A breprazol oral solid preparation and its preparation method and application

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a brepazole oral solid preparation and a preparation method and application thereof. The raw materials for its preparation include: 1 to 20 parts by weight of brepazole, 0.5 to 20 parts by weight of a transition metal salt, 50 to 900 parts by weight of an ethanol aqueous solution, 0.5 to 1.5 parts by weight of an acidic pH regulator, and 150 to 550 parts by weight of other auxiliary ingredients. The dissolution results of the oral solid preparation of the present invention in different dissolution media are highly similar to those of the original product, and are bioequivalent to the original product in vivo, and can replace the original product.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a brepazine oral solid preparation and a preparation method and application thereof. Background Art

[0002] Brepirapazole (also known as: epriprazole) is an atypical antipsychotic drug. It is a partial agonist of serotonin receptor 5-HT1A and dopamine receptors D2 and D3, and is also a partial antagonist of serotonin receptors 5-HT2A and 5-HT2B as well as adrenergic receptors α-1 and α-2, and has a broad binding affinity for other central monoamine receptor subtypes. It is mainly used for the adjuvant treatment of major depressive disorder (MDD) and the treatment of schizophrenia. The product was jointly developed by Lundbeck Pharmaceuticals of Denmark and Otsuka Pharmaceutical Co., Ltd. of Japan. In 2015, Brepirapazole was approved by the FDA for marketing in the United States for the treatment of major depressive disorder (MDD) and schizophrenia. In 2016, it was approved for the maintenance treatment of adult patients with schizophrenia. In 2018, Brepirapazole was approved to enter the European market.

[0003] Brepirapazole is a white or light yellow crystalline powder. It is easily soluble in glacial acetic acid, slightly soluble in N,N-dimethylformamide, and almost insoluble in methanol, ethanol and water. It belongs to BCS II class compounds, i.e. low solubility-high permeability drugs. Its chemical formula is C 25 H 27 N3O2S, with a molecular weight of 433.57 g / mol, has a chemical name of 7-{4-[4-(1-benzothiophen-4-yl)piperazine-1-yl]butoxy}quinoline-2(1H)-one, and has a structural formula as shown below:

[0004]

[0005] The prior art discloses some breprazol oral rapid-release dosage forms. For example, patent CN105078910A discloses a method for preparing breprazol orodisintegrating tablets, in which breprazol is prepared into freeze-dried orodisintegrating tablets by freeze-drying technology, so as to accelerate its disintegration speed and improve dissolution. However, the technology is relatively complicated, special equipment is required for production, the product cost is high, and the prepared preparation is easy to break and is not suitable for transportation, which increases the difficulty of packaging and transportation. Moreover, it cannot be exposed to water when taken, which increases the requirements for patients and is not conducive to the compliance of schizophrenia patients.

[0006] Patent 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.

[0007] Patent CN115252585A provides a brepazine orodispersible film composition, which has a good dissolution rate, no gritty feeling after dissolving in the mouth, uniform appearance, good flexibility, no sedimentation during the film liquid preparation process, and content uniformity meets the requirements. However, for some sensitive people, the use of β-cyclodextrin may cause allergic reactions.

[0008] The existing self-developed oral rapid-release dosage form of brexpiprazole still has the following problems: First, the in vitro dissolution solution (dissolution medium: pH 1.2 hydrochloric acid solution, water, pH 6.8 phosphate buffer solution) is unstable, which can easily lead to inflection points in the dissolution results and no reproducibility (such as Figures 2~4 7# sample in the study), which affects the data accuracy and reliability in the pharmaceutical quality research of this product. Secondly, its in vivo bioavailability is low. Summary of the invention

[0009] In order to solve the above technical problems, the present invention provides a brepazine oral solid preparation and a preparation method and application thereof. The oral solid preparation of the present invention has a high degree of similarity in dissolution results with the original product in different dissolution media, and has bioequivalence with the original product in vivo, and can replace the original product.

