Braxpiprazole oral film preparation as well as preparation method and application thereof

Abstract

The invention provides a brexpiprazole oral film preparation as well as a preparation method and application thereof. The brexpiprazole oral film preparation comprises the following components: an active drug and a film-forming material, the active drug is 7-[4-(4-benzo [B] thiophene-4-yl-1-piperazine) butoxy]-2 (1H)-quinolinone as shown in a formula I and / or a pharmaceutically acceptable salt thereof, and the particle size D90 of the active drug is less than or equal to 70 [mu] m; the film forming material is one or more of hydroxypropyl methylcellulose, polyvinyl alcohol and hydroxy propyl cellulose; and no dimethyl silicone oil is contained. The brexpiprazole oral film preparation disclosed by the invention has the advantages of good dissolution rate, no grit feeling after being dissolved in an oral cavity, uniform appearance, good flexibility, no sedimentation in a film liquid preparation process, and content uniformity meeting requirements. # imgabs0 #

Description

[0001] This application claims the priority of the prior application with patent application number 202311227319.3 filed with the State Intellectual Property Office of China on September 22, 2023, and invention name “A kind of brepazole oral film, its preparation method and application”. Technical Field

[0002] The invention relates to a brepazine oral film, a preparation method and application thereof. Background Art

[0003] Brexetine tablets (trade name: REXULTI) were jointly developed by Otsuka Pharmaceutical Co., Ltd. of Japan and Lundbeck Pharma AB of Denmark, and were approved for marketing by the FDA in July 2015. The dosage form is tablets with specifications of 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg.

[0004] Brepiraazole tablets are clinically used for the treatment of major depression and schizophrenia as 5-HT1A receptor and dopamine D2 receptor agonists and 5-HT2A receptor antagonists. When used for the treatment of major depression, the starting dose is 0.5 mg / day or 1 mg / day, then increased to a target dose of 2 mg once a day, with a maximum recommended dose of 3 mg / day; when used for the treatment of schizophrenia, the starting dose is 1 mg / day, with a recommended target dose of 2 mg to 4 mg once a day, with a maximum recommended dose of 4 mg / day. Brepiraazole has a wide range of activity in multiple monoamine systems, with decreased partial agonist activity for dopamine D2 receptors and increased affinity for specific 5-HT receptors (such as 5-HT1A, 5-HT2A, 5-HT7), with better efficacy and tolerability, and can reduce adverse reactions such as akathisia, restlessness, or insomnia in patients.

[0005] Brepirapazole (7-[4-(4-benzo[B]thiophen-4-yl-1-piperazine)butoxy]-2(1H)-quinolinone) is a white or off-white crystalline powder that is almost insoluble in water and has a bitter and numbing irritation that can cause significant irritation in the oral mucosa.

[0006] The common tablets of breprazol must first disintegrate in the stomach before they can start releasing the drug, and the onset of action is slow, thereby limiting bioavailability. It is also inconvenient to take. As a therapeutic drug for mental illness, the population of this indication is poor in cooperating with treatment, and is prone to refusing treatment, hiding medicine, vomiting medicine, etc. Patent document CN105078910A discloses a method for preparing breprazol orodisintegrating tablets, in which breprazol is prepared into freeze-dried orodisintegrating tablets using freeze-drying technology to accelerate its disintegration rate and improve dissolution. However, the technology is relatively cumbersome, production requires special equipment, the product cost is high, and the prepared preparation is easy to break, which is not suitable for transportation, increasing the difficulty of packaging and transportation. And it cannot be wet when taken, which increases the requirements for patients and is not conducive to the compliance of schizophrenia patients.

[0007] Patent document CN105395528A discloses a brepazine oral fast-dissolving film, but since brepazine is almost insoluble in water and difficult to disperse in a hydrophilic glue, the drug is prone to agglomeration during the coating and drying process, thereby affecting the uniformity of the content of the main drug. At the same time, patients will also experience a discomfort in the mouth after taking it, affecting compliance.

