CN107362148B

CN107362148B - Pharmaceutical composition for treating tumors and preparation method and application thereof

Info

Publication number: CN107362148B
Application number: CN201710623181.7A
Authority: CN
Inventors: 曹恒杰; 陈小宝
Original assignee: Tot Biopharm Co ltd
Current assignee: Tot Biopharm Co ltd
Priority date: 2017-07-27
Filing date: 2017-07-27
Publication date: 2020-04-21
Anticipated expiration: 2037-07-27
Also published as: CN107362148A

Abstract

The invention provides a pharmaceutical composition and a preparation method and application thereof, the pharmaceutical composition comprises vorinostat and pharmaceutically acceptable auxiliary materials, the pharmaceutically acceptable auxiliary materials comprise a filling agent, an adhesive, a disintegrating agent and a lubricant, the pharmaceutical composition is matched with the vorinostat by utilizing the pharmaceutically acceptable auxiliary materials to achieve the purposes of uniform and stable particle size, and faster dissolution characteristic so as to improve the anti-tumor effect of the vorinostat, a fluidized bed top spray granulation method is utilized in the preparation process to ensure uniform and stable particle size of the particles, particularly, one part of the filling agent is specifically selected to be prepared into filling agent slurry to be mixed with the adhesive solution to be used as spray liquid, the other part of the filling agent is specifically selected to be mixed with other materials in a dry powder form to be used as fluidized bed materials, the spray liquid is sprayed to better control the particle size and improve the particle property, the stability is improved, the dissolution rate of the preparation is increased, the process is simple and controllable, and the protection performance to personnel is improved.

Description

Pharmaceutical composition for treating tumors and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicine preparation, and relates to a medicine composition for treating tumors and a preparation method and application thereof.

Background

Tumors (tumors) are second only to cardiovascular and cerebrovascular diseases, the second largest killer that seriously threatens human life and health. At present, the incidence rate of malignant tumors in China is increased at a rate of 2.5% per year, the death rate is increased by about 1.3% per year, and chemotherapy becomes one of the important means for the comprehensive treatment of malignant tumors. Vorinostat (SAHA), chemically known as "N-hydroxy-N' -phenyloctanediamide", is a histone deacetylase inhibitor, and can inhibit the activity of Histone Deacetylase (HDAC), promote acetylation of histone, and finally inhibit growth of cancer cells, and induce differentiation and apoptosis of cancer cells. Cutaneous T cell lymphoma (CTCL, a non-hodgkin's lymphoma) that is exacerbated, persistent and relapsed or ineffective after treatment with two systemic drugs is treated. It has been approved by the FDA in the united states for the treatment of cutaneous T-cell lymphoma.

In addition to killing tumor cells, the traditional intravenous injection also has some chemotherapy reactions, such as leucocyte and platelet reduction, anorexia, nausea, vomiting, alopecia and the like, and more than 30 percent of patients have complications, such as endophlebitis or thrombophlebitis and the like. Many side effects can be avoided by oral chemotherapy. There is therefore a great need to develop suitable oral vorinostat formulations.

Vorinostat, sparingly soluble in methanol, slightly soluble in ethanol or isopropanol, and practically insoluble in dichloromethane or water. Belongs to a slightly soluble antitumor drug. At present, the preparation method of the medicine has the advantages of directly mixing and filling capsules, having high requirements on the fluidity and the granularity of raw and auxiliary materials, having higher difficulty on the filling process due to too thin raw materials, having great influence on the dissolution due to too thick raw materials and being unfavorable for the protection of personnel due to the exposure of dust.

CN101874793A discloses a vorinostat solid preparation, which comprises bulk drug vorinostat and pharmaceutic adjuvants, wherein the pharmaceutic adjuvants are filler, disintegrant and lubricant, and is characterized in that the weight ratio of vorinostat to the filler is 1:0.9-4.5, the weight ratio of vorinostat to the disintegrant is 1:0.0834-0.4170, and the weight ratio of vorinostat to the lubricant is 1: 0.0166-0.0830. The dissolution rate of the vorinostat solid preparation reaches more than 80 percent in 45 minutes, and the highest dissolution rate is about 90 percent. But for vorinostat formulations, higher dissolution rates are desired to achieve better results.

Therefore, there is a need to develop a technology for preparing vorinostat pharmaceutical compositions, which can solve the dissolution rate of the preparation, improve the feasibility of the process, and increase the protection of operators.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a pharmaceutical composition, a preparation method and application thereof.

