A tetrodoxin oral film preparation and its preparation and application

Abstract

The present invention belongs to the field of medicine and provides a tetrodoxin oral film and a preparation method thereof. The oral film comprises an active ingredient, a cosolvent, a film-forming material, a filler, a plasticizer, and a disintegrant; the active ingredient comprises tetrodoxin. The oral film exhibits beneficial effects such as a smooth and uniform surface, good toughness, high folding resistance, fast disintegration time, good stability, a good antidepressant effect, and low toxic side effects.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a tetrodotoxin oral membrane preparation and a preparation and application thereof. Background Art

[0002] Depression is a mental disorder that seriously affects the quality of human life. Its pathogenesis is complex, and there are many risk factors for the disease. The incidence rate is increasing year by year, and it has become a global health problem. Existing treatments for depression mainly include psychotherapy, drug therapy, and electroconvulsive therapy. For patients with relatively mild symptoms, psychotherapy is used to relieve depressive symptoms. Electroconvulsive therapy is mainly used to relieve depression in patients who have not responded to drug treatment. However, in most cases, drug treatment remains the most important and most commonly used treatment for depression. Although an increasing number of antidepressants have been used to treat clinical depression, their side effects are significant and their efficacy is not very ideal. Therefore, the development of new antidepressants has always been a research hotspot.

[0003] Tetrodotoxin (abbreviated as TTX; chemical name: octahydro-12-(hydroxymethyl)-2-imino-5,9:7,10a-dimethyl-10a-hydro-[1,3]dioxo[6,5-d]pyrimidine-4,7,10,11,12-pentanol, molecular formula: C 11 H 17 N3O8, with a molecular weight of 319.27, is a voltage-gated sodium channel (VGSCs) blocker that binds to VGSCs to prevent sodium ions from entering cells, blocking the depolarization and conduction of nerve cell action potentials, thereby inhibiting nerve and muscle excitatory activity, causing paralysis and loss of sensation. Sodium channels have multiple subtypes, distributed in different tissues and organs. For example, Nav1.1, Nav1.2, and Nav1.3 subtypes are highly expressed in the central nervous system (CNS), most Nav1.4 subtypes are located in skeletal muscle, Nav1.5 subtypes are mainly located in the heart, Nav1.6 subtypes are widely distributed in neurons of the central and peripheral nervous systems, Nav1.7 subtypes are distributed in the peripheral nervous system and sympathetic nerves, and Nav1.8 and Nav1.9 are expressed in dorsal root ganglion neurons. In addition, tetrodoxin can specifically bind to L-type calcium channels in human cardiomyocytes, inhibiting nerve excitation and conduction, and affecting a range of physiological processes, including central nervous system function regulation, smooth muscle motility, heartbeat, skeletal muscle contraction, and hormone secretion. It is precisely because tetrodoxin selectively acts on sodium ion channels, inhibiting nerve and muscle excitation and leading to a series of physiological and biochemical reactions that tetrodoxin possesses multiple biological activities, including analgesia, anesthesia, antiarrhythmia, antihypertensive, and drug addiction treatment.

[0004]

[0005] Oral films are oral preparations made by dissolving or evenly dispersing a dose of drug in a film-forming material. These preparations disintegrate in the mouth upon contact with a small amount of saliva, eliminating the need for chewing or swallowing with water. They are a novel rapid-release drug formulation with advantages such as ease of swallowing and rapid onset of action, making them particularly suitable for patients who have difficulty swallowing traditional solid dosage forms. Furthermore, their viscosity makes them difficult to spit out, making them portable and easy to use, allowing them to be taken anytime, anywhere. They are particularly suitable for children and patients with mental illnesses, improving patient compliance.

[0006] The Chronic Unpredictable Animal Stress (CUMS) model simulates some stressors, external physical and environmental stimuli, and the individual's internal environment, such as water deprivation, food deprivation, and sensory deprivation. Over three weeks of stress can cause animals to exhibit reduced motor skills, anhedonia, and elevated plasma corticosteroids, symptoms similar to those of human depression. This realistically simulates some of the causes and symptoms of depression, making it an ideal and reliable animal model for depression. Therefore, by subjecting mice to the recognized chronic unpredictable mild stress model and CUMS modeling, along with drug administration, behavioral assessments and measurements of 5-HT levels in the mouse brain can accurately assess the antidepressant effects of drugs.

[0007] Fluoxetine is a selective serotonin (5-HT) reuptake inhibitor that treats depression primarily by inhibiting 5-HT reuptake by synaptic cells, thereby increasing extracellular 5-HT levels. Fluoxetine has long been a first-line treatment for depression due to its compliance, safety, efficacy (similar to that of tricyclic antidepressants), and effectiveness in a large proportion of patients with depression. It is often used as a positive drug in antidepressant model screening trials.

[0008] The problem to be solved by the present invention is that existing drugs for treating depression have large side effects, unsatisfactory efficacy, and treatment results do not meet expectations and cannot meet clinical needs.

[0009] Therefore, there is still an urgent need in the art for an antidepressant drug with fewer side effects, good effects, and good storage stability for treating depression. Summary of the Invention

[0010] In order to solve the above technical problems, the present invention provides the following technical solutions.

[0011] In a first aspect, the present invention provides an oral film.

[0012] An oral film comprises an active ingredient, a solubilizing agent, a film-forming material, a filler, a plasticizer, and a disintegrant; the active ingredient comprises tetrodoxin; the solubilizing agent comprises an organic acid; the film-forming material comprises at least one of gelatin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, polyvinyl alcohol, and a polyvinyl alcohol / polyethylene glycol copolymer; the filler comprises at least one of soluble starch, β-cyclodextrin, and maltodextrin; the plasticizer comprises at least one of polyethylene glycol 400, triglyceride citric acid, and glycerol; and the disintegrant comprises at least one of pregelatinized starch, sodium alginate, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

[0013] In some embodiments, the organic acid includes at least one of citric acid, formic acid, acetic acid, propionic acid, n-butyric acid, malic acid, tartaric acid, and the like.

[0014] In some embodiments, the active ingredient is present in an amount of 0.01 wt% to 0.90 wt% based on the total weight of the oral film. In some embodiments, the active ingredient is present in an amount of 0.01 wt%, 0.09 wt%, 0.10 wt%, 0.15 wt%, 0.20 wt%, 0.30 wt%, 0.40 wt%, 0.50 wt%, 0.60 wt%, 0.70 wt%, 0.80 wt% or 0.90 wt% based on the total weight of the oral film.

