Brexpiprazole oral thin film agent, preparation method therefor and use thereof

Abstract

Provided in the present invention are a brexpiprazole oral thin film agent, a preparation method therefor and the use thereof. The brexpiprazole oral thin film agent 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 as shown in formula I and / or a pharmaceutically acceptable salt thereof, and the particle size D90 of the active drug is ≤70 μm; the film-forming material is one or more of hydroxypropyl methylcellulose, polyvinyl alcohol and hydroxypropyl cellulose; and the brexpiprazole oral thin film agent is free of dimethyl silicone oil. The brexpiprazole oral thin film agent of the present invention has a good dissolution rate, has no gritty feeling after being dissolved in the oral cavity, is uniform in appearance and good in flexibility, does not settle during the formulation of film liquid, and has a content uniformity that meets the requirements.

Description

A breprazol oral film, its preparation method and application

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

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

[0003] Brexiprazol tablets (trade name: REXULTI) were jointly developed by Otsuka Pharmaceutical Co., Ltd. of Japan and Lundbeck Pharma A / S 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 5-HT1A receptor and dopamine D2 receptor agonists and 5-HT2A receptor antagonists, and are clinically used to treat major depressive disorder and schizophrenia. For major depressive disorder, the starting dose is 0.5 mg / day or 1 mg / day, then increased to a target dose of 2 mg once daily, with a maximum recommended dose of 3 mg / day. For schizophrenia, the starting dose is 1 mg / day, with a recommended target dose of 2 mg to 4 mg once daily, with a maximum recommended dose of 4 mg / day. Brepiraazole has broad activity across multiple monoamine systems, with reduced partial agonist activity at dopamine D2 receptors and increased affinity for specific 5-HT receptors (such as 5-HT1A, 5-HT2A, and 5-HT7). This improves efficacy and tolerability, reducing adverse reactions such as akathisia, restlessness, or insomnia.

[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. It has a bitter and numbing irritation and can cause significant irritation in the oral mucosa.

[0006] Ordinary brepazole tablets must first disintegrate in the stomach before they can begin to release the drug, resulting in a slow onset of action, which limits bioavailability. It is also inconvenient to take. As a therapeutic drug for mental illness, this indication population is poor in cooperating with treatment and is prone to refusing treatment, hiding the drug, vomiting the drug, and the like. Patent document CN105078910A discloses a method for preparing orally disintegrating tablets of brepazole, in which brepazole is prepared into freeze-dried orally disintegrating tablets using freeze-drying technology, which accelerates its disintegration rate and improves dissolution. However, this technology is relatively cumbersome, requires specialized equipment for production, and has a high product cost. In addition, the prepared preparation is easy to break and is not suitable for transportation, which increases the difficulty of packaging and transportation. Furthermore, the preparation cannot be exposed to water when taken, which increases the requirements for patients and is not conducive to the compliance of schizophrenia patients.

[0007] Patent document CN105395528A discloses a brepazole fast-dissolving oral film. However, because brepazole is almost insoluble in water, it is difficult to disperse in a hydrophilic adhesive. During the doctoring and drying process, the drug easily agglomerates, affecting the uniformity of the main drug content. Furthermore, patients experience a discomforting mouthfeel after taking the film, affecting compliance.

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

[0009] Summary of the Invention

[0010] 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]thiophen-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 active drug particle size D 90 ≤70μm; the film-forming material is selected from one or more of hydroxypropyl methylcellulose, polyvinyl alcohol and hydroxypropyl cellulose; the breprazol oral film does not contain dimethicone;

[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 percentage of the mass of the active drug to 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 percentage of the mass of the film-forming material to the total mass of the brepazine oral film.

[0014] According to an embodiment of the present invention, the brepizole 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 percentage of the mass of the plasticizer to 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%. 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 percentage of the mass of the plasticizer to 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, weight, or 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 to 60.0%, for example, 50.0%, 45.0%, 40.0%, 35.0%, 30.4%, 25.0%, 20.0%, 10.0% or 0, where the mass percentage refers to the percentage of the mass of the filler to the total mass of the brepizole 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, where the mass percentage refers to the mass percentage of the colorant to the total mass of the brepizole oral film.

