Brexpiprazole tablet and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a brexpiprazole tablet and a preparation method thereof. The invention provides a brexpiprazole tablet. The brexpiprazole tablet comprises a tablet core and a coating layer, the tablet core is prepared from the following components in parts by weight: 0.25 to 10 parts of brexpiprazole, 20 to 90 parts of a filling agent, 0.5 to 10 parts of an adhesive, 5 to 20 parts of a disintegrating agent and 0.1 to 3 parts of a lubricating agent; wherein the particle size D90 of the brexpiprazole raw material is 20-51 [mu] m, the particle size D50 is 5-20 [mu] m, and the particle size D10 is less than 5 [mu] m; by controlling the particle size distribution of the brexpiprazole raw material, on one hand, the dissolution performance of the tablet is ensured, the consistency of in-vitro dissolution and a reference preparation is high, and when the brexpiprazole is prepared into the tablet, the brexpiprazole can be uniformly mixed even in a prescription with a small proportion; and on the other hand, the particle size range of the brexpiprazole raw material is wide, so that the step of further crushing the brexpiprazole with large particle size can be omitted.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a breprazol tablet and a preparation method thereof. Background Art

[0002] Brepirapazole is the first dopamine D2, 5-HT1A receptor agonist and 5-HT2A receptor antagonist compound jointly developed by Lundbeck Pharmaceuticals of Denmark and Otsuka Corporation of Japan. Compared with aripiprazole, brepirapazole has increased affinity for 5-HT receptors, reduced activity on D2 receptors, better tolerance, and a low incidence of akathisia. It has a better trend in the efficacy of negative symptoms and cognitive function of schizophrenia, and has a fast onset of effect when used as an adjuvant treatment for depression. It is clinically used for schizophrenia and major depression.

[0003] In the prior art, due to its low solubility, the prepared brepazine tablets dissolve slowly, which affects the dissolution and absorption of the drug in the body; or because it accounts for a low proportion in the prescription, it is difficult to mix evenly, and the content of the prepared tablets is uneven.

[0004] CN103889425B discloses a tablet containing 7-[4-(4-benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy]-1H-quinoline-2-one or its salt. The invention ensures the photostability of the tablet by applying a coating layer containing a colorant. The invention clarifies that the coating powder basically does not contain polyethylene glycol and the colorant contains iron oxide.

[0005] CN118453526A discloses a brepazole tablet and a preparation method thereof. The invention controls the particle size of the brepazole raw material, selects hydroxypropylmethyl as a binder, sodium stearyl fumarate as a lubricant, and adds polyethylene glycol to the coating powder. The preparation process is wet granulation. Although the above method solves the problem of low raw material solubility and improves the fluidity of the particles, it still has the following defects: (1) The process is complicated and requires three processes of wet granulation, wet granulation, and drying, involving three equipments of a wet granulator, a granulator, and a drying device, and the production cost is high; (2) The selection range of the coating powder is small and the control range of the raw material particle size is narrow, which increases the production cost; (3) The proportion of brepazole in the prescription is small, and the particle size is small, which is easy to agglomerate into balls. There is a risk of uniform mixing, resulting in uneven drugs, poor stability, poor quality, and inconsistent batch production; (4) The prepared particles have poor compressibility and the tablet hardness is low, which brings difficulties to the coating process, and ultimately leads to uneven drugs, poor stability, and poor quality. Summary of the invention

[0006] Therefore, the first technical problem to be solved by the present invention is to overcome the defects of poor drug stability, poor quality and high production cost of the brepazine tablets produced in the prior art, thereby providing a brepazine tablet with good stability, good quality, more uniformity and can reduce production costs.

[0007] The second technical problem to be solved by the present invention is to overcome the defects of the prior art preparation process of brepazine tablets, such as poor stability and quality of the produced drugs, complex process and high production cost, thereby providing a method for preparing brepazine tablets, wherein the prepared drugs have good stability and quality, simple process and low production cost.