[0008] Therefore, there is an urgent need to develop a dosage form of breprazol that is easy to take, stable in nature, has good patient compliance, high in bioavailability and / or is suitable for industrial production. Summary of the invention

[0009] The present invention provides a brepazine oral film, comprising the following components: an active drug and a film-forming material, wherein the active drug is 7-[4-(4-benzo[B]thiophene-4-yl-1-piperazine)butoxy]-2(1H)-quinolinone (i.e., brepazine) as shown in formula I and / or a pharmaceutically acceptable salt thereof, and the particle size D of the active drug is 90 ≤70μm; the film-forming material is selected from one or more of hydroxypropyl methylcellulose, polyvinyl alcohol and hydroxypropyl cellulose; the brepazole oral film does not contain dimethicone;

[0010]

[0011] According to an embodiment of the present invention, the active drug particle size D 90 ≤70.0μm, can be D 90 ≤65.0μm or D 90≤50.0μm, such as 1.0μm, 2.0μm, 3.0μm, 4.0μm, 5.0μm, 6.0μm, 7.0μm, 8.0μm, 9.0μm, 9.7μm, 10.0μm, 11.0μm, 12.0μm, 13.0μm, 14.0μm, 15.0μm, 16.0μm, 17.0μm, 18.0μm, 19.0μm, 20.0μm, 21.0μm, 22.0μm, 23.0μm, 24.0μm, 25.0μm, 26.0μm, 27.0μm, 27.8μm, 29.0μm, 30.0μm, 31.0μm, 32.0μm, 33.0μm, 34.0μm, 35.0μm, 35.1μm, 36.0μm, 37.0μm, 38.0μm, 39.0μm, 40.0μm, 41.0μm, 42.0μm, 43.0μm, 44.0μm, 45.0μm, 45.6μm, 46.0μm, 47.0μm, 48.0μm, 49.0μm, 50.0μm, 55.0μm, 60.0μm or 65.0μm.

[0012] According to an embodiment of the present invention, the mass percentage of the active drug can be 1.0% to 50.0%, or 4.0% to 40.0%, for example, 40.0%, 35.0%, 30.0%, 25.0%, 23.8%, 20.0%, 16.7%, 15.0%, 13.8%, 10.0%, 8.7% or 4.3%, wherein the mass percentage refers to the mass of the active drug as a percentage of the total mass of the brepazine oral film.

[0013] According to an embodiment of the present invention, the mass percentage of the film-forming material can be 30.0% to 80.0%, or 40.0% to 75.0%, or 40.0% to 70.0%, for example, 65.2%, 61.7%, 57.9%, 56.5%, 50.0% or 47.6%, wherein the mass percentage refers to the mass of the film-forming material as a percentage of the total mass of the brepazine oral film.

[0014] According to an embodiment of the present invention, the brepazine oral film may further include one or more of a plasticizer, a sweetener, a disintegrant, a filler and a colorant.

[0015] According to an embodiment of the present invention, the plasticizer refers to a substance used to lower the glass transition temperature of the film, increase plasticity and toughness, and improve elongation, and is selected from one or more of polyethylene glycol, glycerol, propylene glycol, silicone oil other than dimethyl silicone oil, polypropylene glycol and hexylene glycol.

[0016] According to an embodiment of the present invention, the mass percentage of the plasticizer can be 0-30.0%, or 10.0%-30.0%, for example, 28.0%, 26.0%, 24.1%, 23.8%, 20.8%, 17.4%, 15.0%, 4.0% or 0, and the mass percentage refers to the mass of the plasticizer as a percentage of the total mass of the brepazine oral film.

[0017] According to an embodiment of the present invention, the sweetener refers to a substance that acts as a flavoring agent in the film, and is selected from one or more of aspartame, sucralose, fructose, sucrose, steviol glycosides, glycyrrhizin, flavors, spices, saccharin and saccharin sodium.