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

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

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

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

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

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

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

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

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

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

[0036] Formula 5: 8.7% brepizole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerin, 4.3% steviol glycosides, 4.3% flavor and 0.1% lake; the brepizole D 90 9.7μm;

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

[0038] Formula 7: 8.7% brepizole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerin, 4.3% steviol glycosides, 4.3% flavor and 0.1% lake; the brepizole D 90 27.8μm;

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

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

[0042] According to an embodiment of the present invention, the thickness of the brepizole 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 breprazol oral thin 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 uniformly;

[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, and forming a film to obtain a breprazol 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 breprazole 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 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 breprazole oral thin film of the present invention has at least one of the following advantages:

[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] Definitions and Explanations of Terms

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

[0060] The term "mainly composed of..." means that the sum of the masses of these components accounts for not less than 85% of the total mass of the brepazine oral film, for example not 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 elicits the biological or medical response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician. DETAILED DESCRIPTION

[0063] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative 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 encompassed within the scope of protection that the present invention is intended to protect.

[0064] Unless otherwise stated, 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] purified water * It is a solvent and wetting agent and is removed during the process.

[0067] Preparation method:

[0068] 1) Dissolve water-soluble excipients such as plasticizers, sweeteners, and disintegrants in purified water, and add film-forming materials to dissolve;

[0069] 2) mixing the insoluble excipients in the prescription with the solution obtained in step 1) to obtain a suspension;

[0070] 3) adding the active ingredient to the solution obtained in step 2) and mixing uniformly;

[0071] 4) defoaming the suspension obtained in step 3) to obtain a defoamed suspension;

[0072] 5) coating the defoamed suspension obtained in step 4) on a substrate, drying, and forming a film to obtain a breprazol oral thin film.

[0073] Comparative Examples 1-3

[0074] Repeat Example 4 in the invention patent application 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)

[0075] purified water * It is a solvent and wetting agent and is removed during the process.

[0076] 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 Comparative Example 1 could not accurately complete the subsequent cutting and packaging due to the peeling problem, which was not conducive to mass production.

[0077] However, in Comparative Example 2, the above problems can be effectively avoided by replacing dimethyl silicone oil with glycerol.

[0078] 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.

[0079] The results showed that the brepazole and the film-forming material in CN115192549A dissolved synchronously. When the particle size of brepazole was too large, the film-forming material formed a film during the dissolution process, causing brepazole to be encapsulated in the film-forming matrix, which was not conducive to dispersion. 90 When the particle size 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 D90 When the particle size is greater than 30 μm, qualified finished products can still be produced.

[0080] Test Case

[0081] Content detection method: octadecylsilane bonded silica gel was used as the filler; phosphate buffer-acetonitrile (70:30) was used as the mobile phase; the flow rate was 1.0 ml per minute; the column temperature was 40°C; the detection wavelength was 275 nm; the injection volume was 10 μl, and the running time was 10 minutes.

[0082] Test method for related substances: octadecylsilane bonded silica gel was used as the filler; phosphate buffer was used as the mobile phase A; phosphate buffer-acetonitrile (35:65) was used as the mobile phase B; gradient elution was performed, and the detection wavelength was 275 nm; the flow rate was 1.0 ml per minute; the column temperature was 40°C; and the injection volume was 50 μl.

[0083] Dissolution test methods other than those in Table 3: 900 ml of pH 4.3 acetate buffer containing 0.1% polysorbate 20 was used as the dissolution medium; the rotation speed was 50 rpm; and sampling was performed after 30 minutes.

[0084] Mechanical strength test: Use a texture analyzer (model: R BREPIPRAZOL d TA + , manufacturer: Shanghai Tengba Instrument Technology Co., Ltd.) to conduct mechanical strength tests on the orally disintegrating film preparation of brepizole;

[0085] After powering on, install the tensile test module, perform force calibration and height calibration, and set the height to 2mm;

[0086] Use a thickness gauge and a ruler to measure the thickness and width of the orally dissolving film and calculate the cross-sectional area of ​​the orally dissolving film (mm 2 );

[0087] The orally disintegrating 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.

[0088] Tensile strength (MPa) = maximum force (gf) ÷ 102 ÷ cross-sectional area (mm 2 );

[0089] Percent elongation = maximum force distance (mm) ÷ sample height (mm) × 100%.