[0010] Brepirapazole is a pH-dependent drug. Its solubility varies greatly in solutions with different pH values. It has poor solubility under strong acid, weak acid, neutral and alkaline conditions, and has good solubility only under specific acidic conditions (3.8-4.5). Figure 1 As shown), this characteristic leads to a large difference in the solubility of brepirazole in different pH dissolution media when studying the in vitro dissolution of brepirazole. The present invention utilizes the principle that heteroatoms (such as oxygen and sulfur) contained in the molecular structure of brepirazole can provide lone pairs of electrons, while transition metals can provide empty orbitals, and the two interact to form a complex, thereby adjusting the electronic structure and van der Waals force of the brepirazole molecule, changing the arrangement and stacking mode of its molecules, and thus reducing the interaction energy between brepirazole and the dissolution medium. The present invention unexpectedly found that the method significantly increased the solubility of brepirazole in different dissolution media (pH 1.2 hydrochloric acid solution, water, pH 6.8 phosphate buffer solution) and improved its in vivo absorbability, solving the problems of low solubility of raw materials, low in vivo bioavailability, and unstable in vitro dissolution solutions of the current self-developed brepirazole preparations. Thus, the present invention was obtained.

[0011] In a first aspect, the present invention provides a solid oral preparation of brepazole, the preparation raw materials of which include: 1 to 20 parts by weight of brepazole, 0.5 to 20 parts by weight of a transition metal salt, 50 to 900 parts by weight of an ethanol aqueous solution, 0.5 to 1.5 parts by weight of an acidic pH regulator, and 150 to 550 parts by weight of other auxiliary ingredients.

[0012] In some embodiments, the raw materials for its preparation include: 8 to 12 parts by weight of brepazole, 8 to 12 parts by weight of a transition metal salt, 80 to 900 parts by weight of an ethanol aqueous solution, 0.8 to 1.2 parts by weight of an acidic pH regulator, and 200 to 500 parts by weight of other auxiliary ingredients.

[0013] In some embodiments, the particle size of brexpiprazole is less than 23 μm.

[0014] In some embodiments, the transition metal salt includes but is not limited to one or a combination of two or more of zinc chloride, copper gluconate, manganese sulfate monohydrate, ferric chloride or ferrous chloride, preferably one or a combination of two or more of zinc chloride, copper gluconate, manganese sulfate monohydrate, more preferably zinc chloride.

[0015] In some embodiments, the concentration of the ethanol aqueous solution is 10% to 80% v / v, and can be any specific value or any range within this range, for example, it can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, etc.

[0016] In some embodiments, the oral solid preparation is an orodisintegrating film, an orodisintegrating tablet or a conventional tablet, preferably an orodisintegrating film.

[0017] In some embodiments, when the oral solid preparation is an orally dissolving film, the swelling effect of the film-forming material in pure water is not as good as that in an aqueous solution containing a certain amount of ethanol, but as the concentration of ethanol increases, the glue tends to form agglomerates when stirred. The preferred concentration of the aqueous ethanol solution is 30% to 60% v / v.

[0018] In some embodiments, other auxiliary ingredients can be adapted to any pharmaceutically acceptable auxiliary ingredients according to the specific dosage form of the oral solid preparation. For example, when the oral solid preparation is an orodispersible film, other auxiliary ingredients include but are not limited to film-forming materials, plasticizers, flavoring agents, and coloring agents; when the oral solid preparation is an orodisintegrating tablet or a common tablet, other auxiliary ingredients include but are not limited to fillers, disintegrants, lubricants, glidants, flavoring agents, and coloring agents. The amount of other auxiliary ingredients is most preferably 225 to 460 parts by weight.

[0019] In some embodiments, according to the specific dosage form of the oral solid preparation, the amount of the ethanol aqueous solution is adaptively adjusted within the aforementioned range. For example, when the oral solid preparation is an orodispersible film, the amount of the ethanol aqueous solution is 450 to 900 parts by weight, preferably 600 to 900 parts by weight; when the oral solid preparation is an orodispersible tablet or a conventional tablet, the amount of the ethanol aqueous solution is 50 to 900 parts by weight, preferably 100 to 600 parts by weight.

[0020] In some embodiments, when the oral solid preparation is an orodispersible film, its preparation raw materials include: 8 to 12 parts by weight of brexpiprazole, 8 to 12 parts by weight of a transition metal salt, 150 to 230 parts by weight of a film-forming material, 24 to 36 parts by weight of a plasticizer, 3 to 5 parts by weight of a colorant, 0 to 1.5 parts by weight of a flavoring agent, 600 to 900 parts by weight of an ethanol aqueous solution, and 0.8 to 1.2 parts by weight of an acidic pH regulator.

[0021] In some embodiments, the film-forming material includes but is not limited to one or more of pullulan, gelatin, agar, chitosan, polyvinyl alcohol, pregelatinized starch, hydroxypropyl methylcellulose or hydroxypropyl cellulose, preferably pullulan and hydroxypropyl cellulose, and further preferably, the weight proportion of hydroxypropyl cellulose is less than 50% w / w.