[0018] According to an embodiment of the present invention, the mass percentage of the sweetener can be 0% to 10.0%, or 5.0% to 10.0%, for example, 8.7%, 8.6%, 4.8%, 0.8% and 0.7%, and the mass percentage refers to the percentage of the mass of the sweetener to the total mass of the brepazine oral film.

[0019] According to an embodiment of the present invention, the disintegrant refers to an excipient that promotes the rapid disintegration of the drug into small particles in the gastrointestinal tract, and is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl starch and starch.

[0020] According to an embodiment of the present invention, the mass percentage of the disintegrant can be 0 to 10.0%, for example, 1.0%, 2.0%, 3.0%, 3.4%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0% or 0, and the mass percentage refers to the mass of the plasticizer as a percentage of the total mass of the brepazine oral film.

[0021] According to an embodiment of the present invention, the filler refers to a solid substance added to the material to improve the material properties or increase the volume, increase the weight, and reduce the cost of the material, and is selected from one or more of microcrystalline cellulose, pregelatinized starch, mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose.

[0022] According to an embodiment of the present invention, the mass percentage of the filler can be 0-60.0%, for example, 50.0%, 45.0%, 40.0%, 35.0%, 30.4%, 25.0%, 20.0%, 10.0% or 0, and the mass percentage refers to the percentage of the mass of the filler to the total mass of the brepazine oral film.

[0023] According to an embodiment of the present invention, the colorant refers to a substance that can improve the appearance color of the preparation, can be used to identify the concentration of the preparation, distinguish the application method and reduce the patient's aversion to taking the medicine, and is selected from one or more of titanium dioxide, pigments and lakes.

[0024] According to an embodiment of the present invention, the mass percentage of the colorant can be 0-5.0%, for example 0.1%, 0.5%, 1.0%, 2.0% or 0, and the mass percentage refers to the mass percentage of the colorant to the total mass of the brepazine oral film.

[0025] According to some embodiments of the present invention, the brepazole oral film comprises the following components or is mainly composed of the following components: brepazole, a film-forming material, a plasticizer, a sweetener and a filler; the brepazole D 90 ≤65.0μm.

[0026] According to some embodiments of the present invention, the brepazine oral film comprises the following components or is mainly composed of the following components: brepazine, a film-forming material, a plasticizer, a sweetener and a disintegrant; the brepazine D 90 ≤65.0μm.

[0027] According to some embodiments of the present invention, the brepazine oral film comprises the following components or is mainly composed of the following components: brepazine, a film-forming material, a plasticizer, a colorant and a disintegrant; the brepazine D 90 ≤65.0μm.

[0028] According to some embodiments of the present invention, the brepazine oral film comprises the following components or is mainly composed of the following components: brepazine, film-forming material, plasticizer, sweetener and colorant; the brepazine D 90 ≤65.0μm.

[0029] According to some embodiments of the present invention, the brepazine oral film comprises or is mainly composed of the following components:

[0030] 4.0-15.0% brepazole, 50.0-75.0% hydroxypropyl methylcellulose, 10.0-30.0% glycerol, 5-10% sweetener and 0-0.5% colorant, the brepazole D 90 ≤65.0μm.

[0031] According to an embodiment of the present invention, the brepazine oral film can be selected from any of the following formulations:

[0032] Formulation 1: 16.7% brepazole, 45.0% hydroxypropyl methylcellulose, 16.7% polyvinyl alcohol, 20.8% glycerol and 0.8% sucralose, wherein the brepazole D 90 27.8μm;

[0033] Formula 2: 13.8% brepazol, 57.9% hydroxypropyl methylcellulose, 24.1% glycerol, 0.7% stevioside and 3.5% cross-linked polyvinylpyrrolidone, wherein the brepazol D 90 27.8μm;

