A method for preparing rifampicin capsules

Abstract

The application provides a preparation method of rifampicin capsules, wherein the content of the capsules is rifampicin 135 parts and starch 45-70 parts by weight; the preparation method comprises the steps of preparation of a binder, pretreatment of an auxiliary material, premixing, wet granulation, drying, whole granulation, filling and the like; the prepared rifampicin capsules have a small weight difference, high and stable dissolution rate, and stable quality after accelerated storage for 6 months.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and relates to a preparation method of rifampicin capsules. BACKGROUND

[0002] Rifampicin, chemically named as 3-[[(4-methyl-1-piperazinyl) imino] methyl] rifamycin, has the following structural formula.

[0003]

[0004] Rifampicin is a semi-synthetic antibiotic obtained from rifamycin B, can inhibit bacterial DNA transcription to synthesize RNA, has strong antibacterial effect on tubercle bacillus, also has curative effect on gram-positive or gram-negative bacteria, viruses and the like, and is mainly used for treating tuberculosis, meningitis and staphylococcus aureus infection, and can be used externally to treat trachoma and the like. Rifampicin capsules were first marketed by Sanofi-Aventis Company in Italy in 1967, and were marketed in the United States in 1971. The rifampicin capsules marketed in China are all generic drugs, and the specifications are 150 mg and 300 mg. As a first-line drug for treating pulmonary tuberculosis, the dosage of rifampicin accounts for about one fourth of the total dosage of anti-tuberculosis drugs.

[0005] Rifampicin is almost insoluble in water and belongs to a poorly soluble drug. Direct use of rifampicin without crushing leads to slow dissolution and poor oral absorption. The ultrafine powder crushing technology is usually used to reduce the particle size. Due to the small particle size of the drug, the surface area is increased, the surface free energy is increased, and there is a spontaneous tendency of coalescence. Industrial production is difficult. Meanwhile, rifampicin has light texture and low bulk density, and is easily coagulated into blocks, so that it cannot be smoothly filled into capsules or the content weight in the capsules is greatly different.

[0006] In the preparation of rifampicin capsules, the following problems exist: (1) almost insoluble in water, unstable dissolution, and great difference in dissolution between different batches or even the same batch; (2) rifampicin has light texture and low bulk density, and is easily coagulated into blocks, so that the processing property is poor in the preparation of the drug, leading to great difference in the weight of the capsules.

[0007] Therefore, it is necessary to further study the prescription and preparation process of rifampicin capsules, and to improve the dissolution and stability of rifampicin. SUMMARY

[0008] The inventors of the present application unexpectedly found, in the research of rifampicin capsules, that by controlling the particle size of rifampicin and excipients and optimizing the preparation method, the prepared rifampicin capsules have small weight difference, high and stable dissolution, and stable quality after accelerated storage for 6 months.

[0009] Firstly, the present application provides a preparation method of rifampicin capsules, wherein the content of the capsule is rifampicin 135 parts and starch 45-70 parts by weight fraction; the preparation method comprises the following steps:

[0010] (1) Preparation of the binder

[0011] Put the starch into a bucket, add a small amount of warm water to stir into a suspension, then add boiling water, and stir into a semi-transparent paste to obtain 6%-8% starch slurry.

[0012] (2) Pretreatment of the excipient;

[0013] Put the remaining starch into an oven at 90-100°C for drying for 4-6 hours, the weight loss is not higher than 4%, and the dried starch is screened through a 120-mesh sieve for standby use.

[0014] (3) Premixing and wet granulation

[0015] Premixing: put the rifampicin and starch into a wet granulator, the stirring speed is 60-90 rpm, the cutter speed is 700-900 rpm, and the premixing time is 10-12 minutes;

[0016] Wet granulation: the stirring speed is 90-110 rpm, the cutter speed is 1000-1200 rpm, the binder is added into the granulator, the adding time is 200-220 seconds, and the granulation time after adding is 12-15 minutes;

[0017] Wet granulation: the stirring speed is 300-400 rpm, and the screen mesh is 6 mm;

[0018] (4) Drying and granulation:

[0019] Drying at 65-75°C; the dried granules are added into a granulator, and the screen mesh aperture of the granulator is 2.0 mm;

[0020] (5) Filling: fill the granules into capsules.

[0021] Preferably, the starch is cassava starch.

[0022] Preferably, the content of the capsule is rifampicin 135 parts and starch 50-60 parts by weight fraction.

