A bilayer tablet and a method for preparing the same

Abstract

This invention provides a bilayer tablet and its preparation method. The bilayer tablet comprises a first layer and a second layer. The first layer comprises: 50 parts of dolutegravir or a pharmaceutically acceptable salt thereof (calculated as dolutegravir), 30-60 parts of modified mesoporous silica, 60-80 parts of a first filler, 30-50 parts of a first disintegrant, 300 parts of lamivudine, 80-120 parts of a second filler, 20-30 parts of a second gliding agent, 400-700 parts of a third filler, 100-150 parts of a third disintegrant, 150-200 parts of a first sweetener, and 40-60 parts of a third gliding agent. The second layer comprises: 600 parts of abacavir or a pharmaceutically acceptable salt thereof (calculated as abacavir), 950-1200 parts of a fourth filler, 120-150 parts of a fourth disintegrant, 30-50 parts of a fourth gliding agent, and 30-40 parts of a second sweetener. The first layer is prepared by direct compression of powder into tablets, and then the raw materials for the second layer are blended and compressed onto the first layer to obtain a bilayer tablet. This invention simplifies the operation, improves the production efficiency of pharmaceutical formulations, and facilitates large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a bilayer tablet and its preparation method. Background Technology

[0002] AIDS, or Acquired Immunodeficiency Syndrome, is a fatal infectious disease caused by the human immunodeficiency virus (HIV). This disease severely damages the human immune system, causing various symptoms such as bleeding, high fever, swollen lymph nodes, and weakness. The onset of the disease is generally related to blood infections and sexual contact; some infants are infected through mother-to-child transmission. Long-term antiretroviral therapy (ART) using anti-HIV drugs to inhibit viral replication or invasion in HIV-infected individuals or AIDS patients can effectively prolong their lives and improve their quality of life. The combined use of antiretroviral drugs, known as highly active combination antiretroviral therapy (HAART), is currently the most effective treatment for AIDS. This method uses three or more anti-HIV drugs in combination, which can reduce drug resistance caused by monotherapy and improve antiviral efficacy.

[0003] Dolutegravir is an integrase strand transfer inhibitor (INSTI) that inhibits HIV integrase, blocking the chain transfer process that integrates the HIV genome into the host cell's DNA, thereby inhibiting HIV replication and protein expression. Dolutegravir sodium is approved for use in HIV patients and is recommended as first-line treatment for adults infected with HIV-1 due to its efficacy, high resistance to drug resistance, and tolerability. Lamivudine is a nucleoside antiviral drug, and nucleotides are the raw materials for synthesizing human genetic material DNA and RNA. Nucleoside analogs structurally mimic the structure of nucleotides but do not possess the function of nucleotides. Therefore, during DNA synthesis, nucleoside analogs can be incorporated but cannot synthesize normally functioning nucleic acid chains, thus terminating viral replication. Lamivudine competitively inhibits the synthesis and elongation of viral DNA chains. Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI), and abacavir sulfate is approved for use in combination with other HIV drugs to treat patients infected with HIV.

[0004] Each tablet of TRIUMEQ (dolutegravir sodium) contains 50 mg of dolutegravir sodium (calculated as dolutegravir), 600 mg of abacavir sulfate (calculated as abacavir), and 300 mg of lamivudine. Current technology for preparing TRIUMEQ tablets involves complex processes, including wet granulation, fluidized bed drying, and dry grinding, before mixing the dolutegravir with lamivudine and excipients. This process is not conducive to large-scale production. Summary of the Invention

[0005] In view of this, the present invention aims to provide a bilayer tablet and its preparation method to solve the problem of the relatively complex process in preparing bilayer tablets containing three drugs: dolutegravir, lamivudine and abacavir.

[0006] To achieve the above objectives, the technical solution of the present invention is implemented as follows:

[0007] On one hand, the present invention proposes a bilayer tablet comprising a first layer and a second layer, wherein the first layer comprises the following components in parts by weight: 50 parts of dolutegravir or a pharmaceutically acceptable salt thereof (calculated as dolutegravir), 30-60 parts of modified mesoporous silica, 60-80 parts of a first filler, 30-50 parts of a first disintegrant, 300 parts of lamivudine, 80-120 parts of a second filler, 20-30 parts of a second gliding agent, and so on. The third layer comprises 400-700 parts of a filler, 100-150 parts of a disintegrant, 150-200 parts of a sweetener, and 40-60 parts of a gliding agent; the second layer comprises the following components in parts by weight: 600 parts of abacavir or a pharmaceutically acceptable salt thereof (calculated as abacavir), 950-1200 parts of a filler, 120-150 parts of a disintegrant, 30-50 parts of a gliding agent, and 30-40 parts of a sweetener.