In order to achieve the purpose, the invention adopts the following technical scheme:

in one aspect, the invention provides a pharmaceutical composition comprising vorinostat and pharmaceutically acceptable excipients comprising a filler, a binder, a disintegrant, and a lubricant.

In the invention, the pharmaceutically acceptable auxiliary materials are used for matching with the vorinostat, so that the purposes of uniform and stable particle size, fast dissolution characteristic and improvement of the anti-tumor effect of the vorinostat are achieved.

Preferably, the filler is selected from any one of starch, microcrystalline cellulose or lactose or a combination of at least two thereof, preferably starch.

Preferably, the filler is used in an amount of 170-230 parts by weight, such as 170 parts by weight, 180 parts by weight, 190 parts by weight, 200 parts by weight, 210 parts by weight, 220 parts by weight or 230 parts by weight, relative to 100 parts by weight of vorinostat in the pharmaceutical composition.

Preferably, the binder is selected from any one or a combination of at least two of hypromellose, povidone k30 or starch, preferably hypromellose.

Preferably, the binder is used in an amount of 3 to 10 parts by weight, such as 3 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight or 10 parts by weight, relative to 100 parts by weight of vorinostat in the pharmaceutical composition.

Preferably, the binder is present in the pharmaceutical composition in an amount of 0.5-5% by weight, such as 0.5%, 0.8%, 1%, 1.5%, 1.8%, 2%, 2.3%, 2.5%, 2.8%, 3%, 3.5%, 4%, 4.5% or 5%, preferably 2-3%. In the invention, the dosage of the adhesive is unexpectedly found to have great influence on the particle uniformity of the solvent and the preparation stability, especially the dissolution property, and the faster dissolution speed can be ensured only under the proper dosage of the adhesive, so as to better improve the treatment effect of the medicament.

Preferably, the disintegrant is selected from any one or a combination of at least two of sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropyl cellulose or croscarmellose sodium, preferably low-substituted hydroxypropyl cellulose.

Preferably, the disintegrant is used in an amount of 6 to 15 parts by weight, such as 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight, 10 parts by weight, 11 parts by weight, 12 parts by weight, 13 parts by weight, 14 parts by weight or 15 parts by weight, relative to 100 parts by weight of vorinostat in the pharmaceutical composition.

Preferably, the lubricant is selected from any one or a combination of at least two of silicon dioxide, magnesium stearate, glyceryl behenate, talc or stearic acid.

Preferably, the lubricant is used in an amount of 1.5 to 10 parts by weight, such as 1.5 parts by weight, 1.8 parts by weight, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight or 10 parts by weight, relative to 100 parts by weight of vorinostat in the pharmaceutical composition.

In the invention, as a preferred technical scheme, the pharmaceutical composition comprises the following components in parts by weight:

in the composition of the preferable pharmaceutical composition for treating the tumor, the starch, the hypromellose, the low-substituted hypromellose and the magnesium stearate can be better matched with the pharmaceutical active ingredient vorinostat by selecting the specific filler, the adhesive, the disintegrant and the lubricant, the performance of the preparation is synergistically enhanced, and the pharmaceutical composition for treating the tumor can be promoted to have better stability and faster dissolution speed, so that the treatment effect is better exerted.

Preferably, the dosage form of the pharmaceutical composition for treating tumor of the present invention comprises granules, tablets or capsules, preferably tablets.

In another aspect, the present invention provides a process for the preparation of a pharmaceutical composition as described above, said process employing fluidized bed top spray granulation, said process comprising the steps of:

(1) preparing a part of filler into filler slurry, and mixing the filler slurry and the adhesive solution to obtain spraying liquid;

(2) mixing the rest filler, vorinostat and disintegrant, placing in a fluidized bed, preheating the materials, spraying the spray liquid obtained in the step (1), granulating and drying simultaneously, and sieving to prepare dry granules;

(3) adding a lubricant into the dry particles obtained in the step (2) and mixing to obtain the pharmaceutical composition.

The invention adopts the top spraying granulation of the fluidized bed, and the specific selection of the spray liquid and the materials in the fluidized bed in the granulation process is adopted, namely, a part of filling agent is made into filling agent slurry to be mixed with adhesive to obtain the spray liquid, and the other part of filling agent is mixed with vorinostat and disintegrant to be used as the materials of the fluidized bed.

