A milorine hydrochloride buccal film and a preparation method thereof

Abstract

The application discloses a milorin oral dissolving film and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. According to the mass fraction, the milorin oral dissolving film comprises the following components: 80-105 parts of an ethanol aqueous solution, 0.1-0.75 parts of milorin benzenesulfonate, 5-12 parts of hydroxypropyl methyl cellulose, 0.1-5 parts of a surfactant, 3-10 parts of a plasticizer, and 0 or 0.1-2 parts of a disintegrant. Compared with the existing dosage forms such as tablets which are not easy to swallow, have poor taste, are easy to spit out and the like, the milorin oral dissolving film prepared by the application can be quickly adhered to the oral mucosa and is not easy to spit out after contacting a small amount of saliva in the oral cavity, can be quickly disintegrated, is easy to swallow, does not need to be chewed and watered, and has no grit feeling.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a mirogabalin benzenesulfonate orally dissolving film and a preparation method thereof. BACKGROUND

[0002] The information disclosed in this Background section is only for the purpose of increasing the understanding of the general background of the application and does not necessarily constitute an admission or a recognition that the information forms part of the prior art that is already known in any country in the world.

[0003] Mirogabalin benzenesulfonate is a new type of selective calcium channel alpha2delta ligand, which can preferentially and selectively bind to the alpha2delta-1 subunit of voltage-dependent calcium channels (1 and 2) to play an analgesic effect, and is mainly used for the treatment of diabetic peripheral neuropathic pain, post-herpetic neuralgia and fibromyalgia. At present, the dosage form research of mirogabalin benzenesulfonate mainly focuses on oral preparations, such as sustained-release tablets and oral disintegrating tablets. Oral preparations have limitations, and it is difficult for the elderly, children and patients with difficulty in swallowing to take them, so a mirogabalin benzenesulfonate orally dissolving film that quickly disintegrates when contained in the mouth or placed in water needs to be developed.

[0004] Patent CN 110917164 A discloses a mirogabalin benzenesulfonate sustained-release tablet and a preparation method thereof. However, the patent does not describe a mirogabalin benzenesulfonate orally dissolving film.

[0005] Patent CN 116509811 A discloses a mirogabalin benzenesulfonate sustained-release tablet and a preparation method thereof. The preparation process is simple, and the obtained mirogabalin benzenesulfonate sustained-release tablet has good stability. However, the patent does not describe a mirogabalin benzenesulfonate orally dissolving film.

[0006] Patent CN 115803020 A discloses a mirogabalin benzenesulfonate oral disintegrating tablet that quickly disintegrates when contained in the mouth or placed in water, showing excellent solubility. However, the patent does not describe a mirogabalin benzenesulfonate orally dissolving film. SUMMARY

[0007] In order to solve the problems of the prior art, the present application aims to provide a mirogabalin benzenesulfonate orally dissolving film and a preparation method thereof. The preparation method provided by the present application is simple and efficient, and the obtained mirogabalin benzenesulfonate orally dissolving film quickly adheres to the oral mucosa in the oral cavity, is not easy to spit out, is not easy to break, quickly dissolves, and is easy to swallow.

[0008] In order to achieve the above-mentioned purposes, the technical scheme of the present application is as follows:

[0009] In a first aspect, the present application provides a mirogabalin benzenesulfonate orally dissolving film, which comprises the following components in parts by mass:

[0010] ethanol aqueous solution 80-105 parts, miloramide benzenesulfonate 0.1-0.75 parts, hydroxypropyl methyl cellulose 5-12 parts, surfactant 0.1-5 parts, plasticizer 3-10 parts, disintegrant 0-2 parts.

[0011] In some embodiments of the present application, the hydroxypropyl methyl cellulose is a film forming material.

[0012] In some embodiments of the present application, the miloramide benzenesulfonate oral film formulation uses ethanol aqueous solution as solvent, and per 100 mL of the solvent (ethanol aqueous solution) contains: miloramide benzenesulfonate 0.1-0.75 g, hydroxypropyl methyl cellulose 5-12 g, surfactant 0.1-5 g, plasticizer 3-10 g, disintegrant 0-2 g.

