Compound tablet containing rilpivirine and preparation method thereof

Abstract

The invention provides a rilpivirine-containing compound tablet and a preparation method thereof.The rilpivirine-containing compound tablet comprises 140-180 parts of first particles, 340-360 parts of second particles and 3-10 parts of a lubricant, the first particles are composed of pill cores and coating layers, the pill cores comprise 25-29 parts of rilpivirine hydrochloride, 16.5-27.5 parts of a disintegrating agent, 74-88 parts of a filler and 10-16 parts of a sustained-release material, and the coating layers are coated on the coating layers. The coating layer is prepared from 1.8 to 3.5 parts of silicon dioxide and 0.2 to 0.6 part of polysorbate 20, and the sustained-release material is hydroxypropyl methylcellulose K4M or hydroxypropyl methylcellulose K750. The rilpivirine hydrochloride, the sustained-release material and the like are prepared into the pellet core and finally form the first particle, so that the rilpivirine hydrochloride in the compound tablet can have a dissolution curve equivalent to that of a commercially available tablet, and the prepared tablet is small in weight and good in stability.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a compound tablet containing rilpivirine and a preparation method thereof. Background Art

[0002] Acquired immunodeficiency syndrome (AIDS) is a malignant infectious disease caused by the human immunodeficiency virus (HIV); HIV is an RNA virus that, after infecting host cells, attacks the human immune system and disrupts the immune balance by multiplying in large numbers and destroying CD4+T lymphocytes, thereby reducing the body's resistance and infecting other diseases, leading to various complex infections and death.

[0003] In order to solve the problem of HIV drug resistance, oral combination drugs are used to target multiple HIV proteins or different binding sites on the same protein, which can achieve long-term permanent suppression of HIV and extend the life expectancy of HIV patients. Currently, a variety of combination preparations have been approved for marketing, such as Symfi, Triumeq, Truvada, Atripla, Genvoya, Stribild, etc.

[0004] For example, Chinese patent publication number CN107847450A discloses a double-layer compound tablet containing rilpivirine, emtricitabine, and tenofovir alafenamide, including rilpivirine mixed with excipients as the first layer and emtricitabine, tenofovir alafenamide mixed with excipients as the second layer. The tablet is mixed with and There is good bioequivalence and excellent storage stability. Among them, tenofovir alafenamide was approved for marketing in the United States in November 2016, with the trade name Vemlidy, and its dosage is only 1 / 10 of tenofovir disoproxil, thereby greatly reducing the weight of the above-mentioned tablets (about 650 mg / tablet), greatly improving the patient's compliance with oral medication; however, for special groups such as children and the elderly, improving the convenience and compliance of patients is still crucial. Another technical solution in the Chinese patent with publication number CN107847450A is to prepare a single-layer tablet by directly mixing rilpivirine, emtricitabine, and tenofovir alafenamide with excipients, and the final tablet weight is only 425 mg / tablet, but the above-mentioned tablets have the disadvantages of too fast dissolution of rilpivirine and poor stability of tenofovir alafenamide.

[0005] In view of this, the present invention is proposed. Summary of the invention

[0006] The problem solved by the present invention is that for special groups such as children or the elderly, the existing rilpivirine, emtricitabine, and tenofovir alafenamide compound tablets are difficult to take into account both the convenience of patients and the stability of the active ingredients.

[0007] To solve the above problems, the present invention provides a compound tablet containing rilpivirine, comprising 140-180 parts of first particles, 340-360 parts of second particles and 3-10 parts of lubricants, wherein the first particles are composed of a pellet core and a coating layer, the pellet core comprises 25-29 parts of rilpivirine hydrochloride, 16.5-27.5 parts of a disintegrant, 74-88 parts of a filler, and 10-16 parts of a sustained-release material, and the coating layer comprises 1.8-3.5 parts of silicon dioxide and 0.2-0.6 parts of polysorbate 20, wherein the sustained-release material is hydroxypropyl methylcellulose K4M or hydroxypropyl methylcellulose K750. Preferably, the ratio of silicon dioxide to polysorbate 20 in the coating layer is 3:-4:1. Since polysorbate 20 is in a semi-solid state at room temperature, the coating success can be ensured by the force ratio of polysorbate 20.