[0023] More preferably, the content of the capsule is rifampicin 135 parts and starch 57 parts by weight fraction.

[0024] In step (1), the weight fraction ratio of the starch slurry to rifampicin (36-43):135; preferably 40:135.

[0025] In step (2), the particle size D 90 of the screened starch is 80-90 μm.

[0026] In step (3), the particle size D90 of rifampicin is 25-30 μm. 90

[0027] In step (4), the particle size distribution of the granules after the granulation is as follows:

[0028] Particle size Weight percent 20 mesh or more 8.7％-9.5％ 20-45 mesh 12.8％-15.3％ 45-80 mesh 15.8％-24.1％ 80-100 mesh 22.2％-32.0％ 100-120 mesh 12.2％-15.0％ 120-140 mesh 6.9％-8.6％ 140 mesh or less 4.1％-7.3％

[0029] Further, in step (5), each capsule contains 0.15-0.30 g of rifampicin, preferably 0.15 g, 0.30 g.

[0030] Further, in step (5), the weight of the content of each capsule is 0.20-0.23 g, preferably 0.213 g.

[0031] The present application controls the particle size of rifampicin and optimizes the preparation method, especially the time of adding water to the binder, the granulation time, etc. The rifampicin capsules prepared by the method have small weight difference, high and stable dissolution rate, and stable quality after accelerated storage for 6 months. DETAILED DESCRIPTION

[0032] The present application discloses a preparation method of rifampicin capsules. Those skilled in the art can refer to the content of the present application, combine the relevant principles of pharmaceutical preparations, and appropriately improve the process parameters to realize. It is particularly pointed out that all similar substitutions and changes are obvious to those skilled in the art, and they are considered to be included in the scope of the present application. The application of the present application has been described by the preferred embodiments, and the relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present application to realize and apply the present application technology.

[0033] In order to better understand the present application without limiting the scope of the present application, all numbers, percentages and other numerical values used in this application are understood to be modified by the word "about" in all cases. Each numerical parameter should be considered to be at least as accurate as the measurement tools used to determine it and as rounded off by conventional rounding methods.

[0034] The present application is further illustrated by the following examples, but the examples do not limit the present application in any way.

[0035] The particle size of rifampicin used in the examples of the present application is shown in the following table:

[0036] Component [00000D 90 ]] Rifampin 1 29.4 Rifampin 2 27.5 Rifampin 3 19.8 Rifampin 4 35.2 Rifampin 5 22.4

[0037] Weight difference:

[0038] ​Take 20 capsules, respectively, accurately weigh the weight, pour out the contents, and wipe the shell with a small brush; then accurately weigh the weight of the hard capsule shell, and calculate the average loading of each particle. The loading difference should be 10% compared with the theoretical loading.

[0039] Determination of dissolution curve

[0040] Dissolution medium: pH 4.0 buffer, water; 900 ml

[0041] Rotation speed: 75 rpm

[0042] Sampling time: 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min, 120 min

[0043] Reference preparation: Sanofi; Trade name: Rifadin; Specification: 150 mg

[0044] Example 1: Rifampicin capsules

[0045] I. Prescription composition:

[0046]

[0047] II. Preparation method:

[0048] (1) Preparation of adhesive

[0049] Put 2.6 Kg of starch into a bucket, add a small amount of warm water and stir into a suspension, then add boiling water and stir into a translucent paste, obtaining 6.5% starch paste.

[0050] (2) Pretreatment of adjuvants;

[0051] Put the remaining starch in a 90-100°C oven and dry for 5.5 hours, with a weight loss of 1.2%, pass through a 120 mesh sieve, and the particle size of the starch is 80-90 μm, ready for use. 90

[0052] (3) Premixing, wet granulation

[0053] Premixing: add rifampicin and starch into the wet granulator, stirring speed 80 rpm, cutter speed 900 rpm, premix for 10 minutes;

[0054] Wet granulation: stirring speed 100 rpm, cutter speed 1200 rpm, add adhesive into the granulator, addition time 210 seconds, granulation time after addition 14 minutes;

[0055] Wet granulation: stirring speed 400 rpm, screen 6 mm;

[0056] ​(4) Drying, sizing:

[0057] 65-75°C drying; the dried granules were added to a sizer, the sizer screen mesh size was 2.0 mm; the particle size distribution was as follows:

[0058] Particle size Weight percent 20 mesh or more 8.7％ 20-45 mesh 13.4％ 45-80 mesh 22.0％ 80-100 mesh 28.7％ 100-120 mesh 13.5％ 120-140 mesh 8.3％ 140 mesh or less 5.4％

[0059] (5) Filling: the granules were filled into capsules, each capsule contained rifampicin 150 mg.

