Preparation method of composite tablet

Abstract

The invention provides a preparation method of a composite tablet. The preparation method comprises the following steps: S1, dissolving an adhesive and a wetting agent in water to form a solution; s2, putting the Aviavir, the lactose monohydrate, the filling agent and the disintegrating agent into a fluidized bed granulator, and introducing sterile hot air into the bottom of the fluidized bed granulator; spraying the solution of S1 into the top for wet granulation; s3, drying the wet particles in a fluidized bed to obtain dry particles; s4, uniformly mixing copibuxostat, colloidal silicon dioxide and a filling agent, crushing, sieving, and mixing with the crushed material in the step S3 and a lubricating agent to obtain a first material; s5, uniformly mixing emtricitabine, tenofovir propofol, the filler and the disintegrating agent, continuously and uniformly mixing with the lubricant, crushing and sieving; s6, mixing a disintegrating agent, a lubricating agent and the crushed material obtained in the step S52 to obtain a second material; and S7, performing double-layer tabletting on the first material and the second material. The composite tablet can improve the mixing uniformity of raw material medicines, and ensure the content uniformity and quality stability of medicines produced in different batches.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a method for preparing a composite tablet. Background Art

[0002] AIDS, or acquired immunodeficiency syndrome, is a fatal infectious disease caused by the human immunodeficiency virus (HIV). The disease severely damages the human immune system and can cause various symptoms such as bleeding, high fever, swollen lymph nodes, and weakness. The onset of the disease is generally related to factors such as blood infection, sexual contact, and drug abuse. Some infants and young children are generally infected through mother-to-child transmission. The use of anti-HIV drugs to effectively prolong the life of HIV-infected people or AIDS patients and improve their quality of life by inhibiting viral replication or invasion. The combined use of antiviral drugs is called highly active combined antiretroviral therapy (HAART), which is currently the most effective method for treating AIDS. This method uses three or more anti-HIV drugs for combined treatment, which can reduce the drug resistance caused by single drug use and improve the antiviral efficacy.

[0003] Elvitegravir (EVG) was developed by Gilead and was approved for marketing by the U.S. Food and Drug Administration (FDA) on September 24, 2014, and then by the European Medicines Agency (EMA) on November 12, 2013. Elvitegravir belongs to the class of human immunodeficiency virus type 1 (HIV-1) integrase inhibitors (INSTIs), which prevent the replication of HIV-1 virus by inhibiting the HIV-1 integrase chain transfer activity. The chemical formula of Elvitegravir is as follows:

[0004]

[0005] Cobicistat is a new CYP3A inhibitor developed by Gilead Sciences, Inc., and was approved by the U.S. Food and Drug Administration on September 24, 2014. It is currently the only approved cocktail therapy AIDS drug enhancer. In addition to single-dose, it is also used in combination with other anti-retroviral drugs for the treatment of HIV infection. The chemical formula of cobicistat is as follows:

[0006]

[0007] Emtricitabine (FTC) was developed by Gilead Sciences and first launched in the United States in July 2003. Emtricitabine is a chemically synthesized cytidine analog and a new type of nucleoside reverse transcriptase inhibitor. Emtricitabine undergoes multi-step phosphorylation through the action of intracellular enzymes to form 5'-emtricitabine triphosphate, which inhibits HIV-1 reverse transcriptase by competing for natural substrates and infiltrates into the process of viral DNA synthesis, ultimately leading to the interruption of its DNA chain synthesis. The chemical formula of Emtricitabine is as follows:

[0008]

[0009] Tenofovir alafenamide fumarate (TAF) is a new nucleoside reverse transcriptase inhibitor for the treatment of chronic hepatitis B and acquired immune syndrome (HIV). It is the new drug approved by the US Food and Drug Administration for the treatment of chronic hepatitis B and acquired immune syndrome (HIV) in adults in the past decade. TAF is degraded into the active substance tenofovir in the blood, and then enters the liver cells and is converted into the active metabolite tenofovir bisphosphonate, which inhibits viral polymerase by directly competing with natural deoxyribose substrates, and inhibits the activity of hepatitis B virus and HIV-1 virus reverse transcriptase by inserting into DNA to terminate the chain, thereby exerting the efficacy against hepatitis B virus infection (HBV) and acquired immune syndrome (HIV). Its free state is tenofovir alafenamide. Gilead Sciences first disclosed the preparation method of tenofovir alafenamide in its patent CN1291994C. The chemical formula of tenofovir alafenamide is as follows:

[0010]

[0011] Avitegravir, cobicistat, emtricitabine and tenofovir alafenamide are available on the market. Combination therapy can be used to treat AIDS, which can overcome the shortcomings of single medication. However, since it includes four drugs, it is easy to cause uneven mixing between drugs during preparation, which is not conducive to the stability of tablet quality, and will not only affect industrial large-scale production, but also seriously affect the efficacy of the drug. Summary of the invention

[0012] In view of this, the present invention aims to provide a method for preparing a composite tablet to solve the problem of uneven mixing of the raw materials when preparing drugs with elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide, resulting in unstable content between tablets.