[0008] Preferably, the disintegrant comprises at least one of polyvinyl pyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose and starch.

[0009] Preferably, the disintegrant is composed of any one of sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, starch and polyvinyl pyrrolidone, and the proportion of polyvinyl pyrrolidone in the first particle is 3-5%, such as 3%-4.5%, 3.5-4%, etc. Preferably, the disintegrant is composed of polyvinyl pyrrolidone and cross-linked sodium carboxymethyl cellulose, and the weight ratio of the two is 1:2.

[0010] Preferably, the second granules include 170-200 parts of emtricitabine, 28-30 parts of tenofovir alafenamide hemifumarate, 88-90 parts of filler, 25-30 parts of cross-linked sodium carboxymethyl cellulose, and 3-5 parts of lubricant. Preferably, the second granules include 200 parts of emtricitabine, 28 parts of tenofovir alafenamide hemifumarate, 88 parts of filler, 28 parts of cross-linked sodium carboxymethyl cellulose, and 5 parts of lubricant.

[0011] Preferably, the filler includes at least one of lactose, mannitol, sorbitol, sucrose, microcrystalline cellulose, calcium hydrogen phosphate, and sodium chloride. Preferably, the filler in the second granule is composed of microcrystalline cellulose and sodium chloride in a ratio of 1:1-3, such as 1:1.5, 1:2, 1:2.5, 1:3, etc., and the model of the microcrystalline cellulose is any one of Avicel PH101, PH102, PH103, PH112, and PH113. Preferably, the filler is composed of microcrystalline cellulose and sodium chloride in a ratio of 1:3, and the model of the microcrystalline cellulose is PH112.

[0012] Preferably, the lubricant is any one of magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, stearyl palmitin, glyceryl behenate, sodium stearyl fumarate, colloidal silicon dioxide and talc.

[0013] Preferably, the total weight of the tablet is 480-600 mg / tablet. The total weight of the tablet can be 490-550 mg / tablet, 495-530 mg / tablet, or 498-520 mg / tablet.

[0014] The present invention also provides a method for preparing a compound tablet containing rilpivirine, comprising:

[0015] S1. Preparation of the first particle

[0016] Add the prescribed amount of rilpivirine hydrochloride, disintegrant, filler and sustained-release material into a fluidized bed granulator and mix for 10-15 minutes, add a proper amount of water to the prescribed amount of polyvinyl pyrrolidone to prepare a binder solution, spray the binder solution once to form a pellet core, add a proper amount of water to the prescribed amount of silicon dioxide and polysorbate 20 to prepare a coating liquid, spray the pellet core with the coating liquid twice to form the first granules, and dry them for standby use;

[0017] S2. Preparation of the Second Particle

[0018] Mix 80-100% of the prescribed amount of emtricitabine and the prescribed amount of tenofovir alafenamide hemifumarate, a filler, a lubricant and a disintegrant for 8-12 minutes, then dry granulate to obtain second granules after granulation;

[0019] S3, tableting, coating

[0020] The first granules, the second granules and the lubricant or the first granules, the second granules, the remaining amount of emtricitabine and the lubricant are mixed for 3-5 minutes, tableted and coated.

[0021] Preferably, the particle size D of the first particle in step S1 and the second particle in step S2 is 90 Preferably, the particle size D of the first particles and the second particles is 100-300 μm. 90 150-250μm or 180-220μm or 200μm.

[0022] Preferably, the coating material in step S3 is any one of hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose and hydroxypropyl cellulose, and the specific process parameters of tableting and coating in step S3 are the existing technology.