[0008] To this end, the present invention provides the following technical solutions:

[0009] An embodiment of the present invention provides a brepazine tablet, comprising a tablet core and a coating layer; the tablet core comprises the following components in parts by weight: 0.25 to 10 parts of brepazine, 20 to 90 parts of a filler, 0.5 to 10 parts of a binder, 5 to 20 parts of a disintegrant, and 0.1 to 3 parts of a lubricant; wherein the particle size D90 of the brepazine raw material is 20 to 51 μm, D50 is 5 to 20 μm, and D10 is <5 μm.

[0010] The above-mentioned brepirazole has a wide particle size range. On the one hand, when preparing brepirazole tablets, brepirazole can be mixed evenly even if the proportion of brepirazole in the prescription is small, which ensures the dissolution performance of the tablets. The in vitro dissolution is highly consistent with the reference preparation, and the prepared brepirazole tablets have good stability and quality, and are more uniform. On the other hand, during preparation, the particle size range of the brepirazole raw material that can be selected is wide, and the step of further crushing the large-particle brepirazole can be omitted, making the process simple and the cost lower. Furthermore, by controlling the amount of the binder, combined with the brepirazole tablet preparation method of the present invention, the prepared brepirazole tablets can be made stable and of good quality.

[0011] In some embodiments, the tablet core comprises the following components in parts by weight: 0.25 to 5 parts of brepizole, 75 to 90 parts of filler, 0.5 to 2.5 parts of binder, 10 to 15 parts of disintegrant, and 0.5 to 1.5 parts of lubricant.

[0012] In some embodiments, the coating layer has a weight gain of 2-6% of the weight of the core tablet.

[0013] In some embodiments, the components of the coating layer include at least one of a film former, a plasticizer, an anti-sticking agent, a sunscreen, and a colorant.

[0014] In some embodiments, the components of the coating layer include at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, propylene glycol, glycerin, polyvinyl alcohol, talc, iron oxide, titanium dioxide, aluminum lake and plant pigment.

[0015] In some embodiments, the components of the coating layer include hypromellose, polyethylene glycol, titanium dioxide, talc, and a colorant.

[0016] In a preferred embodiment, in the coating layer, the mass percentage of the polyethylene glycol is 0-30%, preferably 10-30%, such as the mass percentage of the polyethylene glycol can be any one of 0%, 5%, 10%, 11%, 14%, 18%, 20%, 22%, 25%, 27%, 30% or a range between any two values. In the existing original research drugs of brepazole tablets, polyethylene glycol is not used in the coating because it may cause the impurities of brepazole tablets to become higher and the stability to be poor. In some existing generic drugs of brepazole tablets, the proportion of polyethylene glycol in the coating is also very low. However, the present invention has found that the proportion of polyethylene glycol in the coating is below 30%, and it can still maintain stability and low impurity content. Therefore, a certain amount of polyethylene glycol can be used in the coating, which increases the selection range of coating powders. At the same time, since polyethylene glycol is easy to obtain and low in cost, the production cost can be further reduced.

[0017] In some embodiments, the polyethylene glycol can be selected from at least one of PEG200, PEG300, PEG400, PEG600, PEG800, PEG1000, PEG1500, PEG2000, PEG3000, PEG4000, PEG6000, and PEG8000. In some preferred embodiments, the polyethylene glycol is selected from at least one of PEG4000, PEG6000, and PEG8000. In some more preferred embodiments, the polyethylene glycol is selected from PEG6000, and the selection of the polyethylene glycol with the molecular weight can change the coating layer thickness within a wider range without changing its permeability, and maintain the tablet dissolution rate.

[0018] In some embodiments, the filler is selected from one or more of lactose, corn starch, microcrystalline cellulose, and mannitol.

[0019] In some embodiments, the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinyl pyrrolidone. In a preferred embodiment, the binder is selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose. The selection of the binder in combination with the preparation method of the present invention can improve the stability and quality of the prepared drug.

