A film formulation of lumeragonine or a salt thereof and a method for preparing the same

Abstract

The application provides a film preparation of lumerabenzole or a salt thereof and a preparation method thereof, and relates to the technical field of medicines. According to mass fractions, the film preparation comprises the following raw materials: 2-30 parts of lumerabenzole or a pharmaceutically acceptable salt thereof, 40-95 parts of a film forming material, 1-30 parts of a plasticizer and 0.1-5 parts of an antioxidant. The antioxidant is at least one selected from butylated hydroxyanisole, butylated hydroxytoluene and sodium bisulfite. The film preparation is used for drug delivery through an oral mucosa or a sublingual route, can significantly improve the bioavailability of the drug, increase the blood drug concentration, improve the drug content in the brain and the D2 target point occupancy rate, and can effectively enhance the curative effect.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a film preparation of lumiperone or a salt thereof and a preparation method thereof. Background Art

[0002] Lumateperone tosylate (Caplyta) is a new atypical antipsychotic drug developed by Intra-Cellular Therapies.

[0003] In December 2019, the U.S. Food and Drug Administration (FDA) approved lumepirone tosylate for the treatment of schizophrenia in adults. In December 2021, the FDA further approved the expanded indication of lumepirone tosylate, including monotherapy or combination with lithium / valproate for the treatment of depressive episodes associated with bipolar I or II disorder in adults, making it the first and only drug with such an indication.

[0004] Its structural formula is shown below:

[0005]

[0006] Lumiperone tosylate is a 5-hydroxytryptamine isotype 2A (5-HT 2A ) receptor antagonist, D2 receptor presynaptic partial agonist and postsynaptic antagonist, D1 receptor-dependent glutamate modulator, and serotonin reuptake inhibitor.

[0007] Due to the uncertainty of the onset of schizophrenia and the poor compliance of patients when the disease occurs, it is necessary to administer the drug to patients as soon as possible. Therefore, it is very important to prepare lumepirone into a dosage form that is easy to carry, easy to take and can take effect quickly. Lumiperone tosylate is available in the form of capsules on the market, and some companies are also developing orally disintegrating tablets to improve patient compliance.

[0008] For example, Chinese patent CN118557536A specifically relates to a lumeperone orally disintegrating tablet composition, its preparation method, and its use. The raw materials of the lumeperone orally disintegrating tablet composition, calculated by mass percentage, include: 16%-20% lumeperone tosylate, 40%-60% hydrophilic diluent, 10%-20% alkaline diluent, 5%-15% disintegrant, 3%-9% flavoring agent, 0.5%-1% glidant, and 0.2%-2% lubricant.

[0009] Although lumepirone tosylate has satisfactory efficacy, tolerability and safety, and has relatively little effect on weight management, cardiovascular metabolism and extrapyramidal symptoms. However, the drug also faces some challenges. "New Antipsychotic Drug: Lumeperone (Sheng Qinrun, Shen Yifeng, Li Huafang)" records that the absolute bioavailability of a capsule dosage form of lumepirone in humans is 4.4%. Due to its low bioavailability and high first-pass metabolism rate, there are significant differences in the bioavailability of the drug in different patients, which leads to uncertainty in efficacy. In addition, since increasing the dose does not linearly increase the exposure of the drug, it is impossible to achieve a better therapeutic effect by increasing the dose. Moreover, the occupancy rate of lumepirone tosylate at the D2 target is much lower than that of conventional psychiatric drugs, which is only 39%. Therefore, it is difficult to obtain a higher blood exposure through oral administration of lumepirone tosylate capsules.

[0010] In summary, developing a lumepirone tosylate preparation and innovating its preparation method and administration form in order to improve its bioavailability and increase its D2 target occupancy rate are the research focuses of researchers in this field. Summary of the Invention

[0011] To address these issues, the present invention provides a lumepirone tosylate film, which is manufactured by adding appropriate amounts of film-forming materials, plasticizers, disintegrants, stabilizers, and other excipients, and then delivering the drug via the oral mucosa or sublingual route. With the formulation developed by the present invention, this administration method can not only significantly improve the drug's bioavailability, increase blood drug concentration, increase brain drug content, and increase D2 target occupancy, but ultimately effectively enhance its therapeutic efficacy, providing patients with a more efficient and convenient treatment experience.