[0015] In some embodiments, the content of the co-solvent is 0.10 wt% to 5.00 wt%, calculated based on the total weight of the oral film. In some embodiments, the content of the co-solvent is 0.10 wt%, 0.20 wt%, 0.30 wt%, 0.40 wt%, 0.50 wt%, 0.70 wt%, 0.80 wt%, 0.90 wt%, 1.00 wt%, 1.50 wt%, 2.00 wt%, 2.50 wt%, 3.00 wt%, 3.50 wt%, 4.00 wt%, 4.50 wt% or 5.00 wt%, calculated based on the total weight of the oral film.

[0016] In some embodiments, the content of the film-forming material is 31.50 wt% to 47.00 wt% based on the total weight of the oral film. In some embodiments, the content of the film-forming material is 31.50 wt%, 35.00 wt%, 36.00 wt%, 36.25 wt%, 40.00 wt%, 41.39 wt%, 41.50 wt%, 42.00 wt%, 43.00 wt%, 43.50 wt%, 44.00 wt%, 44.01 wt%, 44.09 wt%, 44.10 wt%, 44.50 wt%, 45.00 wt%, 46.00 wt%, 46.09 wt% or 47.00 wt% based on the total weight of the oral film.

[0017] In some embodiments, the content of the hypromellose is 27.00 wt%-37.00 wt% based on the total mass of the oral film. In some embodiments, the content of the hypromellose is 27.00 wt%, 27.10 wt%, 27.20 wt%, 27.21 wt%, 27.25 wt%, 27.30 wt%, 27.40 wt%, 27.50 wt%, 28.00 wt%, 29.00 wt%, 30.00 wt%, 31.00 wt%, 32.00 wt%, 33.00 wt%, 34.00 wt%, 35.00 wt%, 36.00 wt%, 37.00 wt%, 38.00 wt%, 39.00 wt%, 40.00 wt%, 41.00 wt%, 42.00 wt%, 43.00 wt%, 44.00 wt%, 45.00 wt%, 46.00 wt%, 47.00 wt%, 48.00 wt%, 49.00 wt%, 50.00 wt%, 51.00 wt%, 52.00 wt%, 53.00 wt%, 54.00 wt%, 55.00 wt%, 56.00 wt%, 57.00 wt%, 58.00 wt%, 59.00 wt%, 60.00 wt%, 61.00 wt%, 62.00 wt%, 63.00 wt%, 64.00 wt%, 65.00 wt%, 66.00 wt%, 67.00 wt%, 68.00 wt%, 69.00 wt%, 70.00 3.00wt%, 34.00wt%, 34.10wt%, 34.20wt%, 34.30wt%, 34.40wt%, 34.50wt%, 35.00wt%, 35.09wt%, 36.00wt%, 36.50wt%, 36.60wt%, 36.70wt%, 36.80wt%, 36.89wt%, 36.90wt% or 37.00wt%.

[0018] In some embodiments, the content of hydroxypropyl cellulose is 4.00 wt%-10.00 wt% based on the total weight of the oral film. In some embodiments, the content of hydroxypropyl cellulose is 4.00 wt%, 4.50 wt%, 5.00 wt%, 6.00 wt%, 7.00 wt%, 8.00 wt%, 9.00 wt% or 10.00 wt% based on the total weight of the oral film.

[0019] In some embodiments, the content of the filler is 4.50 wt% to 15.00 wt% based on the total weight of the oral film. In some embodiments, the content of the filler is 4.50 wt%, 5.00 wt%, 6.00 wt%, 7.00 wt%, 8.00 wt%, 9.00 wt%, 10.00 wt%, 11.00 wt%, 12.00 wt%, 13.00 wt%, 14.00 wt% or 15.00 wt% based on the total weight of the oral film.

[0020] In some embodiments, the content of the plasticizer is 10.00 wt% to 18.00 wt% based on the total weight of the oral film. In some embodiments, the content of the plasticizer is 10.00 wt%, 11.00 wt%, 12.00 wt%, 13.00 wt%, 14.00 wt%, 15.00 wt%, 16.00 wt%, 17.00 wt% or 18.00 wt% based on the total weight of the oral film.

[0021] In some embodiments, the content of the disintegrant is 25.00 wt% to 36.00 wt% based on the total weight of the oral film. In some embodiments, the content of the disintegrant is 25.00 wt%, 26.00 wt%, 27.00 wt%, 28.00 wt%, 29, 30.00 wt%, 30.00 wt%, 31.00 wt%, 32.00 wt%, 33.00 wt%, 34.00 wt%, 35.00 wt% or 36.00 wt% based on the total weight of the oral film.

[0022] In some embodiments, the cosolvent is acetic acid; the film-forming material is hydroxypropyl methylcellulose and hydroxypropyl cellulose; the filler is maltodextrin; the plasticizer is glycerol; and the disintegrant is pregelatinized starch and low-substituted hydroxypropyl cellulose.

[0023] In some embodiments, the co-solvent is acetic acid; the film-forming material is hydroxypropyl methylcellulose and hydroxypropyl cellulose; the filler is maltodextrin; the plasticizer is glycerol; the disintegrant is pregelatinized starch and low-substituted hydroxypropyl cellulose; calculated based on the total mass of the oral film, the content of the active ingredient is 0.01wt% to 0.90wt%, the content of the co-solvent is 0.10wt% to 5.00wt%, the content of the film-forming material is 31.50wt% to 47.00wt%, the content of the filler is 4.50wt% to 15.00wt%, the content of the plasticizer is 10.00wt% to 18.00wt%, and the content of the disintegrant is 25.00wt% to 36.00wt%.

[0024] In some embodiments, the co-solvent is acetic acid; the film-forming material is hydroxypropyl methylcellulose and hydroxypropyl cellulose; the filler is maltodextrin; the plasticizer is glycerol; the disintegrant is pregelatinized starch and low-substituted hydroxypropyl cellulose; calculated based on the total mass of the oral film, the content of the active ingredient is 0.01wt% to 0.90wt%, the content of the co-solvent is 0.10wt% to 5.00wt%, the content of the film-forming material is 36.20wt%-44.10wt%, the content of the filler is 4.50wt% to 15.00wt%, the content of the plasticizer is 10.00wt% to 18.00wt%, and the content of the disintegrant is 25.00wt% to 36.00wt%.