[0022] In some embodiments, the plasticizer includes, but is not limited to, one or more of polyethylene glycol, ethylene glycol, glycerol, or triacetin, preferably polyethylene glycol 400.

[0023] In some embodiments, colorants include, but are not limited to, one or more of titanium dioxide, pigments, or lakes.

[0024] In some embodiments, flavoring agents include, but are not limited to, one or more of sucralose, fructose, sucrose, stevioside, glycyrrhizin, flavors, spices, saccharin, or saccharin sodium.

[0025] In some embodiments, the acidic pH adjuster includes but is not limited to any one of glacial acetic acid, tartaric acid, lactic acid, citric acid, hydrochloric acid, phosphoric acid, malic acid, fumaric acid or succinic acid, preferably glacial acetic acid, tartaric acid, lactic acid or citric acid, more preferably glacial acetic acid.

[0026] In a second aspect, the present invention provides a method for preparing a brepazine orodispersible film, comprising: mixing and stirring the components, degassing to obtain a glue solution; coating the glue solution into a film with uniform thickness, and drying to obtain a brepazine orodispersible film.

[0027] In some embodiments, the transition metal salt is stirred in an ethanol aqueous solution for 15 to 60 minutes, then brepazole is added, stirring is continued for 20 to 60 minutes, an acidic pH regulator is added to adjust the pH to 3.8 to 4.5, stirring is continued for 3 to 5 hours, and then the remaining components are added, stirred until completely dispersed, and allowed to stand to eliminate bubbles to obtain a glue solution; the glue solution is coated into a drug film with uniform thickness, and then dried at 50 to 90° C. The raw material mixing order and the stirring time control are obtained by optimization, and the prepared finished film has the best appearance, mechanical properties, content and content uniformity.

[0028] In a third aspect, the present invention provides use of the aforementioned brepazine oral solid preparation in the preparation of a drug for treating depression or psychosis.

[0029] Patients who take brepazole are schizophrenia and major depression patients, who are prone to miss doses and actively hide the medicine. The brepazole oral dissolving film provided by the present invention is thin, has a good taste, and is stable in nature. It can be dissolved in the oral cavity within one minute without drinking water, and after taking it, the film adheres tightly to the tongue surface and is not easy to fall off, which greatly improves the compliance of special patients. It is suitable for use as an auxiliary treatment drug for major depression (MDD) or a treatment drug for schizophrenia.

[0030] Drug specifications:

[0031] Taking brepazine orodispersible film as an example, it can be 0.5mg, 1mg or 2mg. The area of ​​the orodispersible film of 0.5mg is 2.5cm 2 The area of ​​the orodispersible film of 1 mg is 5 cm 2 The area of ​​the orodispersible film of 2 mg is 10 cm 2 .

[0032] Dosage:

[0033] 1) Auxiliary treatment for major depression

[0034] The recommended starting dose of brexpiprazole as adjunctive therapy is 0.5 mg or 1 mg once daily, either before or after meals. Based on the patient's clinical response and tolerability, the dose should be increased weekly to 1 mg once daily and then to a target dose of 2 mg. The recommended maximum daily dose is 3 mg. Reassess regularly to determine the continued need for treatment and appropriate dosing.

[0035] 2) Treatment of schizophrenia

[0036] The starting dose of brepazol is 1 mg once a day, before or after meals on days 1 to 4. The target dose of brepazol is 2 mg to 4 mg once a day. Depending on the patient's clinical response and tolerability, increase to 2 mg per day on days 5 to 7 and then to 4 mg on day 8. The recommended maximum daily dose is 4 mg.

[0037] The beneficial effects of the present invention are:

[0038] The brepazine oral solid preparation provided by the present invention particularly introduces a transition metal salt component into the raw material for preparation, and reacts it with brepazine in a certain proportion under acidic conditions to form a complex, so that the finally prepared oral solid preparation has good in vitro dissolution solution stability in different dissolution media, and at the same time improves the bioavailability of brepazine. Its in vitro dissolution results and in vivo bioavailability are highly consistent with the original research product. And the appearance and taste are good, the properties are stable, the compliance of administration is good, and it is suitable for industrial production and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 is the solubility curve of breprazol raw material solution at different pH;

[0040] Figure 2 This is the dissolution curve in hydrochloric acid medium at pH 1.2;

[0041] Figure 3 is the aqueous medium dissolution curve;