[0090] Folding resistance: refers to the number of times the orally dissolving film breaks or has obvious creases after being folded at the same position; specifically, the orally dissolving film is folded 180° in the middle, unfolded, and then folded again to observe whether the orally dissolving film breaks.

[0091] Brapiprazole oral thin films were prepared according to Examples 1-10 and Comparative Examples 2 and 3, and the properties, content, content uniformity, related substances, solubility, dissolution curve, mechanical properties and disintegration time of the brepiprazole oral thin films were tested.

[0092] Table 1 Properties, content, content uniformity and dissolution test results of brepazole oral film

[0093] According to the above results, brepazole oral film was 90 When the particle size is ≤70.0μm, oral thin films with good properties and content uniformity can be prepared, and the content and dissolution rate meet the requirements.

[0094] 1. Test of related substances in breprazole oral thin film

[0095] Table 2 Related substances test list of breprazol oral film

[0096] According to the above results, the related substances of the brepizole oral thin films prepared in Examples 1-10 meet the requirements.

[0097] 2. Dissolution curve test of brepazole oral film

[0098] Dissolution method: According to the second method of 0931 of the general chapter of the fourth part of the Chinese Pharmacopoeia 2020 edition - paddle method, add a sinker: 50 rpm, 900 ml of dissolution medium, and the temperature is 37 ° C.

[0099] Table 3 Dissolution curve test table of breprazol oral film

[0100] The data showed that the dissolution profiles of the brepizole oral thin films of Examples 1-10 were slightly different from that of the control drug (trade name: REXULTI).

[0101] 3. Mechanical strength test of brepizole oral film

[0102] The mechanical strength test results of the brexpiprazole orally disintegrating film preparation are shown in Table 4.

[0103] Table 4 Mechanical strength test table of breprazol orally disintegrating films prepared in Examples 1-10 and Comparative Example 2

[0104] The data show that the tensile strength of the brepizole orally disintegrating 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.

[0105] 4. Disintegration time test of brepazole oral film

[0106] 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 method:

[0107] Randomly select 6 films obtained in each example, one at a time, and gently place them in a watch glass with a diameter of about 8 cm and 20 ml of artificial saliva at 37±1°C. Leave them to stand and observe the time for complete disintegration. The results are shown in Table 5.

[0108] Table 5 Average disintegration time test table of Examples 1-10 and Comparative Example 2

[0109] According to the above results, the oral thin films of the examples and comparative examples of the present invention can disintegrate rapidly in a relatively short period of time.

[0110] 5. Stability test of breprazole oral film

[0111] According to Example 7, brepizole oral thin films were prepared and cut into 1 mg and 2 mg sizes, respectively. After packaging in polyester / aluminum / polyethylene pharmaceutical composite film bags, the stability of the brepizole oral thin films was investigated under long-term test conditions (25°C ± 2°C / 40% RH ± 5% RH) and accelerated test conditions (40°C ± 2°C / 75% RH ± 5% RH). The results are as follows:

[0112] (1) Test results of relevant substances

[0113] (2) Dissolution test results

[0114] (3) Content test results

[0115] (4) Mechanical strength test results

[0116] (5) Folding endurance test results

[0117] Based on the above experimental data, it can be seen that the brepizole orally disintegrating film composition provided by the present invention has the advantages of thin thickness, rapid disintegration, stable properties, good mechanical properties, instant dissolution in the mouth without drinking water, and rapid oral absorption.

[0118] The present invention overcomes the defects of conventional brepirazole tablets in the prior art, such as the need to disintegrate in the stomach before drug release begins, resulting in a slow onset of action, thus limiting bioavailability, inconvenient administration, and poor patient compliance, and provides a brepirazole oral film, a preparation method, and applications thereof. The brepirazole oral film of the present invention has the advantages of thin thickness, good mouthfeel, stable properties, instant dissolution in the oral cavity without the need for drinking water, and rapid oral absorption. Furthermore, the process is simple, the drug loading capacity is high, and the drug content uniformity is good. It solves the problems of poor medication compliance, drug hiding, and drug vomiting in schizophrenia patients, and is particularly suitable for patients with dysphagia.

[0119] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection 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.

Images