[0013] In some embodiments of the present application, the surfactant is at least one selected from poloxamer, polysorbate, polyoxyethylene sorbitan monooleate, sodium dodecyl sulfate, macrogol-15 hydroxystearate, polyethylene glycol, vitamin E, and macrogol succinate, preferably poloxamer and polysorbate, further preferably poloxamer 188 and polysorbate 80 (i.e. Tween 80). Among them, poloxamer 188 can be used as a solid dispersion carrier in addition to being a surfactant, to improve the dissolution of the drug (miloramide benzenesulfonate).

[0014] In some embodiments of the present application, the plasticizer is at least one selected from glycerol, propylene glycol, polyethylene glycol 400, glycerol monooleate, and citric acid glycerol ester, preferably glycerol, propylene glycol, or polyethylene glycol 400, further preferably glycerol.

[0015] In some embodiments of the present application, the disintegrant is at least one selected from lactose, soluble starch, maltodextrin, mannitol, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and sodium alginate, preferably lactose.

[0016] In some embodiments of the present application, the miloramide benzenesulfonate oral film formulation further comprises a flavoring agent, which is at least one selected from sucralose, citric acid hydrate, sucrose, mannitol, maltitol, stevioside, aspartame, acesulfame, and cyclamate, preferably a combination of sucralose and citric acid hydrate, further preferably sucralose.

[0017] In some embodiments of the present application, the miloramide benzenesulfonate oral film formulation comprises the following components in parts by mass:

[0018] 80-105 parts of 50% ethanol aqueous solution, 0.1-0.75 parts of milorine tartrate, 5-12 parts of hydroxypropyl methyl cellulose, 0.1-5 parts of surfactant, 3-10 parts of plasticizer, 0-2 parts of disintegrant, 0.1-1.2 parts of flavoring agent.

[0019] Preferably, the disintegrant is 0 or 0.1-2 parts.

[0020] In some embodiments of the present application, the milorine tartrate oral dissolving film contains, per 100 mL of solvent, 0.1-0.75 g of milorine tartrate, 5-12 g of hydroxypropyl methyl cellulose, 0.1-5 g of surfactant, 3-10 g of plasticizer, 0 or 0.1-2 g of disintegrant, and 0.1-1.2 g of flavoring agent.

[0021] In some embodiments of the present application, the volume ratio of water to ethanol in the 50% ethanol aqueous solution is 4:1-1:4, preferably 1:1.

[0022] The milorine tartrate oral dissolving film contains, by mass fraction, the following components:

[0023] 85-90 parts of 50% ethanol aqueous solution, 0.1-0.75 parts of milorine tartrate, 5-12 parts of hydroxypropyl methyl cellulose, 0.5-2.5 parts of poloxamer 188, 0.1-0.3 parts of polysorbate 80, 3-9 parts of glycerol, propylene glycol or polyethylene glycol 400, 0-2 parts of lactose, and 0.1-1.2 parts of sucralose.

[0024] Preferably, the lactose is 0 or 0.1-2 parts.

[0025] In some embodiments of the present application, the milorine tartrate oral dissolving film contains, by mass fraction, the following components:

[0026] 85-90 parts of 50% ethanol aqueous solution, 0.1-0.75 parts of milorine tartrate, 9-11 parts of hydroxypropyl methyl cellulose, 0.5-2.5 parts of poloxamer 188, 0.1-0.3 parts of polysorbate 80, 5-9 parts of glycerol, propylene glycol or polyethylene glycol 400, 0-0.6 parts of lactose, and 0.2-0.6 parts of sucralose.

[0027] Preferably, the lactose is 0 or 0.1-0.6 parts.

[0028] In some embodiments of the present application, the milorine tartrate oral dissolving film contains, by mass fraction, the following components:

[0029] 50% ethanol aqueous solution 85-90 parts, miloramide benzenesulfonate 0.1-0.75 parts, hydroxypropyl methyl cellulose 9-11 parts, poloxamer 188 0.5-2.5 parts, polysorbate 80 0.1-0.3 parts, glycerol 5-9 parts, lactose 0 or 0.1-0.6 parts, sucralose 0.2-0.6 parts.

[0030] In some embodiments of the present application, the miloramide benzenesulfonate oral film preparation is a film preparation, and the content of the active pharmaceutical ingredient in each film is 2.5 mg-15 mg of miloramide benzenesulfonate.