[0020] In some embodiments, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl cellulose, and sodium carboxymethyl starch. In a preferred embodiment, the low-substituted hydroxypropyl methylcellulose is selected from at least one of LH-11 and LH-21. The selection of the above low-substituted hydroxypropyl methylcellulose can make the tablet disintegrate quickly and stably, with small differences between tablets.

[0021] In some embodiments, the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, hydrogenated vegetable oil, talc, and colloidal silicon dioxide.

[0022] In some embodiments, the filler includes lactose, corn starch and microcrystalline cellulose. In a preferred embodiment, based on the total weight of the tablet, the lactose mass is 45-65 parts by weight, the corn starch is 15-30 parts by weight, and the microcrystalline cellulose is 5-15 parts by weight.

[0023] The present invention discloses a method for preparing the brepazole tablets, comprising the following steps:

[0024] (1) adding a prescribed amount of adhesive to water to prepare an adhesive solution; adding a prescribed amount of brepazole to the adhesive solution, mixing, and obtaining a suspension;

[0025] (2) Add the prescribed amount of filler and disintegrant into the fluidized bed and preheat; then spray the suspension into the fluidized bed, granulate, dry and size the particles;

[0026] (3) adding a prescribed amount of lubricant to the particles obtained in step (2) and mixing;

[0027] (4) Compress the mixture in step (3) into tablets and apply coating.

[0028] Through the above process, by controlling the way of adding the raw material of brepirazole, the binder and water are first prepared into a binder solution, and then the raw material brepirazole is added to prepare a suspension. By adjusting the selected binder, dosage and water, the brepirazole in the suspension is evenly mixed, so that when it is prepared by a fluidized bed, even if brepirazole accounts for a small proportion in the prescription, it can still be mixed evenly with the filler and disintegrant. The prepared brepirazole tablets are uniform, stable and of good quality, and the dissolution performance of the tablets is guaranteed, and the in vitro dissolution is highly consistent with the reference preparation. Further, the brepirazole particles prepared by the above prescription combined with the process have strong compressibility, high tablet core hardness, and the tablet core is not easy to break during coating. The finally prepared brepirazole tablets are uniform, stable and of good quality. Furthermore, in the above process, all are carried out in the fluidized bed equipment, and no raw material transfer or equipment replacement occurs, the process is simple, and the production cost is low.

[0029] In some embodiments, in the step (1), the amount of water added is 50-150% of the total weight of the materials, preferably in the range of 65-135%. The total weight of the materials is the total weight of the filler, binder, disintegrant, and brepizole. By adjusting the amount of water added, on the one hand, brepizole is made more uniform during mixing, and on the other hand, the prepared brepizole particles have strong compressibility, high tablet hardness, and the tablet core is not easy to break during coating. The finally prepared brepizole tablets are uniform, stable, and of good quality.

[0030] In some embodiments, in step (2), the temperature is preheated to above 35°C.

[0031] In some embodiments, in step (2), drying is performed until the moisture content is ≤3.0 wt %.

[0032] In some embodiments, the air inlet temperature, air volume, material preheating temperature, and spraying flow rate of the fluidized bed are all conventional process parameters of the fluidized bed, including but not limited to an air inlet temperature of 55 to 75°C, an air volume of 15 to 40 m 3 / h, the material preheating temperature is above 35°C. Further, the inlet air temperature can be any one of 55°C, 58°C, 60°C, 63°C, 65°C, 68°C, 70°C, 73°C, 75°C or any range between two values. Further, the air volume can be 15m 3 / h、18m 3 / h、20m 3 / h、23m 3 / h、25m 3 / h、28m 3 / h、30m 3 / h、33m 3 / h、35m 3 / h、38m 3 / h、40m 3 / h any value or a range between any two values. The material preheating temperature can be any value above 35°C, 38°C, 40°C, 43°C, 45°C, etc. or a range between any two values.