[0012] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0013] In one aspect, the present invention provides a film preparation of lumiperone or a salt thereof, comprising the following raw materials, calculated by weight: 2-30 parts of lumiperone or a pharmaceutically acceptable salt thereof, 40-95 parts of a film-forming material, 1-30 parts of a plasticizer, and 0.1-5 parts of an antioxidant;

[0014] The film-forming material is selected from at least one of copolyvidone, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, povidone, hydroxypropyl methylcellulose, polyvinyl alcohol, polyoxyethylene, polyethylene glycol, hydroxypropyl cellulose and hydroxyethyl cellulose;

[0015] The plasticizer is selected from at least one of polyethylene glycol, glycerol, propylene glycol, triacetin, triethyl citrate, sorbitol, mannitol, dibutyl phthalate, Span and Tween;

[0016] The antioxidant is selected from at least one of butylated hydroxyanisole, butylated hydroxytoluene and sodium bisulfite.

[0017] Preferably, the following raw materials are contained, by weight: 2-25 parts of lumepirone or a pharmaceutically acceptable salt thereof, 40-92 parts of a film-forming material, 1-20 parts of a plasticizer, and 0.2-5 parts of an antioxidant;

[0018] More preferably, the composition comprises the following raw materials, calculated by weight: 2-12 parts of lumiperone or a pharmaceutically acceptable salt thereof, 45-92 parts of a film-forming material, 1-15 parts of a plasticizer, and 0.2-4 parts of an antioxidant;

[0019] Preferably, the film-forming material is selected from at least one of copovidone, polyoxyethylene and hydroxypropyl methylcellulose; further preferably, the film-forming material is selected from at least one of copovidone and polyoxyethylene; more preferably, the film-forming material is copovidone and polyoxyethylene.

[0020] Preferably, the mass ratio of the copovidone to polyoxyethylene is 2-8:2-8.

[0021] Preferably, the plasticizer is selected from at least one of polyethylene glycol, propylene glycol and polyvinyl pyrrolidone; further preferably, the plasticizer is polyethylene glycol.

[0022] Preferably, the antioxidant is sodium bisulfite.

[0023] Preferably, the raw materials of the film may further include flavoring agents.

[0024] Preferably, the flavoring agent is selected from at least one of sucralose, essence, citric acid, and tartaric acid. Further preferably, the flavoring agent is selected from at least one of sucralose and essence.

[0025] Preferably, the composition comprises the following raw materials in parts by mass: 2-30 parts of lumepirone or a pharmaceutically acceptable salt thereof, 40-95 parts of a film-forming material, 1-30 parts of a plasticizer, 0.1-5 parts of an antioxidant and 0.1-3 parts of a flavoring agent.

[0026] Preferably, the film is used for drug delivery via the oral mucosa or sublingual route.

[0027] Preferably, the lumepirone or a pharmaceutically acceptable salt thereof is lumepirone tosylate.

[0028] In another aspect, the present invention provides a method for preparing the above-mentioned film, which is a hot melt method and comprises the following steps:

[0029] After the raw materials are mixed, they are extruded at a speed of 0.01-100 kg / h and stretched into a film.

[0030] Preferably, the hot melt method comprises the following steps:

[0031] (1) Mixing of raw materials and auxiliary materials;

[0032] (2) adding the mixture to a hot melt extruder at a rate of 0.01-100 kg / h, with the die temperature of the hot melt extruder being 130-190° C. After extrusion, stretching the film to form a film, and adjusting the rotation speed of the film stretching device to obtain films of different thicknesses and widths;

[0033] (3) The prepared film is cut into films of different sizes and shapes using a film cutting machine.

[0034] Preferably, the screw speed of the hot melt extrusion is 20-800 rpm.

[0035] Preferably, when the preparation method is a hot melt method, the raw materials of the film preparation, in parts by mass, comprise the following components:

[0036] 2-28 parts of lumiperone tosylate, 40-66 parts of copovidone, 40-66 parts of polyoxyethylene, 2-10 parts of polyethylene glycol, 0.1-0.5 parts of BHT, and 0.1-1.5 parts of sucralose.