[0008] Furthermore, the first filler, the second filler, the third filler and the fourth filler are selected from at least one of mannitol, lactose and microcrystalline cellulose.

[0009] Furthermore, the first, third, and fourth disintegrants are selected from at least one of croscarmellose sodium, carboxymethyl starch sodium, starch, and croscarmellose.

[0010] Furthermore, the second and third gliding agents are selected from at least one of magnesium stearate, colloidal silica, and talc.

[0011] Furthermore, the first sweetener and the second sweetener are selected from sucrose.

[0012] On the other hand, the present invention also proposes a method for preparing a bilayer tablet, the method comprising the following steps:

[0013] S1. Dolutegravir or its pharmaceutically acceptable salt and mesoporous silica are mixed and dissolved in an appropriate amount of anhydrous ethanol. The anhydrous ethanol is evaporated to remove the ethanol. The residue is then vacuum dried, ground, and the dolutegravir solid dispersion is obtained.

[0014] S2. The first mixture is obtained by mixing the dolutegravir solid dispersion, the first filler and the first disintegrant;

[0015] S3. After micronizing lamivudine, add the second filler and the second gliding agent and mix to obtain the second mixture;

[0016] S4. After mixing the second mixture, the third filler and the third disintegrant, the first mixture and the first sweetener are added simultaneously to obtain the third mixture;

[0017] S5. The third mixture and the third gliding agent are mixed together and compressed into tablets to form the first layer of a bilayer tablet;

[0018] S6. A bilayer tablet is obtained by mixing abacavir or a pharmaceutically acceptable salt thereof, a fourth filler, a fourth disintegrant, a fourth gliding agent and a second sweetener and then compressing the mixture onto the first layer.

[0019] S7. Coating the double-layer tablets.

[0020] Furthermore, in step S3, lamivudine is micronized into powder with a particle size of 20-100 μm.

[0021] Furthermore, in step S7, the double-layer tablets are coated to achieve a coating weight gain of 2%-4% w / w.

[0022] Specifically, the coating materials and coating techniques can be found in existing technologies and will not be detailed here.

[0023] Compared with existing technologies, the tablet and its preparation method described in this invention have the following advantages:

[0024] (1) When preparing the first layer of a double-layer tablet, the method of direct compression of powder is adopted, which simplifies the operation, improves the production efficiency of pharmaceutical preparations, and facilitates large-scale industrial production.

[0025] (2) Without increasing the amount of sweetener, the taste of the double-layer tablets has been improved, making them more suitable for pediatric patients. Detailed Implementation

[0026] The present invention will be further described below with reference to specific embodiments. First, it should be noted that the data in the following experimental examples were obtained by the inventors through numerous experiments. Due to space limitations, only a portion of these data is shown in the specification, and those skilled in the art can understand and implement the present invention based on this data. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the contents of this invention, those skilled in the art can make various modifications or alterations to the invention, and these modifications or alterations also fall within the scope of protection of this application.

[0027] The present invention provides a bilayer tablet comprising a first layer and a second layer. The first layer comprises the following components: 50 parts of dolutegravir or a pharmaceutically acceptable salt thereof (calculated as dolutegravir), 30-60 parts of modified mesoporous silica, 60-80 parts of a first filler, 20-30 parts of a first disintegrant, 300 parts of lamivudine, 50-100 parts of a second filler, 20-30 parts of a second gliding agent, 300-600 parts of a third filler, 100-150 parts of a third disintegrant, 130-200 parts of a first sweetener, and 40-60 parts of a third gliding agent. The second layer comprises the following components in parts by weight: 600 parts of abacavir or a pharmaceutically acceptable salt thereof (calculated as abacavir), 100-130 parts of a fourth filler, 100-150 parts of a fourth disintegrant, and 30-40 parts of a second sweetener.

