Risperidone oral solid film formulation, its manufacturing method and application

Abstract

Each dose unit of the risperidone oral solid film formulation contains 0.10% to 8.00% risperidone, 5.00% to 40.00% flavoring agent, 5.00% to 40.00% stabilizer, 2.00% to 15.00% plasticizer, 0% to 45.00% filler, 2.00% to 8.00% coloring agent, and 25.00% to 70.00% film-forming material, and does not contain polyvinylpyrrolidone or coating materials. The risperidone oral solid film formulation is rapidly soluble and / or immediately released, has a fast dissolution rate and high dissolution rate, is easy to manufacture, has high reproducibility, and is suitable for industrial production.

Description

[Technical Field]

[0001] The present application claims the priority of the prior application filed with the China National Intellectual Property Administration on September 14, 2023, with the application number 202311186977.2 and the title of the invention "Risperidone oral solid film preparation, preparation method and use thereof".

[0002] The present invention relates to a risperidone oral solid film preparation administered in the gastrointestinal tract, a preparation method and use thereof. [Background Art]

[0003] Risperidone is a 5-hydroxytryptamine / dopamine antagonist with a unique balancing mechanism. It is effective against the positive and negative symptoms of schizophrenia, can also improve cognitive function, and helps patients return to society. As a novel atypical antipsychotic drug, risperidone can selectively inhibit the mesolimbic dopaminergic nervous system, and does not cause severe extrapyramidal symptoms like conventional antischizophrenic drugs. It has few adverse reactions during clinical administration, high safety, and relatively low price, so it is currently one of the first-line drugs for anti-schizophrenia.

[0004] Currently, risperidone preparations clinically used in China mainly include tablets (1 mg, 2 mg and 3 mg), dispersible tablets (1 mg), capsules (1 mg), oral solutions (30 mL: 30 mg), orally disintegrating tablets (0.5 mg, 1 mg and 2 mg) and microsphere injections (25 mg, 37.5 mg and 50 mg). The risperidone tablet manufactured by Xian-Janssen Pharmaceutical Ltd. under the trade name "Risperdal" is the first commercially available risperidone tablet in China, and its marketing was approved in 2001.

[0005] Conventional tablets and capsules must be taken with water, making them difficult to administer, especially for children and elderly patients with difficulty swallowing. Furthermore, psychiatric patients often refuse to take them and vomit them up. Orally disintegrating tablets address these issues to some extent, but they leave an unpleasant gritty feeling in the mouth when taken. Additionally, they are fragile during transport, leading to inaccurate dosages and requiring high standards for manufacturing, packaging, and storage. Oral liquids require the use of special measuring cups, making them inconvenient to carry and limiting their broad clinical applications. While the dosage and administration instructions in this product specification indicate a minimum dose of 0.25 mg, there are currently no low-dose oral solid drugs of 0.25 mg on the market.

[0006] To improve medication compliance in psychiatric patients, Patent Document CN101632651A discloses an orally rapidly dissolving film formulation of risperidone containing risperidone, a pharmaceutically acceptable water-soluble polymer auxiliary agent, additives (flavoring agents, coloring agents, opacifiers, plasticizers, preservatives, pH adjusters, and disintegrants), and water. However, this invention ignores the properties of the risperidone raw material itself; that is, the risperidone raw material has a strong bitter taste, and although flavoring agents are included in the formulation, they are insufficient to mask the strong bitter taste of risperidone. Furthermore, because the bitter taste persists for a certain period after the drug comes into direct contact with the taste buds in the mouth during administration, the bitter taste significantly affects medication compliance in psychiatric patients and, to some extent, its clinical application.

[0007] Patent document CN103349657A discloses a risperidone film formulation, inventing a composite film formulation containing multiple acidic and alkaline strip-shaped films to mask the bitter taste of risperidone itself. When taken, the composite film comes into contact with water to form a foamed film, creating a large number of bubbles that paralyze the sense of smell and mask the taste. However, this invention requires the production of multiple strip-shaped films during manufacturing, resulting in a complex and costly manufacturing process that is unsuitable for industrial production.

[0008] Patent document CN108685876A discloses an oral film-type drug composition containing risperidone. Risperidone has low solubility in water, exists in granular form, and has a bitter taste. In this invention, an acidic substance is added to dissolve the risperidone, and then povidone is added to mask the taste, but the product produced by this method has low stability.

[0009] Patent document CN104546806A discloses an oral rapid-dissolving film containing risperidone and a method for manufacturing the same. This invention achieves a taste-blocking effect by encapsulation with cyclodextrin, and the auxiliary agents include cyclodextrin, a film-forming material, a plasticizer, and a flavoring agent. In the manufacturing process, a risperidone inclusion compound is produced using a saturated aqueous solution-ultrasonic cell grinding method, the cyclodextrin and risperidone solution are mixed, treated with ultrasound 100 times, refrigerated in a refrigerator at 4°C for 24 hours, filtered under reduced pressure, dried at 40°C to a constant weight for 4 hours, and then re-ground. Such a manufacturing process is complicated, inefficient, has a low degree of automation, is difficult to industrialize, and does not clearly control the inclusion efficiency in this invention, does not have a step to remove free drugs, and if the inclusion efficiency is low and there is unencapsulated risperidone, the manufactured oral rapid-dissolving film still has the problem of having a bitter taste.

[0010] Patent document CN113842376A discloses an oral rapid-dissolving film containing risperidone and a method for manufacturing it. The active pharmaceutical ingredient and EUDRAGIT® are used as a coating solution, which is then flow-coated onto the surface of mannitol, and further coated with an EUDRAGIT® coating solution to obtain an intermediate containing the active pharmaceutical ingredient. This coating method allows for the formation of a dense coating film that can encase risperidone, completely shielding it from its bitter taste and making it more palatable to patients. Furthermore, after coating, contact between risperidone and oxygen gas and several adjuvants that are incompatible with risperidone can be blocked, effectively reducing the formation of impurities such as oxides and other impurities, resulting in excellent formulation stability. However, this process is complex, difficult to operate, difficult to manufacture, and expensive due to the high price of EUDRAGIT®.

[0011] Patent document CN107028917B describes the manufacture of an oral dissolving film to improve compliance. However, the addition of high concentrations of ethanol as a solvent in the literature presents high manufacturing requirements, certain risks during operation, and environmental contamination.