[0034] Formula 3: 23.8% brepazol, 47.6% polyvinyl alcohol, 23.8% glycerol, 2.4% stevioside and 2.4% flavor, the brepazol D 90 27.8μm;

[0035] Formulation 4: 4.3% brepazole, 34.8% polyvinyl alcohol, 21.7% hydroxypropyl cellulose, 6.5% sucralose, 2.2% flavor and 30.5% microcrystalline cellulose, wherein the brepazole D 90 27.8μm;

[0036] Formula 5: 8.7% brepazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerol, 4.3% stevioside, 4.3% flavor and 0.1% color lake; the brepazole D 90 9.7μm;

[0037] Formula 6: 8.7% brepazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerol, 4.3% stevioside, 4.3% flavor and 0.1% color lake; the brepazole D 90 16.5μm;

[0038] Formula 7: 8.7% brepazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerol, 4.3% stevioside, 4.3% flavor and 0.1% color lake; the brepazole D 90 27.8μm;

[0039] Formula 8: 8.7% brepazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerol, 4.3% stevioside, 4.3% flavor and 0.1% lake; the brepazole D 90 35.1μm;

[0040] Formula 9: 8.7% brepazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerol, 4.3% stevioside, 4.3% flavor and 0.1% lake; the brepazole D 90 45.6μm;

[0041] Formulation 10: 40.0% brepazole, 50.0% polyvinyl alcohol, 4.0% glycerol, 2.0% titanium dioxide and 4.0% cross-linked polyvinylpyrrolidone, wherein the brepazole D 90 It is 45.6μm.

[0042] According to an embodiment of the present invention, the thickness of the brepazine oral film is 10 to 100 μm, for example, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm or 90 μm.

[0043] The present invention also provides a method for preparing the brepazine oral film, which comprises the following steps:

[0044] 1) dissolving one or more water-soluble excipients such as plasticizers, sweeteners, disintegrants, fillers and colorants in purified water, and adding film-forming materials to dissolve;

[0045] 2) mixing the insoluble excipients in the prescription with the solution obtained in step 1) to obtain a suspension;

[0046] 3) adding the active drug to the solution obtained in step 2) and mixing well;

[0047] 4) defoaming the suspension obtained in step 3) to obtain a defoamed suspension;

[0048] 5) coating the defoamed suspension obtained in step 4) on a substrate, drying it, and forming a film to obtain a brepazine oral thin film.

[0049] According to an embodiment of the present invention, the mixing in step 2) is preferably homogeneous mixing.

[0050] The present invention also provides the use of the breprazol oral film in preparing medicines for treating central nervous system diseases.

[0051] According to an embodiment of the present invention, the central nervous system disease may be major depression or schizophrenia.

[0052] The present invention also provides a method for treating central nervous system diseases, which comprises administering a therapeutically effective amount of the breprazol oral thin film to a patient in need thereof.

[0053] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0054] The reagents and raw materials used in the present invention are commercially available.

[0055] Beneficial effects of the present invention:

[0056] The breprazol oral film of the present invention has at least one advantage as shown below:

[0057] It has good solubility, rapid disintegration, no gritty feeling after dissolving in the mouth, uniform appearance, good flexibility, stable properties (such as stable chemical properties, stable solubility, stable mechanical strength and / or stable folding resistance), and no sedimentation occurs during the film liquid preparation process, and the content uniformity meets the requirements.

[0058] Definition and explanation of terms

[0059] The term "plurality" refers to more than two, for example, two, three or more.

[0060] The term "mainly composed of..." means that the sum of the masses of these components accounts for no less than 85% of the total mass of the brepazine oral film, for example no less than 90%, exemplified by 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.

[0061] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0062] The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit the biological or medical response that is being sought by a researcher, veterinarian, medical doctor or other clinician in a tissue, system, animal, individual or human. DETAILED DESCRIPTION

[0063] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0064] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available, or can be prepared by known methods, or selected according to commercial specifications.