[0031] In a second aspect of the present application, a preparation method of the miloramide benzenesulfonate oral film preparation is provided, comprising the following steps:

[0032] The hydroxypropyl methyl cellulose is added to part of the ethanol aqueous solution and stirred until completely swelled;

[0033] The surfactant, miloramide benzenesulfonate, plasticizer, disintegrant and flavoring agent are added to the remaining ethanol aqueous solution, dissolved to obtain a drug-containing solution;

[0034] The drug-containing solution is added to the completely swelled hydroxypropyl methyl cellulose, homogenized, and defoamed to obtain a drug-containing slurry;

[0035] The drug-containing slurry is coated on the surface of a mold, dried, demolded, and cut to obtain the miloramide benzenesulfonate oral film preparation.

[0036] In some embodiments of the present application, the surfactant, miloramide benzenesulfonate, plasticizer, disintegrant and flavoring agent are added to the remaining ethanol aqueous solution, and completely dissolved and dispersed, with a dispersion time of 0.5-2 h.

[0037] In some embodiments of the present application, the drug-containing solution is added to the completely swelled hydroxypropyl methyl cellulose, stirred and homogenized, and then left to stand for defoaming; the stirring time is 0.5-2 h, and the standing time is 0.1-2 h.

[0038] The amino group and carboxyl group exist simultaneously in the molecule of miloramide benzenesulfonate, and impurities may be generated by dehydration at too high a temperature, so the drying temperature should not be too high. In some embodiments of the present application, the drying temperature is 40-60℃, and the drying time is 0.5-4 h.

[0039] Except for the drying step, other preparation steps of the miloramide benzenesulfonate oral film preparation are performed at room temperature or 30℃.

[0040] The present application has the following beneficial effects:

[0041] In view of the fact that the existing milorine tartrate benzenesulfonate preparation does not involve an oral dissolving film, the present application provides a milorine tartrate benzenesulfonate oral dissolving film and a preparation method thereof. The present application uses hydroxypropyl methylcellulose as a film-forming material; uses an ethanol aqueous solution as a solvent, which can fully dissolve the drug and fully swell and disperse the film-forming material, avoid the generation of too many bubbles in the drug-containing slurry, improve the production efficiency, and make the film smoother and more uniform; and uses poloxamer 188 as a dispersion carrier to prepare a solid dispersion with the milorine tartrate benzenesulfonate, which can prevent the precipitation of granular drugs on the surface of the film after the solvent evaporates and improve the disintegration behavior of the drug. Compared with the existing dosage forms such as tablets, which are not easy to swallow, have a poor taste, and are easy to spit out, the milorine tartrate benzenesulfonate oral dissolving film prepared by the present application can quickly adhere to the oral mucosa without being easy to spit out, quickly disintegrate, be easy to swallow, and does not need to be chewed and taken with water, and has no grit feeling.

[0042] The milorine tartrate benzenesulfonate oral dissolving film provided by the present application has a simple and efficient preparation process, and the dosage of the milorine tartrate benzenesulfonate oral dissolving film is flexible and can be prepared into different sizes and dosages. DETAILED DESCRIPTION

[0043] In order for those skilled in the art to more clearly understand the technical solutions of the present application, the technical solutions of the present application will be described in detail below in combination with specific examples.

[0044] The reagents, methods and equipment used in the following examples are conventional reagents, methods and equipment in the technical field unless otherwise specified.

[0045] EXAMPLE

[0046] The preparation method of the milorine tartrate benzenesulfonate oral dissolving film is as follows:

[0047] (1) Dissolve the prescribed amount of hydroxypropyl methylcellulose in 50mL of 50% ethanol aqueous solution at room temperature, and stir for 30min until it is fully swollen.

[0048] (2) Add the prescribed amounts of poloxamer 188, Tween 80, milorine tartrate benzenesulfonate, glycerol, lactose and sucralose to 50mL of 50% ethanol aqueous solution at room temperature, and stir for 40min until they are fully dissolved and dispersed, to obtain a drug-containing solution.

[0049] (3) Add the drug-containing solution obtained in step (2) to the swollen film-forming material at room temperature, stir for 30min until it is uniformly dispersed, and stand for 30min to remove bubbles, to obtain a drug-containing slurry.

[0050] (4) Uniformly coat the drug-containing slurry on a petri dish at room temperature, dry at 60℃ for 45min, demold, cut into 2.0cm x 3.0cm in size, and obtain the milorine tartrate benzenesulfonate oral dissolving film.

