Baloxvir dipivoxil pharmaceutical composition, baloxvir dipivoxil tablet and preparation method

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a baloxvir dipivoxil pharmaceutical composition, a baloxvir dipivoxil tablet and a preparation method. According to the invention, the baloxvir dipivoxil is fully mixed with the spray-dried lactose and the colloidal silicon dioxide, so that the agglomeration behavior of the API is reduced, the dispersion surface area of the API is increased, and the dissolution rate of the product is improved; according to the preparation method, the prepared baloxvir dipivoxil tablet has excellent dissolution performance and is in a stable state all the time during an accelerated test, the problem that the dissolution rate of the baloxvir dipivoxil tablet is remarkably reduced in the accelerated test process is solved, the stability of the product is remarkably improved, the clinical effect of the product is better played, and the preparation method is suitable for industrial production. Therefore, the replacement of an original product can be realized; and the preparation is simple in production process, easy to realize large-scale industrial production, and relatively high in popularization and application value.

Description

Technical Field

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

[0002] Baloxavir Marboxil, whose chemical name is (((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl carbonate, has the following structural formula.

[0003]

[0004] Baloxavir is an antiviral drug and the first influenza virus cap-dependent endonuclease inhibitor. It can selectively inhibit cap-dependent endonucleases, block polymerase function and influenza virus mRNA replication. Compared with known influenza virus drugs and neuraminidase inhibitors, baloxavir targets the earlier stages of the viral replication cycle and has significant advantages such as rapid effects after a single oral administration. Baloxavir has good antiviral activity against influenza A and B viruses, and has a highly effective single oral administration inhibitory effect on H5N1 and H7N9 avian influenza viruses.

[0005] Baloxavir disodium has poor solubility and is difficult to dissolve in media with a pH range of 1.2 to 6.8. Moreover, during stability tests, especially accelerated tests (40°C + 75% RH), the dissolution rate significantly decreases, resulting in a decrease in the bioavailability of the product. Therefore, it is necessary to provide a preparation process that can effectively improve the quality of baloxavir disodium tablets and improve their availability in the gastrointestinal tract. Summary of the invention

[0006] Aiming at the problems that the existing baloxavir dipeptide tablets are difficult to dissolve in media with a pH of 1.2 to 6.8, and the dissolution rate is significantly reduced after an accelerated test, resulting in reduced bioavailability of the product, the present invention provides a baloxavir dipeptide pharmaceutical composition, tablets and a preparation method.

[0007] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0008] A baloxavir dipectin pharmaceutical composition comprises baloxavir dipectin, spray-dried lactose, a filler, colloidal silicon dioxide, carboxymethyl cellulose, hydroxypropyl cellulose and a lubricant.

[0009] After long-term continuous experiments and studies, the inventors found that the main reason for the low dissolution of baloxavir disoproxil tablets is that the API agglomeration phenomenon is obvious after crushing, and there is still agglomeration problem after mixing with other materials, which causes its dispersion surface area in the material to decrease, resulting in low dissolution. During the stability test, especially during the accelerated test, the disintegration of baloxavir disoproxil tablets slows down, and the API agglomerates, so that the dissolution is significantly reduced with the extension of storage time. After long-term experiments, the present invention has found that the products prepared by using conventional fillers, such as ground lactose or sifted lactose, still have obvious API agglomeration phenomenon under microscope. In view of the problem of slow disintegration of the product during the stability test, the inventors found that the use of conventional disintegrants and binders can meet the requirements of dissolution in the initial stage, but in the accelerated test process, especially after 3 months of acceleration, the problem of significantly increased disintegration time appears.

[0010] Through creative thinking, the inventors discovered that using spray-dried lactose as a filler and colloidal silicon dioxide as a glidant can significantly improve the problem of API agglomeration and effectively increase the dissolution rate of the product; at the same time, using carboxymethyl cellulose as a disintegrant and hydroxypropyl cellulose as a binder can effectively ensure the disintegration time of the product during the stability test, solving the problem of significantly reduced solubility of the product during the stability test.

[0011] Furthermore, the filler is microcrystalline cellulose.

[0012] Furthermore, the lubricant includes sodium stearyl fumarate.

[0013] Furthermore, the particle size D90 of the baloxavir dipyroxil is 0.2 μm to 13 μm.

[0014] Preferably, the particle size D90 of the baloxavir dipyroxil is 2 μm to 6 μm.