[0023] Compared with the prior art, the compound tablet containing rilpivirine hydrochloride and the preparation method of the present invention have the following beneficial effects: 1) The present application forms a pellet core by using a sustained-release material and rilpivirine hydrochloride, etc., and uses silicon dioxide and polysorbate 20 to coat the pellet core to form a first particle. Under the synergistic effect of the sustained-release material and the silicon dioxide in the coating layer, the rilpivirine hydrochloride in the single-layer tablet is slowly released, and at the same time, the proportion and dosage of the disintegrant in the first particle are adjusted to make the dissolution law of the compound tablet basically consistent with that of the commercially available double-layer tablet; 2) The coating layer is formed by using silicon dioxide to physically isolate rilpivirine hydrochloride from tenofovir alafenamide hemifumarate, and at the same time, the first particle has good fluidity during the mixing process, and can be used as a pore-forming agent during dissolution to make the first particle stably released based on the dissolution mechanism, and the tablet has good stability and is conducive to uniform mixing; 3) The overall tablet weight of the triple compound tablet is greatly reduced, thereby meeting the medication needs of special groups such as children and the elderly. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The effect of different processes on the dissolution of rilpivirine hydrochloride in compound tablets. DETAILED DESCRIPTION

[0025] In order to make the above-mentioned purposes, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below in conjunction with the accompanying drawings. The technical features in the embodiments of the present application can be combined with each other without conflict.

[0026] The tenofovir alafenamide of the present invention is generally in the form of a pharmaceutically acceptable salt, such as a monofumarate or a hemifumarate, preferably tenofovir alafenamide hemifumarate; similarly, emtricitabine may exist in a solvated or unsolvated form, preferably in the form of emtricitabine free base; rilpivirine may exist in a solvated or unsolvated form, preferably in the form of rilpivirine hydrochloride.

[0027] It should be noted that, unless otherwise specified, the dosages described in this application refer to the amount of the active ingredient tenofovir alafenamide, emtricitabine or rilpivirine. For example, 25 mg of tenofovir alafenamide or 28 mg of tenofovir alafenamide hemifumarate have the same active ingredient, and 25 mg of rilpivirine provides the same amount of rilpivirine as 25 mg of rilpivirine free base, or 27.5 mg of rilpivirine hydrochloride.

[0028] The equipment used for preparing tablets in the present invention includes a HTD-1500 (100L) column hopper mixer, a GK40 dry granulator, a PG28 high-speed tablet press and a BGB-75 high-efficiency coating machine. The operating parameters of the GK40 dry granulator are: feeding speed 8-12HZ, roller pressure 0.7-0.9MPa, and roller speed 10-14HZ. The feeding speed is 6-8rpm, the pressure roller speed is 15-17rpm; the pressure is 4.0-4.5MPa, and the operating parameters of the BGB-75 high-efficiency coating machine are as follows: the main engine speed is 5.0-15.0r / min, the inlet air temperature is 60-100°C, the outlet air temperature is 40-80°C, and the material temperature is controlled at 40-60°C; the atomization pressure is ≥0.45MPa, the peristaltic pump speed is 0-15.0r / min, the coating weight gain is 3.5-4.5%, the air inlet volume of the fluidized bed granulator is 250-270m / h, and the inlet air temperature is 60-70°C.

[0029] Experimental Example 1 Optimization of excipients in the first granule

[0030] The same technical scheme as in Example 3 was adopted to prepare tablets according to the amounts of polyvinyl pyrrolidone and cross-linked sodium carboxymethyl cellulose in the table below. 1000 ml of a solution consisting of sodium acetate at pH 4.5 and 2% polysorbate 20 was added to USP apparatus II, and the dissolution of rilpivirine hydrochloride in the tablets was measured at 37° C. and a paddle speed of 75 RPM at 10 min, 20 min, 40 min, and 60 min. The results are shown in Table 1.

[0031] Table 1 Effect of excipients in the first granule on the dissolution of rilpivirine hydrochloride

[0032]