[0025] In some embodiments, the co-solvent is acetic acid; the film-forming material is hydroxypropyl methylcellulose and hydroxypropyl cellulose; the filler is maltodextrin; the plasticizer is glycerol; the disintegrant is pregelatinized starch and low-substituted hydroxypropyl cellulose; calculated based on the total mass of the oral film, the content of the active ingredient is 0.01wt% to 0.90wt%, the content of the co-solvent is 0.10wt% to 5.00wt%, the content of the film-forming material is 36.25wt5-44.10wt%, the content of the filler is 4.50wt% to 15.00wt%, the content of the plasticizer is 10.00wt% to 18.00wt%, and the content of the disintegrant is 25.00wt% to 36.00wt%.

[0026] In some embodiments, the cosolvent is acetic acid; the film-forming material is hydroxypropyl methylcellulose and hydroxypropyl cellulose; the filler is maltodextrin; the plasticizer is glycerol; the disintegrant is pregelatinized starch and low-substituted hydroxypropyl cellulose; calculated based on the total mass of the oral film, the content of the active ingredient is 0.05wt%, the content of the cosolvent is 0.70wt%, the content of the hydroxypropyl methylcellulose is 27.25wt%, the content of the hydroxypropyl cellulose is 9.00wt%, the content of the filler is 9.00wt%, the content of the plasticizer is 18.00wt%, the content of the pregelatinized starch is 18.00wt%, and the content of the low-substituted hydroxypropyl cellulose is 18.00wt%.

[0027] In some embodiments, the cosolvent is acetic acid; the film-forming material is hydroxypropyl methylcellulose and hydroxypropyl cellulose; the filler is maltodextrin; the plasticizer is glycerol; the disintegrant is pregelatinized starch and low-substituted hydroxypropyl cellulose; calculated based on the total mass of the oral film, the content of the active ingredient is 0.01wt%, the content of the cosolvent is 0.10wt%, the content of the hydroxypropyl methylcellulose is 36.89wt%, the content of the hydroxypropyl cellulose is 4.50wt%, the content of the filler is 4.50wt%, the content of the plasticizer is 18.00wt%, the content of the pregelatinized starch is 18.00wt%, and the content of the low-substituted hydroxypropyl cellulose is 18.00wt%.

[0028] In some embodiments, the cosolvent is acetic acid; the film-forming material is hydroxypropyl methylcellulose and hydroxypropyl cellulose; the filler is maltodextrin; the plasticizer is glycerol; the disintegrant is pregelatinized starch and low-substituted hydroxypropyl cellulose; calculated based on the total mass of the oral film, the content of the active ingredient is 0.90wt%, the content of the cosolvent is 5.00wt%, the content of the hydroxypropyl methylcellulose is 34.10wt%, the content of the hydroxypropyl cellulose is 10.00wt%, the content of the filler is 15.00wt%, the content of the plasticizer is 10.00wt%, the content of the pregelatinized starch is 12.50wt%, and the content of the low-substituted hydroxypropyl cellulose is 12.50wt%.

[0029] In some embodiments, the cosolvent is acetic acid; the film-forming material is hydroxypropyl methylcellulose and hydroxypropyl cellulose; the filler is maltodextrin; the plasticizer is glycerol; the disintegrant is pregelatinized starch and low-substituted hydroxypropyl cellulose; calculated based on the total mass of the oral film, the content of the active ingredient is 0.01wt%, the content of the cosolvent is 0.90wt%, the content of the hydroxypropyl methylcellulose is 35.09wt%, the content of the hydroxypropyl cellulose is 9.00wt%, the content of the filler is 15.00wt%, the content of the plasticizer is 10.00wt%, the content of the pregelatinized starch is 15.00wt%, and the content of the low-substituted hydroxypropyl cellulose is 15.00wt%.

[0030] In some embodiments, the oral film is prepared by a coating method or a casting method.

[0031] In a second aspect, the present invention provides a method for preparing the oral film according to the first aspect.

[0032] A method for preparing the oral film according to the first aspect, comprising:

[0033] 1) mixing a film-forming material, a filler and water to obtain a polymer solution;

[0034] 2) mixing the active ingredient and the aqueous solution containing the cosolvent to obtain a mixed solution 1;

[0035] 3) adding a plasticizer and a water-dispersible disintegrant to the polymer solution, and then mixing with the mixed solution 1 to obtain a drug-containing mixture;

[0036] 4) Degas the drug-containing mixture, then coat or cast it on a glass plate or stainless steel plate, and heat and dry it;

[0037] 5) demoulding and cutting to obtain the oral film.

[0038] In some embodiments, the mass ratio of the total mass of the membrane-forming material and the filler in the polymer solution to water is 1:5-1:8. In some embodiments, the mass ratio of the total mass of the membrane-forming material and the filler in the polymer solution to water is 1:5, 1:6, 1:7 or 1:8.

[0039] In some embodiments, the mass ratio of the total mass of the disintegrant to water is 1:6-1:10. In some embodiments, the mass ratio of the total mass of the disintegrant to water is 1:6, 1:7, 1:8, 1:9 or 1:10.

[0040] In some embodiments, the content of the co-solvent in the aqueous solution containing the co-solvent is 0.1 wt%-0.5 wt%. In some embodiments, the content of the co-solvent in the aqueous solution containing the co-solvent is 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt% or 0.5 wt%.

[0041] In some embodiments, the drying temperature of the heat drying is 40-60° C. In some embodiments, the drying temperature of the heat drying is 40° C., 45° C., 50° C., 55° C., or 60° C.

[0042] In some embodiments, the drying time of the heat drying is 30 min-60 min. In some embodiments, the drying time of the heat drying is 30 min, 35 min, 40 min, 45 min, 50 min, 55 min or 60 min.

[0043] In a third aspect, the present invention provides a use of the oral film described in the first aspect or the oral film obtained by the method described in the second aspect.

[0044] A use of the oral film of the first aspect or the oral film obtained by the method of the second aspect in the preparation of antianxiety, antidepression or sedative drug.

[0045] Beneficial effects

[0046] Compared with the prior art, an embodiment of the present invention has at least one of the following beneficial effects:

[0047] The oral film provided by the present invention has the beneficial effects of smooth and uniform surface, good toughness, high folding resistance, fast disintegration time, good stability, good antidepressant effect, low toxic and side effects, and the like.

[0048] Definition of terms:

[0049] In the foregoing text of the present invention, all numerical values ​​disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. Based on the disclosed numbers, the value of each numerical value may vary by less than ±10% or by a reasonable difference deemed by a person skilled in the art, such as ±1%, ±2%, ±3%, ±4%, or ±5%.

[0050] In the present invention, normal temperature or room temperature refers to ambient temperature, which may be 20°C-30°C; in some embodiments, 22°C-28°C; in some embodiments, 24°C-26°C; in some embodiments, 25°C.