[0028] Specifically, in the preparation of bilayer tablets, lamivudine can be ultra-finely pulverized into powder with a particle size of 20-100 μm using air jet milling.

[0029] The method for preparing modified mesoporous silica is as follows: Mesoporous silica is prepared into a suspension with a mass concentration of 10-15% using ultrasonic vibration technology. The suspension is then directly treated with an air-pressure plasma jet device, followed by centrifugation to obtain a precipitate. The precipitate is washed with anhydrous ethanol and then freeze-dried under vacuum to obtain modified mesoporous silica. The ultrasonic treatment time is 20-40 min, and the ultrasonic treatment temperature is 20-30℃. The air-pressure plasma jet treatment time is 1-7 min, the power is 650-850 W, and the height is 14.13 mm. The centrifugation speed is 2000-3000 rpm, and the centrifugation time is 10-15 min. Anhydrous ethanol washing is performed 3-5 times. Specifically, the preparation method of modified mesoporous silica can be found in CN111991558B.

[0030] Example 1

[0031] To prepare modified mesoporous silica, 50g of dolutegravir and 30g of modified mesoporous silica were weighed, mixed, and dissolved in anhydrous ethanol. The anhydrous ethanol was evaporated to remove the ethanol, and the residue was taken out, vacuum dried, and ground to obtain a dolutegravir solid dispersion.

[0032] The first mixture was obtained by mixing the dolutegravir solid dispersion, 80g of microcrystalline cellulose and 30g of cross-linked sodium carboxymethyl cellulose.

[0033] 300g of lamivudine was micronized into powder with a particle size of 20-100μm, and then 100g of microcrystalline cellulose and 30g of colloidal silica were added and premixed to obtain a second mixture.

[0034] The second mixture, 600g of microcrystalline cellulose and 150g of croscarmellose sodium were mixed together, and the first mixture and 200g of sucrose were added at the same time to obtain the third mixture.

[0035] The third mixture is mixed with 40g of colloidal silica and then compressed into tablets at a speed of 5rpm to form the first layer of a bilayer tablet.

[0036] 702g of abacavir sulfate, 1090g of microcrystalline cellulose, 120g of croscarmellose sodium, 50g of colloidal silica and 40g of sucrose were mixed and compressed onto the first layer to obtain a bilayer tablet. The bilayer tablet was then coated to a coating weight gain of 2%-4% w / w.

[0037] Example 2

[0038] To prepare modified mesoporous silica, 50g of dolutegravir and 60g of modified mesoporous silica were weighed, mixed, and dissolved in anhydrous ethanol. The anhydrous ethanol was evaporated to remove the ethanol, and the residue was taken out, vacuum dried, and ground to obtain a dolutegravir solid dispersion.

[0039] The first mixture was obtained by mixing the dolutegravir solid dispersion, 80g of lactose and 40g of crospovidone.

[0040] 300g of lamivudine was micronized into powder with a particle size of 20-100μm, and then 100g of lactose and 20g of magnesium stearate were added and premixed to obtain a second mixture.

[0041] The second mixture, 550g of lactose, and 150g of crospovidone were mixed together, and then the first mixture and 200g of sucrose were added to obtain the third mixture.

[0042] The third mixture is mixed with 60g of magnesium stearate and then compressed into tablets at a speed of 10rpm to form the first layer of a bilayer tablet.

[0043] 702g of abacavir sulfate, 1200g of lactose, 120g of crospovidone, 30g of magnesium stearate and 30g of sucrose were mixed and compressed onto the first layer to obtain a bilayer tablet. The bilayer tablet was then coated to achieve a coating weight gain of 2%-4% w / w.

[0044] Example 3

[0045] To prepare modified mesoporous silica, 50g of dolutegravir and 50g of modified mesoporous silica were weighed, mixed, and dissolved in anhydrous ethanol. The anhydrous ethanol was evaporated to remove the ethanol, and the residue was taken out, vacuum dried, and ground to obtain a dolutegravir solid dispersion.

[0046] The first mixture was obtained by mixing the dolutegravir solid dispersion, 78g mannitol and 34g starch.

[0047] 300g of lamivudine was micronized into powder with a particle size of 20-100μm, and then premixed with 90g of mannitol and 28g of talc to obtain a second mixture.