[0060] III. Test results:

[0061] 1. The weight difference of the prepared rifampicin capsules was determined, and the results are shown in Table 1.

[0062] Table 1: Weight difference of the rifampicin capsules prepared in Example 1

[0063] Sample Weight difference Conclusion Example 1 -4.42％～4.20％ Regulation

[0064] 2. The dissolution curve of the prepared rifampicin capsules in pH 4.0 water was determined, and the similarity factor was calculated (if the similarity factor is not less than 50, it indicates that the in vitro dissolution is similar to the reference preparation, and the reference preparation can be replaced), and the results are shown in Tables 2-3.

[0065] Table 2: Dissolution curve of the rifampicin capsules prepared in Example 1 in pH 4.0 buffer

[0066]

[0067] Table 3: Dissolution curve of the rifampicin capsules prepared in Example 1 in aqueous solution

[0068]

[0069] Example 2: Rifampicin capsules

[0070] I. Prescription composition:

[0071]

[0072] II. Preparation method: same as Example 1.

[0073] III. Test results:

[0074] 1. The weight difference of the prepared rifampicin capsules was determined, and the results are shown in Table 4.

[0075] Table 4: Weight difference of the rifampicin capsules prepared in Example 2

[0076] Sample Weight difference Conclusion Example 2 -5.68％～7.62％ Regulation

[0077] 2. The prepared rifampicin capsules were subjected to dissolution curve determination in water at pH 4.0, and the results are shown in Tables 5-6.

[0078] Table 5: Dissolution curve of the rifampicin capsules prepared in Example 2 in pH 4.0 buffer

[0079]

[0080] Table 6: Dissolution curve of the rifampicin capsules prepared in Example 2 in aqueous solution

[0081]

[0082]

[0083] From Examples 1-2, it can be seen that the present application only uses rifampicin and starch of specific particle size, the process is simple, and the prepared rifampicin capsules not only have a required weight difference, but also have stable dissolution (RSD of dissolution results at the first time point of 10 min is less than 20%, and RSD of dissolution results from the second time point of 15 min to 120 min is less than 10%), are equivalent to the reference preparation (the similarity factor is not less than 50), and can effectively replace the reference preparation product.

[0084] Comparative Examples 1-3: Effect of rifampicin particle size

[0085] I. Prescription composition: The rifampicin used is shown in the following table, and the rest is the same as in Example 1.

[0086] Comparative Example Rifampin Comparative Example 1 Rifampin 3 Comparative Example 2 Rifampin 4 Comparative Example 3 Rifampin 5

[0087] II. Preparation method: The same as in Example 1.

[0088] III. Test results:

[0089] 1. The prepared rifampicin capsules were subjected to weight difference determination, and the results are shown in Table 7.

[0090] Table 7: Weight difference of the rifampicin capsules prepared in Comparative Examples 1-3

[0091] Sample Weight difference Conclusion Comparative Example 1 -4.64％～4.10％ Regulation Comparative Example 2 -4.62％～5.71％ Regulation Comparative Example 3 -3.88％～5.82％ Regulation

[0092] 2. The prepared rifampicin capsules were subjected to dissolution curve determination in water at pH 4.0, and the results are shown in Tables 8-9.

[0093] Table 8: Dissolution curve of the rifampicin capsules prepared in Comparative Examples 1-3 in pH 4.0 buffer

[0094]

[0095] Table 9: Dissolution curves of rifampicin capsules prepared in aqueous solution for Comparative Examples 1-3

[0096]

[0097] Comparative analysis of Examples 1-2 and Comparative Examples 1-3 revealed that the particle size of rifampicin affects the dissolution of rifampicin capsules; only rifampicin within a specific particle size range (D...) can dissolve. 90 Only rifampicin capsules prepared with a particle size of 25-30 μm can be equivalent to the reference preparation (similarity factor not less than 50) and have stable dissolution (RSD of dissolution results at the first time point of 10 min is less than 20%; RSD of dissolution results from the second time point of 15 min to 120 min is less than 10%).