[0051] The terms "above", "below", "within", etc. are understood to include the number itself, for example, more than two means ≥ two.

[0052] The term "and / or" should be understood to mean any one of the options or a combination of any two or more of the options.

[0053] The term "wt%" stands for mass percentage.

[0054] The term "plurality" refers to a number of 2 or more, such as 2, 3, 4 or 5.

[0055] "TTX" herein means tetrodotoxin.

[0056] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction. DETAILED DESCRIPTION

[0057] The following examples are provided to further illustrate the present invention, but are not intended to limit the scope of the present invention.

[0058] All technical terms used in the present invention have the same meanings as those generally understood by those skilled in the art in the field of the present invention. The "and" / "or" used in the present invention includes any and all combinations of one or more related listed items.

[0059] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0060] Example 1-Example 4: Tetrodoxin Oral Film

[0061] Prescription: See Table 1

[0062] Table 1 Prescription and performance test results of the tetrodotoxin oral film of Examples 1 to 4

[0063]

[0064]

[0065] Preparation method:

[0066] 1) mixing a film-forming material, a filler, and water to obtain a polymer solution, wherein the mass ratio of the total mass of the film-forming material and the filler in the polymer solution to the mass ratio of water is 1:5;

[0067] 2) mixing the active ingredient and an aqueous solution containing a cosolvent to obtain a mixed solution 1; the cosolvent content in the aqueous solution containing the cosolvent is 0.3 wt%;

[0068] 3) adding a plasticizer and a disintegrant dispersed in water to the polymer solution, wherein the mass ratio of the total mass of the disintegrant to the mass of water is 1:8; and then mixing with the mixed solution 1 to obtain a drug-containing mixture;

[0069] 4) Degassing the drug-containing mixture, then coating it on a glass plate, and heating and drying it at a temperature of 50° C. for 40 minutes;

[0070] 5) demoulding and cutting to obtain the oral film.

[0071] Quality testing: The obtained oral films were tested for appearance, folding resistance, active ingredient content (the percentage of the active ingredient tested amount to the active ingredient dosage), film thickness, and disintegration time. The results are shown in Table 1.

[0072] Comparative Example 1-Comparative Example 3: Investigation of film-forming materials

[0073] Prescription: See Table 2.

[0074] Table 2 Investigation formula of film-forming materials

[0075]

[0076]

[0077] Preparation method: Same as Example 1.

[0078] Quality testing: The obtained oral films were tested for appearance, folding resistance, active ingredient content (the percentage of the active ingredient tested amount to the active ingredient dosage), film thickness, and disintegration time. The results are shown in Table 2.

[0079] Conclusion: Compared with other film-forming materials, the film-forming materials provided by the present invention (hydroxypropyl methylcellulose and hydroxypropyl cellulose) have a synergistic effect, which is more conducive to improving the appearance of the obtained oral film, increasing the folding resistance, and accelerating the disintegration time.

[0080] Comparative Examples 4-6: Investigation of Fillers

[0081] Prescription: See Table 3.

[0082] Table 3: Filler formulations investigated

[0083]

[0084] Preparation method: Same as Example 1.

[0085] Quality testing: The obtained oral films were tested for appearance, folding resistance, active ingredient content (the percentage of the active ingredient tested amount to the active ingredient dosage), film thickness, and disintegration time. The results are shown in Table 3.

[0086] Conclusion: Compared with other fillers, the filler (maltodextrin) provided by the present invention is more conducive to improving the folding resistance and toughness of the obtained oral film.

[0087] Comparative Examples 7-9: Investigation of Disintegrants

[0088] Prescription: See Table 4.

[0089] Table 4: Investigation of disintegrant formulations

[0090]

[0091] Preparation method: Same as Example 1.

[0092] Quality testing: The obtained oral films were tested for appearance, folding resistance, active ingredient content (the percentage of the active ingredient tested amount to the active ingredient dosage), film thickness, and disintegration time. The results are shown in Table 4.

[0093] Conclusion: Compared with other disintegrants, the disintegrants provided by the present invention (pregelatinized starch and low-substituted hydroxypropyl cellulose) have a synergistic effect and are more conducive to improving the folding resistance and toughness of the obtained oral film.

[0094] Test Example 1: Stability Investigation

[0095] Determination method of content and related substances of tetrodotoxin oral film preparation:

[0096] Determined by high performance liquid chromatography (General Chapter 0512 of the Chinese Pharmacopoeia 2020 edition).

[0097] Chromatographic conditions and system suitability test

[0098] Chromatographic column: ZORBAX SB-C8 (4.6 mm × 250 mm, 5 μm); mobile phase: sodium octane sulfonate phosphate buffer (8.95 g disodium hydrogen phosphate, 3.90 g sodium dihydrogen phosphate, 0.27 g sodium octane sulfonate, add water to dissolve to 500 mL, shake well, filter, and obtain); flow rate: 0.3 mL min -1 Column temperature: 28°C; excitation wavelength: 365 nm; emission wavelength: 510 nm; post-column derivatization agent: 4 mol·L -1 Sodium hydroxide solution; derivatization agent flow rate is 0.3 mL min -1 Post-column derivatization temperature: 110°C; injection volume: 50 μL. The theoretical plate number calculated based on tetrodotoxin (TTX) should be no less than 2000.

[0099] Assay: Dissolve a 10 mm x 20 mm piece of tetrodoxin oral film (approximately equivalent to 20 μg of TTX) in purified water. Transfer to a 10 mL volumetric flask, dilute to the mark with purified water, and shake well. This serves as the test solution. Inject 50 μL and record the chromatogram. Determine the reference solution using the same method. Calculate the TTX content of each film using the external standard method based on peak area. Ensure that the content is no less than 95.0% of the labeled amount.

[0100] Determination of related substances According to the content determination method, prepare 2μg·mL -1 of the test solution (calculated based on TTX concentration); accurately measure 1.0 ml of the test solution, place it in a 100 ml volumetric flask, add water to dilute to the scale, shake well, and use it as the control solution. According to the chromatographic conditions under the content determination item, inject 50 μl of the control solution into the liquid chromatograph and adjust the detection sensitivity so that the peak height of the main component chromatographic peak is 10% of the full scale; then accurately measure 50 μl of the test solution and the control solution respectively, inject them into the liquid chromatograph, and record the chromatogram to twice the retention time of the main component peak. The sum of the peak areas of the impurities in the chromatogram of the test solution shall not be greater than 4 times the main peak area of ​​the control solution (4.0%).