[0012] In short, there is an urgent need to develop a new dosage form of risperidone that has a good texture, a wide dosage range, is easily accepted by patients, is highly stable, dissolves quickly, has low manufacturing costs, and / or is suitable for industrial production. [Overview of the project]

[0013] The present invention provides a risperidone oral solid film formulation, each dose unit of the risperidone oral solid film formulation containing 0.10% to 8.00% risperidone, 5.00% to 40.00% flavoring agent, 5.00% to 40.00% stabilizer, 2.00% to 15.00% plasticizer, 0% to 45.00% filler, 2.00% to 8.00% coloring agent, and 25.00% to 70.00% film-forming material, where the percentage refers to the percentage of the mass of each component relative to the total mass of the risperidone oral solid film formulation, and the risperidone oral solid film formulation does not contain polyvinylpyrrolidone or coating material.

[0014] According to embodiments of the present invention, each dose unit of the risperidone oral solid film formulation contains 0.1 mg to 3 mg of risperidone, for example, 0.25 mg, 1 mg, or 2 mg of risperidone.

[0015] According to embodiments of the present invention, the coating material refers to a conventional coating material in the art, such as EUDRAGIT®.

[0016] According to embodiments of the present invention, the risperidone content is preferably 0.10% to 8.00%, more preferably 0.40% to 7.00%, for example 6.50%, 6.00%, 5.56%, 5.41%, 5.13%, 5.00%, 4.88%, 4.51%, 4.44%, 4.29%, 4.00%, 3.50%, 3.00%, 2.50%, 2.01%, 1.50%, 1.00%, 0.56%, 0.54%, 0.50%, or 0.45%, where the percentage refers to the percentage of the mass of risperidone relative to the total mass of the risperidone oral solid film formulation.

[0017] According to embodiments of the present invention, the flavoring agent is a substance that performs a flavoring effect in a film formulation, and is one or more selected from sucrose, mannitol, dextran, sucralose, aspartame, menthol, and sodium chloride.

[0018] In some embodiments, the flavoring agent is one or more selected from sucralose, menthol, and sodium chloride.

[0019] In one embodiment, the flavoring agent consists of sucralose, menthol, and sodium chloride, or is composed of sucralose and sodium chloride.

[0020] According to embodiments of the present invention, the content of the flavoring agent is preferably 5.00% to 40.00%, more preferably 6.00% to 35.00%, for example, 32.00%, 30.00%, 27.02%, 25.64%, 25.00%, 24.99%, 24.39%, 22.54%, 22.23%, 21.62%, 21.46%, 20.00%, 15.00%, 10.00%, 8.03%, 7.50%, 7.00%, or 6.50%, where the percentage refers to the percentage of the mass of the flavoring agent relative to the total mass of the risperidone oral solid film formulation.

[0021] According to embodiments of the present invention, the stabilizer refers to a substance that maintains the stability of the finished product, and is one or more selected from citric acid (e.g., anhydrous citric acid or citric acid monohydrate) and / or sodium citrate, tartaric acid, hydrochloric acid, and malic acid. In some embodiments, the stabilizer is selected from citric acid.

[0022] According to embodiments of the present invention, the content of the stabilizer is preferably 5.00% to 40.00%, more preferably 5.00% to 35.00%, for example 5.41%, 5.56%, 6.63%, 9.86%, 10.26%, 10.81%, 14.16%, 14.63%, 15.00%, 17.50%, 20.00%, 22.22%, 25.00%, 30.00%, or 32.00%, where the percentage refers to the percentage of the mass of the stabilizer relative to the total mass of the risperidone oral solid film formulation.

[0023] According to an embodiment of the present invention, the plasticizer is a substance for lowering the glass transition temperature of the film, increasing plasticity and toughness, and improving elongation percentage, and is one or more selected from the group consisting of glycerin, propylene glycol, sorbitol and polyethylene glycol. In some embodiments, the plasticizer is glycerin.

[0024] According to an embodiment of the present invention, the content of the plasticizer is preferably 2.00% to 15.00%, more preferably 2.00% to 13.00%, for example 2.70%, 3.50%, 4.00%, 4.29%, 4.44%, 4.51%, 4.88%, 5.13%, 5.41%, 5.56%, 6.00%, 7.00%, 8.00%, 9.00%, 10.04%, 11.00% or 12.00%, and the percentage refers to the percentage of the mass of the plasticizer based on the total mass of the risperidone oral solid film preparation.

[0025] According to an embodiment of the present invention, the filler refers to a solid substance that can improve the properties of the material after being added to the material, or enhance compatibility, increase weight, and reduce the cost of the material, and is one or more selected from the group consisting of microcrystalline cellulose (MCC), mannitol, starch, pregelatinized starch, maltodextrin, sucrose, lactose, sorbitol and glucose. In some embodiments, the filler is microcrystalline cellulose.

[0026] According to an embodiment of the present invention, the content of the filler is preferably 0 to 45.00%, for example 43.00%, 42.00%, 41.00%, 40.16%, 35.00%, 30.00%, 25.00%, 20.00%, 15.21%, 15.00%, 14.48%, 11.27%, 10.73%, 10.00%, 5.00% or 0, and the percentage refers to the percentage of the mass of the filler based on the total mass of the risperidone oral solid film preparation.

[0027] According to an embodiment of the present invention, the colorant refers to a substance that can improve the appearance color of the preparation, identify the concentration of the preparation, distinguish administration methods, and reduce patients' aversion to medication, and is selected from titanium dioxide.

[0028] According to an embodiment of the present invention, the content of the colorant is preferably 2.00% to 8.00%, more preferably 2.00% to 7.00%, for example 2.00%, 2.15%, 2.23%, 2.25%, 2.44%, 2.56%, 2.70%, 2.77%, 3.01%, 3.50%, 4.00%, 4.50%, 5.00%, 5.41%, 5.50%, 6.00% or 6.50%, and the percentage refers to the percentage of the mass of the colorant in the total mass of the risperidone oral solid film preparation.

[0029] According to an embodiment of the present invention, the film-forming material is a drug carrier, and is selected from hydroxypropyl methylcellulose (HMPC, such as hydroxypropyl methylcellulose E15) and / or polyvinyl alcohol.