[0098] When rifampin with other particle sizes is used, as shown in Comparative Examples 1-3, the prepared rifampin capsules dissolve too quickly (as in Comparative Example 1) or too slowly (as in Comparative Example 2), or are unstable after accelerated storage (as in Comparative Example 3 in Example 3, which showed unstable dissolution after 6 months of accelerated storage), are not equivalent to the reference preparation (similar factor less than 50), and have unstable dissolution (RSD of dissolution results at the first time point of 10 min is higher than 20%; RSD of dissolution results at the second time point of 20 min is higher than 10%).

[0099] Comparative Examples 4-7: Effect of Starch Particle Size in Excipients

[0100] I. Prescription composition: Same as in Example 1.

[0101] II. Preparation method: Adjust the parameters in step (2) to control the starch particle size D. 90 As shown in the table below, the rest is the same as in Example 1.

[0102] Comparative Example Step (1) Comparative Example 4 The particle size D 90 43.2 μm Comparative Example 5 The particle size D of the starch 90 was 69.5 μm Comparative Example 6 Particle size D of the starch 90 was 126.4 μm Comparative Example 7 Particle size D of the starch 90 was 207.5 μm

[0103] III. Test Results:

[0104] 1. The weight difference of the prepared rifampicin capsules was measured, and the results are shown in Table 10.

[0105] Table 10: Weight variation of rifampicin capsules prepared in Comparative Examples 4-7

[0106] Sample Weight difference Conclusion Comparative Example 4 -11.51％～5.06％ Not Regulation Comparative Example 5 -6.52％～7.61％ Regulation Comparative Example 6 -3.56％～3.30％ Regulation Comparative Example 7 -7.73％～12.55％ Not Regulation

[0107] 2. The dissolution curves of the prepared rifampicin capsules were determined in water at pH 4.0, and the results are shown in Table 11.

[0108] Table 11: Dissolution curves of rifampicin capsules prepared in Comparative Examples 6-7 in pH 4.0 buffer solution.

[0109]

[0110] From Table 11, it can be seen that the rifampicin capsules prepared in Comparative Examples 6-7 were equivalent to the reference formulation (the similarity factor was not less than 50), but the in-batch dissolution was unstable (the RSD of the dissolution results at the first time point of 10 min was higher than 20%; the RSD of the dissolution results at the second time point of 15 min was higher than 10%), which did not meet the requirements, and the dissolution curves in water were not determined.

[0111] By comparing and analyzing Example 1 and Comparative Examples 4-7, it was found that the particle size of the starch affected the weight difference and dissolution behavior of the rifampicin capsules. Only the rifampicin capsules prepared from the starch with a specific particle size range (the residual starch was dried in an oven at 100°C for 4-6 hours, the weight loss on drying was not higher than 4%, the starch was sieved through a 120-mesh sieve, and the particle size D 90 was 80-90 μm) could be equivalent to the reference formulation (the similarity factor was not less than 50) and stable in dissolution (the RSD of the dissolution results at the first time point of 10 min was lower than 20%; the RSD of the dissolution results from the second time point of 15 min to 120 min was lower than 10%).

[0112] When other particle sizes of starch were used, as shown in Comparative Examples 4-7, the rifampicin capsules prepared therefrom had a large weight difference (such as Comparative Example 4 and Comparative Example 7) or were unstable in dissolution (such as Comparative Example 5 and Comparative Example 6; the RSD of the dissolution results at the first time point of 10 min was higher than 20%; the RSD of the dissolution results at the second time point of 20 min was higher than 10%). The product quality was greatly different.

[0113] Comparative Examples 8-9: Effect of Binder Concentration

[0114] I. Formulation Composition: Same as Example 1.

[0115] II. Preparation Method: Step (1) is shown in the following table, and the remaining steps are the same as those in Example 1. III.

[0117]

[0118] III. Test Results:

[0119] 1. The weight difference of the rifampicin capsules prepared was determined, and the results are shown in Table 12.

[0120] Table 12: Weight difference of the rifampicin capsules prepared in Comparative Examples 8-9

[0121] Sample Weight difference Conclusion Comparative Example 8 -8.05％～5.01％ Regulation Comparative Example 9 -8.20％～7.02％ Regulation

[0122] 2. The dissolution curves of the rifampicin capsules prepared in water at pH 4.0 were determined, and the results are shown in Tables 13-14.

