Brexpiprazole tablet and preparation method thereof

Abstract

The invention provides a brexpiprazole tablet and a preparation method thereof, and belongs to the technical field of medicines. According to the preparation method disclosed by the invention, firstly, the brexpiprazole raw material medicine and the excipient are pretreated, then premixed, and then mixed with other components for total mixing, tabletting and coating, all the components are mixed more uniformly, and meanwhile, the variety of the filler is controlled, so that the brexpiprazole tablet is relatively low in friability, high in dissolution speed of a finished product and short in disintegration time.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a brepazole tablet and a preparation method thereof. Background Art

[0002] Brexpiprazole is 7-(4-(4-(benzo[b]thiophene)-4-yl-piperazine-1-yl)butoxy)-1H-quinolin-2-one, which can be used to treat or assist in the treatment of schizophrenia, depression and Alzheimer's disease. Its structural formula is shown in the figure below:

[0003]

[0004] The preparation method of brepazine tablets in the prior art is mainly wet granulation, that is, the raw materials are mixed in powder form, a binder is sprayed into the granules, and then the tablets are compressed and coated. However, the tablets prepared by this method are greatly affected by the process, and there are problems such as complex preparation process, long production cycle, low yield of finished products, high energy consumption, etc. Therefore, there is an urgent need for a preparation method of brepazine tablets with simple preparation process, low cost, high yield of finished products and low energy consumption. Summary of the invention

[0005] The object of the present invention is to provide a brepazine tablet and a preparation method thereof. The preparation method provided by the present invention has simple process, low cost, low energy consumption, and the prepared brepazine tablet has high finished product yield, uniform composition, low friability, and fast disintegration and dissolution speed.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing brepazole tablets, comprising the following steps:

[0008] (1) mixing the brepazine API with the excipients, and pre-treating the mixture through a sieve or a granulator to obtain a pre-treated material;

[0009] (2) premixing the pretreated material obtained in step (1) to obtain a premix;

[0010] (3) mixing the premix obtained in step (2) with a filler, a disintegrant and a lubricant and then tableting to obtain brepazine tablets; the filler comprises at least one of pregelatinized starch, directly compressible starch and superfluid starch;

[0011] (4) coating the brepazine tablets obtained in step (3) with a coating solution to obtain brepazine tablets.

[0012] Preferably, the particle size of the brepazine raw material in step (1) is 10 to 50 μm.

[0013] Preferably, the excipient in step (1) comprises at least one of lactose, starch lactose, cellulose lactose and anhydrous calcium hydrogen phosphate.

[0014] Preferably, the aperture of the screen used for the granulator pretreatment in step (1) is 0.5 to 2 mm.

[0015] Preferably, the disintegrant in step (3) comprises at least one of sodium starch glycolate, cross-linked sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose.

[0016] Preferably, the lubricant in step (3) comprises at least one of magnesium stearate, sodium stearyl fumarate and talc.

[0017] Preferably, the total mixing rate in step (3) is 5 to 10 rpm, and the total mixing time is 5 to 20 min.

[0018] Preferably, based on the total mass of the brepirazole API, the excipient in step (1), and the filler, disintegrant and lubricant in step (3) as 100%, the mass percentages of the brepirazole API, the excipient, the filler, the disintegrant and the lubricant are 0.3-5%, 30-60%, 30-60%, 5-15% and 0.5-2%, respectively.

[0019] Preferably, the coating solution in step (4) comprises a coating material and water; the solid content of the coating solution is 10-20%.

[0020] The present invention also provides brepazine tablets prepared by the preparation method described in the above technical scheme.