[0101] Accelerated Stability Study: The oral films obtained from the above examples or comparative examples were placed in simulated market packaging (aluminum-plastic packaging) under accelerated conditions (25°C ± 2°C, relative humidity 60% ± 10%) for 6 months. Samples were taken at the end of January, February, March, and June, focusing on changes in appearance, content, related substances, and other related indicators of the samples. The samples were compared with the January samples to study the effect of a humid and hot environment on the storage quality stability of the oral film products. The test results are shown in Table 5. The results show that after the prepared film samples were accelerated for 6 months under simulated market packaging conditions at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 10%, the related substances in both the examples and comparative examples increased, while the content gradually decreased. Some comparative examples showed significant changes in appearance. The overall stability results of the examples were better than those of the comparative examples. The test results indicate that this product is sensitive to humidity and heat and should be stored at low temperatures.

[0102] Long-term stability investigation: The oral films obtained in the above examples were placed in simulated market packaging (aluminum-plastic packaging) under long-term conditions (temperature of 6°C ± 2°C) for 24 months, and samples were taken at the end of 0, 6, 12, and 24 months, focusing on the changes in the appearance, content, related substances and other related indicators of the samples, and compared with the 0-month samples to study the long-term storage quality stability of the oral film products. The test results are shown in Table 6. The results show that the three batches of film samples prepared were subjected to a long-term test at 6°C ± 2°C for 24 months under simulated market packaging conditions. The related substances of the samples increased, the content decreased slightly, and the overall indicators such as appearance basically met the regulations. Among them, the samples of Example 1 and Example 2 were stored at 6°C ± 2°C for 12 months, and the various indicators such as appearance, content and related substances met the internal control quality standards, and the stability was good; the samples of Example 3 and Example 4 were stored at 6°C ± 2°C for 24 months, and the various indicators such as appearance, content and related substances met the internal control quality standards, and the stability was good.

[0103] Table 5: Accelerated (25°C ± 2°C, relative humidity 60% ± 10%) stability test results

[0104]

[0105]

[0106]

[0107]

[0108] Note: "-" means that the test is discontinued because at least one of the performance test results is poor.

[0109] Table 6: Long-term stability study results

[0110]

[0111]

[0112] in conclusion:

[0113] (1) Compared with other film-forming materials, the film-forming materials (hydroxypropyl methylcellulose and hydroxypropyl cellulose) provided by the present invention are more conducive to improving the stability of the obtained tetrodotoxin oral film.

[0114] (2) Compared with other fillers, the filler (maltodextrin) provided by the present invention is more conducive to improving the stability of the obtained tetrodotoxin oral film.

[0115] (3) Compared with other disintegrants, the disintegrants provided by the present invention (pregelatinized starch and low-substituted hydroxypropyl cellulose) are more conducive to improving the stability of the obtained tetrodotoxin oral film.

[0116] Test Example 2: Pharmacological Experiment

[0117] In order to illustrate that the tetrodotoxin oral film has the effects of anti-anxiety, anti-depression, sedation, etc., we use the following pharmacological experiments to illustrate, wherein the drug-administered group is the tetrodotoxin oral film prepared by the method of Example 4.

[0118] (1) Establishment and experimental process of the chronic unpredictable animal stress (CUMS) model with anxiety-like depression

[0119] 48 C57BL / 6J male mice, 6-8 weeks old, weighing 18-22g, were raised under SPF conditions at a temperature of 23±2°C, a humidity of 45%-55%, and a circadian rhythm of 12h. The mice were given free access to food and water. After the animals adapted to the environment and gained weight for 2 weeks, modeling and drug administration began. Before modeling, a saccharide preference test (SPT) was performed for random grouping of animals. The 48 mice were randomly divided into a blank control group (Con), a model group (CUMS group), a positive control fluoxetine group (Flu, 18 mg / kg), a drug administration group (10 μg / kg TTX group (using the oral film of Example 4, the dosage is calculated as tetrodoxin, i.e., 10 μg tetrodoxin per kg mouse), a 20 μg / kg TTX group (using the oral film of Example 4, the dosage is calculated as tetrodoxin, i.e., 20 μg tetrodoxin per kg mouse) and a 40 μg / kg The TTX group (using the oral film of Example 4, the dosage is calculated as tetrodoxin, that is, 40 μg of tetrodoxin per kg of mouse), 8 mice per group, 4 mice per cage. The model group was given the same volume of normal saline, and the mice in the blank control group were not stimulated, kept with sufficient water and food, and no other conditions were changed. The positive control drug fluoxetine was administered by gavage, and the oral film of tetrodoxin in the treatment group was administered to the mice orally, once a day at 8:00-9:00 in the morning. The model was established by fasting, water deprivation, 45° tilting of the cage, restraint, day and night reversal, wet bedding, swimming in 4°C ice water, clamping the tail, continuous light, and noise interference. The sugar water was monitored during the process. The preference test (SPT) was used to evaluate the animals' anhedonia. After 48 days, the appearance and behavior of the mice were scored. After 56 days (56 days from the start of modeling and drug administration), the CUMS group was stably formed. After the anhedonia, behavioral tests including open field test (OFT), forced swimming (FST), and novel object discrimination (NOR) were started. All behavioral tests were completed within the time range of 56 to 77 days (calculated from the start of modeling and drug administration). After all behavioral tests were completed (i.e. after 11 weeks of continuous drug administration), samples were taken to calculate the organ index and measure the content of 5-hydroxytryptamine (5-HT) in the hippocampus.

[0120] (2) Sugar Preference Test (SPT)

[0121] The SPT experiment consists of a training phase and a testing phase. Before testing, the animals first enter a two-day training phase. On the first day, two water bottles containing 1% sucrose water are placed in the animal cage to acclimate them to drinking sugar water. On the second day, one of the sugar water bottles is replaced with pure drinking water, and the two water bottles are swapped in between to prevent the mice from developing a preference for one bottle. The testing phase then begins. After an 18-hour fast, the animals undergo a two-hour sugar water preference test. Again, the animals are given a bottle of 1% sucrose water and a bottle of drinking water, swapping the two bottles in between. The bottles are weighed before and after the test to monitor the animals' sugar water and drinking water consumption over the two hours. The sugar water preference index (sugar water preference index = sugar water consumption mass / total liquid consumption mass) is then calculated.

[0122] (3) Appearance and behavioral scoring of mice

[0123] Mice with depression-like symptoms have dry and yellow fur that is easy to fall off, slow reaction, and lack of motor performance. Therefore, mice are scored based on the above performance. The scoring criteria are as follows, with a full score of 10 points.