[0033] When hydroxypropyl methylcellulose K4M or K750 is added to the core of the first granule as a sustained-release material, and SiO2 and the like are used as a coating layer for sustained release, the amount of other excipients has a significant effect on the dissolution of rilpivirine in the tablet; the experiment found that when the proportion of polyvinyl pyrrolidone in the first granule was 6%, the tablet was obviously disintegrated into a number of hydrophilic gel-like lumps of different sizes during the dissolution process. As the amount of polyvinyl pyrrolidone in the pharmaceutical composition increased, the volume of these hydrophilic gel-like lumps increased, and the dissolution of rilpivirine hydrochloride slowed down at this time, and the dissolution rate at 60 minutes was significantly low, resulting in poor bioequivalence, and the final tablet weight was also large. When polyvinyl pyrrolidone was 1%, no obvious hydrophilic gel-like lumps were found during the dissolution process, and rilpivirine hydrochloride had an obvious burst release phenomenon. Finally, the dissolution rate of rilpivirine hydrochloride at 60 minutes was greater than 50%, and the bioequivalence was also unsatisfactory. When the proportion of polyvinyl pyrrolidone in the first granule is 4% and the proportion of cross-linked sodium carboxymethyl cellulose is 12%, the tablet disintegrates during the dissolution process to form a significantly smaller mass of a hydrophilic gel-like substance, which not only prevents the sudden release of rilpivirine hydrochloride but also ensures sufficient release in the later stage through a reasonable combination of the two. The release pattern is well consistent with that of commercially available tablets.

[0034] Example 1

[0035] A compound tablet containing rilpivirine, comprising the following ingredients:

[0036]

[0037] Prepared by the following method:

[0038] S1. Preparation of the first particle

[0039] The prescribed amount of rilpivirine hydrochloride, lactose monohydrate, cross-linked sodium carboxymethyl cellulose, and hypromellose were added to a fluidized bed granulator and mixed for 10 minutes. The prescribed amount of polyvinyl pyrrolidone was added with an appropriate amount of water to prepare a binder solution, which was sprayed once to form a pellet core. The average particle size of the pellet core was D 90 =250μm;

[0040] A coating liquid is prepared by adding a proper amount of water to a prescribed amount of silicon dioxide and polysorbate 20. The coating liquid is used to spray the pellet cores twice to form first particles. The first particles are placed in an oven at 50° C. for drying.

[0041] S2. Preparation of the second particle

[0042] The prescribed amount of emtricitabine, tenofovir alafenamide hemifumarate, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose were mixed for 8 minutes and then dry granulated to obtain an average particle size D90 =250 μm second particles.

[0043] S3, tableting, coating

[0044] The first granules, the second granules and magnesium stearate are mixed for 5 minutes, and 1000 tablets are compressed. After coating, the tablets are dried to obtain the product.

[0045] Example 2

[0046] A compound tablet containing rilpivirine, comprising the following ingredients:

[0047]

[0048]

[0049] Prepared by the following method:

[0050] S1. Preparation of the first particle

[0051] The prescribed amount of rilpivirine hydrochloride, starch, sodium starch glycolate, and hypromellose were added to a fluidized bed granulator and mixed for 15 minutes. The prescribed amount of polyvinyl pyrrolidone was added with an appropriate amount of water to prepare a binder solution, which was sprayed once to form a pellet core. The average particle size of the pellet core was D 90 =240μm;

[0052] A coating liquid was prepared by adding a proper amount of water to the prescribed amount of silicon dioxide and polysorbate 20. The coating liquid was used to spray the pellet cores twice to form first particles. The first particles were placed in an oven at 52° C. for drying.

[0053] S2. Preparation of the second particle

[0054] The prescribed amount of emtricitabine, tenofovir alafenamide hemifumarate, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose were mixed for 12 minutes and then dry granulated to obtain an average particle size D 90 =250 μm second particles.

[0055] S3, tableting, coating

[0056] The first granules, the second granules and glyceryl behenate are mixed for 4 minutes, compressed into 1000 tablets, and coated to obtain the product.

[0057] Example 3

[0058] A compound tablet containing rilpivirine, comprising the following ingredients:

[0059]

[0060]

[0061] Prepared by the following method:

[0062] S1. Preparation of the first particle

[0063] The prescribed amount of rilpivirine hydrochloride, maltodextrin, starch, and hydroxypropyl methylcellulose were added to a fluidized bed granulator and mixed for 15 minutes. The prescribed amount of polyvinyl pyrrolidone was added with an appropriate amount of water to prepare a binder solution, which was sprayed once to form a pellet core. The average particle size of the pellet core was D 90 =100 μm;

[0064] A coating liquid was prepared by adding a proper amount of water to the prescribed amount of silicon dioxide and polysorbate 20. The coating liquid was used to spray the pellet cores twice to form first particles. The first particles were placed in an oven at 52° C. for drying.