[0042] Figure 4 This is the dissolution curve in pH 6.8 hydrochloric acid buffer medium. DETAILED DESCRIPTION

[0043] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention is clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0044] Example 1 A breprazol orally dissolving film, the prescription and preparation method are as follows:

[0045] 1. Prescription: as shown in Table 1

[0046] Table 1 Prescription of breprazol orodispersible film

[0047]

[0048] 2. Preparation method:

[0049] (1) Dissolve zinc chloride in 60% v / v ethanol aqueous solution, stir for 15 min, then add brepazole, continue stirring for 20 min, add 2 mol / L glacial acetic acid solution to adjust the pH to 3.8-4.5, continue stirring for 3 h, and obtain solution I;

[0050] (2) Add pullulan, hydroxypropyl cellulose, polyethylene glycol 400, titanium dioxide and sucralose to solution I, stir until completely dispersed, and let stand to eliminate bubbles to obtain a glue solution;

[0051] (3) The adhesive solution is transferred to a conveyor belt, coated with a doctor blade into a film of uniform thickness, and then dried at 60°C to evaporate the solvent to obtain a drug film;

[0052] (4) Cut the film into suitable size and shape (the area of ​​the 0.5 mg orodispersible film is 2.5 cm 2 The area of ​​the orodispersible film of 1 mg is 5 cm 2 The area of ​​the orodispersible film of 2 mg is 10 cm 2 ), and packaged to obtain the brepazine orosoluble film.

[0053] Example 2 A breprazol orally disintegrating tablet, the prescription and preparation method are as follows:

[0054] 1. Prescription: as shown in Table 2

[0055] Table 2 Prescription of Brepirapazole orally disintegrating tablets

[0056]

[0057] 2. Preparation method:

[0058] (1) Dissolve zinc chloride in 60% v / v ethanol aqueous solution, stir for 15 min, then add brepazole, continue stirring for 20 min, add 2 mol / L glacial acetic acid solution to adjust the pH to 3.8-4.5, continue stirring for 3 h, and obtain solution I;

[0059] (2) adding microcrystalline cellulose, mannitol, sucralose, yellow ferric oxide and low-substituted hydroxypropyl cellulose into a wet granulator for premixing to obtain mixed powder I;

[0060] (3) Mixed powder I is softened with solution I, granulated with a 18-40 mesh sieve, dried at 50°C until the moisture content is ≤3.0%, and granulated with a 18-40 mesh sieve to obtain mixed powder II;

[0061] (4) adding magnesium stearate to mixed powder II and further mixing to obtain mixed powder III;

[0062] (5) Add the mixed powder III into a tablet press and press into tablets of suitable hardness to obtain breprazol orally disintegrating tablets.

[0063] Example 3 A breprazol tablet, the prescription and preparation method are as follows:

[0064] 1. Prescription: as shown in Table 3

[0065] Table 3 Prescription of Brepiraazole Tablets

[0066]

[0067] 2. Preparation method:

[0068] (1) Dissolve zinc chloride in 60% v / v ethanol aqueous solution, stir for 15 min, then add brepazole, continue stirring for 20 min, add 2 mol / L glacial acetic acid solution to adjust the pH to 3.8-4.5, continue stirring for 3 h, and obtain solution I;

[0069] (2) adding lactose hydrate, corn starch and microcrystalline cellulose into a wet granulator for premixing to obtain mixed powder I;

[0070] (3) Mixed powder I is softened with solution I, granulated with a 18-40 mesh sieve, dried at 50°C until the moisture content is ≤3.0%, and granulated with a 18-40 mesh sieve to obtain mixed powder II;

[0071] (4) adding magnesium stearate to mixed powder II and further mixing to obtain mixed powder III;

[0072] (5) Adding the mixed powder III into a tablet press and pressing it into tablets of suitable hardness to obtain tablet cores;

[0073] (6) coating the tablet cores obtained in step (5) with a film coating premix to increase the coating weight to 1-5%, thereby obtaining brexpiprazole tablets.

[0074] Experimental example: Study on the screening test of breprazol orodispersible film formulation

[0075] 1. Effect of Brepirapazole Raw Material Particle Size

[0076] 1.1 Using brepiraazole with a raw material particle size range of D90 of 7-190 μm, brepiraazole orodispersible films 1#-6# were prepared according to the prescription and preparation method of Example 1. The dissolution results of the prepared orodispersible films in a pH 1.2 hydrochloric acid medium were compared, and the comparison results with the original preparation (brepiraazole orodispersible tablets, 2F77QDD1 batch, purchased from Otsuka Pharmaceutical, Japan, specification: 1 mg / tablet) are shown in Table 4.