[0051] The specific formulation is shown in Examples 1-24.

[0052] Examples 1-3

[0053] The solvent was screened by using hydroxypropyl methyl cellulose as the film forming material, glycerin as the plasticizer, poloxamer 188 as the solid dispersion carrier, Tween 80 as the surfactant, lactose as the disintegrant, sucralose as the flavoring agent, 50% ethanol as the solvent, and the amount of hydroxypropyl methyl cellulose was 5.0 g. The type of hydroxypropyl methyl cellulose was screened. The formulation is shown in Table 2.

[0054] Table 2 Formulation of milnacianil benzene sulfonate oral dissolving film in Examples 4-6

[0055]

[0056]

[0057] Examples 4-6

[0058] The solvent was screened by using hydroxypropyl methyl cellulose as the film forming material, glycerin as the plasticizer, poloxamer 188 as the solid dispersion carrier, Tween 80 as the surfactant, lactose as the disintegrant, sucralose as the flavoring agent, 50% ethanol as the solvent, and the amount of hydroxypropyl methyl cellulose was 5.0 g. The type of hydroxypropyl methyl cellulose was screened. The formulation is shown in Table 2.

[0059] Table 2 Formulation of milnacianil benzene sulfonate oral dissolving film in Examples 4-6

[0060] Ingredient Example 4 Example 5 Example 6 milnaciantrile benzenesulfonic acid salt 0.25g 0.25g 0.25g HPMC E3 5.0g - - HPMC E5 - 5.0g - HPMC E15 - - 5.0g Glycerin 8.0g 8.0g 8.0g Poloxamer 188 2.0g 2.0g 2.0g Tween 80 0.2g 0.2g 0.2g Lactose 0.5g 0.5g 0.5g Sucralose 0.5g 0.5g 0.5g 50% Ethanol 100 mL 100 mL 100 mL

[0061] Examples 7-9

[0062] The solvent was screened by using hydroxypropyl methyl cellulose as the film forming material, glycerin as the plasticizer, poloxamer 188 as the solid dispersion carrier, Tween 80 as the surfactant, lactose as the disintegrant, sucralose as the flavoring agent, 50% ethanol as the solvent, and the amount of hydroxypropyl methyl cellulose was 5.0 g. The type of hydroxypropyl methyl cellulose was screened. The formulation is shown in Table 2.

[0063] Table 3 Formulation of milnacianil benzene sulfonate oral dissolving film in Examples 7-9

[0064] Ingredient Example 7 Example 8 Example 9 milnaciantrile benzenesulfonic acid salt 0.25g 0.25g 0.25g HPMC E5 6.0g 8.0g 12.0g Glycerin 8.0g 8.0g 8.0g Poloxamer 188 2.0g 2.0g 2.0g Tween 80 0.2g 0.2g 0.2g Lactose 0.5g 0.5g 0.5g Sucralose 0.5g 0.5g 0.5g 50% Ethanol 100 mL 100 mL 100 mL

[0065] Examples 10-12

[0066] The hydroxypropyl methyl cellulose is used as the film forming material, the poloxamer 188 is used as the solid dispersion carrier, the tween 80 is used as the surfactant, the lactose is used as the disintegrant, the sucralose is used as the flavoring agent, the 50% ethanol is used as the solvent, the glycerin, propylene glycol and polyethylene glycol 400 are used as the plasticizer, the amount of the plasticizer is 5.0g, and the type of the plasticizer is screened.

[0067] Table 4: Formulation of miloribine benzenesulfonate oral dissolving film of examples 10-12

[0068]

[0069]

[0070] Examples 13-15

[0071] The hydroxypropyl methyl cellulose is used as the film forming material, the poloxamer 188 is used as the solid dispersion carrier, the tween 80 is used as the surfactant, the lactose is used as the disintegrant, the sucralose is used as the flavoring agent, the 50% ethanol is used as the solvent, the glycerin is used as the plasticizer, the amount of the plasticizer is 3.0-9.0g, and the amount of the glycerin is screened. The formulation is shown in Table 5.