[0021] The present invention provides a method for preparing brepazine tablets, comprising the following steps: (1) mixing brepazine raw materials with excipients, pre-treating with a sieve or a granulator to obtain a pre-treated material; (2) pre-mixing the pre-treated material obtained in the step (1) to obtain a premix; (3) mixing the premix obtained in the step (2) with a filler, a disintegrant and a lubricant, and then tableting to obtain brepazine tablets; the filler comprises at least one of pregelatinized starch, direct-compressible starch and superfluid starch; (4) coating the brepazine tablets obtained in the step (3) with a coating liquid to obtain brepazine tablets. The present invention first pre-treats the brepazine raw materials with excipients, then pre-mixes them, and then mixes them with other components for total mixing, tableting and coating, wherein the components are mixed more evenly, and at the same time, the type of filler is controlled, so that the brepazine tablets have low brittleness, fast dissolution rate of the finished product and short disintegration time. The results of the examples show that the brepazole tablets prepared by the preparation method provided by the present invention have uniform ingredients, a friability of 0.1% for the plain tablets, the finished product meets the dissolution requirements and has a short disintegration time. DETAILED DESCRIPTION

[0022] The present invention provides a method for preparing brepazole tablets, comprising the following steps:

[0023] (1) mixing the brepazine API with the excipients, and pre-treating the mixture through a sieve or a granulator to obtain a pre-treated material;

[0024] (2) premixing the pretreated material obtained in step (1) to obtain a premix;

[0025] (3) mixing the premix obtained in step (2) with a filler, a disintegrant and a lubricant and then tableting to obtain brepazine tablets; the filler comprises at least one of pregelatinized starch, directly compressible starch and superfluid starch;

[0026] (4) coating the brepazine tablets obtained in step (3) with a coating solution to obtain brepazine tablets.

[0027] Unless otherwise specified, the present invention has no particular limitation on the sources of the raw materials, and commercially available products known to those skilled in the art may be used.

[0028] The present invention mixes the brepazine raw material with the excipient, and pre-treats the mixture through a sieve or a granulator to obtain a pre-treated material.

[0029] In the present invention, the particle size of the breprazol API is preferably 10 to 50 μm, more preferably 20 to 50 μm, and further preferably 20 to 40 μm.

[0030] In the present invention, based on the total mass of the brepirazole API, excipients, fillers, disintegrants and lubricants as 100%, the mass percentage of the brepirazole API is preferably 0.3-5%. In an embodiment of the present invention, the mass percentage of the brepirazole API can be specifically 0.3%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5%.

[0031] In the present invention, the excipient preferably includes at least one of lactose, starch lactose, cellulose lactose and anhydrous calcium hydrogen phosphate, and more preferably lactose. The present invention has no particular limitation on the source of the excipient, and commercially available products known to those skilled in the art can be used. In an embodiment of the present invention, the lactose comes from Jiangsu Daoning Pharmaceutical Co., Ltd.; the mesh size of the lactose is 80 mesh.

[0032] In the present invention, the mass percentage of the excipient is preferably 30-60%, based on the total mass of the brepirazole API, excipients, fillers, disintegrants and lubricants as 100%. In an embodiment of the present invention, the mass percentage of the excipient may be specifically 30%, 35%, 40%, 45%, 50%, 55% or 60%. The present invention controls the type and amount of the excipient within the above range, which can further improve the compressibility and disintegration properties of the brepirazole tablets.

[0033] In the present invention, the aperture of the sieve during the screening is preferably 0.5 to 2 mm.

[0034] In the present invention, the aperture of the screen used for pretreatment in the granulator is preferably 0.5-2 mm, that is, the aperture of the screen of the granulator is preferably 0.5-2 mm; the rotation speed of the granulator is preferably 100-300 rpm, more preferably 150-250 rpm. The present invention pretreats the brepazine API and the excipient, which can improve the mixing uniformity of the components.

[0035] After obtaining the pretreated material, the present invention premixes the pretreated material to obtain a premix.

[0036] In the present invention, the premixing rate is preferably 5 to 10 rpm, more preferably 6 to 9 rpm, and further preferably 7 to 8 rpm; the premixing time is preferably 5 to 15 min, and more preferably 10 min. The present invention performs premixing and controls the premixing rate and time, which can further improve the mixing uniformity of each component.