[0030] According to an embodiment of the present invention, the content of the film-forming material is preferably 25.00% to 70.00%, more preferably 25.00% to 65.00%, for example 60.00%, 55.56%, 55.00%, 54.05%, 51.28%, 50.00%, 48.78%, 45.07%, 44.44%, 42.92%, 40.00%, 35.00%, 30.12%, 28.00% or 26.00%, and the percentage refers to the percentage of the mass of the film-forming material in the total mass of the risperidone oral solid film preparation.

[0031] According to an embodiment of the present invention, the risperidone oral solid film preparation comprises, per dosage unit: The risperidone oral solid film formulation contains, or is mainly composed of, 1.00% to 3.00% risperidone, 5.00% to 10.00% flavoring agent, 5.00% to 10.00% stabilizer, 7.00% to 13.00% plasticizer, 35.00% to 45.00% filler, 2.00% to 5.00% coloring agent, and 25.00% to 40.00% film-forming material, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation by which the mass of each component is accounted for, and the risperidone oral solid film formulation does not contain polyvinylpyrrolidone or coating material. Preferably, the flavoring agent is composed of sucralose and sodium chloride, for example, the mass ratio of sucralose to sodium chloride is 1:(1~3), for example, 1:1, 1:1.5, 1:1.6, 1:1.7, 1:2, or 1:2.5. The stabilizer is citric acid, the plasticizer is glycerin, the filler is microcrystalline cellulose, the colorant is titanium dioxide, and the film-forming material is hydroxypropyl methylcellulose.

[0032] According to embodiments of the present invention, the risperidone oral solid film formulation described in the present invention is Formulation 1 consists of 5.56% risperidone, 8.33% sucralose, 2.77% menthol, 13.89% sodium chloride, 5.56% anhydrous citric acid, 5.56% glycerin, 2.77% titanium dioxide, and 55.56% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 2 consists of 5.41% risperidone, 8.11% sucralose, 13.51% sodium chloride, 10.81% anhydrous citric acid, 5.41% glycerin, 2.70% titanium dioxide, and 54.05% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 3 consists of 5.41% risperidone, 8.10% sucralose, 5.41% menthol, 13.51% sodium chloride, 5.41% anhydrous citric acid, 2.70% glycerin, 5.41% titanium dioxide, and 54.05% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 4 consists of 5.41% risperidone, 8.10% sucralose, 5.41% menthol, 13.51% sodium chloride, 5.41% anhydrous citric acid, 2.70% glycerin, 5.41% titanium dioxide, and 54.05% polyvinyl alcohol, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 5 consists of 5.41% risperidone, 8.10% sucralose, 5.41% menthol, 13.51% sodium chloride, 5.41% anhydrous citric acid, 5.41% glycerin, 2.70% titanium dioxide, and 54.05% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 6 consists of 5.13% risperidone, 7.69% sucralose, 5.13% menthol, 12.82% sodium chloride, 10.26% anhydrous citric acid, 5.13% glycerin, 2.56% titanium dioxide, and 51.28% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 7 consists of 4.88% risperidone, 7.32% sucralose, 4.88% menthol, 12.19% sodium chloride, 14.63% anhydrous citric acid, 4.88% glycerin, 2.44% titanium dioxide, and 48.78% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 8 consists of 4.44% risperidone, 6.67% sucralose, 4.44% menthol, 11.12% sodium chloride, 22.22% anhydrous citric acid, 4.44% glycerin, 2.23% titanium dioxide, and 44.44% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 9 consists of 4.00% risperidone, 6.00% sucralose, 4.00% menthol, 10.00% sodium chloride, 30.00% anhydrous citric acid, 4.00% glycerin, 2.00% titanium dioxide, and 40.00% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulations 10-12 consist of 2.01% risperidone, 3.01% sucralose, 40.16% microcrystalline cellulose, 5.02% sodium chloride, 6.63% citric acid monohydrate, 10.04% glycerin, 3.01% titanium dioxide, and 30.12% hydroxypropyl methylcellulose. The percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 13 consists of 0.56% risperidone, 6.76% sucralose, 4.51% menthol, 11.27% sodium chloride, 9.86% citric acid monohydrate, 4.51% glycerin, 15.21% microcrystalline cellulose, 2.25% titanium dioxide, and 45.07% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 14 consists of 4.51% risperidone, 6.76% sucralose, 4.51% menthol, 11.27% sodium chloride, 9.86% citric acid monohydrate, 4.51% glycerin, 11.26% microcrystalline cellulose, 2.25% titanium dioxide, and 45.07% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 15 consists of 0.54% risperidone, 6.44% sucralose, 4.29% menthol, 10.73% sodium chloride, 14.16% citric acid monohydrate, 4.29% glycerin, 14.48% microcrystalline cellulose, 2.15% titanium dioxide, and 42.92% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 16 may be any of the following: 4.29% risperidone, 6.44% sucralose, 4.29% menthol, 10.73% sodium chloride, 14.16% citric acid monohydrate, 4.29% glycerin, 10.73% microcrystalline cellulose, 2.15% titanium dioxide, and 42.92% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation by mass of each component.

[0033] The present invention further provides a method for producing the risperidone oral solid film formulation, and the production method is as follows: Step 1 involves mixing two, more, or all of the prescribed amounts of solvent, flavoring agent, stabilizer, plasticizer, colorant, filler, and film-forming material, uniformly stirring with an electric motor or emulsifying under vacuum, and degassing under vacuum to obtain a drug-containing glue-like liquid. Step 2 involves adding the drug-containing glue-like liquid obtained in Step 1 to a film manufacturing machine, coating the film, and drying it to obtain a dry film intermediate. Step 3 includes cutting and packaging the dry film intermediate obtained in Step 2 to obtain the risperidone oral solid film formulation.

[0034] According to embodiments of the present invention, in step 2, the drying temperature is preferably 60±10℃, and the drying time is preferably 20 min.

[0035] According to embodiments of the present invention, the risperidone oral solid film formulation may be a risperidone rapid-dissolving and / or immediate-release oral solid film formulation administered in the gastrointestinal tract.

[0036] According to embodiments of the present invention, the thickness of the dry film of the risperidone oral solid film formulation is 10 μm to 200 μm, for example, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, or 100 μm.