[0033] To this end, the present invention provides the following technical solutions:

[0034] The technical solution of the present invention has the following advantages:

[0035] 1. The present invention provides a brepazole tablet, comprising a tablet core and a coating layer; the tablet core comprises the following components in parts by weight: 0.25-10 parts of brepazole, 20-90 parts of a filler, 0.5-10 parts of a binder, 5-20 parts of a disintegrant, and 0.1-3 parts of a lubricant; wherein the particle size D90 of the brepazole raw material is 20-51 μm, D50 is 5-20 μm, and D10 is <5 μm; in the above prescription, by controlling the particle size distribution of the brepazole raw material, on the one hand, the dissolution performance of the tablet is guaranteed, and the in vitro dissolution is highly consistent with the reference preparation, so that when preparing brepazole tablets, the brepazole can be mixed evenly even if the proportion of brepazole in the prescription is small, so that the prepared brepazole tablets have good stability and quality, and are more uniform. On the other hand, the particle size range of the brepazole raw material is wide, and the step of further crushing the large-particle brepazole can be omitted, so that the preparation process is simple and the cost is lower. Furthermore, by controlling the amount of the binder, combined with the method for preparing the brepizole tablets of the present invention, the prepared brepizole tablets can have good stability, good quality and be more uniform.

[0036] 2. The present invention provides a brepazine tablet, wherein the components of the coating layer include at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, propylene glycol, glycerol, polyvinyl alcohol, talcum powder, iron oxide, titanium dioxide, aluminum lake and plant pigment; polyethylene glycol can be added to the coating powder or aluminum lake can be used as a colorant to ensure the stability of the coated tablet, while expanding the scope of use of the coating powder and reducing costs.

[0037] 3. The present invention provides a brepazine tablet, wherein the mass percentage of the polyethylene glycol in the coating layer is 0 to 30%, preferably 10 to 30%. The present invention has found that when the proportion of polyethylene glycol in the coating is below 30%, stability can still be maintained and the impurity content is low, so a certain amount of polyethylene glycol can be used in the coating, which increases the selection range of the coating powder. At the same time, since polyethylene glycol is easily available and low in cost, the production cost can be further reduced.

[0038] 5. The present invention provides a method for preparing brepazine tablets, comprising the following steps: (1) adding a prescribed amount of binder into water to prepare a binder solution; adding a prescribed amount of brepazine into the binder solution, mixing, and obtaining a suspension; (2) adding a prescribed amount of filler and disintegrant into a fluidized bed, preheating; then spraying the suspension into the fluidized bed, granulating, drying, and granulating; (3) adding a prescribed amount of lubricant into the granules obtained in step (2), mixing; and (4) tableting and coating the mixture in step (3). In the above method, by controlling the particle size of the brepirazole raw material in the prescription and the prescription and the method of adding the brepirazole raw material, on the one hand, the dissolution performance of the tablets is guaranteed, and the in vitro dissolution is highly consistent with the reference preparation; on the other hand, it not only solves the risk of uneven mixing caused by a small proportion of the brepirazole raw material, but also expands the particle size range of the brepirazole raw material. At the same time, the prepared particles are more uniform and loose, and the particle fluidity, compressibility and tablet hardness are all improved. Therefore, the process of the present invention is simple, the production cost is low, it is conducive to industrial production, and the brepirazole tablets with stable and controllable quality are obtained. DETAILED DESCRIPTION

[0039] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0040] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0041] In the following examples, polyethylene glycol 6000 is selected as the polyethylene glycol.

[0042] In the following examples, the low-substituted hydroxypropyl cellulose is selected from low-substituted hydroxypropyl cellulose LH-11.

[0043] The reference preparation involved in the following examples is brexpiprazole tablets (trade name "Rexulti") marketed in the United States by Otsuka Pharmaceutical Co Ltd.

[0044] The detection methods used in the embodiments or comparative examples of the present invention are as follows:

[0045] (1) Bulk density: Determined according to the first method of fixed mass method in Part 4 0993 Bulk density determination of the 2020 Pharmacopoeia.

[0046] (2) Tap density: measured according to the first method of fixed mass method of bulk density determination in Part 4, 0993 of the 2020 edition of the Pharmacopoeia.