[0072] Table 5: Formulation of miloribine benzenesulfonate oral dissolving film of examples 13-15

[0073] Ingredient Example 13 Example 14 Example 15 milnaciantrile benzenesulfonic acid salt 0.25g 0.25g 0.25g HPMC E5 10.0g 10.0g 10.0g Glycerin 3.0g 6.0g 9.0g Poloxamer 188 2.0g 2.0g 2.0g Tween 80 0.2g 0.2g 0.2g Lactose 0.5g 0.5g 0.5g Sucralose 0.5g 0.5g 0.5g 50% Ethanol 100 mL 100 mL 100 mL

[0074] Examples 16-18

[0075] The hydroxypropyl methyl cellulose is used as the film forming material, the glycerin is used as the plasticizer, the tween 80 is used as the surfactant, the lactose is used as the disintegrant, the sucralose is used as the flavoring agent, the 50% ethanol is used as the solvent, the poloxamer 188 is used as the solid dispersion carrier, and the amount of the poloxamer 188 is 1.0-3.0g. The formulation is shown in Table 6.

[0076] Table 6: Formulation of miloribine benzenesulfonate oral dissolving film of examples 16-18

[0077] Ingredient Example 16 Example 17 Example 18 milnaciantrile benzenesulfonic acid salt 0.25g 0.25g 0.25g HPMC E5 10.0g 10.0g 10.0g Glycerin 8.0g 8.0g 8.0g Poloxamer 188 0g 1.0g 3.0g Tween 80 0.2g 0.2g 0.2g Lactose 0g 1.0g 2.0g Sucralose 0.5g 0.5g 0.5g 50% Ethanol 100 mL 100 mL 100 mL

[0078] Examples 19-21

[0079] The hydroxypropyl methyl cellulose is used as the film forming material, the glycerin is used as the plasticizer, the poloxamer 188 is used as the solid dispersion carrier, the tween 80 is used as the surfactant, the sucralose is used as the flavoring agent, the 50% ethanol is used as the solvent, and the lactose is used as the disintegrant, and the amount of the lactose is 0-2.0g. The formulation is shown in Table 7.

[0080] Table 7: Formulation of miloribine benzenesulfonate oral dissolving film of examples 19-21

[0081]

[0082]

[0083] Examples 22-24

[0084] Using hydroxypropyl methylcellulose as film forming material, glycerin as plasticizer, poloxamer 188 as solid dispersion carrier, Tween 80 as surfactant, lactose as disintegrant, 50% ethanol as solvent; sucralose as flavoring agent, the amount of which was screened from 0.2 to 1.0 g. The prescription is shown in Table 8.

[0085] Table 8 Formulation of milnacian pilocarpine benzenesulfonate oral dissolving film of Examples 19-21

[0086]

[0087]

[0088] The appearance, peelability, folding endurance and disintegration time of the milnacian pilocarpine benzenesulfonate oral dissolving films prepared in Examples 1-24 were investigated. The standards for appearance evaluation are shown in Table 9.

[0089] Table 9 Standards for appearance evaluation

[0090]

[0091] The peelability evaluation standards are shown in Table 10.

[0092] Table 10 Peelability evaluation standards

[0093]

[0094] Folding endurance: the self-prepared milnacian pilocarpine benzenesulfonate oral dissolving film was repeatedly folded to the same side at an angle of 180° until it broke, and the number of folds at the time of breakage was recorded, which was the folding endurance.

[0095] Disintegration time: the self-prepared milnacian pilocarpine benzenesulfonate oral dissolving film was fixed on a paper clip and placed in 30 mL of distilled water at 37°C, and gently shaken, and the time for complete disintegration of the film at this temperature was recorded, which was the disintegration time.

[0096] The detection results of the appearance, folding endurance, peelability and disintegration time of Examples 1-24 are shown in Table 11.

[0097] Table 11 Detection results of Examples 1-24

[0098]

[0099]

[0100]