[0065] Example 1-10: The prescription is as follows (% in the table is weight percentage)

[0066]

[0067]

[0068] Purified water * It is a solvent and wetting agent and is removed during the process.

[0069] Preparation method:

[0070] 1) Dissolve water-soluble excipients such as plasticizers, sweeteners, disintegrants, etc. in purified water, and add film-forming materials to dissolve;

[0071] 2) mixing the insoluble excipients in the prescription with the solution obtained in step 1) to obtain a suspension;

[0072] 3) adding the active ingredient to the solution obtained in step 2) and mixing well;

[0073] 4) defoaming the suspension obtained in step 3) to obtain a defoamed suspension;

[0074] 5) coating the defoamed suspension obtained in step 4) on a substrate, drying it, and forming a film to obtain a brepazine oral thin film.

[0075] Comparative Examples 1-3

[0076] Repeat Example 4 in the invention patent application of CN115192549A to prepare Comparative Example 1; replace the dimethyl silicone oil in Comparative Example 1 with glycerol to prepare Comparative Example 2. The formula is as follows (% in the table is weight percentage)

[0077]

[0078] Purified water * It is a solvent and wetting agent and is removed during the process.

[0079] During the preparation of Comparative Example 1, it was found that after dimethyl silicone oil was added to the prescription (Comparative Example 1), the drug film would peel off from the substrate by itself during the drying process. Since manual cutting was used in the small-scale trial stage, no problem was found. However, after the prescription was transferred to large equipment, it was found that due to the peeling problem, Comparative Example 1 could not accurately complete the subsequent cutting and packaging, which was not conducive to mass production.

[0080] However, in Comparative Example 2, the above problems can be effectively avoided by replacing dimethyl silicone oil with glycerol.

[0081] The applicant repeated Example 5 in the invention patent CN115192549A to prepare Comparative Example 3: the prescription is as shown above (% in the table is weight percentage), and the prescription was prepared using the process in CN115192549A and the process of the embodiment of the present invention respectively.

[0082] The results show that the brepazole and the film-forming material in CN115192549A are dissolved synchronously. When the particle size of brepazole is too large, the film-forming material forms a film during the dissolution process, causing brepazole to be enclosed in the film-forming matrix, which is not conducive to dispersion. 90When the diameter is greater than 30 μm, the mixing uniformity of the glue solution is poor. However, the present invention optimizes the process, dissolves the film-forming material first, and then adds brepazole. Under the action of the high-speed shearing machine, brepazole can be well dispersed, so brepazole D 90 When the particle size is greater than 30 μm, qualified finished products can still be produced.

[0083] Test Case

[0084] Content detection method: octadecylsilane bonded silica gel is used as filler; phosphate buffer-acetonitrile (70:30) is used as mobile phase; the flow rate is 1.0 ml per minute; the column temperature is 40°C; the detection wavelength is 275 nm; the injection volume is 10 μl, and the running time is 10 minutes.

[0085] Testing method for related substances: octadecylsilane bonded silica gel is used as filler; phosphate buffer is used as mobile phase A; phosphate buffer-acetonitrile (35:65) is used as mobile phase B; gradient elution is performed, and the detection wavelength is 275nm; the flow rate is 1.0ml per minute; the column temperature is 40℃; and the injection volume is 50μl.

[0086] Dissolution test methods other than those in Table 3: 900 ml of pH 4.3 acetate buffer containing 0.1% polysorbate 20 is used as the dissolution medium; the rotation speed is 50 revolutions per minute; and sampling is performed after 30 minutes.