[0047] (3) Carr's index: compressibility index, calculated according to Part 4 0993 of the 2020 edition of the Pharmacopoeia.

[0048] (4) Angle of repose: In a static equilibrium state, the acute angle between the naturally accumulated slope of the powder and the bottom level is called the angle of repose. It is formed by electromagnetic vibration to make the powder fall naturally onto a specific platform. The size of the angle of repose directly reflects the fluidity of the powder. The smaller the angle of repose, the better the fluidity. The larger the angle of repose, the worse the fluidity. The angle of repose is also called the angle of rest or the natural slope angle. Use the angle of repose meter to test, set the measurement parameters to 3, the feeding time to 200s, the feeding speed to 4, fix the vibrating screen plate, click on the feed button, and use a small spoon to add the sample to the screen. The sample passes through the screen and falls onto the sample table through the discharge port and gradually forms a cone. When the sample fills the sample table to form a symmetrical cone and powder falls around the circumference of the platform, stop feeding. After feeding is completed, click the "Measure Angle of Repose" button, the instrument will capture the image for rapid analysis and calculation, and then display the calculation results. Measure 3 times at the same time and calculate the average value.

[0049] (5) Dissolution: The dissolution rate was determined according to Part IV 0931 of the Chinese Pharmacopoeia 2020, using pH 6.8 + 1.0 wt% Tween 80 solution as the dissolution medium, a volume of 900 mL, a rotation speed of 50 rpm, and sampling at 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes to test the dissolution rate of the samples;

[0050] f2 evaluation: According to the Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Preparations, calculate the similarity of the dissolution curves of the reference preparation and the homemade preparation.

[0051] Example 1

[0052] This embodiment provides a brepazine tablet, and its prescription is as follows:

[0053] Table 1. Prescription

[0054]

[0055] Preparation method:

[0056] (1) Weighing: Weigh each material according to the prescription list in Table 1;

[0057] (2) Preparation of raw material-binder suspension: Add the prescribed amount of binder to water that is 80% of the total weight of the materials (the total weight of the binder, filler, disintegrant, and brepizole), stir and dissolve to obtain a binder solution; add the prescribed amount of brepizole thereto, stir and disperse evenly, and set aside;

[0058] (3) Granulation: Add the above-prescribed amount of filler, disintegrant and other materials into the fluidized bed, set the air inlet temperature to 55-75°C and the air volume to 15-40m 3 / h, preheat the material to above 35°C (in this embodiment, the inlet air temperature is 65°C and the air volume is 27m 3 / h, preheat the material to 35°C), start spraying the raw material-binder suspension obtained in (2) to prepare particles, and continue drying in the fluidized bed until the moisture content is ≤3.0%; then sieve the obtained particles with a mesh size of 24 to 40 to obtain uniform internal particles, and measure the particle size distribution of the obtained particles;

[0059] (4) mixing: uniformly mixing the particles obtained in step (2) and a prescribed amount of lubricant;

[0060] (5) Tableting and coating: The granules mixed evenly in step (3) are tabletted and coated, and the weight gain of the coating is controlled to be 4-6% of the weight of the tablet core.

[0061] Example 2

[0062] The difference between this embodiment and embodiment 1 is that the particle size of the raw material medicine is: D10 is 0.54 μm, D50 is 5.49 μm, and D90 is 21.03 μm.

[0063] Example 3

[0064] The difference between this embodiment and embodiment 1 is that the particle size of the raw material medicine is: D10 is 1.54 μm, D50 is 10.32 μm, and D90 is 41.01 μm.

[0065] Example 4

[0066] The difference between this embodiment and embodiment 1 is that the particle size of the raw material drug is: D10 is 1.89 μm, D50 is 15.78 μm, and D90 is 50.31 μm.