[0124] Ⅰ The mouse's limbs, head, neck, back, tail and other parts of the hair color are scored. Yellow color is scored as 0 points, shiny black is scored as 1 point, and the total score is 5 points for the 5 parts.

[0125] Ⅱ The degree of hair shedding of mice was scored, with 0 points if the hair easily fell off when grasped and 1 point if the hair did not fall off easily.

[0126] Ⅲ The difficulty of grabbing the mouse during oral administration was scored, with 0 points for easy grabbing and 1 point for difficult grabbing.

[0127] IV The degree of struggle of the mice during oral administration was scored: no struggle was scored as 0 points, slight struggle accompanied by soft screams was scored as 1 point, and severe struggle or screams were scored as 2 points.

[0128] (4) Open field test (OFT)

[0129] This experiment uses a mouse open field detection system. Before the test, the animals are first administered with drugs and placed in the test room 1 hour in advance. Then, the mice are placed one by one in a closed autonomous activity box in the same direction. They are first adapted for 30 seconds, and then the activity of the mice in the open field is recorded within 5 minutes, with a focus on detecting the duration of the mice's exploration in the central area of ​​the open field.

[0130] (5) Forced swim test (FST)

[0131] A forced swimming apparatus (40 cm x 12 cm cylindrical resin tub) was filled with water at 23 ± 2°C to a depth of approximately 10 cm. Mice were placed in the apparatus and their behavior was recorded for 6 minutes, with the first 2 minutes representing the mouse's acclimatization time. The cumulative immobility time for the next 4 minutes was then recorded. Immobility criteria: When a mouse is floating, it is considered immobile if it only gently paddles with one foot or moves slightly to keep its head above the water without struggling. The mouse's behavior was analyzed and recorded using the EthosVision-XT8.0 video analysis system.

[0132] (6) Novel Object Recognition Test (NOR)

[0133] First, place the mice in the autonomous activity box to adapt for 5 minutes. Then, place two identical objects (A1, A2) 5 cm away from the box walls on both sides, and let the mice explore freely for 5 minutes. Finally, replace one of the objects (A2) with a new object (B1). Continue to record the mice's discrimination time for the two objects within 5 minutes, and calculate the novel object discrimination index (novel object discrimination index (%) = new object (B1) observation time / total observation time of new (B1) and old (A1) objects × 100%).

[0134] (7) Organ index calculation and hippocampal sample separation

[0135] After all behavioral tests were completed (i.e., after 11 consecutive weeks of drug administration), the animals were weighed. One hour after drug administration (each group was administered the same dosage and method as described in "(1) Establishment and Experimental Procedure of the Chronic Unpredictable Animal Stress (CUMS) Model with Anxiety-like Depression"), the eyeballs were removed for blood collection, and the animals were sacrificed by cervical dislocation. Organs were dissected and weighed, and the organ index (organ weight / body weight) was calculated. Hippocampal tissue samples were immediately isolated on ice, accurately weighed, and stored at -80°C.

[0136] (8) Determination of 5-hydroxytryptamine (5-HT) content in the hippocampus

[0137] After homogenizing the harvested hippocampal tissue, 5-HT levels were measured using an ELISA. Hippocampal samples from each group were mixed and added to PBS at a ratio of 1 g:9 mL. After ultrasonic homogenization and centrifugation, the supernatant was aspirated and tested. The absorbance (OD) of each well was measured at 450 nm. The blank well was used as the zero value. Using ELISA Calc software, the standard curve regression equation was calculated based on the standard concentration and OD values. A logistic curve was used as the fitting model. The OD values ​​of the hippocampal supernatant samples were then substituted into the equation to calculate the concentration.

[0138] Statistical analysis: GraphPad Prime 8.0.2 was used for data analysis and graphing. All experimental results are expressed as mean ± standard error (SEM). The two groups were analyzed using the independent sample T test. P < 0.05 indicated a statistically significant difference, P < 0.01 indicated a significant statistical difference, and P < 0.001 indicated an extremely significant statistical difference.

[0139] Experimental results

[0140] (1) Results of the Sugar Preference Test (SPT)

[0141] During modeling, SPT was monitored. SPT was performed on day 56 of the CUMS model. The CUMS model group showed a significantly lower sucrose preference of 29.47% compared to the blank control group. The results are shown in Table 6, indicating that the CUMS model has stabilized and behavioral testing can begin. Fluoxetine (18 mg / kg), a positive agent, increased sucrose preference by 22.39%. All doses showed some improvement, with the 20 μg / kg TTX group showing a significant improvement in sucrose preference, with the sucrose preference index increasing by 31.34%.

[0142] Table 6: 2-hour sugar water preference index of mice in each group measured on day 56

[0143] Group Sugar water preference index (%) Compared with blank group (%) Compared with the model group (%) Blank group 0.95±0.01 - - Model Group 0.67±0.03## -29.47 - 10 μg / kg TTX group 0.80±0.00＊ - 19.40 20 μg / kg TTX group 0.88±0.03＊ - 31.34 40 μg / kg TTX group 0.80±0.00＊ - 19.40 Fluoxetine group 0.82±0.03＊ - 22.39

[0144] ## p<0.01Compared with the blank group, ＊ p<0.05 compared with the model group.

[0145] The “comparison between the model group and the blank group” in the table represents: (sugar water preference index of the model group-sugar water preference index of the blank group) / sugar water preference index of the blank group*100%.

[0146] The “comparison with model group” in the table represents the ratio of the drug-administered group and the positive group to the model group: (sugar preference index of each group - sugar preference index of model group) / sugar preference index of model group*100%.

[0147] The calculation methods for "comparison with blank group" and "comparison with model group" in other tables are similar.

[0148] (2) Appearance and behavioral scoring of mice

[0149] On the 48th day of the experiment, the appearance and behavioral scores of the mice were scored as shown in Table 7. The score of the model group was significantly reduced by 50.91% compared with the blank control group; the positive drug fluoxetine group showed significant improvement, reaching 51.14%; all dose groups of the test drug showed significant improvement in appearance and behavioral responses, among which the 20μg / kg TTX group showed the most significant improvement, reaching 46.86%, indicating that TTX has the ability to improve anxiety.