[0037] The present invention further provides applications of the risperidone oral solid film formulation in the manufacture of drugs for treating and / or preventing neuropsychiatric disorders and / or mental disorders.

[0038] According to embodiments of the present invention, the neuropsychiatric disorders and mental disorders include schizophrenia, psychiatric disorders, Alzheimer's disease, frontotemporal dementia, vascular dementia, Lewy body dementia, senile dementia, mild cognitive impairment, benign memory loss, closed head injury, autism spectrum disorder, Asperger's syndrome, fragile X syndrome, attention deficit hyperactivity disorder, attention deficit disorder, obsessive-compulsive disorder, tic disorder, childhood learning disability, premenstrual syndrome, depression, major depressive disorder, anesthesia, suicidal ideation and / or behavior, and bipolar disorder. The group consists of harm, anxiety disorders, panic disorder, post-traumatic stress disorder, chronic unpredictable mild stress, eating disorders, addiction, personality disorders, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, Friedreich's ataxia, Tourette syndrome, nocturnal enuresis, non-epileptic seizures, blepharospasm, Duchenne muscular dystrophy, stroke, chronic pain, neuropathic pain, hyperalgesia, allodynia, diabetic polyneuropathy, epileptic seizures, and epilepsy.

[0039] The present invention further provides applications of the risperidone oral solid film formulation in the manufacture of drug formulations.

[0040] According to embodiments of the present invention, the drug formulation is a drug formulation for treating and / or preventing neuropsychiatric disorders and / or mental disorders. Preferably, the neuropsychiatric disorders and mental disorders are limited as described above.

[0041] According to embodiments of the present invention, the drug formulation may be a risperidone rapid-dissolving and / or immediate-release oral solid film formulation administered in the gastrointestinal tract.

[0042] The present invention further provides a method for treating and / or preventing neuropsychiatric disorders and / or mental disorders, the method comprising the step of providing a therapeutically effective amount of the risperidone oral solid film formulation to a patient in need of treatment and / or prevention of neuropsychiatric disorders and / or mental disorders.

[0043] According to embodiments of the present invention, the neuropsychiatric disorders and mental disorders have the meanings described above.

[0044] In one embodiment, the neuropsychiatric disorder and / or mental disorder is schizophrenia.

[0045] All reagents and raw materials used in this invention are commercially available.

[0046] The beneficial effects of the present invention are as follows:

[0047] The inventors discovered that risperidone belongs to the category of drugs with low solubility and high permeability. Due to its low solubility and slow dissolution in the gastrointestinal tract, drug absorption is limited, the strong bitter taste of risperidone is not easily masked, and patient compliance with oral medication is poor. The risperidone oral solid film formulation administered in the gastrointestinal tract according to the present invention has at least one of the following advantages.

[0048] Firstly, the oral film formulation is rapidly dissolving and / or immediately releasing, dissolves quickly, and can be completely dissolved in 10 minutes in four different elution media: water, 0.1 mol / L hydrochloric acid solution, pH 4.5 acetate-sodium acetate buffer, and pH 6.8 phosphate buffer, and has a high degree of dissolution. Secondly, the oral film formulation has a good texture and good patient compliance. Thirdly, the oral film formulation has high stability, for example, it has high stability under high temperature, high humidity, light shielding, accelerated and long-term conditions. Fourth, its manufacturing method is easy to operate, highly reproducible, and suitable for industrial production.

[0049] Definitions and explanations of terms The term "oral film formulation for each dose unit" refers to an oral film formulation for each unit dose, that is, an oral film formulation containing the above-mentioned percentages of risperidone, flavoring agent, stabilizer, plasticizer, filler, colorant, and film-forming material is placed in a single packaging unit.

[0050] The term "multiple species" refers to two or more species, for example, two, three, or more.

[0051] The term "mainly composed of..." means that the sum of the masses of these components accounts for 85% or more of the total mass of the risperidone oral solid film formulation, for example, 90% or more, and exemplary, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0052] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans.

[0053] The term "therapeutic dose" refers to the amount of an active compound or drug that a researcher, veterinarian, physician, or other clinician is seeking to produce a biological or medical response in a tissue, system, animal, individual, or human. [Brief explanation of the drawing]

[0054] [Figure 1] This figure shows the distribution of the main impurities in formulations 5-7 of Example 3.

[0055] [ka] This line shows the impurity content when citric acid is used at a rate of 2 mg / sheet and left at 50°C. [ka] This shows the impurity content curve when the amount of citric acid used is 4 mg / sheet and the sample is left at 50°C. [ka] This line shows the impurity content when 6 mg of citric acid is used per sheet and the sheet is left at 50°C. [Modes for carrying out the invention]

[0056] The technical means of the present invention will be described in more detail below with reference to specific examples. The following examples are merely illustrative and interpretive, and should not be interpreted as limiting the scope of protection of the present invention. All technologies realized based on the above-described aspects of the present invention are included within the scope of protection of the present invention.

[0057] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available or may be manufactured by known methods, or may be selected according to the product's instructions.

[0058] The method for detecting the API content is as follows:

[0059] The measurements were taken using high-performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, General Rules for the Four Parts, 0512).

[0060] For the chromatography conditions, octadecylsilane-bonded silica gel was used as the packing material (we recommend using RD-C18, 4.6 mm × 150 mm, 5 μm, manufactured by Zhongfu Technology Co., Ltd., or a chromatography column with equivalent efficacy), ammonium acetate buffer (5 g of ammonium acetate dissolved in 1000 ml of water)-methanol (40:60) was used as the mobile phase, the flow rate was 1.0 ml / min, the column temperature was 30°C, the detection wavelength was 275 nm, the injection volume was 10 μl, and the operating time was 10 minutes.

[0061] The detection method for the related substances is as follows:

[0062] The measurements were taken using high-performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, General Rules for the Four Parts, 0512).