[0065] S2. Preparation of the second particle

[0066] The prescribed amount of emtricitabine, tenofovir alafenamide hemifumarate, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose were mixed for 12 minutes and then dry granulated to obtain an average particle size D 90 = second particles of 100 μm;

[0067] S3, tableting, coating

[0068] The first granules, the second granules and hydrogenated vegetable oil are mixed for 4 minutes, 1000 tablets are compressed and coated.

[0069] Example 4

[0070] A compound tablet containing rilpivirine, comprising the following ingredients:

[0071]

[0072]

[0073] Prepared by the following method:

[0074] S1. Preparation of the first particle

[0075] The prescribed amount of rilpivirine hydrochloride, maltodextrin, starch, and hydroxypropyl methylcellulose were added to a fluidized bed granulator and mixed for 15 minutes. The prescribed amount of polyvinyl pyrrolidone was added with an appropriate amount of water to prepare a binder solution, which was sprayed once to form a pellet core. The average particle size of the pellet core was D 90 =80μm;

[0076] A coating liquid was prepared by adding a proper amount of water to the prescribed amount of silicon dioxide and polysorbate 20. The coating liquid was used to spray the pellet cores twice to form first particles. The first particles were placed in an oven at 52° C. for drying.

[0077] S2. Preparation of the second particle

[0078] The prescribed amount of emtricitabine, tenofovir alafenamide hemifumarate, microcrystalline cellulose (model PH113), cross-linked sodium carboxymethyl cellulose, sodium chloride and magnesium stearate were mixed for 12 minutes and then dry granulated to obtain an average particle size D 90 = second particles of 250 μm;

[0079] S3, tableting, coating

[0080] The first granules, the second granules and the remaining amount of emtricitabine and magnesium stearate are mixed for 4 minutes, compressed into 1000 tablets, and coated to obtain the product.

[0081] Example 5

[0082] A compound tablet containing rilpivirine, comprising the following ingredients:

[0083]

[0084] Prepared by the following method:

[0085] S1. Preparation of the first particle

[0086] The prescribed amount of rilpivirine hydrochloride, maltodextrin, starch, and hydroxypropyl methylcellulose were added to a fluidized bed granulator and mixed for 15 minutes. The prescribed amount of polyvinyl pyrrolidone was added with an appropriate amount of water to prepare a binder solution, which was sprayed once to form a pellet core. The average particle size of the pellet core was D 90 =250μm;

[0087] A coating liquid was prepared by adding a proper amount of water to the prescribed amount of silicon dioxide and polysorbate 20. The coating liquid was used to spray the pellet cores twice to form first particles. The first particles were placed in an oven at 52° C. for drying.

[0088] S2. Preparation of the second particle

[0089] The prescribed amount of emtricitabine, tenofovir alafenamide hemifumarate, microcrystalline cellulose (model PH113), cross-linked sodium carboxymethyl cellulose, sodium chloride and magnesium stearate were mixed for 10 minutes and then dry granulated to obtain an average particle size D 90 =250 μm second particles.

[0090] S3, tableting, coating

[0091] The first granules, the second granules and the remaining amount of emtricitabine and magnesium stearate are mixed for 5 minutes, compressed into 1000 tablets, and coated to obtain the product.

[0092] Comparative Example 1

[0093] The same components as in Example 3 were used for preparation, with the only difference being that the prescribed amount of silicon dioxide, polysorbate 20 and polyvinyl pyrrolidone were used to prepare a binder solution, and the binder solution was sprayed once to form a pellet core as the first particle.

[0094] Comparative Example 2

[0095] The same components as in Example 3 were used for preparation, with the only difference being that the hypromellose K4M was replaced by hypromellose K15M.

[0096] Comparative Example 3

[0097] A single-layer tablet was prepared according to the components and method of Example 8 in Publication No. CN107847450A.

[0098] Comparative Example 4

[0099] Odefsey is commercially available from Gilead.

[0100] The tablets prepared in Example 3, Comparative Examples 1-3 and commercially available tablets were subjected to dissolution tests on rilpivirine hydrochloride. The test conditions were as follows: 1000 ml of a solution consisting of sodium acetate at pH 4.5 and 2% polysorbate 20 was added to USP apparatus II and tested at 37°C and a paddle speed of 75 RPM. The results are shown in Table 1. Figure 1 .