[0048] The second mixture, 600g of mannitol, and 150g of starch were mixed together, and then the first mixture and 180g of sucrose were added to obtain the third mixture.

[0049] The third mixture is mixed with 50g of magnesium stearate and then compressed into tablets at a speed of 8rpm to form the first layer of a bilayer tablet.

[0050] 702g of abacavir sulfate, 950g of mannitol, 150g of starch, 50g of talc and 40g of sucrose were mixed and compressed onto the first layer to obtain a double-layer tablet. The double-layer tablet was then coated to achieve a coating weight gain of 2%-4% w / w.

[0051] Example 4

[0052] To prepare modified mesoporous silica, 50g of dolutegravir and 30g of modified mesoporous silica were weighed, mixed, and dissolved in anhydrous ethanol. The anhydrous ethanol was evaporated to remove the ethanol, and the residue was taken out, vacuum dried, and ground to obtain a dolutegravir solid dispersion.

[0053] The first mixture was obtained by mixing the dolutegravir solid dispersion, 60g of lactose and 50g of sodium carboxymethyl cellulose.

[0054] 300g of lamivudine was micronized into powder with a particle size of 20-100μm, and then 80g of lactose and 30g of colloidal silica were added and premixed to obtain a second mixture.

[0055] The second mixture, 700g of microcrystalline cellulose and 100g of croscarmellose sodium were mixed together, and the first mixture and 150g of sucrose were added at the same time to obtain the third mixture.

[0056] The third mixture is mixed with 60g of magnesium stearate and then compressed into tablets at a speed of 5rpm to form the first layer of a bilayer tablet.

[0057] 702g of abacavir sulfate, 1085g of lactose, 140g of croscarmellose sodium, 40g of magnesium stearate and 35g of sucrose were mixed and compressed onto the first layer to obtain a bilayer tablet. The bilayer tablet was then coated to achieve a coating weight gain of 2%-4% w / w.

[0058] Comparative Example 1

[0059] To prepare modified mesoporous silica, 50g of dolutegravir and 30g of modified mesoporous silica were weighed, mixed, and dissolved in anhydrous ethanol. The anhydrous ethanol was evaporated to remove the ethanol, and the residue was taken out, vacuum dried, and ground to obtain a dolutegravir solid dispersion.

[0060] The first mixture was obtained by mixing the dolutegravir solid dispersion, 80g of microcrystalline cellulose and 30g of cross-linked sodium carboxymethyl cellulose.

[0061] 300g of lamivudine was micronized into powder with a particle size of 20-100μm, and then mixed with 700g of microcrystalline cellulose, 30g of colloidal silica and 150g of cross-linked sodium carboxymethyl cellulose. At the same time, the first mixture and 200g of sucrose were added to obtain a third mixture.

[0062] The third mixture is mixed with 40g of colloidal silica and then compressed into tablets at a speed of 5rpm to form the first layer of a bilayer tablet.

[0063] The preparation method of the first layer of Comparative Example 1 is the same as that of Example 1, except that the micronized lamivudine is not premixed, but directly mixed with 700g microcrystalline cellulose, 30g colloidal silica, 150g cross-linked sodium carboxymethyl cellulose, and then the first mixture and 200g sucrose are added.

[0064] Comparative Example 2

[0065] To prepare modified mesoporous silica, 50g of dolutegravir and 30g of modified mesoporous silica were weighed, mixed, and dissolved in anhydrous ethanol. The anhydrous ethanol was evaporated to remove the ethanol, and the residue was taken out, vacuum dried, and ground to obtain a dolutegravir solid dispersion.

[0066] The first mixture was obtained by mixing the dolutegravir solid dispersion, 80g of microcrystalline cellulose and 30g of cross-linked sodium carboxymethyl cellulose.

[0067] 300g of lamivudine was passed through a 30-50 mesh sieve and then premixed with 100g of microcrystalline cellulose and 30g of colloidal silica to obtain a second mixture.

[0068] The second mixture, 600g of microcrystalline cellulose and 150g of croscarmellose sodium were mixed together, and the first mixture and 200g of sucrose were added at the same time to obtain the third mixture.

[0069] The third mixture is mixed with 40g of colloidal silica and then compressed into tablets at a speed of 5rpm to form the first layer of a bilayer tablet.