[0150] Table 7: Total score of mice

[0151] Group Fraction Compared with blank group (%) Compared with the model group (%) Blank group 7.13±0.83 - - Model Group 3.50±0.53### -50.91 - 10 μg / kg TTX group 4.75±0.71＊＊ - 35.71 20 μg / kg TTX group 5.14±0.69＊＊＊ - 46.86 40 μg / kg TTX group 4.86±0.69＊＊＊ - 38.86 Fluoxetine group 5.29±0.49＊＊＊ - 51.14

[0152] ### p<0.001Compared with the model group and the blank group, ＊＊ p<0.01, ＊＊＊ p<0.001 compared with the model group.

[0153] (3) Open field test (OFT)

[0154] The results of the OFT experiment are shown in Table 8. Compared to the blank control group, the model group mice spent 53.74% less time in the central zone, a significant reduction (P < 0.01), indicating the establishment of a depression model. Fluoxetine (18 mg / kg), a positive drug, prolonged the mice's time in the central zone by 61.50%. Furthermore, all doses significantly increased the time mice spent in the central zone, with the 20 μg / kg TTX group showing the most significant increase, extending the mice's time in the central zone by 66.37%. This suggests that TTX has the potential to alleviate anxiety and combat depression.

[0155] Table 8: Time spent exploring the center area of ​​the open field

[0156] Group Duration (s) Compared with blank group (%) Compared with the model group (%) Blank group 9.77±3.00 - - Model Group 4.52±1.36## -53.74 - 10 μg / kg TTX group 6.57±0.77＊ - 45.35 20 μg / kg TTX group 7.52±1.23＊＊ - 66.37 40 μg / kg TTX group 6.65±1.05＊ - 47.12 Fluoxetine group 7.30±2.03＊ - 61.50

[0157] ## p<0.01Compared with the blank group, ＊ p<0.05, ＊＊ p<0.01 compared with the model group.

[0158] (4) Forced swim (FST)

[0159] The results of the FST experiment are shown in Table 9. Compared with the blank control group, the immobility time of the model group mice was prolonged by 31.11%, which was significantly prolonged (P<0.001). Compared with the model group mice, the positive drug fluoxetine group and the various dose groups could effectively shorten the immobility time of the mice, especially the 20 μg / kg TTX group, which shortened the immobility time of the mice by 19.69%, indicating that TTX has an antidepressant effect.

[0160] Table 9: Immobility time of mice in FST experiment

[0161] Group Immobility time (s) Compared with blank group (%) Compared with the model group (%) Blank group 147.08±10.36 - - Model Group 192.84±16.04### 31.11 - 10 μg / kg TTX group 163.23±17.89＊＊ - -15.35 20 μg / kg TTX group 154.87±25.09＊ - -19.69 40 μg / kg TTX group 164.46±27.12＊ - -14.72 Fluoxetine group 156.23±37.09＊ - -18.98

[0162] ### p<0.001Compared with the model group and the blank group, ＊ p<0.05, ＊＊ p<0.01 compared with the model group.

[0163] (5) Novel Object Recognition Test (NOR)

[0164] The results of the NOR experiment are shown in Table 10. The novel object discrimination index of the model group mice decreased by 38.67% compared to the blank control group, indicating that the model group had developed a loss of interest. Compared with the model group, the novel object discrimination index of the positive drug fluoxetine group increased by 35.62%. Both the medium and high dose groups improved novel object discrimination ability, with the 20 μg / kg TTX group showing the greatest improvement, reaching 37.63%. This suggests that TTX can improve the loss of interest in CUMS mice and has the potential to alleviate anxiety and depression.

[0165] Table 10: Novelty Observation Index of Mice in NOR

[0166] Group Discrimination index (%) Compared with blank group (%) Compared with the model group (%) Blank group 71.40±11.03 - - Model Group 43.79±9.80## -38.67 - 10 μg / kg TTX group 49.59±23.16 - 13.25 20 μg / kg TTX group 60.27±6.64＊＊ - 37.63 40 μg / kg TTX group 57.41±20.88 - 31.10 Fluoxetine group 59.39±13.55＊ - 35.62

[0167] ## p<0.01Compared with the blank group, ＊ p<0.05, ＊＊ p<0.01 compared with the model group.

[0168] (6) Organ index

[0169] After behavioral testing was completed (i.e., after 11 weeks of continuous dosing), organ testing results are shown in Table 11. The positive fluoxetine group showed a significant increase in liver index and a very significant increase in kidney index, suggesting that long-term fluoxetine use may cause liver and kidney damage. In contrast, no significant effects were observed in any of the dosing groups, indicating that long-term administration of the tetrodotoxin oral film provided herein is unlikely to cause liver and kidney damage.

[0170] Table 11: Organ index of mice in each group

[0171] Group Liver index (×100) Renal index (×1000) Spleen index (×1000) Blank group 4.55±0.30 5.46±0.18 2.62±0.30 Model Group 4.85±0.40 5.47±0.16 <![CDATA[2.96±0.39 # ]]> 10 μg / kg TTX group 4.92±0.44 5.61±0.29 3.01±0.17 20 μg / kg TTX group 4.84±0.41 5.71±0.34 2.82±0.15 40 μg / kg TTX group 4.85±0.32 5.82±0.53 3.63±1.08 Fluoxetine group <![CDATA[5.31±0.36 ＊ ]]> <![CDATA[6.14±0.27 ＊＊＊ ]]> 3.02±0.37

[0172] # p<0.05Compared with the blank group, ＊ p<0.05, ＊＊＊ p<0.001 compared with the model group

[0173] (7) 5-HT content in the hippocampus

[0174] The results of 5-HT content determination in the hippocampus are shown in Table 12. Compared with the blank control group, the 5-HT content in the hippocampus of the model group was reduced by 69.55%. Compared with the model group mice, the 5-HT levels in the positive drug fluoxetine group and the groups treated with each dose were significantly increased, especially the 5-HT level in the 20 μg / kg TTX group increased by 130.28%, indicating that TTX can effectively relieve anxiety and has an antidepressant effect.

[0175] Table 12: Effects of each group on hippocampal 5-HT levels

[0176] Group 5-HT (ng / mL) Compared with blank group (%) Compared with the model group (%) Blank group 219.94±33.86 - - Model Group 66.97±13.96## -69.55 - 10 μg / kg TTX group 133.46±63.88＊ - 99.28 20 μg / kg TTX group 154.22±63.41＊ - 130.28 40 μg / kg TTX group 138.37±55.69＊ - 106.61 Fluoxetine group 148.67±48.14＊＊ - 121.99

[0177] ## p<0.01Compared with the blank group, ＊ p<0.05, ＊＊ p<0.01 compared with the model group.