[0077] Table 4 Comparison of dissolution results in pH 1.2 hydrochloric acid medium

[0078]

[0079] The results showed that different particle sizes of raw materials had a significant effect on in vitro dissolution. The larger the particle size, the slower the dissolution. The particle size of brepazole was below 23 μm, the film was more uniform, the appearance was smooth and flat, there were no visible particles, and the dissolution was similar to that of the original preparation.

[0080] 1.2 Animal experiment on beagle dogs:

[0081] (1) Test materials:

[0082] The prepared 1#, 2#, 3#, 4#, and 6# brepirazole orodispersible films were compared with the original preparation (brepirazole orodispersible tablets, 2F77QDD1 batch, purchased from Otsuka Pharmaceutical, Japan, specification: 1 mg / tablet) for bioavailability test.

[0083] (2) Test method:

[0084] Eight healthy beagles were selected, and a randomized double crossover test design was adopted, that is, the eight beagles were randomly divided into two groups, namely the control group and the test group. The control group took 1 mg of brepazine orodisintegrating tablets orally, and the test group took 1#, 2#, 3#, 4#, and 6# brepazine orodisintegrating films respectively. 4 mL of blood was collected in a heparinized test tube before taking the medicine and 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after taking the medicine, and the plasma was separated. Store at minus 16°C for testing. A crossover test was carried out at intervals of one week to calculate the relative bioavailability of each brepazine orodisintegrating film, and to evaluate the bioequivalence of the brepazine orodisintegrating film provided by the present invention to the brepazine orodisintegrating tablets.

[0085] The relative bioavailability was determined by using Rexulti(R) produced by Otsuka Pharmaceutical Co., Ltd. of Japan as the standard control to determine the relative bioavailability of breprazol orodispersible film (A). Based on the measured drug concentration data in plasma, DAS3.2.8 software was used to calculate its main pharmacokinetic parameters and perform equivalence analysis. The results are shown in Table 5.

[0086] Table 5 Relative bioavailability determination results

[0087]

[0088] 2. Effect of transition metal salt types

[0089] 2.1 Preparation of dissolution media: refer to the "Guidelines for the determination and comparison of dissolution curves of common solid preparations and common oral solid preparations" to prepare a total of 4 media: pH 1.2 hydrochloric acid solution, pH 4.3 acetate buffer, pH 6.8 phosphate buffer and purified water;

[0090] Dissolution conditions: medium temperature 37°C, medium volume 900 ml, paddle method, rotation speed 50 rpm, sampling point 10 min;

[0091] Experimental steps: Take 2 pieces of orally dissolving films prepared with different types of metal salts, place them in a dissolution cup, take a sample after 10 minutes, take a liquid volume of 20 ml, and place it at room temperature for 0 hours. Take a sample and filter it after 2 hours, take the filtrate, and detect the change of dissolution rate over time to investigate the solution stability of brepirazole orally dissolving films prepared with different types of metal salts in various pH dissolution media. The implementation prescription is shown in Table 6, and the preparation method is the same as Example 1:

[0092] Table 6 Implementation prescription

[0093]

[0094] 2.2 The solution stability results of different dissolution media are shown in Table 7:

[0095] Table 7 Solution stability test results of different brexpiprazole orally dissolving films in various pH dissolution media

[0096]

[0097] 2.3 Dissolution curves of different dissolution media Figures 2~4 shown.

[0098] 2.4 Conclusion: By stirring the transition metal compound and the raw material in a certain proportion under acidic conditions to form a complex and then forming a film, the medium solution after film formation is more stable and has better reproducibility than that of the untreated raw material. At the same time, the solubility of brepazole in the three dissolution media is also improved, making the in vitro dissolution highly consistent with the original preparation.

[0099] 2.5 Animal experiment on beagle dogs: The experimental method was the same as before.

[0100] Table 8 Relative bioavailability determination results

[0101]

[0102] From the above results, it can be seen that all samples are qualified, but the overall F value of 7# without adding metal salt is lower than that of 8#~10# with adding metal salt, which indicates that the added metal salt significantly improves the overall bioavailability of the preparation.

[0103] 3. Effect of the amount of transition metal salt, the implementation formula is shown in Table 9, and the preparation method is the same as Example 1:

[0104] Table 9 Implementation prescription

[0105]

[0106] Beagle dog bioavailability study: The test method is the same as before.