[0013] To achieve the above object, the technical solution of the present invention is achieved as follows:

[0014] The present invention provides a method for preparing a composite tablet, comprising the following steps:

[0015] S1. Weigh 6-8 parts of adhesive and 10-12 parts of wetting agent and dissolve them in an appropriate amount of water to form a solution;

[0016] S2. Weigh 150 parts of elvitegravir, 8-12 parts of lactose monohydrate, 120-140 parts of filler and 40-50 parts of disintegrant into a fluidized bed granulator and mix thoroughly, while introducing sterile hot air into the bottom of the fluidized bed granulator; atomize the solution obtained in step S1 and spray it from the top of the fluidized bed granulator for wet granulation;

[0017] S3. The wet granules are dried in a fluidized bed to obtain dry granules, which are then crushed through a 18-24 mesh sieve;

[0018] S4. Weigh 150 parts of cobicistat, 150-175 parts of colloidal silicon dioxide, and 70-90 parts of filler, mix well, and crush through a 18-24 mesh sieve, and mix the crushed material of step S3 and 6-8 parts of lubricant to obtain a first material;

[0019] S5. Weigh 200 parts of emtricitabine, 10 parts of tenofovir alafenamide, 55-80 parts of filler, 8-10 parts of disintegrant, mix well, and continue to mix well with 4-8 parts of lubricant, and crush through a 18-24 mesh sieve;

[0020] S6. Weigh 10-15 parts of a disintegrant, 6-10 parts of a lubricant and the crushed material obtained in step S52 and mix them to obtain a second material;

[0021] S7. Perform double-layer tableting on the first material and the second material.

[0022] Furthermore, in step S5, the following preparation method is adopted:

[0023] S51. Weigh 200 parts of emtricitabine, 10 parts of tenofovir alafenamide, and part of the filler, mix and grind to obtain particles with a particle size of 20-50 μm;

[0024] S52. After mixing the granules of step S51 and the remaining filler, add 8-10 parts of disintegrant and 4-8 parts of lubricant and continue to mix, and crush through a 18-24 mesh sieve.

[0025] Among them, the method of loading cobicistat onto silica is referred to CN102307573B.

[0026] Furthermore, in step S2, the temperature of the hot air is 45-60°C.

[0027] Furthermore, in step S51, the amount of some fillers used accounts for 2 / 3 of the total amount of fillers.

[0028] Furthermore, the binder is selected from at least one of hydroxypropyl methylcellulose and sodium carboxymethyl cellulose.

[0029] Furthermore, the wetting agent is selected from sodium lauryl sulfate.

[0030] Furthermore, the filler is selected from at least one of mannitol, silicified microcrystalline cellulose, and microcrystalline cellulose.

[0031] Furthermore, the disintegrant is selected from at least one of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, and hydroxypropyl cellulose.

[0032] Furthermore, the lubricant is selected from at least one of magnesium stearate, calcium stearate and glyceryl behenate.

[0033] Compared with the prior art, the method for preparing a composite tablet of the present invention has the following advantages:

[0034] (1) The composite tablets prepared by the present invention using elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide in combination can improve the mixing uniformity of the raw materials, which is beneficial to ensure the content uniformity and quality stability of the drugs produced in different batches, reduce the difference between different batches of tablets, and ensure the efficacy.

[0035] (2) The composite tablet of the present invention has a high tabletting yield and can reduce sticking between the tablet and the tablet press. DETAILED DESCRIPTION

[0036] The present invention will be further described below in conjunction with specific embodiments. It should be noted that the data in the following experimental examples are obtained by the inventor through a large number of experiments. Due to space limitations, only a part of them is shown in the specification, and those of ordinary skill in the art can understand and implement the present invention under these data. These embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these changes or modifications also fall within the scope protected by the present application.