Preferably, the step (1) of preparing a part of the filler into the filler slurry refers to preparing the filler slurry by dispersing a part of the filler in the formula amount with purified water.

Preferably, the filler slurry has a mass percent concentration of 6-13%, e.g., 6%, 6.3%, 6.5%, 6.8%, 7%, 7.5%, 7.8%, 8%, 8.5%, 8.8%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, or 13%. If the filler slurry concentration is too dilute, the particle formability is poor, and if the filler slurry concentration is too high, the spraying of the slurry and the binder solution is affected, the spray head is blocked, and the spraying cannot be completed smoothly.

Preferably, the binder solution in step (1) is prepared by dissolving or dispersing the binder in purified water. Preferably, the concentration of the binder solution is 8-10%, for example, 8%, 8.3%, 8.5%, 8.8%, 9%, 9.3%, 9.5%, 9.8% or 10%, if the concentration of the binder solution is too low, the binding force is insufficient, resulting in unstable particles, and if the concentration of the binder solution is too high, the spraying of the slurry and the binder solution is affected, resulting in the blockage of the spray header, and the spraying cannot be completed smoothly.

Preferably, the preheating of the material in step (2) is to preheat the material to 40-50 ℃, such as 40 ℃, 43 ℃, 45 ℃, 48 ℃ or 50 ℃.

Preferably, during the granulation in step (2), the operating parameters of the fluidized bed are set as follows: the opening degree of the air door is 100%, the frequency of the fan is 15-30 Hz (for example, 15Hz, 18Hz, 20Hz, 22Hz, 24Hz, 26Hz, 28Hz or 30Hz), the air inlet temperature is 60-80 ℃ (for example, 60 ℃, 62 ℃, 65 ℃, 68 ℃, 70 ℃, 73 ℃, 75 ℃, 78 ℃ or 80 ℃), the air outlet temperature is 20-40 ℃ (for example, 20 ℃, 23 ℃, 25 ℃, 28 ℃, 30 ℃, 33 ℃, 35 ℃, 38 ℃ or 40 ℃), the material temperature is 30-50 ℃ (for example, 30 ℃, 33 ℃, 35 ℃, 38 ℃, 40 ℃, 43 ℃, 45 ℃, 48 ℃ or 50 ℃), the atomization pressure is 0.10-0.40 MPa (for example, 0.10MPa, 0.15MPa, 0.20MPa, 0.25MPa, 0.30MPa, 0.35MPa or 0.40MPa), and the rotation speed of the peristaltic pump is 10-70 rpm (for example, 10rpm, 15rpm, 18rpm, 20rpm, 25rpm, 30rpm, 35rpm, 40rpm, 45rpm, 50rpm, 55rpm, 60rpm, 65rpm or 70 rpm).

Preferably, the sieving in step (2) is a 20-24 mesh (e.g., 20 mesh, 21 mesh, 22 mesh, 23 mesh or 24 mesh) sieve.

Preferably, the step (3) further comprises the step of preparing the mixture into corresponding dosage forms after adding the lubricant and mixing.

Preferably, in the step (3), after adding the lubricant and mixing, the mixture is tableted and coated with a film coating to prepare the tablet.

As a preferable technical scheme of the present invention, when the pharmaceutical composition includes vorinostat, starch, hypromellose, low-substituted hypromellose, and magnesium stearate, the preparation method of the pharmaceutical composition includes the following steps:

(1) preparing a part of starch in the formula amount into starch slurry, and mixing the starch slurry and a hydroxypropyl methylcellulose solution to obtain a spray solution;

(2) placing the rest starch, vorinostat and low-substituted hypromellose in a fluidized bed, preheating the materials, spraying the spray liquid obtained in the step (1), granulating and drying simultaneously, and sieving to prepare dry granules;

(3) adding magnesium stearate into the dry granules obtained in the step (2) and mixing to obtain the pharmaceutical composition.

On the other hand, the invention provides the application of the pharmaceutical composition in preparing antitumor drugs.

Compared with the prior art, the invention has the following beneficial effects:

(1) the invention utilizes the pharmaceutically acceptable auxiliary materials to match with the vorinostat so as to achieve the purposes of uniform and stable particle size, faster dissolution characteristic and improvement of the anti-tumor effect of the vorinostat.