[0015] Furthermore, the average particle size of the spray-dried lactose is 50 μm to 150 μm.

[0016] Preferably, the average particle size of the spray-dried lactose is 80 μm to 140 μm.

[0017] The particle size of the spray-dried lactose matches the particle size of baloxavir disoproxil, which can improve the dispersion and uniformity of material mixing during the preparation process, and plays a very important role in ensuring the uniformity and release characteristics of the baloxavir disoproxil content in the preparation.

[0018] Furthermore, the spray-dried lactose is 50% to 60% of the total mass of the baloxavir dipyramide pharmaceutical composition.

[0019] Furthermore, the colloidal silicon dioxide accounts for 0.5% to 2% of the total mass of the baloxavir dipyramide pharmaceutical composition.

[0020] The preferred addition amount of spray-dried lactose and colloidal silicon dioxide can significantly improve the problem of API agglomeration, increase the dispersion surface area of ​​API, and thus improve the dissolution rate of the product.

[0021] Furthermore, the carboxymethyl cellulose accounts for 5% to 15% of the total mass of the baloxavir dipyramide pharmaceutical composition.

[0022] Furthermore, the hydroxypropylcellulose accounts for 3% to 7% of the total mass of the baloxavir dipyramide pharmaceutical composition.

[0023] The preferred amount of carboxymethyl cellulose and hydroxypropyl cellulose added can ensure that during the stability test, the disintegration time of the product will not be significantly increased compared to the initial stage, thereby significantly improving the stability of the product during storage.

[0024] Furthermore, the filler is 5% to 15% of the total mass of the baloxavir dipyramide pharmaceutical composition.

[0025] The preferred amount of filler added can improve the compressibility of the material, reduce the dosage deviation of the baloxavir dipyramide raw material in the preparation, and promote dissolution and disintegration.

[0026] Furthermore, the lubricant is 0.5% to 2% of the total mass of the baloxavir dipyramide pharmaceutical composition.

[0027] The preferred amount of lubricant added can improve the compressibility during tablet production, and in addition, can also improve the hardness and smoothness of the prepared tablets.

[0028] Furthermore, the baloxavir dipivoxil pharmaceutical composition also includes a gastric soluble coating premix.

[0029] The present invention also provides a baloxavir dipectomyclic acid tablet, which is prepared from any one of the above-mentioned baloxavir dipectomyclic acid pharmaceutical compositions.

[0030] As a specific embodiment of the present invention, the baloxavir disoproxil tablet contains 20.0 mg of baloxavir disoproxil (single dose).

[0031] As a specific embodiment of the present invention, each baloxavir disoproxil tablet comprises: baloxavir disoproxil 20.0 mg, spray-dried lactose 61 mg to 73.2 mg, hydroxypropyl cellulose 3.66 mg to 8.54 mg, carboxymethyl cellulose 6.1 mg to 18.3 mg, colloidal silicon dioxide 0.61 mg to 2.44 mg, microcrystalline cellulose 6.1 mg to 18.3 mg, and sodium stearyl fumarate 0.61 mg to 2.44 mg.

[0032] The present invention also provides a method for preparing the baloxavir dipeptide tablets, comprising the following steps:

[0033] S1, mixing baloxavir disoproxil, spray-dried lactose and colloidal silicon dioxide uniformly to obtain a premixed material;

[0034] S2, adding carboxymethyl cellulose and hydroxypropyl cellulose to the premixed material, mixing evenly, and wet granulating to obtain granules;

[0035] S3, uniformly mixing the granules with the filler and the lubricant, and tableting to obtain baloxavir dipivoxil tablets.

[0036] The preparation method of the baloxavir fumarate tablet provided by the present invention comprises the following steps: baloxavir fumarate is fully mixed with spray-dried lactose and colloidal silicon dioxide, thereby reducing the agglomeration of baloxavir fumarate and increasing the dispersion surface area of ​​baloxavir fumarate, which is beneficial to improving the dissolution rate of the product. Meanwhile, a combination of a disintegrant carboxymethyl cellulose and a binder hydroxypropyl cellulose is adopted, thereby effectively improving the dissolution characteristics of the product, and the dissolution rate is kept in a stable state during the stability period, thereby solving the problem that the dissolution rate of baloxavir fumarate is significantly decreased during an accelerated test, and thus significantly improving the stability of baloxavir fumarate during storage, thereby improving the bioavailability of the baloxavir fumarate tablet in the gastrointestinal tract, and realizing a good replacement for the original product.