[0107] According to the measured drug concentration data in plasma, DAS3.2.8 software was used to calculate its main pharmacokinetic parameters and perform equivalence analysis. The results are shown in Table 10.

[0108] Table 10 Relative bioavailability determination results

[0109]

[0110] The above results show that the weight ratio of zinc chloride to brepazole has good bioequivalence in the range of 1:5~1.5:1.

[0111] 4. Influence of film-forming materials

[0112] The mechanical strength and demoulding performance of the prepared orally dissolving films with different film-forming material ratios are compared. The implementation formula is shown in Table 11. The preparation method is the same as that in Example 1:

[0113] Table 11 Implementation prescription

[0114]

[0115] The results show that when only pullulan is used as the film-forming material, the film is brittle and easy to fall off from the backing. Properly increasing the amount of hydroxypropyl cellulose can improve the toughness of the film and increase the adsorption force between the film and the backing. The higher the proportion of hydroxypropyl cellulose, the greater the adsorption force between the film and the backing, and the more difficult it is to peel off. When the weight proportion of hydroxypropyl cellulose in the film-forming material reaches more than 50%, the film is difficult to peel off and the film-forming performance is poor.

[0116] 5. Effect of flavor enhancers

[0117] Comparison of taste test under different dosages of sucralose, taste evaluation method: The scoring method is used for taste evaluation. The full score of the taste test is 100 points. The tester tastes the homemade film, that is, 1 / 4 of the 0.5mg brepazine orosoluble film is tasted. Each attempt needs to be separated by 30 minutes, and then score. Evaluation can be carried out according to the indicators: no astringency, no sandy feeling, light astringency or slight sandy feeling, obvious astringency and slight sandy feeling, obvious astringency and obvious sandy feeling. A total of 10 people participated in the test, and the average value was taken as the taste evaluation result. The implementation prescription is shown in Table 12:

[0118] Table 12 Implementation prescription

[0119]

[0120] The results showed that within a certain dosage range, as the dosage of sucralose increased, the taste of the orodispersible film was significantly improved. When the dosage of sucralose increased to a certain amount, the taste no longer improved, and the taste was too sweet when the dosage of sucralose was too large.

[0121] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

Claims

1. A breprazol orodispersible film, characterized in that: The raw materials for its preparation are: 8 to 12 parts by weight of brepazole, 8 to 12 parts by weight of a transition metal salt, 150 to 230 parts by weight of a film-forming material, 24 to 36 parts by weight of a plasticizer, 3 to 5 parts by weight of a colorant, 1 to 1.5 parts by weight of a flavoring agent, 600 to 900 parts by weight of an ethanol aqueous solution, and 0.8 to 1.2 parts by weight of an acidic pH regulator; The particle size of the breprazol is less than 23 μm; The transition metal salt is selected from zinc chloride, copper gluconate or manganese sulfate monohydrate; The weight ratio of the transition metal salt to brepazole is 1:5 to 1.5:1; The film-forming material is pullulan and hydroxypropyl cellulose, and the weight proportion of hydroxypropyl cellulose in the film-forming material is less than 50% w / w; The concentration of the ethanol aqueous solution is 30% to 60% v / v; The preparation method of the breprazol orally dissolving film is as follows: Stir the transition metal salt in an ethanol aqueous solution for 15 to 60 minutes, then add brepazole, continue stirring for 20 to 60 minutes, add an acidic pH adjuster to adjust the pH to 3.8 to 4.5, continue stirring for 3 to 5 hours, then add the remaining components, stir until completely dispersed, let stand to eliminate bubbles, and obtain a glue solution; after coating the glue solution into a drug film of uniform thickness, dry it at 50 to 90°C.

2. A method for preparing the breprazol orodispersible film according to claim 1, characterized in that: The preparation method is: Stir the transition metal salt in an ethanol aqueous solution for 15 to 60 minutes, then add brepazole, continue stirring for 20 to 60 minutes, add an acidic pH adjuster to adjust the pH to 3.8 to 4.5, continue stirring for 3 to 5 hours, then add the remaining components, stir until completely dispersed, let stand to eliminate bubbles, and obtain a glue solution; after coating the glue solution into a drug film of uniform thickness, dry it at 50 to 90°C.

3. Use of the breprazol orodispersible film according to claim 1 in the preparation of drugs for treating depression or mental illness.

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