[0037] In the present invention, the premixing is preferably carried out in a total mixer. The present invention has no particular limitation on the model of the total mixer, and a commercial product well known to those skilled in the art can be used.

[0038] After obtaining the premix, the present invention mixes the premix with a filler, a disintegrant and a lubricant and then compresses the mixture into tablets to obtain brepazine tablets.

[0039] In the present invention, the filler comprises at least one of pregelatinized starch, directly compressible starch and superfluid starch, preferably superfluid starch. The present invention has no particular limitation on the source of the filler, and commercial products well known to those skilled in the art can be used. In an embodiment of the present invention, the superfluid starch is from Colorcon.

[0040] In the present invention, based on the total mass of the brepirazole API, excipients, fillers, disintegrants and lubricants as 100%, the mass percentage of the filler is preferably 30-60%. In an embodiment of the present invention, the mass percentage of the filler can be specifically 30%, 35%, 40%, 45%, 50%, 55% or 60%. The present invention controls the type and amount of the filler within the above range, which can further improve the disintegration performance of the brepirazole tablets.

[0041] In the present invention, the disintegrant preferably includes at least one of sodium starch glycolate, cross-linked sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose, and is more preferably low-substituted hydroxypropyl cellulose. The present invention has no particular limitation on the source of the disintegrant, and commercial products well known to those skilled in the art can be used. In an embodiment of the present invention, the low-substituted hydroxypropyl cellulose is from Japan Soda, model LH21.

[0042] In the present invention, based on the total mass of the brepirazole API, excipients, fillers, disintegrants and lubricants as 100%, the mass percentage of the disintegrant is preferably 5-15%. In an embodiment of the present invention, the mass percentage of the disintegrant can be specifically 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15%. The present invention controls the type and amount of the disintegrant within the above range, which can further improve the disintegration performance of the brepirazole tablets.

[0043] In the present invention, the lubricant preferably includes at least one of magnesium stearate, sodium stearyl fumarate and talc, more preferably sodium stearyl fumarate or magnesium stearate. The present invention has no particular limitation on the source of the lubricant, and commercial products well known to those skilled in the art can be used. In an embodiment of the present invention, the sodium stearyl fumarate is from JRS, Germany.

[0044] In the present invention, the mass percentage of the lubricant is preferably 0.5-2%, based on the total mass of the brepirazole API, excipients, fillers, disintegrants and lubricants as 100%. In an embodiment of the present invention, the mass percentage of the lubricant can be specifically 0.5%, 0.8%, 1%, 1.5% or 2%. The present invention controls the type and amount of the lubricant within the above range, which can further improve the fluidity of each component and improve the appearance quality of the brepirazole tablets.

[0045] In the present invention, the total mixing rate is preferably 5 to 10 rpm, more preferably 6 to 9 rpm, and further preferably 7 to 8 rpm; the total mixing time is preferably 5 to 20 min, and more preferably 10 to 20 min. The present invention controls the total mixing rate and time to further improve the mixing uniformity of each component.

[0046] In the present invention, the total mixing is preferably carried out in a total mixer. The present invention has no particular limitation on the type of the total mixer, and a commercially available product well known to those skilled in the art can be used.

[0047] In the present invention, the main pressure of tableting is preferably 3 to 10 kN. In an embodiment of the present invention, the main pressure of tableting can be specifically 3 kN, 4 kN, 5 kN, 6 kN, 7 kN, 8 kN, 9 kN or 10 kN. In the present invention, the main pressure is the value of the main pressure of the tablet press when the tablet press (Beijing Chuangbo Jiawei Technology Co., Ltd.) is used to press brepazole tablets of corresponding hardness (about 50N).

[0048] In the present invention, the rotation speed of the tableting feeder is preferably 20 to 50 rpm. In an embodiment of the present invention, the rotation speed of the tableting feeder can be specifically 20 rpm, 30 rpm, 40 rpm or 50 rpm.

