film-forming materials, and the effect of these ratios on the properties of the film was compared by calculating the results for a lot of 1000 pieces. The amount of each component used (in grams) is as follows:

[0086] Formula 6: Standard amount 0.8mg, weight per piece 20mg, raw material content 4.0%, lot quantity 1000 pieces Formula 7: Standard amount 0.4 mg, weight per piece 10 mg, raw material content 4.0%, lot quantity 1000 pieces

[0087] [Table 22]

[0088] process According to the formula, ramelteon, vinylpyrrolidone copolymer, polyoxyethylene, cross-linked polyvinylpyrrolidone, sucralose, sorbitol, and dibutylhydroxytoluene were placed in a mixer and mixed at 12 rpm for 5 minutes. The mixture was then placed in the feeder of a heated melt extruder, with the barrel temperature set to 80°C, 100°C, 130°C, 140°C, 140°C, 140°C, 140°C, 140°C, the opening module temperature to 140°C, the film stretching speed to 2, and the screw rotation speed to 50 rpm. After film formation, the film was cut to the appropriate size and shape and packaged.

[0089] result The ramelteon film preparation prepared by the above-described formulation and process exhibited good film-forming properties, a smooth surface, uniform color and gloss, and a rapid disintegration rate.

[0090] Disintegration time: Measured using the disintegration time testing method described in Appendix 0921 of the 2020 edition of the "Chinese Pharmacopoeia".

[0091] [Table 23]

[0092] Tensile test data

[0093] [Table 24]

[0094] Within a mixing ratio of vinylpyrrolidone copolymer to polyoxyethylene in the range of 1:(0.25~4), films could be formed in all cases, and the industrial technology was feasible. Film agents with a high proportion of vinylpyrrolidone copolymer had high mechanical strength but slightly poor ductility. Film agents with a high proportion of polyoxyethylene had low mechanical strength and poor ductility.

[0095] Example 7 Six healthy male beagle dogs weighing 12 ± 1.0 kg were selected. No drugs were administered for 14 days prior to the experiment. Fasting began at 8 PM the day before the experiment, and on the day of the experiment at 9 AM, drugs were administered intravenously (a proportional 1 sample), orally (ROZEREM, 8 mg standard dose from previous studies), and sublingually (prescriptions 2, 3, 4, and 5). Blood drug concentrations were measured. After the measurements were completed, a 14-day washout period was performed. The administration was repeated, and blood drug concentrations were measured again. Tmax, Cmax, and AUC were compared for various drug administration methods. Sampling times were 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 6 hours.

[0096] [Table 25]

[0097] The data from Example 7 revealed that oral absorption can increase the bioavailability of ramelteon. The sublingual film showed a relative bioavailability nearly 29 times higher than that of tablets in previous studies, and the peak time was shortened to 7 minutes, approaching that of the injectable form. Furthermore, the performance of the sublingual film of this patent is superior to that of tablets in previous studies, and it was revealed that a smaller dosage is needed for similar effects, and sleep onset occurs even more rapidly.

[0098] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention are all within the scope of protection of the present invention.

Claims

1. A sublingual film preparation comprising ramelteon, a film-forming material, and at least one or more of a plasticizer, a disintegrant, a flavoring agent or sweetener, and a stabilizer, wherein the ramelteon is in an amorphous state.

2. The sublingual film preparation according to claim 1, characterized in that the particle size of ramelteon in the film preparation is in a molecular state dispersion.

3. The sublingual film preparation according to claim 1, characterized in that the ramelteon content is 0.1 to 5% by weight.

4. The sublingual film preparation according to claim 1, characterized in that the thickness of the film preparation is 5 to 1000 μm, preferably 10 to 500 μm, and the weight of the film preparation is 10 to 400 mg, preferably 10 to 100 mg.

5. The sublingual film preparation according to claim 1, characterized in that it contains at least 0.1 to 5 parts by weight of rameltheon, 10 to 99 parts by weight of film-forming material, 0.1 to 20 parts by weight of plasticizer, 0.1 to 20 parts by weight of disintegrant, 0.1 to 10 parts by weight of flavoring or sweetening agent, and 0.0 to 10 parts by weight of stabilizer.

6. The sublingual film preparation according to claim 1, wherein the film-forming material is selected from one or more of vinylpyrrolidone copolymer, Soluplus®, polyvinylpyrrolidone, hypromellose, polyvinyl alcohol, polyoxyethylene, polyethylene glycol, hydroxypropylcellulose, and hydroxyethylcellulose, preferably the film-forming material is selected from at least one of vinylpyrrolidone copolymer, polyoxyethylene, and Soluplus, and more preferably the film-forming material is selected from vinylpyrrolidone copolymer and polyoxyethylene.

7. The sublingual film preparation according to claim 6, characterized in that the weight ratio of the vinylpyrrolidone copolymer to the polyoxyethylene is 1:(0.25 to 4), and preferably, the weight ratio of the vinylpyrrolidone copolymer to the polyoxyethylene is 1:(0.5 to 2).

8. The sublingual film preparation according to claim 1, characterized in that the plasticizer is selected from one or more of polyethylene glycol, glycerin, propylene glycol, triacetin, triethyl citrate, sorbitol, mannitol, and dibutyl phthalate.

9. The sublingual film preparation according to claim 1, characterized in that the disintegrant is selected from one or more of the following: low-substituted hypromellose, low-substituted hydroxypropylcellulose, starch, methylcellulose, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose sodium, polaricrin potassium, and microcrystalline cellulose.

10. The sublingual film preparation according to claim 1, characterized in that the sweetener is selected from one or more of aspartame, mannitol, glycerin, fructose, xylitol, sucralose, sorbitol, saccharin, sodium saccharin, stevioside, sucrose, acesulfame potassium, maltitol, sodium cyclamate, alitame, and lactitol.

11. The sublingual film preparation according to claim 1, characterized in that the flavoring agent is selected from one or more of menthol, sodium citrate, trehalose, anhydrous citric acid, fragrance essence, ethyl propionate, and diethyl malonate.

12. The sublingual film preparation according to claim 1, characterized in that the stabilizer is selected from one or more of butylhydroxyanisole, citric acid, dibutylhydroxytoluene, sodium ascorbate, vitamin, sodium sulfite, and fumaric acid.

13. (1) After weighing the ramelteon, film-forming material, plasticizer, disintegrant, flavoring agent or sweetener, and stabilizer, put them in a mixer and mix them. (2) The steps of placing the mixture into equipment that heats, melts, and extrudes it at a speed of 0.01 to 100 kg / h, stretching it after extrusion using a film stretcher to form a film, adjusting the rotation speed of the film stretcher to obtain films of various thicknesses and widths, and (3) A step in which the prepared film is cut into film materials of various sizes and shapes using a film cutting machine. A method for preparing a sublingual film preparation according to any one of claims 1 to 12, characterized by comprising at least [a certain element].

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