[0037] Furthermore, after tableting, the process further comprises: coating the compressed plain tablets to obtain a baloxavir dipyramide coating agent.

[0038] Furthermore, the coating weight gain is controlled to be 2% to 5%. Specifically, a high-efficiency coating agent is used for coating.

[0039] Specifically, in S2, carboxymethyl cellulose and hydroxypropyl cellulose are added to the premixed material and mixed evenly, and purified water in an amount of 20% to 30% by mass of the mixed material is added to perform wet granulation to obtain granules.

[0040] Furthermore, in S3, a high-speed tablet press is used for tableting, and the tablet weight difference is controlled within ±5%, and the hardness is controlled within 80N to 150N.

[0041] The present invention fully mixes baloxavir estrogen with spray-dried lactose and colloidal silicon dioxide in advance, and then mixes with a disintegrant carboxymethyl cellulose and a binder hydroxypropyl cellulose for wet granulation to prepare baloxavir estrogen tablets. The prepared baloxavir estrogen tablets have a faster disintegration speed and dissolution rate, and compared with a reference preparation, the stability is significantly improved during storage, which helps to increase the absorption and bioavailability of the product, can achieve a good replacement for the original research product, and the preparation process is simple, the repeatability is good, and it is easy to achieve industrial mass production, and has a high value of promotion and application. DETAILED DESCRIPTION

[0042] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0043] In order to better illustrate the present invention, further examples are given below.

[0044] Example 1

[0045] This embodiment provides a baloxavir dipeptide tablet, and the prescription dosage (single tablet dosage) is shown in the following table:

[0046]

[0047]

[0048] The preparation method of the above-mentioned baloxavir dipeptide tablets is as follows:

[0049] Step 1, adding baloxavir dipyramide, spray-dried lactose and colloidal silicon dioxide into a wet granulator, starting the stirring speed at 200 rpm and the shear speed at 800 rpm, mixing for 8 minutes to obtain a premixed material;

[0050] Step 2: Add hydroxypropyl cellulose and carboxymethyl cellulose NS-300 to the above premixed materials, start stirring at a speed of 200 rpm and a shear speed of 800 rpm, mix for 5 minutes, add purified water, perform wet granulation, start stirring at a speed of 200 rpm and a shear speed of 2000 rpm, granulate for 3 minutes, and obtain granules;

[0051] Step 3, add the above granules and microcrystalline cellulose into a hopper mixer, mix at a speed of 10 rpm for 20 minutes, then add sodium stearyl fumarate, continue mixing for 8 minutes, and use a high-speed tablet press to tablet to obtain a plain tablet, the tablet weight difference is required to be ±5%, and the hardness is 80-150N;

[0052] Step 4: Use a high-efficiency coating agent to coat the above-mentioned plain tablets, and the coating weight gain is 4%.

[0053] Example 2

[0054] This embodiment provides a baloxavir dipeptide tablet, and the prescription dosage (single tablet dosage) is shown in the following table:

[0055]

[0056]

[0057] The preparation method of the above-mentioned baloxavir dipeptide tablets is as follows:

[0058] Step 1, adding baloxavir dipyramide, spray-dried lactose and colloidal silicon dioxide into a wet granulator, starting the stirring speed at 200 rpm and the shear speed at 800 rpm, mixing for 8 minutes to obtain a premixed material;

[0059] Step 2: Add hydroxypropyl cellulose and carboxymethyl cellulose NS-300 to the above premixed materials, start stirring at a speed of 200 rpm and a shear speed of 800 rpm, mix for 5 minutes, add purified water, perform wet granulation, start stirring at a speed of 200 rpm and a shear speed of 2000 rpm, granulate for 3 minutes, and obtain granules;

[0060] Step 3, add the above granules and microcrystalline cellulose into a hopper mixer, mix at a speed of 10 rpm for 20 minutes, then add sodium stearyl fumarate, continue mixing for 8 minutes, and use a high-speed tablet press to tablet to obtain a plain tablet, the tablet weight difference is required to be ±5%, and the hardness is 80-150N;

[0061] Step 4: Use a high-efficiency coating agent to coat the above-mentioned plain tablets, and the coating weight gain is 4%.