[0049] In the present invention, the tableting speed is preferably 50,000 to 300,000 tablets / h. In an embodiment of the present invention, the tableting speed may specifically be 50,000 tablets / h, 100,000 tablets / h, 150,000 tablets / h, 200,000 tablets / h, 250,000 tablets / h or 300,000 tablets / h.

[0050] In the present invention, the hardness of the brepazine tablet is preferably 20 to 70 N. In an embodiment of the present invention, the hardness of the brepazine tablet may be specifically 20 N, 30 N, 40 N, 50 N, 60 N or 70 N. The present invention controls the various parameters during tableting within the above range, so that the brepazine tablet has good hardness and surface quality, and further improves its disintegration, dissolution and other properties.

[0051] After obtaining the brepirazoline tablets, the present invention uses a coating solution to coat the brepirazoline tablets to obtain brepirazoline tablets.

[0052] In the present invention, the coating solution preferably comprises a coating material and water.

[0053] In the present invention, the coating material preferably includes hypromellose, yellow iron oxide, black iron oxide and talc. The present invention has no particular limitation on the source of the coating material, and commercially available products known to those skilled in the art can be used. In an embodiment of the present invention, the coating material is Colorcon / 03A610007-CN, green.

[0054] In the present invention, the water is preferably purified water.

[0055] In the present invention, the solid content of the coating solution is preferably 10-20%. In an embodiment of the present invention, the solid content of the coating solution can be specifically 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%.

[0056] In the present invention, the coating solution is preferably prepared before use. The present invention has no special limitation on the preparation method of the coating solution, and the coating material and water can be mixed evenly. In the present invention, the preparation method of the coating solution is preferably: under stirring conditions, the coating material is added to water and mixed to obtain a coating solution. The present invention has no special limitation on the stirring method and rate, and the stirring method and rate familiar to those skilled in the art can be used. In the present invention, the mixing time is preferably 45 to 60 minutes.

[0057] In the present invention, the mass of the coating material in the coating solution is preferably 2-4% of the mass of the brepazine tablets. In an embodiment of the present invention, the mass of the coating material in the coating solution can be specifically 2%, 3% or 4% of the mass of the brepazine tablets. The present invention controls the amount of the coating material in the coating solution within the above range, which can have a better coating effect.

[0058] In the present invention, the coating is preferably carried out in a high-efficiency coating machine. In the present invention, the brepazine tablets are preferably placed in a porous coating pan of the high-efficiency coating machine, and then the coating liquid is sprayed. After the coating liquid is sprayed, it is dried in the high-efficiency coating pan to obtain brepazine tablets. The present invention does not specifically limit the model of the high-efficiency coating machine, and commercially available products well known to those skilled in the art can be used.

[0059] In the present invention, the drying temperature is preferably 40 to 60° C., more preferably 50° C.; the drying time is preferably 5 to 15 min, more preferably 10 min.

[0060] In the present invention, the mass of a single brepazole tablet is preferably 80 to 100 mg.

[0061] The present invention adopts a powder direct compression method to prepare the brepazole tablets. During the preparation process, granulation and drying are not required, the preparation process is simple, the cost is low, and the finished product yield is high. The material of the powder direct compression can ensure the material particle size and compressibility, ensure the rapid disintegration of the tablet and the dissolution of the drug, and the drug will not be affected by moisture and heat. The type and amount of each component are controlled, so that the product disintegrates and dissolves quickly and has good stability, and is suitable for industrial production.

[0062] The present invention also provides brepirazole tablets prepared by the preparation method described in the above technical solution. The brepirazole tablets prepared by the present invention have fast disintegration and dissolution speed and good stability.

[0063] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. 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.