[0063] For the chromatography conditions, octadecylsilane-bound silica gel was used as the packing material (Waters XSelect HSS C18, 4.6 mm × 250 mm, 3.5 μm or a chromatography column with equivalent efficacy is recommended), ammonium acetate buffer (5 g of ammonium acetate dissolved in 1000 ml of water) - acetonitrile (70:30) was used as mobile phase A, and methanol was used as mobile phase B. Gradient elution was performed according to the table below, with a detection wavelength of 260 nm, a flow rate of 1.0 ml / min, a column temperature of 30 °C, and an injection volume of 30 μl. [Table 1A]

[0064] (Example 1) [Table 1]

[0065] Regarding the manufacturing methods for Formulation 1 and Formulation 2 In Step 1, after adding the solvent, flavoring agent, stabilizer, plasticizer, colorant, active pharmaceutical ingredient, and film-forming material in the formulation amounts shown in Table 1, the mixture is uniformly stirred by electric motor or emulsified under vacuum, and then degassed under vacuum to obtain a drug-containing glue-like liquid. In Step 2, the drug-containing glue-like liquid obtained in Step 1 is added to the film manufacturing machine, the film is applied, and it is dried, with the drying parameters set to 60±10℃ / 20min, to obtain a dry film intermediate. In step 3, the dry film intermediate obtained in step 2 was cut and packaged to obtain a risperidone oral solid film formulation.

[0066] (Example 2) The prescription is as follows: [Table 2]

[0067] Regarding the manufacturing methods for Formulations 3 and 4 In Step 1, after adding the solvent, flavoring agent, stabilizer, plasticizer, colorant, active pharmaceutical ingredient, and film-forming material in the formulation amounts shown in Table 2, the mixture is uniformly stirred by electric motor or emulsified under vacuum, and then degassed under vacuum to obtain a drug-containing glue-like liquid. In Step 2, the drug-containing glue-like liquid obtained in Step 1 is added to the film manufacturing machine, the film is applied, and it is dried, with the drying parameters set to 60±10℃ / 20min, to obtain a dry film intermediate. In step 3, the dry film intermediate obtained in step 2 was cut and packaged to obtain a risperidone oral solid film formulation.

[0068] The obtained oral film formulation samples were subjected to stability tests by being left at a high temperature of 50°C. Samples were removed on days 5, 10, and 30, and the content of relevant substances was examined. The aggregated data is shown in Table 3. [Table 3]

[0069] As can be seen from the 30-day data at 50°C for formulations 3 and 4, when the film-forming material is hydroxypropyl methylcellulose, both single impurities and total impurities are low, and stability is high.

[0070] (Example 3) Prescriptions are tallied as follows: [Table 4]

[0071] Regarding the manufacturing methods for prescriptions 5-9 In Step 1, after adding the solvent, flavoring agent, stabilizer, plasticizer, colorant, active pharmaceutical ingredient, and film-forming material in the formulation amounts shown in Table 4, the mixture is uniformly stirred by electric motor or emulsified under vacuum, and then degassed under vacuum to obtain a drug-containing glue-like liquid. In Step 2, the drug-containing glue-like liquid obtained in Step 1 is added to the film manufacturing machine, the film is applied, and it is dried, with the drying parameters set to 60±10℃ / 20min, to obtain a dry film intermediate. In step 3, the dry film intermediate obtained in step 2 was cut and packaged to obtain a risperidone oral solid film formulation.

[0072] Oral film formulation samples obtained from formulations 5-7 were subjected to stability tests by being left at a high temperature of 50°C. Samples were taken out on days 5, 10, and 30, and the content of the relevant substances was examined. The aggregated data is shown in Table 5. [Table 5] Figure 1 shows the content of the main impurity, RRT1.14.

[0073] (Example 4) The prescription list for the three strengths of risperidone oral solid film, 0.25 mg, 1 mg, and 2 mg, is as follows: [Table 6]

[0074] Regarding the manufacturing methods for prescriptions 10-12 In Step 1, after adding the solvent, flavoring agent, stabilizer, plasticizer, active pharmaceutical ingredient, colorant, filler, and film-forming material in the formulation amounts shown in Table 6, the mixture is uniformly stirred by electric motor or emulsified under vacuum, and then degassed under vacuum to obtain a drug-containing glue-like liquid. In Step 2, the drug-containing glue-like liquid obtained in Step 1 is added to the film manufacturing machine, the film is applied, and it is dried, with the drying parameters set to 60±10℃ / 20min, to obtain a dry film intermediate. In step 3, the dry film intermediate obtained in step 2 was cut and packaged to obtain a risperidone oral solid film formulation.

[0075] Furthermore, the elution of risperidone oral solid film formulations of formulations 10-12 was investigated using four different elution media: water, 0.1 mol / L hydrochloric acid solution, pH 4.5 acetate-sodium acetate buffer, and pH 6.8 phosphate buffer. The elution test conditions were based on Method 2 of the 2020 edition of the Chinese Pharmacopoeia, General Rules for Four Parts 0931, i.e., the paddle method, with a sedimentation basket added, a elution media volume of 500 ml, and a rotation speed of 50 revolutions per minute. Sampling times were 5, 10, 15, 30, and 60 minutes, and each sample was measured by HPLC. The elution results are summarized in Table 7. [Table 7] [Table 8] [Table 9] As can be seen from the dissolution data above, formulations of different strengths all dissolve rapidly in four different media, effectively improving the oral absorption of such drugs.

[0076] (Example 5) Table 10 shows the changes in pH values ​​of risperidone aqueous solutions at different concentrations, with citric acid amounts of 4 mg and 6 mg being used. [Table 10] As can be seen from the data above, the pH value of risperidone aqueous solutions of different concentrations changes within the same citric acid dosage system. [Table 11]

[0077] Exemplary manufacturing methods for formulations 13-16 In Step 1, after adding the solvent, flavoring agent, stabilizer, plasticizer, active pharmaceutical ingredient, colorant, filler, and film-forming material in the formulation amounts shown in Table 11, the mixture is uniformly stirred by electric motor or emulsified under vacuum, and then degassed under vacuum to obtain a drug-containing glue-like liquid. In Step 2, the drug-containing glue-like liquid obtained in Step 1 is added to the film manufacturing machine, the film is applied, and it is dried, with the drying parameters set to 60±10℃ / 20min, to obtain a dry film intermediate. In step 3, the dry film intermediate obtained in step 2 was cut and packaged to obtain a risperidone oral solid film formulation.

[0078] Risperidone oral solid film formulation samples from formulations 13-16 were subjected to stability tests by being left at a high temperature of 50°C. Each sample was removed on the 10th day, and the content of related substances was examined. The aggregated data is shown in Table 12. [Table 12] As the data shows, when citric acid is present at 4 mg / sheet, both product specifications are sufficiently stable, and the relevant substances meet the quality standards of the finished product based on the active pharmaceutical ingredient.