[0101] Depend on Figure 1 It can be seen that the single-layer composite tablet containing rilpivirine prepared in Example 3 of the present application is prepared by using hydroxypropyl methylcellulose K4M as a sustained-release material and rilpivirine hydrochloride, etc. to prepare the pill core, and the dosage ratio of polyvinyl pyrrolidone and cross-linked carboxymethyl cellulose sodium as disintegrants is optimized, thereby avoiding the sudden release of rilpivirine hydrochloride and dissolving stably, and using silicon dioxide and polysorbate 20 as coating layers to avoid physical contact between rilpivirine hydrochloride and tenofovir alafenamide hemifumarate, not only making silicon dioxide on the surface of the first particles, increasing the fluidity of the material is conducive to uniform mixing, but also making the tablet disintegrate after entering the human body, and forming a self-microemulsion drug delivery system by dissolving the surface of the first particles, playing the role of a pore-forming agent, thereby improving the solubility of rilpivirine hydrochloride in the human body; and polysorbate 20 as a surfactant has amphiphilicity, ensuring that rilpivirine hydrochloride still maintains a good absorption rate after entering the body. Compared with Comparative Example 4, the weight of the tablets prepared in Example 3 of the present application was significantly reduced, and the dissolution rate of rilpivirine hydrochloride in the tablets was significantly reduced and finally had a dissolution curve that was basically consistent with that of commercially available tablets. Examples 1-2 and 4-5 had a dissolution curve that was basically consistent with that of Example 3, which will not be described in detail here.

[0102] In Comparative Example 1, silicon dioxide, polysorbate 20 and polyvinyl pyrrolidone were used to prepare a binder solution to form a pellet core. The pellet core surface had no coating layer, which resulted in the dissolution of rilpivirine hydrochloride being faster than that of Example 3 under the same conditions; and after the type of sustained-release material-hydroxypropyl methylcellulose was changed in Comparative Example 2, the dissolution of rilpivirine hydrochloride was significantly slower than that of the commercially available product. Since emtricitabine and tenofovir alafenamide hemifumarate belong to BCS Class I and Class III drugs, respectively, more than 90% of emtricitabine and tenofovir alafenamide hemifumarate in the above-mentioned tablets are released within 20 minutes, which will not be described in detail.

[0103] The tablets prepared in Examples 1-5 and Comparative Examples 1-4 and the commercially available tablets were placed under accelerated conditions (40°C-RH75%) for 3 months, and the total impurity content of the degradation products of tenofovir alafenamide hemifumarate was detected. The results are shown in Table 2. The detection methods of the degradation products of tenofovir alafenamide hemifumarate, rilpivirine hydrochloride, and emtricitabine degradation products are prior art and will not be described in detail here.

[0104] Table 2 Total impurity content of tenofovir alafenamide hemifumarate degradation products in different groups

[0105]

[0106]

[0107] As can be seen from Table 2, in Examples 1-5 of the present application, a coating layer is sprayed on the surface of the pellet core containing rilpivirine hydrochloride to form the first particles, thereby avoiding physical contact between rilpivirine and tenofovir alafenamide hemi-fumarate, and effectively avoiding the degradation of tenofovir alafenamide hemi-fumarate; at the same time, in Examples 4-5, by directly adding part of emtricitabine during the mixing process, the proportion of tenofovir alafenamide hemi-fumarate in the local environment of the second particles is increased while meeting the normal tableting requirements, and the contact between tenofovir alafenamide hemi-fumarate and emtricitabine is reduced. The contact probability of tricitabine can be further improved to further improve its stability; at the same time, when the sodium chloride: microcrystalline cellulose PH113 in the second granules is 1:3, the stability of tenofovir alafenamide hemifumarate can be further improved. The possible reasons are: sodium chloride is a neutral compound with stable physical and chemical properties, and its own hygroscopicity is very low, it has good compatibility and is easily soluble in water, which is beneficial to the dissolution and release of the active ingredient after the process is improved. Compared with the common PH102, the water content of microcrystalline cellulose PH113 itself is extremely low.