[0037] Example 1

[0038] S1. Weigh 7 g of hydroxypropyl methylcellulose and 11 g of sodium lauryl sulfate and dissolve them in 150 ml of water to form a solution;

[0039] S2. Weigh 150 g of elvitegravir, 10 g of lactose monohydrate, 130 g of microcrystalline cellulose and 45 g of cross-linked polyvinylpyrrolidone into a fluidized bed granulator and mix thoroughly, while introducing 50° C. sterile hot air into the bottom of the fluidized bed granulator; atomize the solution obtained in step S1 and spray it from the top of the fluidized bed granulator for wet granulation;

[0040] S3. The wet granules are dried in a fluidized bed to obtain dry granules, which are then crushed through a 18-24 mesh sieve;

[0041] S4. Weigh 150 g of cobicistat, 160 g of colloidal silicon dioxide, and 82 g of microcrystalline cellulose, mix and grind through a 18-24 mesh sieve, and mix the crushed material from step S3 and 7 g of calcium stearate to obtain a first material;

[0042] S5. Weigh 200 g of emtricitabine, 10 g of tenofovir alafenamide, 62 g of microcrystalline cellulose, and 9 g of crospovidone, and mix well, and then continue to mix well with 6 g of calcium stearate, and crush through a 18-24 mesh sieve;

[0043] S6. Weigh 13 g of cross-linked polyvinylpyrrolidone, 8 g of calcium stearate and the crushed material obtained in step S52 and mix them to obtain a second material;

[0044] S7. Perform double-layer tableting on the first material and the second material.

[0045] Example 2

[0046] S1. Weigh 6 g of hydroxypropyl methylcellulose and 10 g of sodium lauryl sulfate and dissolve them in 100 ml of water to form a solution;

[0047] S2. Weigh 150 g of elvitegravir, 8 g of lactose monohydrate, 140 g of mannitol and 50 g of cross-linked carboxymethyl cellulose sodium into a fluidized bed granulator and mix thoroughly, while introducing sterile hot air at 45 ° C into the bottom of the fluidized bed granulator; atomize the solution obtained in step S1 and spray it from the top of the fluidized bed granulator for wet granulation;

[0048] S3. The wet granules are dried in a fluidized bed to obtain dry granules, which are then crushed through a 18-24 mesh sieve;

[0049] S4. Weigh 150 g of cobicistat, 170 g of colloidal silicon dioxide, and 70 g of mannitol, mix and crush through a 18-24 mesh sieve, and mix the crushed material of step S3 and 6 g of magnesium stearate to obtain a first material;

[0050] S5. Weigh 200 g of emtricitabine, 10 g of tenofovir alafenamide, and 36.67 g of mannitol, mix and grind to obtain particles with a particle size of 20-50 μm, mix the above particles with 18.33 g of mannitol, add 8 g of cross-linked sodium carboxymethyl cellulose and 6 g of magnesium stearate, continue mixing, and grind through a 18-24 mesh sieve;

[0051] S6. Weigh 15 g of cross-linked sodium carboxymethyl cellulose, 6 g of magnesium stearate and the crushed material obtained in step S52 and mix to obtain a second material;

[0052] S7. Perform double-layer tableting on the first material and the second material.

[0053] Example 3

[0054] S1. Weigh 8 g of hydroxypropyl methylcellulose and 12 g of sodium lauryl sulfate and dissolve them in 300 ml of water to form a solution;

[0055] S2. Weigh 150 g of elvitegravir, 12 g of lactose monohydrate, 120 g of silicified microcrystalline cellulose and 40 g of sodium carboxymethyl starch into a fluidized bed granulator and mix thoroughly, while introducing sterile hot air at 60° C. into the bottom of the fluidized bed granulator; atomize the solution obtained in step S1 and spray it from the top of the fluidized bed granulator for wet granulation;

[0056] S3. The wet granules are dried in a fluidized bed to obtain dry granules, which are then crushed through a 18-24 mesh sieve;

[0057] S4. Weigh 150 g of cobicistat, 150 g of colloidal silicon dioxide, and 90 g of silicified microcrystalline cellulose, mix and grind through a 18-24 mesh sieve, and mix the crushed material of step S3 and 8 g of behenic acid glyceride to obtain a first material;

[0058] S5. Weigh 200 g of emtricitabine, 10 g of tenofovir alafenamide, and 53.33 g of silicified microcrystalline cellulose, mix and grind to obtain particles with a particle size of 20-50 μm, mix the above particles with 26.67 g of silicified microcrystalline cellulose, add 10 g of sodium carboxymethyl starch and 8 g of behenic acid glyceride, continue mixing, and grind through a 18-24 mesh sieve;

[0059] S6. Weigh 10 g of sodium carboxymethyl starch, 10 g of glyceryl behenate and the crushed material obtained in step S52 and mix to obtain a second material;

[0060] S7. Perform double-layer tableting on the first material and the second material.