(2) The invention utilizes the fluidized bed top spraying granulation method in the preparation process to ensure that the particle size is uniform and stable, particularly, one part of filler is specifically selected to be prepared into filler slurry to be mixed with adhesive solution to be used as spraying liquid, the other part of filler is mixed with other materials in a dry powder form to be used as fluidized bed materials, the particle size is better controlled through spraying of the spraying liquid, the property of the particles is improved, the stability is improved, the dissolution rate of the preparation is increased, the process is simple and controllable, and the protection performance to personnel is improved.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.

Example 1

In this example, the formulation of the pharmaceutical composition is as follows:

a fluidized bed one-step granulation process is adopted, a part of starch is added, and a part of starch is prepared into starch slurry to be mixed with hydroxypropyl methylcellulose solution to be used as spraying liquid, and the method comprises the following steps:

(1) dispersing 50g of starch with purified water to prepare starch slurry, wherein the mass percentage concentration of the starch slurry is 13%, weighing hydroxypropyl methylcellulose in a prescription amount and purified water to prepare a hydroxypropyl methylcellulose solution (the concentration is 10%), and mixing the starch slurry and the hydroxypropyl methylcellulose solution to obtain a spray solution;

(2) mixing the rest starch with vorinostat and low-substituted hypromellose, placing in a fluidized bed, preheating at 40-50 deg.C, spraying the spray solution obtained in step (1), granulating and drying simultaneously, sieving, and making into dry granule;

(3) and (3) adding magnesium stearate into the dry granules obtained in the step (2), mixing, and tabletting to obtain tablets of the pharmaceutical composition.

Wherein, during the granulation in the step (2), the working parameters of the fluidized bed are set as follows:

operating parameters	Control range of granulation stage
		Air door opening degree	100％
Fan frequency (Hz)	15～30
		Air inlet temperature (DEG C)	60～80
Air outlet temperature (DEG C)	20～40
		Temperature of the material (. degree.C.)	30～50
Atomization pressure/MPa	0.10～0.40
		Peristaltic pump speed/rpm	10～70

Example 2

composition (I)	Unit dose/mg	Percent/%)
			Vorinostat	100	31.25
Starch	199.2	62.25
			Hydroxypropyl methylcellulose	6.4	2.0
Low-substituted hydroxypropyl cellulose	12.8	4.0
			Magnesium stearate	1.6	0.5

(1) dispersing 30g of starch with purified water to prepare starch slurry, wherein the mass percentage concentration of the starch slurry is 10%, weighing hydroxypropyl methylcellulose in a prescription amount and purified water to prepare a hydroxypropyl methylcellulose solution (the concentration is 10%), and mixing the starch slurry and the hydroxypropyl methylcellulose solution to obtain a spray solution;

operating parameters	Control range of granulation stage
		Air door opening degree	100％
Fan frequency (Hz)	15～25
		Air inlet temperature (DEG C)	70～80
Air outlet temperature (DEG C)	25～35
		Temperature of the material (. degree.C.)	40～50
Atomization pressure/MPa	0.10～0.30
		Peristaltic pump speed/rpm	20～60

Example 3

composition (I)	Unit dose/mg	Percent/%)
			Vorinostat	100	31.25
Starch	196	61.2％
			Hydroxypropyl methylcellulose	9.6	3.0
Low-substituted hydroxypropyl cellulose	12.8	4.0
			Magnesium stearate	1.6	0.5

The pharmaceutical composition is prepared by adopting a fluidized bed one-step granulation process, wherein one part of starch is added as dry powder, and the other part of starch is prepared into starch slurry and mixed with hypromellose solution to be used as spray liquid, and the steps are as follows:

(1) dispersing 25g of starch with purified water to prepare starch slurry, wherein the mass percentage concentration of the starch slurry is 6%, weighing hydroxypropyl methylcellulose in a prescription amount and purified water to prepare a hydroxypropyl methylcellulose solution (the concentration is 8%), and mixing the starch slurry and the hydroxypropyl methylcellulose solution to obtain a spray solution;

Example 4

This example differs from example 1 only in that the formulation of the pharmaceutical composition is as follows:

the preparation method and the selection of the process conditions are the same as those in example 1.