[0108] In Comparative Example 1, when silicon dioxide, polysorbate 20 and polyvinyl pyrrolidone are used to prepare a binder solution to form a pellet core, or when rilpivirine hydrochloride is located in the coating layer in Comparative Example 2, part of the rilpivirine hydrochloride in the corresponding first granules will directly contact tenofovir alafenamide hemifumarate, resulting in poor stability of the final tablet. In the accelerated stability test, no impurities were detected in emtricitabine and rilpivirine hydrochloride in the tablets prepared in Examples 1-5 of the present application, and good stability was always maintained.

[0109] Although the present invention is disclosed as above, the present invention is not limited thereto. Any person skilled in the art can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the scope defined by the claims.

Claims

1. A compound tablet containing rilpivirine, characterized in that: The invention comprises 140-180 parts of first particles, 340-360 parts of second particles and 3-10 parts of lubricant, wherein the first particles are composed of a pellet core and a coating layer, the pellet core comprises 25-29 parts of rilpivirine hydrochloride, 16.5-27.5 parts of a disintegrant, 74-88 parts of a filler and 10-16 parts of a sustained-release material, the coating layer comprises 1.8-3.5 parts of silicon dioxide and 0.2-0.6 parts of polysorbate 200, wherein the sustained-release material is hydroxypropyl methylcellulose K4M or hydroxypropyl methylcellulose K750.

2. The rilpivirine-containing compound tablet according to claim 1, characterized in that: The disintegrant comprises at least one of polyvinyl pyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose and starch.

3. The rilpivirine-containing compound tablet according to claim 2, characterized in that: The disintegrant is composed of any one of sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, starch and polyvinyl pyrrolidone, and the proportion of the polyvinyl pyrrolidone in the first particle is 3-5%.

4. The rilpivirine-containing compound tablet according to claim 1, characterized in that: The second granules include 170-200 parts of emtricitabine, 25-30 parts of tenofovir alafenamide hemifumarate, 88-90 parts of filler, 28-30 parts of cross-linked sodium carboxymethyl cellulose, and 3-5 parts of lubricant.

5. The rilpivirine-containing compound tablet according to claim 5, characterized in that: The filler includes at least one of lactose, mannitol, sorbitol, sucrose, microcrystalline cellulose, calcium hydrogen phosphate, and sodium chloride.

6. The rilpivirine-containing compound tablet according to claim 5, characterized in that: The lubricant is any one of magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, stearyl palmitin, glyceryl behenate, sodium stearyl fumarate, colloidal silicon dioxide and talc.

7. The rilpivirine-containing compound tablet according to claim 1, characterized in that: The total weight of the tablet is 490-600 mg / tablet.

8. The method for preparing the rilpivirine-containing compound tablet according to any one of claims 1 to 7, characterized in that: include: S1. Preparation of the first particle Add the prescribed amount of rilpivirine hydrochloride, disintegrant, filler and sustained-release material into a fluidized bed granulator and mix for 10-15 minutes, add a proper amount of water to the prescribed amount of polyvinyl pyrrolidone to prepare a binder solution, spray the binder solution once to form a pellet core, add a proper amount of water to the prescribed amount of silicon dioxide and polysorbate 20 to prepare a coating liquid, spray the pellet core with the coating liquid twice to form the first granules, and dry them for standby use; S2. Preparation of the Second Particle Mix 80-100% of the prescribed amount of emtricitabine and the prescribed amount of tenofovir alafenamide hemifumarate, a filler, a lubricant and a disintegrant for 8-12 minutes, then dry granulate to obtain second granules after granulation; S3, tableting, coating The first granules, the second granules and the lubricant or the first granules, the second granules, the remaining amount of emtricitabine and the lubricant are mixed for 3-5 minutes, tableted and coated.

9. The method for preparing the rilpivirine-containing compound tablet according to claim 8, characterized in that: The particle size D of the first particle in step S1 and the second particle in step S2 90 100-300μm.

10. The method for preparing the rilpivirine-containing compound tablet according to claim 8, characterized in that: In step S3, the coating material is any one of hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.

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