[0178] Test Example 3: Toxicology Experiment

[0179] In order to illustrate the high safety of the tetrodotoxin oral film in clinical use, an acute toxicity test was performed, wherein each dosage group was a tetrodotoxin oral film prepared by the method of Example 3.

[0180] Experimental methods

[0181] Sixty Kunming mice, half male and half female, were acclimated in an SPF barrier system for three days. The animals were then weighed, labeled, and randomly divided into groups. Based on preliminary experimental results, five dose groups (500 μg / kg to 1000 μg / kg) were established, along with a blank control group, for a total of six groups: 500 μg / kg, 588 μg / kg, 692 μg / kg, 814 μg / kg, and 958 μg / kg (the dosage in each group is calculated as tetrodoxin; for example, the 500 μg / kg group indicates an oral film containing 500 μg of tetrodoxin per kg of mouse). The mice were orally administered once and observed for seven days after dosing. Any mortality or symptoms of poisoning were recorded. The experimental results are shown in Table 13.

[0182] Table 13: Acute toxicity test results of tetrodotoxin oral film

[0183]

[0184]

[0185] Observation of animal poisoning symptoms: After administration, mice showed lethargy, decreased spontaneous activity, vasoconstriction, rapid breathing, and violent struggles when dying.

[0186] SPSS.17 software was used to perform statistical analysis on the experimental data. The Bliss calculation method was used to substitute the 958 μg / kg group, 814 μg / kg group, 692 μg / kg group, 588 μg / kg group and 500 μg / kg group into the calculation to obtain the LD 50 It is 919μg / kg.

[0187] Oral LD ​​combined with tetrodotoxin oral film 50 The results of this experiment suggest that the LD 50 1 / 40-1 / 20 of the dose has a good antidepressant effect and is a relatively safe dose, indicating that the oral film of tetrodotoxin has good clinical compliance, high safety and no toxic side effects when used in the long term.

[0188] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. An oral film, comprising an active ingredient, a solubilizing agent, a film-forming material, a filler, a plasticizer, and a disintegrant; the active ingredient comprises tetrodoxin; the solubilizing agent is acetic acid; the film-forming material comprises hydroxypropyl methylcellulose and hydroxypropyl cellulose; the filler is maltodextrin; the plasticizer is glycerol; and the disintegrant comprises pregelatinized starch and low-substituted hydroxypropyl cellulose; and, calculated based on the total mass of the oral film, the active ingredient is present in an amount of 0.01 wt % to 0.90 wt %, the solubilizing agent is present in an amount of 0.10 wt % to 5.00 wt %, the film-forming material is present in an amount of 31.50 wt % to 47.00 wt %, the filler is present in an amount of 4.50 wt % to 15.00 wt %, the plasticizer is present in an amount of 10.00 wt % to 18.00 wt %, and the disintegrant is present in an amount of 25.00 wt % to 36.00 wt %. 2 . The oral film according to claim 1 , wherein the content of the film-forming material is 36.20 wt % to 44.10 wt % based on the total mass of the oral film. 3 . The oral film according to claim 1 , wherein the content of the film-forming material is 36.25 wt % to 44.10 wt % based on the total mass of the oral film.

4. The oral film according to claim 1, wherein, calculated based on the total mass of the oral film, the content of the active ingredient is 0.05 wt %, the content of the cosolvent is 0.70 wt %, the content of the hypromellose is 27.25 wt %, the content of the hydroxypropyl cellulose is 9.00 wt %, the content of the filler is 9.00 wt %, the content of the plasticizer is 18.00 wt %, the content of the pregelatinized starch is 18.00 wt %, and the content of the low-substituted hydroxypropyl cellulose is 18.00 wt %.

5. The oral film according to claim 1, wherein, calculated based on the total mass of the oral film, the content of the active ingredient is 0.01 wt %, the content of the cosolvent is 0.10 wt %, the content of the hypromellose is 36.89 wt %, the content of the hydroxypropyl cellulose is 4.50 wt %, the content of the filler is 4.50 wt %, the content of the plasticizer is 18.00 wt %, the content of the pregelatinized starch is 18.00 wt %, and the content of the low-substituted hydroxypropyl cellulose is 18.00 wt %.

6. The oral film according to claim 1, wherein, calculated based on the total mass of the oral film, the content of the active ingredient is 0.90 wt %, the content of the cosolvent is 5.00 wt %, the content of the hypromellose is 34.10 wt %, the content of the hydroxypropyl cellulose is 10.00 wt %, the content of the filler is 15.00 wt %, the content of the plasticizer is 10.00 wt %, the content of the pregelatinized starch is 12.50 wt %, and the content of the low-substituted hydroxypropyl cellulose is 12.50 wt %.

7. The oral film according to claim 1, wherein, calculated based on the total mass of the oral film, the content of the active ingredient is 0.01 wt %, the content of the cosolvent is 0.90 wt %, the content of the hypromellose is 35.09 wt %, the content of the hydroxypropyl cellulose is 9.00 wt %, the content of the filler is 15.00 wt %, the content of the plasticizer is 10.00 wt %, the content of the pregelatinized starch is 15.00 wt %, and the content of the low-substituted hydroxypropyl cellulose is 15.00 wt %.

8. The oral film according to any one of claims 1 to 7, which is prepared by a coating method or a casting method.

9. A method for preparing the oral film according to any one of claims 1 to 8, comprising: 1) Mixing the film-forming material, filler and water to obtain a polymer solution; 2) mixing the active ingredient and the aqueous solution containing the cosolvent to obtain a mixed solution 1; 3) adding a plasticizer and a water-dispersible disintegrant to the polymer solution, and then mixing the mixture with the mixed solution 1 to obtain a drug-containing mixture; 4) Degas the drug-containing mixture, then coat or cast it on a glass plate or stainless steel plate and heat dry it; 5) demoulding and cutting to obtain the oral film.

10. The method according to claim 9, wherein in step 1), the mass ratio of the total mass of the membrane-forming material and the filler in the polymer solution to the mass of water is 1:5-1:8; and / or The mass ratio of the total mass of the disintegrant to water in the water-dispersible disintegrant is 1:6-1:10; and / or The content of the co-solvent in the aqueous solution containing the co-solvent is 0.1wt%-0.5wt%; and / or The drying temperature of the heating drying is 40°C-60°C; and / or The drying time of the heating drying is 30 min-60 min.

11. Use of the oral film according to any one of claims 1 to 8 or the oral film prepared by the method according to any one of claims 9 to 10 in the preparation of antianxiety or antidepressant drugs.

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