[0070] The preparation method of the first layer of Comparative Example 2 is the same as that of Example 1, except that lamivudine is passed through a 30-50 mesh sieve instead of being micronized in Example 1.

[0071] Comparative Example 3

[0072] The first mixture was obtained by mixing 52.6g of dolutegravir sodium, 110g of microcrystalline cellulose, and 30g of croscarmellose sodium.

[0073] 300g of lamivudine was micronized into powder with a particle size of 20-100μm, and then 100g of microcrystalline cellulose and 30g of colloidal silica were added and premixed to obtain a second mixture.

[0074] The second mixture, 600g of microcrystalline cellulose and 150g of croscarmellose sodium were mixed together, and the first mixture and 200g of sucrose were added at the same time to obtain the third mixture.

[0075] The third mixture is mixed with 40g of colloidal silica and then compressed into tablets at a speed of 5rpm to form the first layer of a bilayer tablet.

[0076] The preparation method of the first layer of Comparative Example 3 is the same as that of Example 1, except that the step of preparing dolutegravir solid dispersion by mixing dolutegravir or its pharmaceutically available salt with modified mesoporous silica is omitted, and dolutegravir sodium is directly used for subsequent processing.

[0077] Comparative Example 4

[0078] The preparation method of the bilayer tablets in Comparative Example 4 is the same as that in Example 1, except that the sweetener sucrose is replaced with potassium acesulfame potassium.

[0079] Each of the above Examples 1-4 and Comparative Examples 1-4 yielded 1000 tablets.

[0080] Comparative Example 5

[0081] The preparation method of Comparative Example 5 is the same as that in CN115803018A.

[0082] The formulation in Comparative Example 5 requires high-speed shearing, wet granulation, and particle drying to prepare dolutegravir granules, which not only requires multiple pieces of equipment, increasing costs, but also makes the preparation process more complex. The present invention provides a bilayer tablet and its preparation method, employing specific processing methods based on the characteristics of different active pharmaceutical ingredients. A dolutegravir solid dispersion is prepared by mixing a relatively small amount of dolutegravir with modified mesoporous silica. A relatively large amount of lamivudine is micronized and pre-mixed with fillers and glidants. Then, through the combination of excipients, the first layer of the dolutegravir and lamivudine bilayer can be prepared using a direct powder compression method, eliminating the need for wet granulation and particle drying steps.

[0083] The powder formed by mixing the third mixture and the third gliding agent prepared in Examples 1-4, and the powder formed by mixing the third mixture and the third gliding agent prepared in Comparative Examples 1-3 (i.e., the powder used to form the first layer of tablets) were used. The angle of repose was measured using the fixed cone base method, with a cone base diameter (2R) of 5.2 cm. The stacking height h of the powder was also measured. The angle of repose α = arctg(h / R). Specific experimental results are shown in Table 1.

[0084] Table 1

[0085]

[0086] As shown in Table 1, the powders obtained in Examples 1-4 of this invention have good flowability and compressibility, and the first layer of the prepared bilayer tablets has a smooth surface without cracking. Bilayer tablets obtained by compressing abacavir or its pharmaceutically acceptable salts onto the first layer also compress smoothly without cracking. However, the powder formed by mixing the third mixture and colloidal silica in Comparative Example 1 has poor flowability. For lamivudine, while micronization increases the specific surface area of ​​the active pharmaceutical ingredient, improving dissolution and aiding in better mixing with other components, it also reduces flowability, making direct mixing with other excipients for tableting impossible. Therefore, in this invention, after micronizing lamivudine, it is first mixed with a certain amount of a second filler and a second flow aid to obtain a second mixture, and then a large amount of a third filler and a third disintegrant are added, thereby helping to improve flowability. Comparative Example 1, by changing the order of addition of lamivudine and pharmaceutical excipients, did not improve the flowability of lamivudine and made tableting difficult. In Comparative Example 2, lamivudine was prepared using a direct sieving method instead of the micronization process of this invention. Compared to dolutegravir in pharmaceutical formulations, lamivudine requires a larger dosage and is extremely prone to uneven mixing with other excipients, affecting the tableting process and resulting in an uneven surface of the first layer of the finished product. Comparative Example 3 omitted the use of modified mesoporous silica to prepare the tetrovir solid dispersion of this invention. The drug particles were prone to agglomeration, resulting in a dry powder. Comparative Example 3 was directly tableted, resulting in tablets with poor compressibility.