[0037] In another aspect, the present invention provides a method for preparing the above-mentioned film, which is a solvent method.

[0038] Preferably, the solvent method comprises the following steps:

[0039] Step 1: Mix the film-forming material with the solvent, add the solubilizer and flavoring agent, and stir to obtain a glue solution;

[0040] Step 2: Spread the glue evenly to form a film.

[0041] Preferably, the solvent is selected from water or alcohol.

[0042] Preferably, when the preparation method is a solvent method, the raw materials of the film preparation, in parts by mass, comprise the following components:

[0043] 10-30 parts of lumiperone tosylate, 45-65 parts of film-forming material, 5-10 parts of propylene glycol, 5-15 parts of polyvinyl pyrrolidone, 1-2 parts of sucralose, and 0.3-0.8 parts of fruit flavor.

[0044] Preferably, the film-forming material is selected from polyvinyl alcohol or hypromellose.

[0045] Preferably, the weight of the film is 25 mg or 50 mg.

[0046] Preferably, the dosage of the API in the film is 2 mg or 4 mg (calculated as lumiperone).

[0047] Compared with the prior art, the present invention has the following beneficial effects:

[0048] The present invention introduces an innovative lumiperone tosylate film formulation that delivers the drug via the oral mucosa or sublingual route. This formulation significantly improves drug bioavailability, rapidly increases blood drug concentrations, and enhances brain drug levels and D2 target occupancy, ultimately effectively enhancing its therapeutic efficacy and providing patients with a more efficient and convenient treatment experience.

[0049] 2. The film prepared by the present invention is prepared by adding appropriate amounts of film-forming materials, plasticizers, disintegrants, stabilizers and other auxiliary materials to prepare a film with a smooth appearance, uniform thickness, rapid disintegration, good mechanical properties, and lumepirone tosylate in amorphous or microcrystalline form. It has good solubility and stability, and its bioavailability is significantly higher than that of the original capsule.

[0050] 3. The lumepirone tosylate oral film of the present invention has good solubility, can completely disintegrate within 30 seconds, and is rapidly absorbed by the oral mucosa. DETAILED DESCRIPTION

[0051] In order to make the technical means, creative features, purpose and effect of the present invention easy to understand, the present invention is further illustrated below in conjunction with specific embodiment, but the following embodiment is only a preferred embodiment of the present invention, not all. Based on the embodiment in the embodiment, other embodiments obtained by those skilled in the art without making creative work all fall within the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their source is not specifically limited. The technology and scientific terms used in the embodiment have the meaning commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0052] Source of raw materials:

[0053] Lumiperone tosylate was purchased from Wuhan Hanxiang Biotechnology Co., Ltd.

[0054] Copolyvidone was purchased from BASF with a molecular weight of 45,000-70,000.

[0055] Polyoxyethylene was purchased from The Dow Chemical Company, USA, with a molecular weight of approximately 200,000.

[0056] Polyethylene glycol was purchased from Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd. with a molecular weight of 5000-7000.

[0057] Example 1

[0058] A film preparation of lumiperone or its salt

[0059] The prescription is as follows:

[0060] Table 1. Example 1 prescription

[0061]

[0062] The preparation method is hot melt method:

[0063] Weighing: Accurately weigh the raw and auxiliary materials in the batch prescription quantity and set aside;

[0064] Mixing: First take the raw material and copovidone, pass through a 30-mesh sieve; then add the remaining materials and pass through a 30-mesh sieve together with the above materials.

[0065] Hot melt extrusion: A hot melt extruder was used to prepare lumepirone tosylate film. The extrusion temperatures were set at 80, 100, 125, 145, 145, 145, 145°C, the film outlet temperature was set at 145°C, the feed rate was 0.6 kg / h, the screw speed was 50 rpm, and the film drawing speed was 2 rpm. The parameters were subsequently adjusted according to the material state.

[0066] Cutting: The prepared film is cut into films of different sizes and shapes by a film cutting machine.

[0067] Examples 2-4

[0068] A film preparation of lumiperone or its salt

[0069] The prescription is as follows:

[0070] Table 2. Prescriptions for Examples 2-4

[0071]

[0072] The preparation method is the same as that in Example 1.