[0061] Example 4

[0062] S1. Weigh 7 g of hydroxypropyl methylcellulose and 11 g of sodium lauryl sulfate and dissolve them in 150 ml of water to form a solution;

[0063] S2. Weigh 150 g of elvitegravir, 10 g of lactose monohydrate, 130 g of microcrystalline cellulose and 45 g of cross-linked polyvinylpyrrolidone into a fluidized bed granulator and mix thoroughly, while introducing 50° C. sterile hot air into the bottom of the fluidized bed granulator; atomize the solution obtained in step S1 and spray it from the top of the fluidized bed granulator for wet granulation;

[0064] S3. The wet granules are dried in a fluidized bed to obtain dry granules, which are then crushed through a 18-24 mesh sieve;

[0065] S4. Weigh 150 g of cobicistat, 160 g of colloidal silicon dioxide, and 82 g of microcrystalline cellulose, mix and grind through a 18-24 mesh sieve, and mix the crushed material from step S3 and 7 g of calcium stearate to obtain a first material;

[0066] S5. Weigh 200 g of emtricitabine, 10 g of tenofovir alafenamide, and 41.33 g of microcrystalline cellulose, mix and grind to obtain particles with a particle size of 20-50 μm, mix the above particles with 20.67 g of microcrystalline cellulose, add 9 g of cross-linked polyvinylpyrrolidone and 6 g of calcium stearate, continue mixing, and grind through a 18-24 mesh sieve;

[0067] S6. Weigh 13 g of cross-linked polyvinylpyrrolidone, 8 g of calcium stearate and the crushed material obtained in step S52 and mix them to obtain a second material;

[0068] S7. Perform double-layer tableting on the first material and the second material.

[0069] Example 5

[0070] S1. Weigh 7 g of hydroxypropyl methylcellulose and 11 g of sodium lauryl sulfate and dissolve them in 150 ml of water to form a solution;

[0071] S2. Weigh 150 g of elvitegravir, 10 g of lactose monohydrate, 130 g of microcrystalline cellulose and 45 g of cross-linked polyvinylpyrrolidone into a fluidized bed granulator and mix thoroughly, while introducing 50° C. sterile hot air into the bottom of the fluidized bed granulator; atomize the solution obtained in step S1 and spray it from the top of the fluidized bed granulator for wet granulation;

[0072] S3. The wet granules are dried in a fluidized bed to obtain dry granules, which are then crushed through a 18-24 mesh sieve;

[0073] S4. Weigh 150 g of cobicistat, 160 g of colloidal silicon dioxide, and 82 g of microcrystalline cellulose, mix and grind through a 18-24 mesh sieve, and mix the crushed material from step S3 and 7 g of calcium stearate to obtain a first material;

[0074] S5. Weigh 200 g of emtricitabine, 10 g of tenofovir alafenamide, and 41.33 g of microcrystalline cellulose, mix and grind to obtain particles with a particle size of 20-50 μm, mix the above particles with 20.67 g of microcrystalline cellulose, add 9 g of hydroxypropyl cellulose and 6 g of calcium stearate, continue mixing, and grind through a 18-24 mesh sieve;

[0075] S6. Weigh 13 g of hydroxypropyl cellulose, 8 g of calcium stearate and the crushed material obtained in step S52 and mix them to obtain a second material;

[0076] S7. Perform double-layer tableting on the first material and the second material.

[0077] The only difference between Example 5 and Example 4 is that the disintegrant selected when preparing the second material in Example 4 is cross-linked polyvinylpyrrolidone, while the disintegrant selected when preparing the second material in Example 5 is hydroxypropyl cellulose.