[0079] In summary, the risperidone oral solid film according to the present invention has a good texture, is easily accepted and used by patients, and has high pharmaceutical stability. Furthermore, it has low manufacturing costs, is suitable for industrial production, and causes minimal environmental pollution.

[0080] (Comparative Example 1) [Table 13]

[0081] Regarding the manufacturing method of Formulation A In Step 1, after adding the solvent, flavoring agent, stabilizer, plasticizer, active pharmaceutical ingredient, colorant, and film-forming material in the formulation amounts shown in Table 13, the mixture is uniformly stirred by electric motor or emulsified under vacuum, and then degassed under vacuum to obtain a drug-containing glue-like liquid. In Step 2, the drug-containing glue-like liquid obtained in Step 1 is added to the film manufacturing machine, the film is applied, and it is dried (drying parameters set to 60±10℃ / 20min) to obtain a dry film intermediate. In step 3, the dry film intermediate obtained in step 2 was cut and packaged to obtain a risperidone oral solid film formulation.

[0082] After tasting the resulting product, it was found to have a strong bitter taste and was unable to mask the flavoring agent.

[0083] (Comparative Example 2) The preparation was carried out by referring to the method of Example 1 of CN107028917A, and the formulation is as follows: [Table 14] The formula was manufactured according to the manufacturing method of CN107028917A. After tasting the resulting product, it was found to have a strong bitter taste and was unable to mask the flavoring agent.

[0084] (Comparative Example 3) The formulation, manufactured by reference to the exemplary method of CN108685876A (Example 3), is as follows: [Table 15] Following the manufacturing method described in CN108685876A, the formula was manufactured, and after tasting the resulting product, it was found to have a strong bitter taste and to be unable to mask the flavoring agent.

[0085] Furthermore, according to paragraph 0006 of the specification of CN113842376A, this formulation has poor stability after being left for 10 days under high temperature conditions of 60°C, and the presence of an unknown single impurity exceeding the limit (actually measured at 0.59% on day 5 and 0.94% on day 10, with a limit of 0.2%) may affect the safety of patient administration to some extent.

[0086] (Example 6) Based on the "Technical Guidelines Principles for the Design and Evaluation of the Texture of Pediatric Drugs (Draft Public Comment)" and the literature "Application and Development Research of Volunteer Sensory Tests in the Taste Evaluation of Drugs [J]. Chinese Pharmaceutical Journal, 2017, 52(22):1971-1975", the palatability of prescriptions A, B, C and prescriptions 10-16 was evaluated using a comprehensive bitterness grade evaluation method and a multifactor assessment method.

[0087] Based on the quality characteristics of the oral dissolving films, palatability was evaluated using bitterness, bitterness, sweetness, numbing taste, and oral foreign body sensation as the main scoring items, with appearance and sweetness being added as bonus items. The defined grades, scoring ranges, and evaluation results are as follows. [Table 16(1)] [Table 16(2)] Texture evaluations were performed on the above formulations. In comparative formulations A, B, and C, bitterness was not eliminated in any of them, indicating that texture improvement was necessary. Formulations 10 to 16 of the present invention had an acceptable texture, were free of bitterness, and were excellent.

[0088] (Example 7) Stability testing of prescriptions 11 and 12 Samples with internal packaging (polyester / aluminum / cast polyethylene chemical composite film) were left under high temperature (50°C) and high humidity conditions (90%RH ± 5%RH), and samples were taken and detected on days 0, 5, 10, and 30. Samples without packaging were left under high temperature (50°C), and samples were taken and detected on days 0, 5, 10, and 30. Additionally, samples with the packaging box removed and internal packaging were subjected to light irradiation conditions (total illuminance ≥ 1.2 × 10⁻¹⁰). 6 lux·hr, total ultraviolet irradiance ≥ 200 W·hr / m 2The samples were left under the specified conditions and sampled on the 10th day for detection. Samples with internal packaging (polyester / aluminum / cast polyethylene medicinal composite film) were left under accelerated conditions (40℃±2℃, 75%RH±5%RH) and sampled at 0, 1, 3, and 6 months for detection. Samples with internal packaging (polyester / aluminum / cast polyethylene medicinal composite film) were left under long-term conditions (25℃±2℃, 60%RH±5%RH) and sampled at 0, 3, and 6 months for detection.

[0089] 1. Stability testing of influencing factors [Table 17(1)] [Table 17(2)] [Table 17(3)] Formulation 11, with or without internal packaging, is stable at high temperatures of 50°C, and Formulation 11 with internal packaging is stable under high humidity and light irradiation conditions. [Table 18(1)] [Table 18(2)] [Table 18(3)] Formulation 12, with or without internal packaging, is stable at high temperatures of 50°C, and Formulation 12 with internal packaging is stable under high humidity and light irradiation conditions.

[0090] 2. Acceleration Stability Test [Table 19(1)] [Table 19(2)] Formulation 11 (1 mg specification) was left for 6 months under the specified packaging conditions (polyester / aluminum / cast polyethylene medicinal composite film (internal packaging)) at 40°C ± 2°C and 75% RH ± 5% RH. Compared to 0 months, there were no significant differences in any of the survey indicators, and all were within acceptable limits.

[0091] [Table 20(1)] [Table 20(2)] Formulation 12 (2 mg specification) was left for 6 months under the specified packaging conditions (polyester / aluminum / cast polyethylene medicinal composite film (internal packaging)) at 40°C ± 2°C and 75% RH ± 5% RH. Compared to 0 months, there were no significant differences in any of the survey indicators, and all were within acceptable limits.

[0092] 3. Long-term stability testing [Table 21] Formulation 11 (1 mg specification) was left for 6 months under the specified packaging conditions (polyester / aluminum / cast polyethylene medicinal composite film (internal packaging)) at 25°C ± 2°C and 60% RH ± 5% RH. Compared to 0 months, there were no significant differences in any of the survey indicators, and all were within acceptable limits.

[0093] [Table 22] Formulation 12 (2 mg specification) was left for 6 months under the specified packaging conditions (polyester / aluminum / cast polyethylene medicinal composite film (internal packaging)) at 25°C ± 2°C and 60% RH ± 5% RH. Compared to 0 months, there were no significant differences in any of the survey indicators, and all were within acceptable limits.