[0123] Table 13: Dissolution profiles of the rifampicin capsules prepared in Comparative Examples 8-9 in pH 4.0 buffer

[0124]

[0125] Table 14: Dissolution profiles of the rifampicin capsules prepared in Comparative Examples 8-9 in aqueous solution

[0126]

[0127] Comparative analysis of Example 1 and Comparative Examples 8-9 in combination with Example 3 found that the concentration of the binder affected the dissolution stability of the rifampicin capsules when wet granulation was used. Only the rifampicin capsules prepared using a specific concentration of starch paste (6%-8%) as the binder were equivalent (similar factor no less than 50) to the reference preparation and were stable in dissolution (RSD of the dissolution results at the first time point 10 min was less than 20%; RSD of the dissolution results from the second time point 15 min to 120 min was less than 10%).

[0128] When other concentrations of starch paste were used as the binder (such as Comparative Examples 8-9), the dissolution of the rifampicin capsules prepared was unstable after accelerated storage for 6 months (RSD of the dissolution results at the first time point 10 min was more than 20%; RSD of the dissolution results at the second time 20 min was more than 10%), as shown in Tables 18 and 19 in Example 3, indicating poor stability after storage.

[0129] I. Prescription composition: same as Example 1.

[0130] II. Preparation method: adjust the stirring speed, cutter speed, granulation time in step (3), and the screen mesh aperture of the finishing machine in step (4), and the particle size distribution after finishing in step (4) is shown in the following table. Steps (1), (2), and (5) are the same as Example 1.

[0131] Particle size Comparative Example 10 Comparative Example 11 Comparative Example 12 Comparative Example 13 20 mesh or more 5.0％ 7.7％ 10.7％ 15.0％ 20-45 mesh 9.7％ 10.0％ 12.3％ 16.8％ 45-80 mesh 14.9％ 15.9％ 14.5％ 24.0％ 80-100 mesh 39.2％ 36.0％ 37.2％ 24.9％ 100-120 mesh 17.7％ 15.1％ 12.9％ 14.5％ 120-140 mesh 7.4％ 9.0％ 8.3％ 3.0％ 140 mesh or less 6.1％ 6.3％ 4.1％ 1.8％

[0132] III. Test results:

[0133] 1. The weight difference of the rifampicin capsules prepared was tested, and the results are shown in Table 15.

[0134] Table 15: Weight difference of the rifampicin capsules prepared in Comparative Examples 10-13

[0135] Sample Weight difference Conclusion Comparative Example 10 -13.40％～11.61％ Not Regulation Comparative Example 11 -9.37％～6.33％ Regulation Comparative Example 12 -7.44％～8.77％ Regulation Comparative Example 13 -9.59％～12.42％ Not Regulation

[0136] 2. The dissolution curves of the rifampicin capsules prepared in Comparative Examples 11 and 12 were determined in pH 4.0 buffer solution, and the results are shown in Tables 16-17.

[0137] Table 16: Dissolution curves of the rifampicin capsules prepared in Comparative Examples 11-12 in pH 4.0 buffer solution

[0138]

[0139] Table 18: Dissolution curves of the rifampicin capsules prepared in Comparative Examples 11-12 in water

[0140]

[0141] Since the dissolution of the rifampicin capsules in Comparative Example 12 was unstable in pH 4.0 buffer solution, the dissolution in water was not determined.

[0142] Comparative analysis of Example 1 and Comparative Examples 10-13 showed that the particle size distribution after sizing affected the weight difference and dissolution behavior of the rifampicin capsules. When the range of the particle size distribution was different, the rifampicin capsules prepared had a large weight difference (as shown in Comparative Example 10 and Comparative Example 13) or were unstable in dissolution (as shown in Comparative Example 11 and Comparative Example 12, the RSD of the dissolution results at the first time point of 10 min was higher than 20%, and the RSD of the dissolution results at the second time of 20 min was higher than 10%), and the product quality difference was large.

[0143] Comparative Examples 14-15: Effect of starch

[0144] I. Prescription composition: The starches are shown in the following table, and the rest are the same as in Example 1.

[0145] Comparative Example Starch Comparative Example 14 Soluble starch Comparative Example 15 Potato starch

[0146] II. Preparation method: same as Example 1

[0147] III. Test results:

[0148] 1. The weight difference of the rifampicin capsules prepared was determined, and the results are shown in Table 19.

[0149] Table 19: Weight difference of the rifampicin capsules prepared in Comparative Examples 14-15

[0150] Sample Weight difference Conclusion Comparative Example 14 -7.42％～6.98％ Regulation Comparative Example 15 -8.22％～6.47％ Regulation

[0151] 2. The dissolution curves of the rifampicin capsules prepared were determined in pH 4.0 buffer solution, and the results are shown in Table 20.