[0087] The bilayer tablets prepared in Examples 1-4 and the bilayer tablets in Comparative Examples 4-5 were administered orally to 20 male volunteers aged 20-35 and 20 female volunteers aged 20-35, respectively. Most volunteers reported that the amount and rate of saliva secretion after the drug entered the mouth were sufficient for swallowing. 98% of the volunteers reported a slight bitter taste in the bilayer tablets of Comparative Examples 4-5, while the bilayer tablets of Examples 1-4 had no unpleasant taste. This is presumably because modified mesoporous silica was added to the bilayer tablets prepared in this invention. Mesoporous silica contains oxygen-containing polar groups, which increases its hydrophilicity. Through the selection of a specific sweetener, sucrose, it can adhere well to the surface of the hydrophilic mesoporous silica. Furthermore, dolutegravir active pharmaceutical ingredient is highly dispersed in the mesoporous silica, and the micronized lamivudine and dolutegravir solid dispersions are also highly dispersed, ensuring uniform dispersion of sucrose in the drug formulation, reducing sucrose aggregation, and better masking unpleasant tastes. Comparative Example 4 changed the type of sweetener, resulting in a slightly bitter taste when taken orally.

[0088] 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 principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a double-layer tablet, characterized in that, The bilayer tablet comprises a first layer and a second layer. The first layer comprises the following components in parts by weight: 50 parts of dolutegravir or a pharmaceutically acceptable salt thereof (calculated as dolutegravir), 30-60 parts of modified mesoporous silica, 60-80 parts of a first filler, 30-50 parts of a first disintegrant, 300 parts of lamivudine, 80-120 parts of a second filler, 20-30 parts of a second gliding agent, 400-700 parts of a third filler, and a third disintegrant... The first layer comprises 100-150 parts of a first sweetener, 150-200 parts of a second sweetener, and 40-60 parts of a third gliding agent; the second layer comprises the following components in parts by weight: 600 parts of abacavir or a pharmaceutically acceptable salt thereof (calculated as abacavir), 950-1200 parts of a fourth filler, 120-150 parts of a fourth disintegrant, 30-50 parts of a fourth gliding agent, and 30-40 parts of a second sweetener, wherein the first and second sweeteners are selected from sucrose; The preparation method of bilayer tablets includes the following steps: S1. Dolutegravir or its pharmaceutically acceptable salt and mesoporous silica are mixed and dissolved in an appropriate amount of anhydrous ethanol. The anhydrous ethanol is evaporated to remove the ethanol. The residue is then vacuum dried, ground, and the dolutegravir solid dispersion is obtained. S2. The first mixture is obtained by mixing the dolutegravir solid dispersion, the first filler and the first disintegrant; S3. After micronizing lamivudine, add the second filler and the second gliding agent and mix to obtain the second mixture; S4. After mixing the second mixture, the third filler and the third disintegrant, the first mixture and the first sweetener are added simultaneously to obtain the third mixture; S5. The third mixture and the third gliding agent are mixed together and compressed into tablets to form the first layer of a bilayer tablet; S6. A bilayer tablet is obtained by mixing abacavir or a pharmaceutically acceptable salt thereof, a fourth filler, a fourth disintegrant, a fourth gliding agent and a second sweetener and then compressing the mixture onto the first layer. S7. Coating the double-layer tablets.

2. The method for preparing a double-layer tablet according to claim 1, characterized in that, The first filler, the second filler, the third filler and the fourth filler are selected from at least one of mannitol, lactose and microcrystalline cellulose.

3. The method for preparing a double-layer tablet according to claim 1, characterized in that, The first, third, and fourth disintegrants are selected from at least one of croscarmellose sodium, carboxymethyl starch sodium, starch, and croscarmellose.

4. The method for preparing a double-layer tablet according to claim 1, characterized in that, The second and third gliding agents are selected from at least one of magnesium stearate, colloidal silica, and talc.

5. The method for preparing a double-layer tablet according to claim 1, characterized in that, In step S3, lamivudine is micronized into powder with a particle size of 20-100 μm.

6. The method for preparing a double-layer tablet according to claim 1, characterized in that, In step S7, the double-layer tablets are coated until the coating weight gain is 2%-4% w / w.

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