[0064] Example 1

[0065] A preparation method of brepazine tablets comprises: (1) mixing 145.5 g lactose (Jiangsu Daoning Pharmaceutical Co., Ltd., 80 mesh) and 10 g brepazine raw material (20-40 μm), pre-treating through a 1.0 mm sieve, and then pre-mixing at a speed of 8 rpm for 10 min in a total mixer, and then adding 245 g superfluid starch (Colorcon), 45 g low-substituted hydroxypropyl cellulose (Japan Soda, LH21) and 4.5 g sodium stearyl fumarate (Germany JRS), mixing at a speed of 8 rpm for 10 min, and then tableting to obtain 5000 brepazine tablets, the main tableting pressure is 7.2 kN, the rotation speed of the tableting feeder is 20 rpm, the tableting speed is 50,000 tablets / h, the hardness of the brepazine tablets is 55N, and the total mass of lactose, brepazine API, superfluid starch, low-substituted hydroxypropyl cellulose and sodium stearyl fumarate is 100%, and the mass percentages of lactose, brepazine API, superfluid starch, low-substituted hydroxypropyl cellulose and sodium stearyl fumarate are 32.33%, 2.22%, 54.45%, 10% and 1%, respectively;

[0066] (2) Under stirring conditions, the coating material (Colorcon / 03A610007-CN, green) was added to purified water and mixed for 45 minutes to obtain a coating solution with a solid content of 10%. The brepazine tablets were placed in a porous coating pan of a high-efficiency coating machine, and then 135 g of the coating solution (including 13.5 g of the coating material) was sprayed. After the coating solution was sprayed, it was dried at 50° C. for 10 minutes in a high-efficiency coating pan to obtain brepazine tablets. The mass of the coating material in the coating solution was 3% of the mass of the brepazine tablets.

[0067] Example 2

[0068] The mass percentages of lactose, brepazine API, superfluid starch, low-substituted hydroxypropyl cellulose and sodium stearyl fumarate in step (1) of Example 1 were replaced with 54.45%, 2.22%, 32.33%, 10% and 1%, respectively, and the main pressure during tableting was replaced with 6.3 kN. At this time, the hardness of the brepazine tablets was 53 N, and the other parameters were the same as those in Example 1.

[0069] Example 3

[0070] The sodium stearyl fumarate in step (1) of Example 1 was replaced by magnesium stearate, and the main pressure during tableting was replaced by 7.1 kN. At this time, the hardness of the brepazine tablets was 51 N, and the other parameters were the same as those in Example 1.

[0071] Example 4

[0072] The sieving pretreatment in step (1) of Example 1 was replaced by pretreatment in a granulator, the rotation speed of the granulator was 200 rpm, the mesh size of the granulator was 1 mm, and the main pressure during tableting was replaced by 6.5 kN. At this time, the hardness of the brepazine tablets was 51 N, and the other parameters were the same as in Example 1.

[0073] Example 5

[0074] The total mixing time in step (1) of Example 1 was replaced with 15 min, and the other parameters were the same as those of Example 1.

[0075] Example 6

[0076] The total mixing time in step (1) of Example 1 was replaced with 20 min, and the other parameters were the same as those of Example 1.

[0077] Comparative Example 1

[0078] The lactose in step (1) of Example 1 was replaced by mannitol, the superfluid starch was replaced by corn starch, and the main pressure during tableting was replaced by 8.5 kN. At this time, the hardness of the brepazine tablets was 45 N, and the other parameters were the same as those in Example 1.

[0079] Comparative Example 2

[0080] The superfluid starch in step (1) of Example 1 was replaced by microcrystalline cellulose, and the main pressure during tableting was replaced by 5.3 kN. At this time, the hardness of the brepazine tablets was 47 N, and the other parameters were the same as those in Example 1.

[0081] Comparative Example 3

[0082] The pretreatment and premixing in step (1) of Example 1 were omitted, and the components were directly mixed in a total mixer at a rate of 8 rpm for 10 min. The main pressure during tableting was replaced with 6.9 kN. At this time, the hardness of the brepazine tablets was 48 N. The other parameters were the same as in Example 1.

[0083] Comparative Example 4

[0084] The particle size of the brepazine raw material in step (1) of Example 1 is replaced by D 90 >50 μm, the main pressure during tableting is replaced with 7.5 kN, at which time the hardness of the brepazine tablet is 50 N, and the other parameters are the same as those in Example 1.