Example 5

composition (I)	Unit dose/mg	Percent/%)
			Vorinostat	100	31.15
Starch	210	65.42
			Hydroxypropyl methylcellulose	3	0.93
Low-substituted hydroxypropyl cellulose	6	1.9
			Magnesium stearate	2	0.6

Comparative example 1

In this comparative example, the formulation of the pharmaceutical composition was the same as in example 1, except that this comparative example was prepared using wet granulation, the procedure was as follows:

(1) premixing: sequentially placing all starch, vorinostat and low-substituted hydroxypropyl cellulose in a mixer, stirring (150 + -20 rpm), mixing for 5min,

(2) and (3) wet granulation: weighing the hydroxypropyl methylcellulose with the prescription amount and purified water to prepare a hydroxypropyl methylcellulose solution. The binder solution was uniformly added while stirring (150. + -.20 rpm), and then granulated for 3min while shearing (1500. + -.50 rpm) while stirring (150. + -.20 rpm). Sieving with 16 mesh sieve, and grading.

(3) Boiling and drying: fluidized bed drying is carried out according to the following parameters, and the drying can be stopped when the drying weight loss of the particles is less than 3.5 percent (measured by a rapid moisture meter, 105 ℃ and 3 min).

Operating parameters	Control range of granulation stage
		Air door opening degree	100％
Fan frequency (Hz)	15～30
		Air inlet temperature (DEG C)	60～80
Air outlet temperature (DEG C)	20～40
		Temperature of the material (. degree.C.)	30～50

(4) Final mixing: magnesium stearate was added, mixing speed: 12 + -2 rpm for 4min, and tableting to obtain tablets of the pharmaceutical mixture.

Comparative example 2

In this comparative example, the formulation of the pharmaceutical composition was the same as in example 2, except that in this comparative example, when the pharmaceutical composition was prepared using a fluidized bed one-step granulation process, starch was all added as a dry powder to the fluidized bed as a material. The preparation steps are as follows:

(1) weighing hydroxypropyl methylcellulose with the prescription amount and purified water to prepare a hydroxypropyl methylcellulose solution as a spraying solution;

(2) sequentially mixing all starch, vorinostat and low-substituted hydroxypropyl cellulose for 5min, placing in a fluidized bed after mixing, preheating materials, spraying the spray liquid obtained in the step (1), granulating and drying simultaneously, and sieving to prepare dry granules;

Wherein, the operation parameter setting of the fluidized bed is the same as that of the example 2 during the granulation in the step (2).

The pharmaceutical compositions prepared in examples and comparative examples were subjected to dissolution measurement. The measurement method was a paddle method, dissolution measurement was performed with 1000ml of a 0.1mol/L hydrochloric acid solution as a dissolution medium at a rotation speed of 75rpm, and the measurement results of examples 1 to 5 and comparative examples 1 to 4 are summarized in Table 1.

TABLE 1

5min

10min

15min

30min

45min

60min

Example 1

42.3％

85.3％

102.5％

102.0％

102.8％

102.0％

Example 2

40.8％

83.6％

100.4％

101.5％

102.6％

102.1％

Example 3

38.5％

70.8％

88.4％

98.3％

100.4％

101.1％

Example 4

33.7％

74.3％

87.4％

98.6％

101.2％

100.8％

Example 5

32.9％

72.3％

88.0％

98.8％

101％

101.5％

Comparative example 1

27.6％

69.4％

86.3％

98.0％

101.4％

102.4％

Comparative example 2

35.0％

75.3％

89.5％

100.3％

101.5％

102.0％

As can be seen from the data in Table 1, the results of example 1 and comparative example 1 show that, under the condition of the same prescription, the dissolution of the vorinostat obtained by one-step granulation in a fluidized bed is superior to that obtained by the conventional wet granulation process; from the results of example 2 and comparative example 2, it can be seen that, in the same formulation, when vorinostat is subjected to fluidized bed one-step granulation, a part of starch is added in a dry state and a part of starch is added in a slurry state, and the dissolution of the composition is superior to that of the fluidized bed one-step granulation in which starch is added in a dry state. As can be seen from comparison of example 1 with examples 4 to 5, the content of the binder has a relatively large influence on the dissolution of the pharmaceutical composition preparation under otherwise identical conditions, and when the content of the binder is 2% in example 1, the dissolution results are significantly better than those of the pharmaceutical composition preparations prepared in examples 4 and 5.

The particle size distributions of the dry particles were compared between examples 1-3 and comparative examples 1-2. The determination method is a screening method, screens of 20 meshes, 40 meshes, 60 meshes, 80 meshes and 100 meshes are respectively adopted for screening, and the determination results are shown in table 2.