[0152] Table 20: Dissolution curves of the rifampicin capsules prepared in Comparative Examples 14-15 in pH 4.0 buffer solution

[0153]

[0154] The rifampicin capsules of Comparative Examples 14-15 are not stable in dissolution in pH 4.0 buffer solution, so the dissolution in water is not determined.

[0155] Comparative analysis of Example 1 and Comparative Examples 14-15 shows that the composition of starch affects the dissolution behavior of the rifampicin capsules. When other types of starch are used, such as commonly used soluble starch, potato starch, the rifampicin capsules prepared are not stable in dissolution (as shown in Comparative Example 14, Comparative Example 15, the RSD of the dissolution results at the first time point 10 min is higher than 20%; the RSD of the dissolution results at the second time 20 min is higher than 10%), and the product quality difference is large.

[0156] Example 3: Stability test

[0157] The rifampicin capsules prepared in Example 1-Example 2, Comparative Example 1, Comparative Example 3, Comparative Example 8-9 are placed under the condition of temperature 40℃±2℃; relative humidity 75%±5% (accelerated) for 6 months, and sampled at the end of the 6th month. The dissolution curves in pH 4.0, water are determined, and the results are shown in Tables 21-22.

[0158]

[0159]

[0160] The rifampicin capsules prepared in Example 1-Example 2 of the present application are placed under accelerated conditions for 6 months, and the dissolution behavior does not change significantly, which shows that the rifampicin capsules prepared by the present application are stable in dissolution.

[0161] The rifampicin capsule compositions prepared in Comparative Example 1, Comparative Example 8-9 are not stable in batch dissolution after being placed under accelerated conditions for 6 months.

Claims

1. A method for preparing a rifampicin capsule, the capsule content being rifampicin 135 parts and starch 45-70 parts by weight; the method comprising the following steps: (1) Preparation of the binder Put the starch into a bucket, add a small amount of warm water to stir into a suspension, then add boiling water, stir into a translucent paste, and obtain 6%-8% starch slurry; (2) Pretreatment of the excipient; The remaining starch is dried in an oven at 90-100°C for 4-6 hours, with a loss of weight of not more than 4%, and sieved through a 120 mesh sieve. The particle size D 90 of the sieved starch is 80-90 μm; ready for use. (3) Premixing and wet granulation Premixing: rifampicin, starch are added into the wet granulator, the stirring speed is 60-90 rpm, the cutter speed is 700-900 rpm, and the premixing time is 10-12 minutes; wherein the particle size D 90 of rifampicin is 25-30 μm; Wet granulation: the stirring speed is 90-110 rpm, the cutter speed is 1000-1200 rpm, the binder is added to the granulation, the addition time is 200-220 seconds, and the granulation time after addition is 12-15 minutes; Wet granulation: the stirring speed is 300-400 rpm, and the screen mesh is 6 mm; (4) Drying and granulation: Drying at 65-75℃; the dried granules are added to the granulator, the granulator screen mesh size is 2.0 mm; the particle size distribution of the granules after granulation is: the weight percentage of more than 20 mesh is 8.7%-9.5%, the weight percentage of 20-45 mesh is 12.8%-15.3%, the weight percentage of 45-80 mesh is 15.8%-24.1%, the weight percentage of 80-100 mesh is 22.2%-32.0%, the weight percentage of 100-120 mesh is 12.2%-15.0%, the weight percentage of 120-140 mesh is 6.9%-8.6%, and the weight percentage of less than 140 mesh is 4.1%-7.3%; (5) Filling: fill the granules into capsules; The starch is cassava starch. In step (1), the weight ratio of the starch slurry to rifampicin is 36-43:

135.

2. The production method according to claim 1, wherein The capsule content is rifampicin 135 parts and starch 50-60 parts by weight.

3. The production method according to claim 1, wherein The capsule content is rifampicin 135 parts and starch 57 parts by weight.

4. The production method according to claim 1, wherein In step (1), the weight ratio of the starch slurry to rifampicin is 40:

135.

5. The production method according to claim 1, wherein In step (5), each capsule contains 0.15-0.30 g of rifampicin.

6. The production method according to claim 5, wherein In step (5), each capsule contains 0.15 g of rifampicin.

7. The production method according to claim 5, wherein In step (5), each capsule contains 0.30 g of rifampicin.

8. The production method according to claim 1, wherein In step (5), the weight of the content of each capsule is 0.20-0.23 g.

9. The production method according to claim 8, wherein In step (5), the weight of the content of each capsule is 0.213 g.

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