[0078] Comparative Example 1

[0079] S1. Weigh 7 g of hydroxypropyl methylcellulose and 11 g of sodium lauryl sulfate and dissolve them in 150 ml of water to form a solution;

[0080] S2. Weigh 150 g of avitegravir, 10 g of lactose monohydrate, 130 g of microcrystalline cellulose and 45 g of cross-linked polyvinylpyrrolidone into a fluidized bed granulator and mix thoroughly, and spray the solution obtained in step S1 onto the mixture of avitegravir, lactose monohydrate, microcrystalline cellulose and cross-linked polyvinylpyrrolidone to perform wet granulation;

[0081] S3. The wet granules are dried in a fluidized bed to obtain dry granules, which are then crushed through a 18-24 mesh sieve;

[0082] S4. Weigh 150 g of cobicistat, 160 g of colloidal silicon dioxide, and 82 g of microcrystalline cellulose, mix and grind through a 18-24 mesh sieve, and mix the crushed material from step S3 and 7 g of calcium stearate to obtain a first material;

[0083] S5. Weigh 200 g of emtricitabine, 10 g of tenofovir alafenamide, and 41.33 g of microcrystalline cellulose, mix and grind to obtain particles with a particle size of 20-50 μm, mix the above particles with 20.67 g of microcrystalline cellulose, add 9 g of hydroxypropyl cellulose and 6 g of calcium stearate, continue mixing, and grind through a 18-24 mesh sieve;

[0084] S6. Weigh 13 g of hydroxypropyl cellulose, 8 g of calcium stearate and the crushed material obtained in step S52 and mix them to obtain a second material;

[0085] S7. Perform double-layer tableting on the first material and the second material.

[0086] The only difference between Comparative Example 1 and Example 5 is that in Comparative Example 1, no sterile hot air is introduced in step S2.

[0087] Comparative Example 2

[0088] S1. Weigh 7 g of hydroxypropyl methylcellulose and 11 g of sodium lauryl sulfate and dissolve them in 150 ml of water to form a solution;

[0089] S2. Weigh 150 g of elvitegravir, 10 g of lactose monohydrate, 130 g of microcrystalline cellulose and 45 g of cross-linked polyvinylpyrrolidone into a fluidized bed granulator and mix thoroughly, while introducing 50° C. sterile hot air into the bottom of the fluidized bed granulator; atomize the solution obtained in step S1 and spray it from the top of the fluidized bed granulator for wet granulation;

[0090] S3. The wet granules are dried in a fluidized bed to obtain dry granules, which are then crushed through a 18-24 mesh sieve;

[0091] S4. Weigh 150 g of cobicistat, 160 g of colloidal silicon dioxide, and 82 g of microcrystalline cellulose, mix and grind through a 18-24 mesh sieve, and mix the crushed material from step S3 and 7 g of calcium stearate to obtain a first material;

[0092] S5. Weigh 200 g of emtricitabine, 10 g of tenofovir alafenamide, and 41.33 g of microcrystalline cellulose, mix and grind to obtain particles with a particle size of 20-50 μm, and continue to mix the above particles with 20.67 g of microcrystalline cellulose, 9 g of hydroxypropyl cellulose, and 6 g of calcium stearate, and grind through a 18-24 mesh sieve;

[0093] S6. Weigh 13 g of hydroxypropyl cellulose, 8 g of calcium stearate and the crushed material obtained in step S52 and mix them to obtain a second material;

[0094] S7. Perform double-layer tableting on the first material and the second material.

[0095] The difference between Comparative Example 2 and Example 5 is only that the operation of step S5 is different.

[0096] Comparative Example 3

[0097] Comparative Example 3: Tablets were prepared using the method of Example 4 in CN102307573B.

[0098] The composite tablets of Examples 1-5 and the tablets of Comparative Examples 1-3 prepared in different batches were respectively taken for content determination, and the specific results are shown in Tables 1 and 2.

[0099] Table 1

[0100]

[0101]

[0102] Table 2

[0103]

[0104] It can be seen from Table 1 and Table 2 that the composite tablets of Examples 2-5 prepared by the method of the present application, when sampling different batches, the content differences of the raw materials Avitegravir, cobicistat, emtricitabine and tenofovir are small, indicating that the composite tablets of the present application have good mixing uniformity, which is conducive to ensuring the content uniformity and quality stability of the drugs produced under different batches, reducing the difference between different batches of tablets, and ensuring the efficacy. When the tablets of Comparative Example 1 are measured in different batches, the content of Avitegravir varies greatly. It is speculated that the possible reason is that when the first material is prepared, the present application adopts the method of passing hot air at the bottom of the fluidized bed granulator, and passing the spray formed by the adhesive at the top of the fluidized bed granulator. The mixture formed by Avitegravir and its corresponding auxiliary materials is continuously rolled in the fluidized bed granulator by the hot air passed from the bottom, which not only helps the adhesive and wetting agent to wet and wrap Avitegravir, but also the hot air passed can play a drying role, and the solution wrapped on the surface of the mixture is evaporated, and this process is repeated continuously, which is conducive to forming a porous structure. When the porous structure of elvitegravir and cobicistat are mixed, they have good embedding strength, which helps to reduce agglomeration and make the mixture more uniform. Comparative Example 1 lacks the introduction of hot air, which is not conducive to the uniformity of mixing between the drugs.