[0067] Example 5

[0068] The difference between this embodiment and embodiment 1 is that the coating formula is replaced, as shown in the following table:

[0069] Table 2. Prescription

[0070]

[0071] Example 6

[0072] The difference between this embodiment and embodiment 1 is that the coating formula is replaced, as shown in the following table

[0073] Table 3. Prescription

[0074]

[0075] Example 7

[0076] The difference between this embodiment and embodiment 1 is that the coating formula is replaced, as shown in the following table

[0077] Table 4. Prescription

[0078]

[0079] Example 8

[0080] The difference between this embodiment and embodiment 1 is that the amount of water added is 50% of the total weight of the materials (the total weight of the binder, filler, disintegrant, and brepazole).

[0081] Example 9

[0082] The difference between this embodiment and embodiment 1 is that the amount of water added is 150% of the total weight of the materials (the total weight of the binder, filler, disintegrant, and brepazole).

[0083] Example 10

[0084] This embodiment provides a brepazine tablet, and its prescription is as follows:

[0085] Table 5. Prescription

[0086]

[0087] (1) Weighing: Weigh each material according to the prescription list in Table 1;

[0088] (2) Preparation of raw material-binder suspension: Add the prescribed amount of binder to water which is 65% of the total weight of the materials (total weight of binder, filler, disintegrant, and brepizole), stir and dissolve to obtain a binder solution; add the prescribed amount of brepizole thereto, stir and disperse evenly, and set aside;

[0089] (3) Granulation: Add the above-prescribed amount of filler, disintegrant and other materials into the fluidized bed, set the air inlet temperature to 55°C and the air volume to 40m 3 / h, preheat the material to 36°C, start spraying the raw material-binder suspension obtained in (2) to prepare particles, and continue drying until the moisture content is ≤3.0%; then sieve the obtained particles, the mesh number of which is 24-40, to obtain uniform internal particles, and measure the particle size distribution of the obtained particles;

[0090] (4) mixing: uniformly mixing the particles obtained in step (2) and a prescribed amount of lubricant;

[0091] (5) Tableting and coating: The granules mixed evenly in step (3) are tabletted and coated, and the weight gain of the coating is controlled to be 4-6% of the weight of the tablet core.

[0092] Embodiment 11

[0093] This embodiment provides a brepazine tablet, and its prescription is as follows:

[0094] Table 6. Prescription

[0095]

[0096] (1) Weighing: Weigh each material according to the prescription list in Table 1;

[0097] (2) Preparation of raw material-binder suspension: Add the prescribed amount of binder to water that is 135% of the total weight of the materials (the total weight of the binder, filler, disintegrant, and brepazine), stir and dissolve to obtain a binder solution; add the prescribed amount of brepazine thereto, stir and disperse evenly, and set aside;

[0098] (3) Granulation: Add the above-prescribed amount of filler, disintegrant and other materials into the fluidized bed, set the air inlet temperature to 75°C and the air volume to 15m 3 / h, preheat the material to 37°C, start spraying the raw material-binder suspension obtained in (2) to prepare particles, and dry to a moisture content of ≤3.0%; then sieve the obtained particles with a mesh size of 24 to 40 to obtain uniform internal particles, and measure the particle size distribution of the obtained particles;

[0099] (4) mixing: uniformly mixing the particles obtained in step (2) and a prescribed amount of lubricant;

[0100] (5) Tableting and coating: The granules mixed evenly in step (3) are tabletted and coated, and the weight gain of the coating is controlled to be 4-6% of the weight of the tablet core.

[0101] Comparative Example 1

[0102] The difference between this comparative example and Example 1 is that the particle size of brepizole is D10 of 0.450 μm, D50 of 4.05 μm, and D90 of 17.07 μm.

[0103] Comparative Example 2

[0104] The difference between this comparative example and Example 1 is that the particle sizes of brepizole are: D10 is 2.45 μm, D50 is 20.05 μm, and D90 is 53.66 μm.