[0094] (Example 8) Mechanical strength and disintegration time tests for formulations 11 and 12 Tensile strength test: Regarding mechanical performance, after startup, the tensile force measurement module is attached, force calibration and height calibration are performed, and the height is set to 2 mm.

[0095] The thickness and width of the oral dissolving film are detected using a thickness gauge and a straight ruler, and the cross-sectional area (mm²) of the oral dissolving film is determined. 2 We calculated the values ​​and performed six parallel tests.

[0096] The oral dissolving film, whose thickness and width were detected, was fixed to a texture analyzer, and the detected cross-section was positioned perpendicular to the elongation direction of the device. The maximum force and sample height were then recorded.

[0097] Tensile strength (MPa) = Maximum force (gf) / 10² / Cross-sectional area (mm²) 2 ), Elongation = Maximum force distance (mm) / Sample height (mm) × 100%.

[0098] For measuring decay time in small amounts of solvent, the sample was placed in a petri dish containing 20 mL of phosphate buffer solution at a temperature of (37 ± 0.5) °C and a pH of 6.8. The time it took for the sample to completely dissolve was recorded as the decay time.

[0099] The packaging in Tables 23-24 refers to the internal packaging, which is a polyester / aluminum / cast polyethylene pharmaceutical composite film.

[0100] [Table 23] [Table 24] Embodiments of the present invention have been described above. However, the present invention is not limited to the embodiments described above. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A risperidone oral solid film formulation, wherein each dose unit of the risperidone oral solid film formulation contains 0.10% to 8.00% risperidone, 5.00% to 40.00% flavoring agent, 5.00% to 40.00% stabilizer, 2.00% to 15.00% plasticizer, 0% to 45.00% filler, 2.00% to 8.00% coloring agent, and 25.00% to 70.00% film-forming material, wherein the percentage refers to the percentage of the mass of each component relative to the total mass of the risperidone oral solid film formulation, and the risperidone oral solid film formulation does not contain polyvinylpyrrolidone or coating material.

2. The risperidone oral solid film formulation according to claim 1 is characterized in that each dose unit of the risperidone oral solid film formulation contains 0.1 mg to 3 mg of risperidone, for example, 0.25 mg, 1 mg, or 2 mg of risperidone.

3. The aforementioned flavoring agent is one or more selected from sucrose, mannitol, dextran, sucralose, aspartame, menthol, and sodium chloride. and / or, The stabilizer is one or more selected from citric acid and / or sodium citrate, tartaric acid, hydrochloric acid, and malic acid. and / or, The aforementioned plasticizer is one or more selected from glycerin, propylene glycol, sorbitol, and polyethylene glycol. and / or, The filler is one or more selected from microcrystalline cellulose, mannitol, starch, pregelatinized starch, maltodextrin, sucrose, lactose, sorbitol, and glucose. and / or, The aforementioned coloring agent is selected from titanium dioxide. and / or, The risperidone oral solid film formulation according to claim 1, characterized in that the film-forming material is selected from hydroxypropyl methylcellulose and / or polyvinyl alcohol.

4. The content of the flavoring agent is 5.00% to 40.00%, preferably 6.00% to 35.00%, where the percentage refers to the percentage of the mass of the flavoring agent relative to the total mass of the risperidone oral solid film formulation. and / or, The content of the stabilizer is 5.00% to 40.00%, preferably 5.00% to 35.00%, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation that the mass of the stabilizer represents. and / or, The content of the plasticizer is 2.00% to 15.00%, preferably 2.00% to 13.00%, where the percentage refers to the percentage of the mass of the plasticizer relative to the total mass of the risperidone oral solid film formulation. and / or, The content of the filler is 0 to 45.00%, preferably 0 to 43.00%, where the percentage refers to the percentage of the mass of the filler relative to the total mass of the risperidone oral solid film formulation. and / or, The content of the coloring agent is 2.00% to 8.00%, preferably 2.00% to 7.00%, where the percentage refers to the percentage of the mass of the coloring agent relative to the total mass of the risperidone oral solid film formulation. and / or, The content of the film-forming material is 25.00% to 70.00%, preferably 25.00% to 65.00%, where the percentage refers to the percentage of the mass of the film-forming material relative to the total mass of the risperidone oral solid film formulation. Preferably, the risperidone oral solid film formulation contains, The risperidone oral solid film formulation contains, or is mainly composed of, 1.00% to 3.00% risperidone, 5.00% to 10.00% flavoring agent, 5.00% to 10.00% stabilizer, 7.00% to 13.00% plasticizer, 35.00% to 45.00% filler, 2.00% to 5.00% coloring agent, and 25.00% to 40.00% film-forming material, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation by which the mass of each component is equal to the total mass of the risperidone oral solid film formulation, and the risperidone oral solid film formulation does not contain polyvinylpyrrolidone or coating material. Preferably, the flavoring agent is composed of sucralose and sodium chloride, the stabilizer is citric acid, the plasticizer is glycerin, the filler is microcrystalline cellulose, the coloring agent is titanium dioxide, and the film-forming material is hydroxypropyl methylcellulose, as described in claim 3.