[0073] Examples 5-6

[0074] A film preparation of lumiperone or its salt

[0075] The prescription is as follows:

[0076] Table 3. Prescriptions for Examples 5-6

[0077]

[0078] The preparation method is the same as that in Example 1.

[0079] Examples 7-8

[0080] A film preparation of lumiperone or its salt

[0081] The prescription is as follows:

[0082] Table 4. Prescriptions for Examples 7-8

[0083]

[0084] Preparation method, solvent method:

[0085] Accurately weigh the prescribed amount of polyvinyl alcohol (PVA) and add 10 times the amount of purified water to the PVA volume. Stir thoroughly to dissolve the PVA. Slowly add the prescribed amount of propylene glycol, lumepirone tosylate, polyvinyl pyrrolidone, sucralose, and fruit flavoring, sequentially, and stir at 1000 rpm for 1 hour to prepare the adhesive solution. Apply the adhesive using a coating machine. Install the backing material and adjust the coating thickness to approximately 80 ± 5 μm. Set the coating speed to 10 rpm and evenly apply the adhesive solution to the backing to form a film. Dry at 40 ± 5°C. After drying, the film will be intact, with good flexibility and mechanical strength.

[0086] Cutting: The prepared film is cut into films of different sizes and shapes by a film cutting machine.

[0087] Examples 9-10

[0088] A film preparation of lumiperone or its salt

[0089] The prescription is as follows:

[0090] Table 5. Prescriptions for Examples 9-10

[0091]

[0092]

[0093] Preparation method, solvent method:

[0094] Accurately weigh the prescribed amount of hypromellose and add it to an 8-fold amount of 60% ethanol-water solution. Stir thoroughly to swell it. Then, slowly add the prescribed amount of propylene glycol, lumepirone tosylate, polyvinylpyrrolidone, sucralose, and fruit flavoring, stirring at 1000 rpm for 1 hour to prepare the adhesive solution. Apply the adhesive using a coating machine. Install the backing material and adjust the coating thickness to approximately 80 ± 5 μm. Set the coating speed to 10 rpm and evenly apply the adhesive solution to the backing to form a film. Dry at 40 ± 5°C. After drying, the film forms a complete, flexible, and mechanically strong film.

[0095] Cutting: The prepared film is cut into films of different sizes and shapes by a film cutting machine.

[0096] Examples 11-13

[0097] A film preparation of lumiperone or its salt

[0098] The prescription is as follows:

[0099] Table 6. Prescriptions for Examples 11-13

[0100]

[0101] The preparation method is the same as Example 1.

[0102] Examples 14-16

[0103] A film preparation of lumiperone or its salt

[0104] The prescription is as follows:

[0105] Table 7. Prescriptions for Examples 14-15

[0106]

[0107] The preparation method is the same as Example 1.

[0108] Example 16

[0109] A film preparation of lumiperone or its salt

[0110] The prescription is as follows:

[0111] Table 8. Prescription of Example 16

[0112] prescription Example 16 Name of raw materials Prescription ratio (%) Lumeperone Tosylate 11.50 Copolyvidone 33.30 Polyoxyethylene 48.96 polyethylene glycol 5.0 Sucralose 1.0 BHT 0.24

[0113] Preparation method, hot melt method:

[0114] Weighing: Accurately weigh the raw and auxiliary materials in the batch prescription quantity and set aside;

[0115] Mixing: First take the raw material and copovidone, pass through a 30-mesh sieve; then add the remaining materials and pass through a 30-mesh sieve together with the above materials.

[0116] Hot melt extrusion:

[0117] A hot melt extruder was used to conduct experiments to prepare lumiperone tosylate film. The temperature, feed speed, and film drawing speed were set as shown in Table 9.

[0118] Table 9. Parameters of Example 16

[0119]

[0120] Examples 17-20

[0121] A film preparation of lumiperone or its salt

[0122] The prescription is as follows:

[0123] Table 10. Prescriptions for Examples 17-20

[0124]

[0125]

[0126] Preparation method, hot melt method: same as Example 1.

[0127] Comparative Example 1

[0128] A film preparation of lumiperone or its salt

[0129] The prescription is as follows:

[0130] Table 11. Comparative Example 1 Prescription

[0131]

[0132] The preparation method is the same as Example 1.