[0087] Mechanical strength test: Use a texture analyzer (model: R TA + , manufacturer: Shanghai Tengba Instrument Technology Co., Ltd.) to conduct mechanical strength test on brepazine orodispersible film preparation;

[0088] After powering on, install the tensile test module, perform force calibration and height calibration, and set the height to 2mm;

[0089] Use a thickness gauge and a ruler to measure the thickness and width of the orodispersible film, and calculate the cross-sectional area of ​​the orodispersible film (mm 2 );

[0090] The orodispersible film after thickness and width testing was fixed on the texture analyzer so that the tested cross section was perpendicular to the stretching direction of the device, and the maximum force and sample height were recorded.

[0091] Tensile strength (MPa) = maximum force (gf) ÷ 102 ÷ cross-sectional area (mm 2 );

[0092] Percent elongation = maximum force distance (mm) ÷ sample height (mm) × 100%.

[0093] Folding resistance: refers to the number of folds at the same position before the film breaks or has obvious creases. Specifically, the film is folded 180 degrees in the middle, unfolded, and then folded again to observe whether the film breaks.

[0094] According to Examples 1-10 and Comparative Examples 2 and 3, brepizole oral thin films were prepared, and the properties, content, content uniformity, related substances, dissolution, dissolution curve, mechanical properties and disintegration time of the brepizole oral thin films were tested.

[0095] Table 1 Properties, content, content uniformity and dissolution test results of brepazine oral film

[0096]

[0097]

[0098] According to the above results, brepazine oral film was 90 When the particle size is ≤70.0μm, oral thin films with good properties and content uniformity can be obtained, and the content and dissolution rate meet the requirements.

[0099] 1. Test of related substances in brepazine oral film

[0100] Table 2 Test table of related substances of breprazol oral film

[0101]

[0102] According to the above results, the related substances of the breprazol oral thin films prepared in Examples 1-10 meet the requirements.

[0103] 2. Dissolution curve test of brepazine oral film

[0104] Dissolution method: According to the second method of 0931 of the fourth part of the 2020 edition of the Chinese Pharmacopoeia-paddle method, add a sinker: 50rpm, 900ml of dissolution medium, and the temperature is 37°C.

[0105] Table 3 Dissolution curve test table of breprazol oral film

[0106]

[0107] The data show that the dissolution curves of the breprazol oral thin films of Examples 1-10 are slightly different from that of the control drug (trade name: REXULTI).

[0108] 3. Mechanical strength test of brepazole oral film

[0109] The mechanical strength test results of the brepazine orodispersible film preparation are shown in Table 4.

[0110] Table 4 Mechanical strength test table of breprazol orally dissolving films prepared in Examples 1-10 and Comparative Example 2

[0111]

[0112]

[0113]

[0114] The data show that the tensile strength of the brepazine orally dissolving films prepared in Examples 1-10 of the present invention is good, while the tensile strength of Comparative Example 2 is poor and the film is brittle.

[0115] 4. Disintegration time test of brepazine oral film

[0116] The disintegration time of the breprazol oral thin films prepared in Example 1 of the present invention and Comparative Example 2 was determined by the following specific determination method:

[0117] Randomly select 6 pieces of the drug film obtained in each example, take one piece each time, and gently place it in a watch glass with a diameter of about 8 cm and filled with 20 ml of artificial saliva at 37±1°C. Under static state, observe the time for complete disintegration. The results are shown in Table 5.

[0118] Table 5 Average disintegration time test table of Examples 1-10 and Comparative Example 2

[0119]

[0120]

[0121] According to the above results, the oral thin films of the examples and comparative examples of the present invention can be rapidly disintegrated in a relatively short time.