[0062] Example 3

[0063] This embodiment provides a baloxavir dipeptide tablet, and the prescription dosage (single tablet dosage) is shown in the following table:

[0064]

[0065] The preparation method of the above-mentioned baloxavir dipeptide tablets is as follows:

[0066] Step 1, adding baloxavir dipyramide, spray-dried lactose and colloidal silicon dioxide into a wet granulator, starting the stirring speed at 200 rpm and the shear speed at 800 rpm, mixing for 8 minutes to obtain a premixed material;

[0067] Step 2: Add hydroxypropyl cellulose and carboxymethyl cellulose NS-300 to the above premixed materials, start stirring at a speed of 200 rpm and a shear speed of 800 rpm, mix for 5 minutes, add purified water, perform wet granulation, start stirring at a speed of 200 rpm and a shear speed of 2000 rpm, granulate for 3 minutes, and obtain granules;

[0068] Step 3, add the above granules and microcrystalline cellulose into a hopper mixer, mix at a speed of 10 rpm for 20 minutes, then add sodium stearyl fumarate, continue mixing for 8 minutes, and use a high-speed tablet press to tablet to obtain a plain tablet, the tablet weight difference is required to be ±5%, and the hardness is 80-150N;

[0069] Step 4: Use a high-efficiency coating agent to coat the above-mentioned plain tablets, and the coating weight gain is 4%.

[0070] Comparative Example 1

[0071] This comparative example provides a baloxavir dipeptide tablet, which is different from Example 1 only in that the spray-dried lactose in Example 1 is replaced with ground lactose of equal mass. The specific prescription dosage (single tablet dosage) is shown in the following table:

[0072]

[0073] The preparation method of the above-mentioned baloxavir dipeptide tablets is as follows:

[0074] Step 1, adding baloxavir dipyramide, ground lactose and colloidal silicon dioxide into a wet granulator, starting the stirring speed at 200 rpm, the shear speed at 800 rpm, and mixing for 8 minutes to obtain a premixed material;

[0075] Step 2: Add hydroxypropyl cellulose and carboxymethyl cellulose NS-300 to the above premixed materials, start stirring at a speed of 200 rpm and a shear speed of 800 rpm, mix for 5 minutes, add purified water, perform wet granulation, start stirring at a speed of 200 rpm and a shear speed of 2000 rpm, granulate for 3 minutes, and obtain granules;

[0076] Step 3, add the above granules and microcrystalline cellulose into a hopper mixer, mix at a speed of 10 rpm for 20 minutes, then add sodium stearyl fumarate, continue mixing for 8 minutes, and use a high-speed tablet press to tablet to obtain a plain tablet, the tablet weight difference is required to be ±5%, and the hardness is 80-150N;

[0077] Step 4: Use a high-efficiency coating agent to coat the above-mentioned plain tablets, and the coating weight gain is 4%.

[0078] Comparative Example 2

[0079] This comparative example provides a baloxavir dipeptide tablet, which is different from Example 1 only in that the carboxymethylcellulose NS-300 in Example 1 is replaced with an equal amount of cross-linked sodium carboxymethylcellulose. The specific prescription dosage (single tablet dosage) is shown in the following table:

[0080]

[0081] The preparation method of the above-mentioned baloxavir dipeptide tablets is as follows:

[0082] Step 1, adding baloxavir dipyramide, spray-dried lactose and colloidal silicon dioxide into a wet granulator, starting the stirring speed at 200 rpm and the shear speed at 800 rpm, mixing for 8 minutes to obtain a premixed material;

[0083] Step 2: Add hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose to the premixed material, start stirring at a speed of 200 rpm and a shear speed of 800 rpm, mix for 5 minutes, add purified water, perform wet granulation, start stirring at a speed of 200 rpm and a shear speed of 2000 rpm, granulate for 3 minutes, and obtain granules;

[0084] Step 3, add the above granules and microcrystalline cellulose into a hopper mixer, mix at a speed of 10 rpm for 20 minutes, then add sodium stearyl fumarate, continue mixing for 8 minutes, and use a high-speed tablet press to tablet to obtain a plain tablet, the tablet weight difference is required to be ±5%, and the hardness is 80-150N;

[0085] Step 4: Use a high-efficiency coating agent to coat the above-mentioned plain tablets, and the coating weight gain is 4%.