[0101] The test results of Examples 1-3 show that the concentration of the solvent affects the appearance, peelability and disintegration time of the film preparation, and when an appropriate concentration of ethanol aqueous solution is used as the solvent, the drug can be fully dissolved, and the swelling of the polymer material can be prevented to generate too many bubbles, so that the film preparation has a good appearance, suitable folding resistance and disintegration time; the test results of Examples 4-9 show that the type and amount of the film-forming agent affect the folding resistance and disintegration time of the film preparation, and selecting a suitable film-forming agent is an important factor in the preparation process of the oral film; the test results of Examples 10-12 show that the type of the plasticizer affects the folding resistance of the oral film, and when glycerol is used as the plasticizer, the appearance is smooth and flat, and there is no obvious bubble, and compared with propylene glycol and polyethylene glycol 400, no oily substance is exuded on the surface of the film preparation; the test results of Examples 13-15 and Example 2 show that the plasticizer can increase the folding resistance of the film preparation, but too much addition will lead to the extension of the disintegration time, so the amount should be paid attention to during use; the test results of Examples 16-18 and Example 2 show that poloxamer 188 affects the appearance and disintegration time of the film preparation, and when the amount is too much, the properties of the film-forming agent are affected to cause poor film-forming property, and an appropriate amount of poloxamer 188 can prevent the drug particles from being precipitated on the surface of the film preparation after the solvent is volatilized, and at the same time, the disintegration time of the film preparation is improved, and then the drug dissolution behavior is improved (here, the “improved drug dissolution behavior” means that the film preparation is better dispersed in water due to the reduction of the aggregation of the particles or agglomerated drug, so that the disintegration time is shortened, and the disintegration time results of Examples 16, 17, 2 and 18 are shortened with the increase of the amount of poloxamer 188); the test results of Examples 19-21 and Example 2 show that the disintegrating agent can shorten the disintegration time within a certain range, but too much amount of the disintegrating agent cannot be fully compatible with the drug-containing slurry to cause the rough appearance of the film preparation and the extension of the disintegration time, so the amount should be paid attention to during use; the test results of Examples 22-24 and Example 2 show that the flavoring agent can improve the taste of the film preparation, and the amount of the flavoring agent can slightly affect the appearance and other properties of the film.

[0102] In summary, the present application relates to a milorine tartrate oral film preparation and a preparation method thereof, the preparation method is simple and efficient, the milorine tartrate oral film preparation obtained by using the method is quickly adhered to the oral mucosa in the oral cavity and is not easy to spit out, and the dosage is flexible, not easy to break, quickly dissipated, easy to swallow.

[0103] The milorine tartrate oral film preparation prepared by Example 2 has a drug loading of 5 mg / tablet, and in order to prepare a milorine tartrate oral film preparation of 10 mg / tablet, Examples 25-26 are added for exploration.

[0104] Example 25 has the same prescription as Example 2, and the difference lies in that the addition amount of milorine tartrate is 0.5 g.

[0105] The prescription of Example 26 is the same as that of Example 2, except that the film dosage is cut into a size of 3 cm x 4 cm.

[0106] The test results are shown in Table 12.

[0107] Table 12 Test results of Example 25, Example 26

[0108]

[0109] Table 12 shows that adjusting the amount of miloramide benzenesulfonate or changing the film dosage cutting size has negligible effect on the folding endurance and disintegration time of the film dosage.

[0110] The drug loading of the present application ranges from 2.5-15 mg, and various specifications can be prepared to adapt to the medication needs of different medication populations.

[0111] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Various modifications and changes can be made by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A melt-in-mouth film of milorilbaine besylate, characterized in that, by mass, the following components are included: 80 ~ 105 parts of an aqueous ethanol solution, 0.1 ~ 0.75 parts of milnacian benzene sulfonate, 5 ~ 12 parts of hydroxypropyl methyl cellulose, 0.1 ~ 5 parts of a surfactant, 3 ~ 10 parts of a plasticizer, and 0 ~ 2 parts of a disintegrant; The milnacian benzene sulfonate oral dissolving film is a film-shaped preparation, and the content of the active pharmaceutical ingredient in each film is 2.5 mg ~ 15 mg of milnacian benzene sulfonate; The surfactant is poloxamer 188; The plasticizer is glycerol, propylene glycol or polyethylene glycol 400; The volume ratio of water to ethanol in the aqueous ethanol solution is 1:

1.

2. The orally disintegrating film of milorilbaine besylate according to claim 1, wherein The plasticizer is glycerol.

3. The orally disintegrating film of milorilbaine besylate according to claim 1, wherein The disintegrant is at least one selected from the group consisting of lactose, soluble starch, maltodextrin, mannitol, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose and sodium alginate.

4. The orally disintegrating film of milorilbaine besylate according to claim 3, wherein The disintegrant is lactose.

5. The orally disintegrating film of milorilbaine besylate according to claim 1, wherein The milnacian benzene sulfonate oral dissolving film further includes a flavoring agent, and the flavoring agent is at least one selected from the group consisting of sucralose, citric acid hydrate, sucrose, mannitol, maltitol, steviosin, aspartame, acesulfame potassium and cyclamate.