[0122] 5. Stability test of breprazol oral film

[0123] According to Example 7, brepazine oral thin films were prepared and cut into 1 mg and 2 mg sizes, respectively. After being packaged in polyester / aluminum / polyethylene pharmaceutical composite film bags, the stability of brepazine oral thin films was investigated under long-term test (25°C ± 2°C / 40% RH ± 5% RH) and accelerated test (40°C ± 2°C / 75% RH ± 5% RH) conditions. The results are as follows:

[0124] (1) Test results of relevant substances

[0125]

[0126] (2) Dissolution test results

[0127] Specification Day 0 Accelerate June Long term 6 months 1mg 97％ 92％ 94％ 2mg 90％ 90％ 88％

[0128] (3) Content test results

[0129] Specification Day 0 Accelerate June Long term 6 months 1mg 99.7％ 99.7％ 99.4％ 2mg 99.2％ 99.4％ 99.1％

[0130] (4) Mechanical strength test results

[0131]

[0132]

[0133] (5) Folding endurance test results

[0134]

[0135]

[0136] Based on the above experimental data, it can be seen that the brepazine orodispersible film composition provided by the present invention has the advantages of thin thickness, rapid disintegration, stable properties, good mechanical properties, instant dissolution in the oral cavity without drinking water, and fast oral absorption.

[0137] The present invention overcomes the defects of the prior art that the common brepirazole tablets must be disintegrated in the stomach before the drug can be released, the effect is slow, the bioavailability is limited, the administration is inconvenient, the patient compliance is poor, and the like, and provides a brepirazole oral film, a preparation method and application thereof. The brepirazole oral film of the present invention has the advantages of thin thickness, good taste, stable properties, instant dissolution in the oral cavity without drinking water, and fast oral absorption speed. At the same time, the process is simple, the drug loading amount is high, and the drug content uniformity is good, which solves the problems of poor medication compliance and drug hiding and drug vomiting in schizophrenia patients, and is particularly suitable for patients with dysphagia.

[0138] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A breprazol oral film, characterized in that: The breprazol oral film comprises the following components: an active drug and a film-forming material, wherein the active drug is 7-[4-(4-benzo[B]thiophene-4-yl-1-piperazine)butoxy]-2(1H)-quinolinone and / or a pharmaceutically acceptable salt thereof as shown in Formula I, and the particle size of the active drug is D 90 ≤70μm; the film-forming material is one or more of hydroxypropyl methylcellulose, polyvinyl alcohol and hydroxypropyl cellulose; the brepazole oral film does not contain dimethyl silicone oil; 2. The breprazol oral film according to claim 1, characterized in that: The active drug particle size D 90 ≤65.0μm or D 90 ≤50.0μm; and / or, The mass percentage of the active drug is 1.0% to 50.0% or 4.0% to 40.0%, and the mass percentage refers to the percentage of the mass of the active drug to the total mass of the brepazine oral film.

3. The breprazol oral film according to claim 1, characterized in that: The mass percentage of the film-forming material is 30.0% to 80.0% or 40.0% to 75.0%, and the mass percentage refers to the percentage of the mass of the film-forming material to the total mass of the brepazine oral film.

4. The breprazol oral film according to claim 1, characterized in that: The brepazine oral film further comprises one or more of a plasticizer, a sweetener, a disintegrant, a filler and a colorant.

5. The breprazol oral film according to claim 4, characterized in that: The plasticizer is selected from one or more of polyethylene glycol, glycerol, propylene glycol, silicone oil other than dimethyl silicone oil, polypropylene glycol and hexylene glycol; and / or, The sweetener is selected from one or more of aspartame, sucralose, fructose, sucrose, steviol glycosides, glycyrrhizin, flavors, spices, saccharin and saccharin sodium; and / or, The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl starch and starch; and / or, The filler is selected from one or more of microcrystalline cellulose, pregelatinized starch, mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose; and / or, The colorant is selected from one or more of titanium dioxide, pigments and lakes.