TABLE 2

As can be seen from the results of table 2, the dry particle size distribution was broad and the coarse particles were large when the wet granulation described in comparative example 1 was used. The dry granules prepared by one-step granulation in the fluidized bed in the embodiments 1 to 5 and the comparative example 2 have narrow particle size distribution range, are uniform and stable, and are more beneficial to feasibility and stability of a subsequent tabletting process.

The applicant states that the pharmaceutical composition, the preparation method and the application thereof are illustrated by the above examples, but the invention is not limited to the above examples, i.e. the invention is not limited to the above examples. It will be apparent to those skilled in the art that any modification of the present invention, equivalent substitutions of selected materials and additions of auxiliary components, selection of specific modes and the like, which are within the scope and disclosure of the present invention, are contemplated by the present invention.

Claims

1. The preparation method of the pharmaceutical composition is characterized in that the pharmaceutical composition comprises Voilipinotal and pharmaceutically acceptable auxiliary materials, wherein the pharmaceutically acceptable auxiliary materials comprise a filler, a binder, a disintegrant and a lubricant;

the filling agent is starch, the adhesive is hydroxypropyl methylcellulose, the disintegrating agent is low-substituted hydroxypropyl cellulose, and the lubricant is magnesium stearate;

the method adopts fluidized bed top spray granulation, and comprises the following steps:

2. The method as claimed in claim 1, wherein the filler is used in an amount of 170 parts by weight to 230 parts by weight relative to 100 parts by weight of vorinostat in the pharmaceutical composition.

3. The preparation method according to claim 1 or 2, wherein the binder is used in an amount of 3 to 10 parts by weight, relative to 100 parts by weight of vorinostat, in the pharmaceutical composition.

4. The method of claim 1 or 2, wherein the binder is present in the pharmaceutical composition in an amount of 0.5 to 5% by weight.

5. The method of claim 1 or 2, wherein the binder is present in the pharmaceutical composition in an amount of 2-3% by weight.

6. The production method according to claim 1 or 2, characterized in that the disintegrant is used in an amount of 6 to 15 parts by weight, relative to 100 parts by weight of vorinostat, in the pharmaceutical composition.

7. The preparation method according to claim 1 or 2, wherein the lubricant is used in an amount of 1.5 to 10 parts by weight relative to 100 parts by weight of vorinostat in the pharmaceutical composition.

8. The preparation method of claim 1, wherein the pharmaceutical composition comprises the following components in parts by weight:

vorinostat 100 shares

170 portions of starch and 230 portions

3-10 parts of hydroxypropyl methylcellulose

6-15 parts of low-substituted hydroxypropyl cellulose

1.5-10 parts of magnesium stearate.

9. The method of any one of claims 1 or 8, wherein the pharmaceutical composition is in the form of granules, tablets or capsules.

10. The method of claim 9, wherein the pharmaceutical composition is in the form of a tablet.

11. The method according to claim 1, wherein the step (1) of preparing a part of the filler into the filler slurry is a step of preparing the filler slurry by dispersing a part of the filler in the formulation amount with purified water.

12. The production method according to claim 11, wherein the filler slurry has a concentration of 6 to 13% by mass.

13. The method according to claim 1, wherein the binder solution in step (1) is prepared by dissolving or dispersing a binder in purified water.

14. The method of claim 13, wherein the concentration of the binder solution is 8-10%.

15. The method according to claim 1, wherein the preheating the material in the step (2) is preheating the material to 40-50 ℃.

16. The method according to claim 1, wherein the operating parameters of the fluidized bed during the granulation in step (2) are set as follows: the opening degree of the air door is 100%, the frequency of the fan is 15-30 Hz, the air inlet temperature is 60-80 ℃, the air outlet temperature is 20-40 ℃, the material temperature is 30-50 ℃, the atomization pressure is 0.10-0.40 MPa, and the rotation speed of the peristaltic pump is 10-70 rpm.

17. The method according to claim 1, wherein the sieving in step (2) is performed by a 20-24 mesh sieve.

18. The method according to claim 1, wherein the step (3) further comprises a step of preparing the mixture into corresponding dosage forms after adding and mixing the lubricant.

19. The method according to claim 1, wherein the step (3) comprises, after adding the lubricant and mixing, tabletting the mixture and coating the film to form the tablet.