[0105] Comparative Example 3

[0106] The difference between this comparative example and Example 1 is that the preparation method is:

[0107] The prescribed amount of binder, filler, disintegrant and brepazole are mixed evenly, 40% of the total amount of the above materials is added to the mixture to make a soft material of water, and then passed through a 16-mesh sieve for wet granulation; the wet granules are added to a fluidized bed and dried until the moisture content is less than 3.0%. After the dry granules are passed through an 18-mesh sieve for granulation, the prescribed amount of magnesium stearate is added, and the mixture is mixed evenly and then tableted.

[0108] Comparative Example 4

[0109] The difference between this comparative example and Example 1 is that the preparation method is:

[0110] The prescribed amount of binder, filler, disintegrant and brepazole are mixed evenly, 20% of the total amount of the above materials is added to the mixture to make a soft material made of water, and then passed through a 16-mesh sieve for wet granulation; the wet granules are added to a fluidized bed and dried until the moisture content is less than 3.0%. After the dry granules are passed through an 18-mesh sieve for granulation, the prescribed amount of magnesium stearate is added, and the mixture is mixed evenly and then tableted.

[0111] Comparative Example 5

[0112] The difference between this comparative example and Example 1 is that the preparation method is as follows: the amount of water added is 40% of the total weight of the materials (the total weight of the binder, filler, disintegrant and brepazole).

[0113] Experimental Example 1 Investigation of different particle size distributions of breprazol

[0114] The brepazine tablets prepared in Examples 1-4 and Comparative Examples 1-2 were examined. The results are shown in the following table.

[0115] Table 7: Evaluation results of Examples 1 to 4 and Comparative Examples 1 to 2

[0116]

[0117]

[0118] It can be seen from the above table that the particle size of brepirazole: D10 is 0.450μm, D50 is 4.05μm, D90 is 17.07μm, and the tablet dissolves faster; the particle size of brepirazole is: D10 is 2.45μm, D50 is 20.05μm, D90 is 53.66μm, and the tablet dissolves slower. Only when D10: <5μm, D50 is 5-20μm, and D90 is 20-50μm, the dissolution is highly consistent with the reference preparation (f2>50), and the obtained brepirazole tablets have good stability and quality, and are more uniform.

[0119] Experimental Example 2 Investigation of different polyethylene glycols

[0120] The brepazine tablets prepared in Examples 1, 5-6 and Comparative Example 3 were examined.

[0121] Table 8: Evaluation results of Examples 1, 5-7

[0122]

[0123] It can be seen from the above results that the addition of polyethylene glycol in the prescription can expand the selection range of coating powders. Compared with the case without adding polyethylene glycol (reference preparation), the dissolution of this product is highly consistent with the reference preparation, and the change of related substances is not higher than that of the reference preparation. The dosage of polyethylene glycol in Example 5 is 30%, and the dissolution is highly consistent with the reference preparation. The increase in related substances is slightly faster, but not higher than that of the reference preparation. The preferred range of polyethylene glycol is 10 to 30%.

[0124] Experimental Example 7 Investigation of different preparation methods

[0125] The brepazine tablets prepared in Example 1, Examples 8-9 and Comparative Examples 3-5 were examined.

[0126] Table 9: Evaluation results of Examples 1, 8-9, and Comparative Examples 3-5

[0127]

[0128] It can be seen from the above results that in terms of tablet hardness, the tablet hardness obtained by the wet granulation process in Comparative Examples 3 to 4 is relatively low, 2-4. During the coating process, the tablet core is easily broken, which brings great difficulties to the coating, resulting in poor stability and poor quality of the final brepirazole tablets. Comparative Example 5 adopts the preparation process of the present invention, but the amount of water added in the preparation of the binder-raw material suspension is 40%, resulting in the tablet hardness prepared by it being relatively low, 2-4. During the coating process, the tablet core is easily broken, which brings great difficulties to the coating. The tablet hardness prepared in Example 1, Example 8, and Example 9 is relatively high, 4-6. During the coating process, the tablet core is not easy to break, and the coating is easy. The final brepirazole tablets have good stability and quality, and do not waste materials, reducing costs.