[0085] Take 10 brepazine tablets prepared in Examples 1 to 4 and Comparative Examples 1 to 4 respectively, and measure their hardness (average value), friability and disintegration time. The hardness is measured using a hardness tester (Tianjin Tianda Tianfa Technology Co., Ltd.). The disintegration time determination method is determined by the disintegration time determination method of Part IV of the 2020 Chinese Pharmacopoeia 0921. The friability determination method is determined by the friability determination method of Part IV of the 2020 Chinese Pharmacopoeia 0923, and the results are shown in Table 1.

[0086] Table 1 Hardness, friability and disintegration time of brepazine tablets prepared in Examples 1 to 4 and Comparative Examples 1 to 4

[0087] Main pressure(kN) Hardness(N) Friability (%) Disintegration time (seconds) Example 1 7.2 55 0.1 65 Example 2 6.3 53 0.1 72 Example 3 7.1 51 0.1 59 Example 4 6.5 51 0.1 61 Comparative Example 1 8.5 45 0.3 57 Comparative Example 2 5.3 47 0.1 83 Comparative Example 3 6.9 48 0.1 67 Comparative Example 4 7.5 50 0.1 69

[0088] As can be seen from Table 1, the friability weight loss of Comparative Example 1 is high because of the poor wear resistance of corn starch. The main pressure of Comparative Example 1 increased, the tablet hardness did not increase significantly, and the capping phenomenon occurred during the tableting process, proving that the compressibility is not as good as Example 1. Comparative Example 2 is compared with Example 1, and the compressibility is improved, but the tablet disintegration time is the longest. Other examples and comparative examples prove that the particle size of the raw material, the ratio of lactose and superfluid starch, magnesium stearate and sodium stearyl fumarate do not affect the compressibility of the total mixed material and the tablet disintegration.

[0089] The finished product yields of the breprazol tablets prepared in Examples 1 to 4 and Comparative Examples 1 to 4 were tested, and the results are shown in Table 2.

[0090] Table 2 Yield of finished product of breprazol tablets prepared in Examples 1 to 4 and Comparative Examples 1 to 4

[0091] Example 1 Example 2 Example 3 Example 4 Yield 97％ 97％ 95％ 99％ Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Yield 98％ 97％ 96％ 97％

[0092] In the total mixing stage of Example 1, Example 4 and Comparative Example 3, step (1), samples were taken at 11 different positions in the hopper to obtain the particle contents at different positions and investigate the mixing uniformity of the materials. The results are shown in Table 3.

[0093] Table 3 Mixing uniformity of Example 1, Example 4 and Comparative Example 3

[0094]

[0095] As can be seen from Table 3, the mixing effect of Example 1 and Example 4 is good, indicating that the pretreatment dispersion method of lactose and API can be sieving and granulating. The sampling results of 11 positions in Comparative Example 3 are very different, indicating that they are not mixed evenly, indicating that not pretreating lactose and API has a great impact on the mixing effect. The reason is that the micronized API has static electricity, which will cause agglomeration, and the agglomerated lumps have a certain strength, which needs to be broken by sieving or granulating.

[0096] The dissolution of the brepazole tablets prepared in Examples 1 to 4 and Comparative Examples 1, 2, and 4 was tested according to the FDA method, using 900 mL of a sodium acetate aqueous solution with a pH of 4.3 as the medium, using a paddle method at a speed of 50 rpm, and simultaneously measuring the dissolution of the original product The dissolution results are shown in Table 4.

[0097] Table 4 Brepirapirazole tablets prepared in Examples 1 to 4 and Comparative Examples 1, 2, and 4 and original research products Dissolution

[0098]

[0099] As can be seen from Table 4, Example 1 and Comparative Example 4 show that the micronized powder can be more similar to the original formulation. Examples 1, 2, and 3 can all meet the dissolution requirements. Comparative Example 1 dissolves quickly. Comparative Example 2 dissolves quickly in the early stage and incompletely in the later stage, which may be caused by the adsorption or sedimentation of microcrystalline cellulose.