5. Formulation 1 consists of 5.56% risperidone, 8.33% sucralose, 2.77% menthol, 13.89% sodium chloride, 5.56% anhydrous citric acid, 5.56% glycerin, 2.77% titanium dioxide, and 55.56% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 2 consists of 5.41% risperidone, 8.11% sucralose, 13.51% sodium chloride, 10.81% anhydrous citric acid, 5.41% glycerin, 2.70% titanium dioxide, and 54.05% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 3 consists of 5.41% risperidone, 8.10% sucralose, 5.41% menthol, 13.51% sodium chloride, 5.41% anhydrous citric acid, 2.70% glycerin, 5.41% titanium dioxide, and 54.05% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 4 consists of 5.41% risperidone, 8.10% sucralose, 5.41% menthol, 13.51% sodium chloride, 5.41% anhydrous citric acid, 2.70% glycerin, 5.41% titanium dioxide, and 54.05% polyvinyl alcohol, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 5 consists of 5.41% risperidone, 8.10% sucralose, 5.41% menthol, 13.51% sodium chloride, 5.41% anhydrous citric acid, 5.41% glycerin, 2.70% titanium dioxide, and 54.05% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 6 consists of 5.13% risperidone, 7.69% sucralose, 5.13% menthol, 12.82% sodium chloride, 10.26% anhydrous citric acid, 5.13% glycerin, 2.56% titanium dioxide, and 51.28% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation by mass of each component. Formulation 7 consists of 4.88% risperidone, 7.32% sucralose, 4.88% menthol, 12.19% sodium chloride, 14.63% anhydrous citric acid, 4.88% glycerin, 2.44% titanium dioxide, and 48.78% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 8 consists of 4.44% risperidone, 6.67% sucralose, 4.44% menthol, 11.12% sodium chloride, 22.22% anhydrous citric acid, 4.44% glycerin, 2.23% titanium dioxide, and 44.44% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation by mass. Formulation 9 consists of 4.00% risperidone, 6.00% sucralose, 4.00% menthol, 10.00% sodium chloride, 30.00% anhydrous citric acid, 4.00% glycerin, 2.00% titanium dioxide, and 40.00% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulations 10-12 consist of 2.01% risperidone, 3.01% sucralose, 40.16% microcrystalline cellulose, 5.02% sodium chloride, 6.63% citric acid monohydrate, 10.04% glycerin, 3.01% titanium dioxide, and 30.12% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 13 consists of 0.56% risperidone, 6.76% sucralose, 4.51% menthol, 11.27% sodium chloride, 9.86% citric acid monohydrate, 4.51% glycerin, 15.21% microcrystalline cellulose, 2.25% titanium dioxide, and 45.07% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 14 consists of 4.51% risperidone, 6.76% sucralose, 4.51% menthol, 11.27% sodium chloride, 9.86% citric acid monohydrate, 4.51% glycerin, 11.26% microcrystalline cellulose, 2.25% titanium dioxide, and 45.07% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. Formulation 15 consists of 0.54% risperidone, 6.44% sucralose, 4.29% menthol, 10.73% sodium chloride, 14.16% citric acid monohydrate, 4.29% glycerin, 14.48% microcrystalline cellulose, 2.15% titanium dioxide, and 42.92% hydroxypropyl methylcellulose, where the percentage refers to the percentage of the total mass of the risperidone oral solid film formulation. The risperidone oral solid film formulation according to claim 1, characterized in that it comprises 4.29% risperidone, 6.44% sucralose, 4.29% menthol, 10.73% sodium chloride, 14.16% citric acid monohydrate, 4.29% glycerin, 10.73% microcrystalline cellulose, 2.15% titanium dioxide, and 42.92% hydroxypropyl methylcellulose, wherein the percentage is selected from formulation 16, where the mass of each component represents the percentage of the total mass of the risperidone oral solid film formulation.

6. The risperidone oral solid film formulation according to claim 1, characterized in that the thickness of the dry film is 10 μm to 200 μm.

7. Step 1 involves mixing two or more of the prescribed amounts of solvent, flavoring agent, stabilizer, plasticizer, colorant, filler, and film-forming material, uniformly stirring with an electric motor or emulsifying under vacuum, and degassing under vacuum to obtain a drug-containing glue-like liquid. Step 2 involves adding the drug-containing glue-like liquid obtained in Step 1 to a film manufacturing machine, coating the film, and drying it to obtain a dry film intermediate. A method for producing a risperidone oral solid film formulation according to any one of claims 1 to 6, comprising step 3, which involves cutting and packaging the dry film intermediate obtained in step 2 to obtain the risperidone oral solid film formulation.

8. An application of the risperidone oral solid film formulation according to any one of claims 1 to 6 in the manufacture of a drug for treating and / or preventing neuropsychiatric disorders and / or mental disorders, Preferably, the neuropsychiatric disorders and mental disorders include schizophrenia, psychiatric disorders, Alzheimer's disease, frontotemporal dementia, vascular dementia, Lewy body dementia, senile dementia, mild cognitive impairment, benign memory loss, closed head injury, autism spectrum disorder, Asperger's syndrome, fragile X syndrome, attention deficit hyperactivity disorder, attention deficit disorder, obsessive-compulsive disorder, tic disorder, childhood learning disability, premenstrual syndrome, depression, major depressive disorder, anesthesia, suicidal ideation and / or behavior, bipolar disorder, anxiety disorder, panic disorder An application characterized by being selected from the group consisting of: dyslexia, post-traumatic stress disorder, chronic unpredictable mild stress, eating disorders, addiction, personality disorders, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, Friedreich's ataxia, Tourette syndrome, nocturnal enuresis, non-epileptic seizures, blepharospasm, Duchenne muscular dystrophy, stroke, chronic pain, neuropathic pain, hyperalgesia, allodynia, diabetic polyneuropathy, epileptic seizures, and epilepsy.

9. An application of the risperidone oral solid film formulation according to any one of claims 1 to 6 in the manufacture of a drug formulation, Preferably, the drug formulation is a drug formulation for treating and / or preventing neuropsychiatric disorders and / or mental disorders, and preferably, the neuropsychiatric disorders and mental disorders are schizophrenia, psychiatric disorders, Alzheimer's disease, frontotemporal dementia, vascular dementia, Lewy body dementia, senile dementia, mild cognitive impairment, benign memory loss, closed head injury, autism spectrum disorder, Asperger's syndrome, fragile X syndrome, attention deficit hyperactivity disorder, attention deficit disorder, obsessive-compulsive disorder, tic disorder, childhood learning disability, premenstrual syndrome, depression, major depressive disorder, anesthesia, and self-inflicted illness. An application characterized by being selected from the group consisting of homicidal thoughts and / or acts, bipolar disorder, anxiety disorder, panic disorder, post-traumatic stress disorder, chronic unpredictable mild stress, eating disorders, addiction, personality disorders, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, Friedreich's ataxia, Tourette syndrome, nocturnal enuresis, non-epileptic seizures, blepharospasm, Duchenne muscular dystrophy, stroke, chronic pain, neuropathic pain, hyperalgesia, allodynia, diabetic polyneuropathy, epileptic seizures, and epilepsy.

10. The application according to claim 9, characterized in that the drug formulation is a risperidone rapid-dissolving and / or immediate-release oral solid film formulation administered in the gastrointestinal tract.

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