[0133] Comparative Example 2

[0134] A film preparation of lumiperone or its salt

[0135] The prescription is as follows:

[0136] Table 12. Comparative Example 2 Prescription

[0137]

[0138] The preparation method is the same as Example 1.

[0139] Comparative Example 3

[0140] A film preparation of lumiperone or its salt

[0141] The prescription is as follows:

[0142] Table 13. Comparative Example 3 Prescription

[0143]

[0144] The preparation method is the same as Example 1.

[0145] Comparative Example 4

[0146] A film preparation of lumiperone or its salt

[0147] The prescription is as follows:

[0148] Table 14. Comparative Example 4 Prescription

[0149] prescription Comparative Example 4 Name of raw materials Prescription ratio (%) Lumeperone Tosylate 11.50 Copolyvidone 33.50 Polyoxyethylene 49.00 polyethylene glycol 5.00 Sucralose 1.0 BHT / BHA / Sodium bisulfite /

[0150] The preparation method is the same as Example 1.

[0151] Comparative Example 5

[0152] A film preparation of lumiperone or its salt

[0153] The recipe is the same as that of Example 1, and the preparation method only changes its parameters, specifically:

[0154] The preparation method is hot melt method:

[0155] Weighing: Accurately weigh the raw and auxiliary materials in the batch prescription quantity and set aside;

[0156] Mixing: First take the raw material and copovidone, pass through a 30-mesh sieve; then add the remaining materials and pass through a 30-mesh sieve together with the above materials.

[0157] Hot melt extrusion: A hot melt extruder was used to prepare lumepirone tosylate film. The extrusion temperatures were set at 80, 100, 115, 125, 125, 125, 125°C, the film outlet temperature was set at 125°C, the screw speed was 50 rpm, and the film drawing speed was 2 rpm. The parameters were subsequently adjusted according to the material state.

[0158] Cutting: The prepared film is cut into films of different sizes and shapes by a film cutting machine.

[0159] Test Example 1

[0160] Tensile strength and disintegration time test results

[0161] Disintegration time: Determined by the disintegration time test method in Appendix 0921 of the 2020 edition of the Chinese Pharmacopoeia;

[0162] Tensile strength: Use a medical packaging performance tester to conduct tensile tests on different batches of film preparations. Cut samples from each batch with a length of 5 cm, set the clamp spacing to 20 mm, and the test speed to 5 mm / min. Test 3 samples from each batch and record the average tensile strength.

[0163] Table 15. Results of Examples 1-10

[0164]

[0165] Table 16. Results of Examples 11-20

[0166]

[0167]

[0168] Table 17. Results of Example 16

[0169] prescription 16-1a 16-1b 16-1c 16-1d 16-1e Tensile strength (MPa) 28 27 28 27 26 Disintegration time (s) 9 10 9 9 8 Appearance normal normal normal normal normal

[0170] Table 18. Results of Comparative Examples 1-5

[0171]

[0172] As shown in Tables 15-18, when the ratio of copolyvidone to polyethylene oxide exceeded the ratio range specified in this patent, both Comparative Examples 2 and 3 failed to successfully form films. Furthermore, when the film-drawing temperature deviated from the process parameter range specified in this patent, while Comparative Example 5 was able to form a film, the film surface exhibited a noticeable graininess, and its appearance did not meet product standards. While the film morphology of Comparative Example 4 was normal, the rapid growth of related impurities during stability testing did not meet quality requirements.

[0173] In contrast, the films of Examples 1 to 15 all had normal appearances, and their tensile strength and disintegration times all met the product standard requirements. This demonstrates that the quality and performance of the films can be effectively guaranteed by strictly adhering to the formulation ranges and process parameters defined in this patent.

[0174] Test Example 2

[0175] The films prepared in Examples 1, 14-15, and Comparative Example 4 were placed in aluminum bags, sealed, and placed in a stability box (55° C., RH 75%). The relevant substances were detected by high performance liquid chromatography. The data are as follows:

[0176] Table 19. Stability

[0177]

[0178]

[0179] Test Example 3

[0180] Animals: 6 male albino guinea pigs weighing 270-330 g.