[0086] Comparative Example 3

[0087] This embodiment provides a baloxavir dipeptide tablet, which is different from Example 1 only in that the spray-dried lactose in Example 1 is replaced with an equal amount of ground lactose, and the hydroxypropyl cellulose is replaced with an equal amount of povidone, and the carboxymethyl cellulose NS-300 is replaced with an equal amount of cross-linked sodium carboxymethyl cellulose. The prescription dosage (single tablet dosage) is shown in the following table:

[0088]

[0089]

[0090] The preparation method of the above-mentioned baloxavir dipeptide tablets is as follows:

[0091] Step 1, adding baloxavir dipyramide, ground lactose and colloidal silicon dioxide into a wet granulator, starting the stirring speed at 200 rpm, the shear speed at 800 rpm, and mixing for 8 minutes to obtain a premixed material;

[0092] Step 2: Add povidone and cross-linked sodium carboxymethyl cellulose to the premixed material, start stirring at a speed of 200 rpm and a shear speed of 800 rpm, mix for 5 minutes, add purified water, perform wet granulation, start stirring at a speed of 200 rpm and a shear speed of 2000 rpm, granulate for 3 minutes, and obtain granules;

[0093] Step 3, add the above granules and microcrystalline cellulose into a hopper mixer, mix at a speed of 10 rpm for 20 minutes, then add sodium stearyl fumarate, continue mixing for 8 minutes, and use a high-speed tablet press to tablet to obtain a plain tablet, the tablet weight difference is required to be ±5%, and the hardness is 80-150N;

[0094] Step 4: Use a high-efficiency coating agent to coat the above-mentioned plain tablets, and the coating weight gain is 4%.

[0095] Quality Research

[0096] 1. Dissolution curve

[0097] The baloxavir disoproxil tablets prepared in Examples 1 to 3 and Comparative Examples 1 to 3 were compared with a commercially available original drug (baloxavir disoproxil tablets, trade name: Batch No.: 0065) was placed under accelerated conditions (40°C + 75% RH) for 3 months, and samples were taken for dissolution testing.

[0098] Dissolution test method: According to the dissolution test method (Appendix XC Method 2 of Part II of the 2020 edition of the Chinese Pharmacopoeia), 900 mL of pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer containing 0.07% (w / v) hexadecyltrimethylammonium bromide (CTAB) were used as dissolution media, the speed was set to 50 r / min, and the dissolution of baloxavir in the product was tested by sampling for 45 minutes. The results are shown in Tables 1 to 3.

[0099] Table 1 Dissolution in pH 1.2 hydrochloric acid medium containing 0.07% CTAB for 45 min

[0100] sample Day 0 Accelerate January Accelerate February Accelerate March Example 1 96.7％ 96.2％ 96.1％ 95.7％ Example 2 95.4％ 95.2％ 95.2％ 94.5％ Example 3 95.7％ 95.6％ 95.0％ 94.6％ Comparative Example 1 94.5％ 92.1％ 88.2％ 83.1％ Comparative Example 2 90.6％ 87.5％ 82.2％ 76.7％ Comparative Example 3 90.7％ 84.6％ 79.2％ 71.5％ Original research products 94.7％ 91.8％ 86.4％ 82.7％

[0101] Table 2 Dissolution in pH 4.5 acetate buffer containing 0.07% CTAB for 45 min

[0102] sample Day 0 Accelerate January Accelerate February Accelerate March Example 1 98.8％ 98.3％ 98.1％ 97.7％ Example 2 99.2％ 98.7％ 98.5％ 98.5％ Example 3 98.7％ 98.5％ 98.0％ 98.3％ Comparative Example 1 96.5％ 93.0％ 89.4％ 83.7％ Comparative Example 2 93.1％ 88.2％ 82.9％ 78.5％ Comparative Example 3 92.6％ 84.8％ 80.5％ 73.6％ Original research products 98.3％ 93.7％ 86.2％ 82.4％

[0103] Table 3 Dissolution in pH 6.8 phosphate buffer containing 0.07% CTAB for 45 min

[0104] sample Day 0 Accelerate January Accelerate February Accelerate March Example 1 99.7％ 99.1％ 98.5％ 98.2％ Example 2 98.4％ 98.2％ 97.7％ 97.5％ Example 3 98.7％ 98.4％ 98.3％ 98.0％ Comparative Example 1 94.5％ 92.1％ 88.2％ 86.1％ Comparative Example 2 95.7％ 90.5％ 84.7％ 78.4％ Comparative Example 3 94.4％ 88.6％ 81.4％ 74.3％ Original research products 98.7％ 95.8％ 90.4％ 85.6％