[0105] Compared with the composite tablets of Examples 2-5, the tablets of Example 1 and Comparative Example 2 have a large difference in the contents of emtricitabine and tenofovir alafenamide when different batches are measured. In Example 2-5, when preparing the second material, the filler is added in batches, part of the filler is first mixed and crushed with emtricitabine and its excipients to obtain particles, and part of the filler is used to wrap and adsorb emtricitabine during the crushing process to reduce agglomeration, and then the remaining filler continues to be mixed with the particles, and the remaining filler is used as a carrier to promote the fluidity of the drug particles and improve the mixing uniformity of the drug particles. At the same time, the improved fluidity also helps the subsequent tableting.

[0106] The composite tablets of Examples 1-5 and Comparative Examples 1-3 were tableted by the method described above. 1000 tablets were tableted by each method. Whether the tablet press and the particles were sticky during the tableting process was observed. If the tablet surface was not smooth or had broken marks, it indicated that the particles and the tablet press were sticky, indicating that the tableting was unsuccessful. The specific tableting results are shown in Table 3.

[0107] Table 3

[0108] Serial number Film formation rate (%) Example 1 89 Example 2 92 Example 3 93 Example 4 93 Example 5 98 Comparative Example 1 90 Comparative Example 2 90 Comparative Example 3 89

[0109] As shown in Table 3, the tablets of Example 5 have the highest yield rate during tableting, up to 98%. In the preparation process of the second material of Example 5, hydroxypropyl cellulose is selected as the disintegrant. It is speculated that hydroxypropyl cellulose has a certain porosity, which is beneficial to its rough structure. When mixed with the raw material, it can produce a certain mosaic effect with the raw material, which helps to improve the hardness of the composite tablet and improve the yield rate of tableting. In the preparation process of the first material, since avitegravir forms a porous structure, the mixed mosaic with cobicistat helps to increase the hardness of the tablet, so there is no need to limit the type of disintegrant when preparing the first material.

[0110] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a composite tablet, characterized in that: The steps include: S1. Weigh 6-8 parts of adhesive and 10-12 parts of wetting agent and dissolve them in an appropriate amount of water to form a solution; S2. Weigh 150 parts of elvitegravir, 8-12 parts of lactose monohydrate, 120-140 parts of filler and 40-50 parts of disintegrant into a fluidized bed granulator and mix thoroughly, while introducing sterile hot air into the bottom of the fluidized bed granulator; atomize the solution obtained in step S1 and spray it from the top of the fluidized bed granulator for wet granulation; S3. The wet granules are dried in a fluidized bed to obtain dry granules, which are then crushed through a 18-24 mesh sieve; S4. Weigh 150 parts of cobicistat, 150-175 parts of colloidal silicon dioxide, and 70-90 parts of filler, mix well, and crush through a 18-24 mesh sieve, and mix the crushed material of step S3 and 6-8 parts of a lubricant to obtain a first material; S5. Weigh 200 parts of emtricitabine, 10 parts of tenofovir alafenamide, 55-80 parts of filler, 8-10 parts of disintegrant, mix well, and continue to mix well with 4-8 parts of lubricant, and crush through a 18-24 mesh sieve; S6. Weigh 10-15 parts of a disintegrant, 6-10 parts of a lubricant and the crushed material obtained in step S52 and mix them to obtain a second material; S7. Perform double-layer tableting on the first material and the second material.

2. The method for preparing a composite tablet according to claim 1, characterized in that: In step S2, the temperature of the hot air is 45-60°C.

3. The method for preparing the composite tablet according to claim 1, characterized in that: The binder is selected from at least one of hydroxypropyl methylcellulose and sodium carboxymethyl cellulose.

4. The method for preparing a composite tablet according to claim 1, characterized in that: The wetting agent is selected from sodium lauryl sulfate.

5. The method for preparing a composite tablet according to claim 1, characterized in that: The filler is selected from at least one of mannitol, silicified microcrystalline cellulose and microcrystalline cellulose.

6. The method for preparing a composite tablet according to claim 1, characterized in that: The disintegrant is selected from at least one of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone and hydroxypropyl cellulose.

7. The method for preparing a composite tablet according to claim 1, characterized in that: The lubricant is selected from at least one of magnesium stearate, calcium stearate and glyceryl behenate.

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