[0181] Animal Dosing: After fasting for 12 hours, albino guinea pigs were orally administered 3 mg / kg (calculated as lumeperone) of lumepirone tosylate solution (6.516 mg of lumepirone tosylate powder was accurately weighed and placed in a 15 mL centrifuge tube, 4.530 mL of purified water was added, and sonication was performed until dissolved to obtain a lumepirone tosylate solution.) and 0.3 mg / kg (calculated as lumeperone) of the lumepirone tosylate film prepared in Example 1 was administered sublingually.

[0182] Blood collection method: blood is collected from the vascular plexus at the upper corner of the eye.

[0183] The specific dosage is as follows:

[0184] Table 20. Dosage route

[0185]

[0186] Table 21. Results

[0187]

[0188] As shown in Tables 20-21, sublingual absorption of lumepirone tosylate film exhibits a shorter time to peak concentration (Tmax) and a higher peak concentration (Cmax) compared to oral administration of lumepirone tosylate solution. This route of administration facilitates rapid passage of lumepirone tosylate across the blood-brain barrier, thereby increasing its occupancy at the D2 target site and significantly enhancing its efficacy. Furthermore, relevant data also demonstrate that sublingual administration of lumepirone tosylate film significantly improves the drug's absolute bioavailability.

[0189] Test Example 4

[0190] Animals: Beagles, male, four, average weight 10 kg.

[0191] Animal administration: 10 mg (calculated as lumiperone) of the lumepirone tosylate film prepared in Example 1, Comparative Examples 1-5, and Example 15 of CN110430879 was administered sublingually.

[0192] Table 22. Results

[0193]

[0194] As shown in Table 22, the lumepirone tosylate film prepared in Example 1 of the present invention can reach T faster. max And the onset of action is conducive to increasing the occupancy of the D2 target, which may provide better therapeutic effects. Compared with some sudden and acute psychotic symptoms, it can take effect faster.

[0195] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A film preparation of lumiperone or its salt, characterized in that: The composition comprises the following raw materials in parts by mass: 2-30 parts of lumepirone or a pharmaceutically acceptable salt thereof, 40-95 parts of a film-forming material, 1-30 parts of a plasticizer, and 0.1-5 parts of an antioxidant; The lumiperone or a pharmaceutically acceptable salt thereof is lumiperone tosylate; The antioxidant is selected from at least one of butylated hydroxyanisole, butylated hydroxytoluene and sodium bisulfite; The film-forming material is copolyvidone and polyoxyethylene; the mass ratio of the copolyvidone to polyoxyethylene is 2-8:2-8; and the plasticizer is polyethylene glycol.

2. The film according to claim 1, characterized in that The preparation comprises the following raw materials in parts by mass: 2-25 parts of lumiperone or a pharmaceutically acceptable salt thereof, 40-92 parts of a film-forming material, 1-20 parts of a plasticizer and 0.2-5 parts of an antioxidant.

3. The film according to claim 1, characterized in that The preparation comprises the following raw materials in parts by mass: 2-12 parts of lumiperone or a pharmaceutically acceptable salt thereof, 45-92 parts of a film-forming material, 1-15 parts of a plasticizer and 0.2-4 parts of an antioxidant.

4. The film according to claim 1, characterized in that The antioxidant is sodium bisulfite.

5. The film according to claim 1, characterized in that The raw materials of the film may further include flavoring agents.

6. The film according to claim 5, characterized in that The flavoring agent is selected from at least one of sucralose, essence, citric acid, and tartaric acid.

7. The film according to claim 5, characterized in that The preparation comprises the following raw materials in parts by mass: 2-30 parts of lumiperone or a pharmaceutically acceptable salt thereof, 40-95 parts of a film-forming material, 1-30 parts of a plasticizer, 0.1-5 parts of an antioxidant and 0.1-3 parts of a flavoring agent.

8. The film according to claim 1, characterized in that The film is used for drug delivery via the oral mucosa or sublingual route.

9. The method for preparing the film according to any one of claims 1 to 8, characterized in that: It is a hot melt method, which includes the following steps: After the raw materials are mixed, they are extruded at a speed of 0.01-100 kg / h and stretched into a film.

10. The preparation method according to claim 9, characterized in that The screw speed of the hot melt extrusion is 20-800 rpm.

11. The method for preparing the film according to any one of claims 1 to 8, characterized in that: It is a solvent method.

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