6. The breprazol oral film according to claim 4, characterized in that: The mass percentage of the sweetener is 0-10.0%, and the mass percentage refers to the mass percentage of the sweetener to the total mass of the brepazine oral film; and / or, The mass percentage of the plasticizer is 0 to 30.0%, and the mass percentage refers to the mass percentage of the plasticizer to the total mass of the brepazine oral film; and / or, The mass percentage of the disintegrant is 0 to 10.0%, and the mass percentage refers to the mass percentage of the plasticizer to the total mass of the brepazine oral film; and / or, The mass percentage of the filler is 0-60.0%, and the mass percentage refers to the mass percentage of the filler to the total mass of the brepazine oral film; and / or, The mass percentage of the colorant is 0-5.0%, and the mass percentage refers to the mass percentage of the colorant to the total mass of the brepazine oral film; Preferably, the brepazole oral film comprises the following components or is mainly composed of the following components: brepazole, film-forming material, plasticizer, sweetener and colorant; the brepazole D 90 ≤65.0μm; Preferably, the brepazine oral film comprises the following components or is mainly composed of the following components: 4.0-15.0% brepazole, 50.0-75.0% hydroxypropyl methylcellulose, 10.0-30.0% glycerol, 5-10% sweetener and 0-0.5% colorant, the brepazole D 90 ≤65.0μm.

7. The breprazol oral film according to claim 1, characterized in that: The breprazol oral film of the present invention is any one of the following formulas: Formulation 1: 16.7% brepazole, 45.0% hydroxypropyl methylcellulose, 16.7% polyvinyl alcohol, 20.8% glycerol and 0.8% sucralose, wherein the brepazole D 90 27.8μm; Formula 2: 13.8% brepazol, 57.9% hydroxypropyl methylcellulose, 24.1% glycerol, 0.7% stevioside and 3.5% cross-linked polyvinylpyrrolidone, wherein the brepazol D 90 27.8μm; Formula 3: 23.8% brepazol, 47.6% polyvinyl alcohol, 23.8% glycerol, 2.4% stevioside and 2.4% flavor, the brepazol D 90 27.8μm; Formulation 4: 4.3% brepazole, 34.8% polyvinyl alcohol, 21.7% hydroxypropyl cellulose, 6.5% sucralose, 2.2% flavor and 30.5% microcrystalline cellulose, wherein the brepazole D 90 27.8μm; Formula 5: 8.7% brepazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerol, 4.3% stevioside, 4.3% flavor and 0.1% color lake; the brepazole D 90 9.7μm; Formula 6: 8.7% brepazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerol, 4.3% stevioside, 4.3% flavor and 0.1% color lake; the brepazole D 90 16.5μm; Formula 7: 8.7% brepazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerol, 4.3% stevioside, 4.3% flavor and 0.1% color lake; the brepazole D 90 27.8μm; Formula 8: 8.7% brepazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerol, 4.3% stevioside, 4.3% flavor and 0.1% lake; the brepazole D 90 35.1μm; Formula 9: 8.7% brepazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerol, 4.3% stevioside, 4.3% flavor and 0.1% lake; the brepazole D 90 45.6μm; Formulation 10: 40.0% brepazole, 50.0% polyvinyl alcohol, 4.0% glycerol, 2.0% titanium dioxide and 4.0% cross-linked polyvinylpyrrolidone, wherein the brepazole D 90 It is 45.6μm.

8. The method for preparing the breprazol oral thin film according to any one of claims 1 to 7, characterized in that: The preparation method comprises the following steps: 1) dissolving one or more water-soluble excipients such as plasticizers, sweeteners, disintegrants, fillers and colorants in purified water, and adding film-forming materials to dissolve; 2) mixing the insoluble excipients in the prescription with the solution obtained in step 1) to obtain a suspension; 3) adding the active drug to the solution obtained in step 2) and mixing well; 4) defoaming the suspension obtained in step 3) to obtain a defoamed suspension; 5) coating the defoamed suspension obtained in step 4) on a substrate, drying it, and forming a film to obtain a brepazine oral thin film.

9. Use of the breprazol oral film according to any one of claims 1 to 8 in the preparation of a medicament for treating central nervous system diseases.

10. The use according to claim 9, characterized in that: The central nervous system disease is major depression or schizophrenia.

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