6. The orally disintegrating film of milorilbaine besylate according to claim 5, wherein The flavoring agent is a combination of sucralose and citric acid hydrate.

7. The orally disintegrating film of milorilbaine besylate according to claim 6, wherein The flavoring agent is sucralose.

8. The orally disintegrating film of milorilbaine besylate according to claim 1, wherein The milnacian benzene sulfonate oral dissolving film includes, by mass, the following components: 80 ~ 105 parts of an aqueous ethanol solution, 0.1 ~ 0.75 parts of milnacian benzene sulfonate, 5 ~ 12 parts of hydroxypropyl methyl cellulose, 0.1 ~ 5 parts of a surfactant, 3 ~ 10 parts of a plasticizer, and 0 ~ 2 parts of a disintegrant; 9. The orally disintegrating film of milorilbaine besylate according to claim 8, wherein The disintegrant is 0 or 0.1 ~ 2 parts by mass.

10. The milnacian benzene sulfonate oral dissolving film of claim 1, wherein The milnacian benzene sulfonate oral dissolving film includes, by mass, the following components: 85 ~ 90 parts of a 50% aqueous ethanol solution, 0.1 ~ 0.75 parts of milnacian benzene sulfonate, 5 ~ 12 parts of hydroxypropyl methyl cellulose, 0.5 ~ 2.5 parts of poloxamer 188, 0.1 ~ 0.3 parts of polysorbate 80, 3 ~ 9 parts of glycerol, propylene glycol or polyethylene glycol 400, 0 ~ 2 parts of lactose, and 0.1 ~ 1.2 parts of sucralose.

11. The orally disintegrating film of milorilbaine besylate according to claim 10, wherein The lactose is 0 or 0.1 ~ 2 parts.

12. The orally dissolving film of milorilbaine besylate according to claim 11, wherein The lactose is 0 or 0.1 ~ 0.6 parts.

13. The orally disintegrating film of milorilbaine besylate according to claim 1, wherein The milnacian benzene sulfonate oral dissolving film includes, by mass, the following components: 85 ~ 90 parts of a 50% aqueous ethanol solution, 0.1 ~ 0.75 parts of milnacian benzene sulfonate, 9 ~ 11 parts of hydroxypropyl methyl cellulose, 0.5 ~ 2.5 parts of poloxamer 188, 0.1 ~ 0.3 parts of polysorbate 80, 5 ~ 9 parts of glycerol, 0 or 0.1 ~ 0.6 parts of lactose, and 0.2 ~ 0.6 parts of sucralose.

14. A process for the preparation of a melt-in-mouth film of milnacian pamoate phenylsulfonate according to any one of claims 1 to 13, characterized in that, The method includes the following steps: The hydroxypropyl methyl cellulose is added to part of the aqueous ethanol solution and stirred until completely swollen; The surfactant, milnacian benzene sulfonate, plasticizer, disintegrant and flavoring agent are added to the remaining aqueous ethanol solution, dissolved, and a drug-containing solution is obtained; The drug-containing solution is coated on a release film to obtain the milnacian benzene sulfonate oral dissolving film. The drug-containing solution is added into the completely swollen hydroxypropyl methyl cellulose, homogenized, defoamed to obtain a drug-containing slurry; The drug-containing slurry is coated on the surface of a mold, dried, demolded, and cut to obtain the product.

15. The process for the preparation of the orally disintegrating film of milorinib besylate as claimed in claim 14 wherein, The surfactant, milorine tartrate, plasticizer, disintegrant, and flavoring agent are added into the remaining aqueous ethanol solution, and completely dissolved and dispersed, with a dispersion time of 0.5-2 h. Or, the drug-containing solution is added into the completely swollen hydroxypropyl methyl cellulose, stirred and homogenized, and defoamed after standing; the stirring time is 0.5-2 h, and the standing time is 0.1-2 h.

16. The process for the preparation of orally disintegrating films of milnacian pivalose according to claim 14, characterized in that, The drying is performed at a temperature of 40-60°C for 0.5-4 h; Except for the drying step, other preparation steps of the milorine tartrate buccal film are performed at room temperature or 30°C.

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