[0105] As a result, the baloxavir disoximate tablets prepared in Examples 1 to 3 of the present invention have stable dissolution during the accelerated test, and no significant downward trend has been shown. Compared with the examples, in Comparative Example 1, spray-dried lactose was replaced with ground lactose, and in Comparative Example 2, the disintegrant carboxymethyl cellulose NS-300 was replaced with cross-linked sodium carboxymethyl cellulose, and in Comparative Example 3, the filler, disintegrant and binder were all replaced. During the accelerated test, the dissolution of the product showed a significant downward trend, and the product stability decreased significantly. It is proved that the stability of the product prepared in the embodiment of the present invention is significantly improved, and it is better than the original product, and can achieve a good replacement for the original product.

[0106] In summary, the embodiment of the present invention fully mixes baloxavir disoproxil with spray-dried lactose and colloidal silicon dioxide, reduces the agglomeration behavior of API, increases the dispersion surface area of ​​API, improves the solubility of the product, and adopts a combination of disintegrant carboxymethyl cellulose + binder hydroxypropyl cellulose in the prescription, so that the prepared baloxavir disoproxil tablets have excellent dissolution performance and are in a stable state during the accelerated test, which solves the problem of significant decrease in the solubility of baloxavir disoproxil tablets during the accelerated test, significantly improves the stability of the product, is more conducive to the clinical effect of the product, and can achieve the replacement of the original research product; and the preparation production process is simple, easy to realize industrial large-scale production, and has a high value of promotion and application.

[0107] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A baloxavir dipyramide pharmaceutical composition, characterized in that: The invention comprises baloxavir disoproxil, spray-dried lactose, a filler, colloidal silicon dioxide, carboxymethyl cellulose, hydroxypropyl cellulose and a lubricant.

2. The baloxavir dipivoxil pharmaceutical composition according to claim 1, wherein the filler is microcrystalline cellulose; and / or The lubricant includes sodium stearyl fumarate.

3. The baloxavir dipyramide pharmaceutical composition according to claim 1, characterized in that: The particle size D90 of the baloxavir dipyramide is 0.2 μm to 13 μm; and / or The average particle size of the spray-dried lactose is 50 μm to 150 μm.

4. The baloxavir dipyramide pharmaceutical composition according to claim 1, characterized in that: The particle size D90 of the baloxavir dipyramide is 2 μm to 6 μm; and / or The average particle size of the spray-dried lactose is 80 μm to 140 μm.

5. The baloxavir dipyramide pharmaceutical composition according to claim 1 or 2, characterized in that: The spray-dried lactose is 50% to 60% of the total mass of the baloxavir dipyramide pharmaceutical composition; and / or The colloidal silicon dioxide accounts for 0.5% to 2% of the total mass of the baloxavir dipyramide pharmaceutical composition.

6. The baloxavir dipyramide pharmaceutical composition according to claim 1 or 2, characterized in that: The carboxymethyl cellulose is 5% to 15% of the total mass of the baloxavir dipyramide pharmaceutical composition; and / or The hydroxypropylcellulose accounts for 3% to 7% of the total mass of the baloxavir dipyramide pharmaceutical composition.

7. The baloxavir dipyramide pharmaceutical composition according to claim 1 or 2, characterized in that: The filler is 5% to 15% of the total mass of the baloxavir dipyramide pharmaceutical composition; and / or The lubricant accounts for 0.5% to 2% of the total mass of the baloxavir dipyramide pharmaceutical composition.

8. A baloxavir dipeptide tablet, characterized in that: The baloxavir dipivoxil pharmaceutical composition is prepared from the baloxavir dipivoxil pharmaceutical composition according to any one of claims 1 to 7.

9. A method for preparing the baloxavir dipeptide tablet according to claim 8, characterized in that: The steps include: S1, mixing baloxavir disoproxil, spray-dried lactose and colloidal silicon dioxide uniformly to obtain a premixed material; S2, adding carboxymethyl cellulose and hydroxypropyl cellulose to the premixed material, mixing evenly, and wet granulating to obtain granules; S3, uniformly mixing the granules with the filler and the lubricant, and tableting to obtain baloxavir dipivoxil tablets.

10. The method for preparing baloxavir dipivoxil tablets according to claim 9, characterized in that: After tableting, the method further comprises: coating the compressed plain tablets to obtain baloxavir ester coating agent.

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