[0129] In terms of in vitro dissolution, the dissolution of the brepazine tablets obtained by the wet granulation process in Comparative Examples 3-5 was slow, and the consistency with the reference preparation was low (f2 < 50), while the tablets prepared in Example 1 and Examples 8-9 had high dissolution and high consistency with the reference preparation (f2 > 50).

[0130] Experimental Example 8 Investigation of different dosage ratios

[0131] The brepazine tablets prepared in Example 1 and Examples 10-11 were examined.

[0132] Table 10: Evaluation results of Examples 1, 10 to 11

[0133]

[0134] From the above results, it can be seen that the tablets of Example 1, Example 10 and Example 11 have high hardness, high in vitro dissolution, and high consistency with the reference preparation.

[0135] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A breprazol tablet, characterized in that: The invention comprises a tablet core and a coating layer; the tablet core comprises the following components in parts by weight: 0.25 to 10 parts of brepizole, 20 to 90 parts of a filler, 0.5 to 10 parts of a binder, 5 to 20 parts of a disintegrant, and 0.1 to 3 parts of a lubricant; wherein the particle size D90 of the brepizole raw material is 20 to 51 μm, D50 is 5 to 20 μm, and D10 is less than 5 μm.

2. The breprazol tablet according to claim 1, characterized in that: The tablet core comprises the following components in parts by weight: 0.25 to 5 parts of breprazol, 75 to 90 parts of filler, 0.5 to 2.5 parts of binder, 10 to 15 parts of disintegrant, and 0.5 to 1.5 parts of lubricant; Optionally, the coating layer has a weight gain of 2-6% of the mass of the tablet core.

3. The breprazol tablet according to claim 1 or 2, characterized in that: The coating layer comprises at least one of a film former, a plasticizer, an anti-adherent, a sunscreen and a colorant; Optionally, the components of the coating layer include at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, propylene glycol, glycerin, polyvinyl alcohol, talc, iron oxide, titanium dioxide, aluminum lake and plant pigment.

4. The breprazol tablet according to claim 3, characterized in that: The components of the coating layer include hypromellose, polyethylene glycol, titanium dioxide, talc and a colorant.

5. The breprazol tablet according to claim 4, characterized in that: In the coating layer, the mass percentage of the polyethylene glycol is 0 to 30%, preferably 10 to 30%.

6. The breprazol tablet according to any one of claims 1 to 5, characterized in that: The filler is selected from one or more of lactose, corn starch, microcrystalline cellulose, and mannitol; And / or, the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinyl pyrrolidone; and / or, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl cellulose, and sodium carboxymethyl starch; And / or, the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, hydrogenated vegetable oil, talc, and colloidal silicon dioxide.

7. The breprazol tablet according to claim 6, characterized in that: The filler comprises lactose, corn starch and microcrystalline cellulose; based on the total weight of the tablet, the lactose mass is 45 to 65 parts by weight, the corn starch mass is 15 to 30 parts by weight, and the microcrystalline cellulose mass is 5 to 15 parts by weight.

8. A method for preparing the breprazol tablet according to any one of claims 1 to 7, characterized in that: The steps include: (1) adding a prescribed amount of an adhesive to water to prepare an adhesive solution; adding a prescribed amount of brepazole to the adhesive solution, mixing, and obtaining a suspension; (2) Add the prescribed amount of filler and disintegrant into the fluidized bed and preheat; then spray the suspension into the fluidized bed, granulate, dry and size the particles; (3) adding a prescribed amount of lubricant to the particles obtained in step (2) and mixing; (4) Compress the mixture in step (3) into tablets and apply coating.

9. The preparation method according to claim 8, characterized in that: In the step (1), the amount of water added is 50-150% of the total weight of the materials, preferably in the range of 65-135%; the total weight of the materials is the total weight of the filler, binder, disintegrant and brepazine.

10. The preparation method according to claim 8 or 9, characterized in that: In the step (2), preheating to above 35°C; And / or, in the step (2), drying is performed until the moisture content is ≤3.0 wt%.

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