[0100] The mixing uniformity of the total mixing in Example 1 and Examples 5 to 6 was investigated. At different total mixing time points of 10 min, 15 min, and 20 min, samples were taken from 11 locations at the upper, middle, and lower parts of the total mixing hopper to measure the mixing uniformity. The results are shown in Table 5.

[0101] Table 5 Mixing uniformity of different total mixing times of Example 1 and Example 5-6

[0102]

[0103]

[0104] As can be seen from Table 5, the sample contents at all sampling points of the mixing uniformity are within the range of ±10% of the average content, and the RSD is less than 5.0%, and the mixing uniformity is qualified. This shows that the materials can be mixed uniformly when the total mixing time is between 10 and 20 minutes.

[0105] The brepazole tablets prepared in Example 1 and the original product After being placed at 60°C for 10 days and 30 days, samples were taken to determine the content of related substances.

[0106] Take brepazine tablets or original product 20 tablets were accurately weighed and ground into fine powder using an agate mortar. An appropriate amount of fine powder (equivalent to 10 mg of brepazole) was accurately weighed and placed in a 20 mL volumetric flask. An appropriate amount of methanol was added and ultrasonicated for 20 min to dissolve the brepazole. The mixture was cooled and diluted to the scale with methanol. The mixture was shaken and filtered. The filtrate was used as the test solution. The results are shown in Table 6.

[0107] Table 6 Brepirapazole tablets prepared in Example 1 and original research products Test results of related substances at 60℃ for different days

[0108]

[0109] It can be seen from Table 6 that the impurity growth rate of Example 1 is faster than that of the original drug. This indicates that the brepazine tablets prepared by this method have higher stability.

[0110] In summary, the brepazole tablets prepared by the present invention meet the dissolution requirements and have high stability.

[0111] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing brepazole tablets, comprising the following steps: (1) mixing the brepazine API with the excipients, and pre-treating the mixture through a sieve or a granulator to obtain a pre-treated material; (2) premixing the pretreated material obtained in step (1) to obtain a premix; (3) mixing the premix obtained in step (2) with a filler, a disintegrant and a lubricant and then tableting to obtain brepazine tablets; the filler comprises at least one of pregelatinized starch, directly compressible starch and superfluid starch; (4) coating the brepazine tablets obtained in step (3) with a coating solution to obtain brepazine tablets.

2. The preparation method according to claim 1, characterized in that: The particle size of the brepazine raw material in the step (1) is 10 to 50 μm.

3. The preparation method according to claim 1, characterized in that: The excipient in step (1) includes at least one of lactose, starch lactose, cellulose lactose and anhydrous calcium hydrogen phosphate.

4. The preparation method according to claim 1, characterized in that: The aperture of the screen used for the granulator pretreatment in step (1) is 0.5 to 2 mm.

5. The preparation method according to claim 1, characterized in that: The disintegrant in step (3) comprises at least one of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose.

6. The preparation method according to claim 1, characterized in that: The lubricant in step (3) includes at least one of magnesium stearate, sodium stearyl fumarate and talc.

7. The preparation method according to claim 1, characterized in that: The total mixing rate in step (3) is 5 to 10 rpm, and the total mixing time is 5 to 20 min.

8. The preparation method according to claim 1, characterized in that: Taking the total mass of the brepazine API, the excipients in step (1), and the filler, disintegrant and lubricant in step (3) as 100%, the mass percentages of the brepazine API, the excipients, the filler, the disintegrant and the lubricant are 0.3-5%, 30-60%, 30-60%, 5-15% and 0.5-2%, respectively.

9. The preparation method according to claim 1, characterized in that: The coating solution in step (4) comprises coating material and water; the solid content of the coating solution is 10-20%.

10. Brepirapazole tablets prepared by the preparation method according to any one of claims 1 to 9.

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