Compound tablet of emtricitabine, propylene glycol and tenofovir and preparation method thereof

Abstract

The application provides a compound tablet of emtricitabine, propylene glycol and tenofovir and a preparation method, the compound tablet of emtricitabine, propylene glycol and tenofovir comprises a tablet core, and the tablet core comprises 300-330 parts of first granules, 20-40 parts of emtricitabine and 3-5 parts of a lubricant, wherein the first granules are composed of 28 parts of semi-fumarate tenofovir alafenamide, 160-180 parts of emtricitabine, 85-90 parts of a filling agent, 25-30 parts of a disintegrating agent and 3-5 parts of a lubricant, and the particle size D 90 100-300 μm. The compound tablet of emtricitabine, propylene glycol and tenofovir is prepared by using dry granulation combined with direct compression, has small modification to the existing process, is convenient for production and processing, has more excellent storage stability under the condition that the dissolution performance and mixing uniformity are equivalent to those of a commercial preparation, and is especially excellent under illumination.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to an emtricitabine-propofol-tenofovir combination tablet and its preparation method. Background Technology

[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, multiplies rapidly and destroys CD4+ T lymphocytes to attack the human immune system and disrupt immune balance. This leads to a decrease in the body's resistance and infection with other diseases, resulting in various complex infections and death.

[0003] To address the issue of HIV drug resistance, oral combination drugs can be used to target multiple HIV proteins or different binding sites on the same protein, achieving long-term permanent suppression of HIV and extending the life expectancy of HIV patients. Currently, several combination formulations have been approved for marketing.

[0004] Tenofovir alafenamide fumarate, developed by Gilead Sciences, Inc. (developed under license number GS-7340), is a second oral prodrug of tenofovir. It is formed by modifying the prodrug groups on the two hydroxyl groups of the phosphate group in the structure of tenofovir disoproxil fumarate (TDF), replacing dipyridoxine with an amide and a phenolic ester. Because TAF is almost entirely absorbed in the blood and directly transported to lymphocytes and macrophages where it is broken down into tenofovir, then phosphorylated to form the active ingredient, it requires a smaller dosage and has fewer side effects under the same conditions.

[0005] The drug name for the combined use of tenofovir alafenamide and emtricitabine is emtricitabine alafenamide tablets (II), which was first approved by the US FDA in 2016 under the English brand name Descovy; and was approved for marketing in China in 2018 for the treatment of HIV-1 infection in adults and adolescents. Gilead's Chinese patent CN107847450A discloses a drug formulation containing tenofovir and emtricitabine, comprising 200 mg emtricitabine, 28 mg tenofovir alafenamide hemifumarate, 28 mg croscarmellose sodium, 88 mg microcrystalline cellulose, and 7 mg magnesium stearate. The formulation is prepared by dry granulation of emtricitabine, tenofovir alafenamide hemifumarate, microcrystalline cellulose, and croscarmellose sodium, followed by mixing with magnesium stearate, compression, and coating, with a tablet weight of 350 mg / tablet. The storage stability of the above-mentioned tablets containing tenofovir alafenamide is poor, especially in the presence of emtricitabine; while placing a desiccant inside the packaging bottle can improve stability, the operation is obviously very cumbersome.

[0006] In view of this, the present invention is hereby proposed. Summary of the Invention

[0007] The problem addressed by this invention is that the stability of tenofovir alafenamide in existing compound tablets still needs to be improved.

[0008] To address the aforementioned problems, this invention provides an emtricitabine-propionol-tenofovir combination tablet, comprising a tablet core. The tablet core includes 300-330 parts of a first particle, 20-40 parts of emtricitabine, and 3-5 parts of a lubricant. The first particle is composed of 28 parts of tenofovir alafenamide hemifumarate, 160-180 parts of emtricitabine, 85-90 parts of a filler, 25-30 parts of a disintegrant, and 3-5 parts of a lubricant, with a particle size D... 90 It is 100-300μm.

[0009] Preferably, the particle size D of the first particle 90 The particle size D of the emtricitabine is 150-250 μm. 90 The particle size is 150-200 μm. Preferably, the particle size D of the first particle is... 90 It is 200μm.

[0010] Preferably, the emtricitabine-propionol-tenofovir combination tablets comprise 307-327 parts of the first granule, 20-40 parts of emtricitabine, and 3-5 parts of lubricant, wherein the first granule comprises 28 parts of tenofovir alafenamide hemifumarate, 160-180 parts of emtricitabine, 88 parts of filler, and 28 parts of disintegrant.

[0011] Preferably, the lubricant is any one of magnesium stearate, stearic acid, hydrogenated vegetable oil, glyceryl behenate, and sodium fumarate stearate.

[0012] Preferably, the disintegrant is any one of starch, cellulose, cross-linked PVP, sodium glycolate starch, and sodium carboxymethyl cellulose.

[0013] Preferably, the filler is at least one selected from microcrystalline cellulose, mannitol, lactose monohydrate, and sodium chloride. Preferably, the filler is composed of microcrystalline cellulose and sodium chloride in a ratio of 1:0.5-1:3, wherein the microcrystalline cellulose is of type Avicel PH113.

[0014] This invention also provides a method for preparing emtricitabine-propionol-tenofovir combination tablets, comprising the following steps:

[0015] S1. Tenofovir disoproxil fumarate and emtricitabine are pulverized and the particle size D is controlled. 90 150-200μm, ready for use;

[0016] S2. Mix the prescribed amounts of tenofovir alafenamide hemifumarate, emtricitabine, filler, disintegrant, and lubricant, and then dry granulate them using a dry granulator to obtain the first granules.

[0017] S3. Mix the first granules, the remaining emtricitabine, and the lubricant using a three-dimensional mixer for 5-10 minutes. Press the material into 350mg tablet cores, making a total of 1000 tablets, and then perform film coating.

[0018] Preferably, the particle size D of emtricitabine after pulverization in step S1 is... 90 It is 150μm.

[0019] Preferably, the process parameters for dry granulation are: feeding speed 10-20 Hz, roller pressure 0.6-0.9 MPa, and roller speed 12-18 Hz. Specifically, it can be a feeding speed of 16 Hz, roller pressure of 0.8 MPa, and roller speed of 12 Hz; or a feeding speed of 12 Hz, roller pressure of 0.9 MPa, and roller speed of 15 Hz; or a feeding speed of 18 Hz, roller pressure of 0.7 MPa, and roller speed of 18 Hz.

[0020] Compared with the prior art, the emtricitabine-propofol-tenofovir combination tablets and preparation method of the present invention have the following beneficial effects: 1) By directly compressing a portion of emtricitabine into tablets and granulating them, the local content of propofol-tenofovir in the first granule is increased while the contact probability with emtricitabine is reduced, thereby improving its stability and ensuring that the prepared first granule has good flowability; 2) The applicant found that different types of microcrystalline cellulose can affect the stability of the mixture; at the same time, it was unexpectedly found that sodium chloride and microcrystalline cellulose produce a synergistic effect when mixed at a ratio of 1:3, and the stability of the material can be further improved; in addition, replacing weakly basic magnesium stearate with hydrogenated vegetable oil can improve the stability under light conditions; 3) By optimizing the particle size of the first granule and emtricitabine, the content of the active pharmaceutical ingredient in the tablet can be mixed with the same uniformity as commercially available formulations. Detailed Implementation

[0021] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, specific embodiments of the present invention are described in detail below. The tenofovir alafenamide described in the present invention is generally in the form of a pharmaceutically acceptable salt, such as monofumarate or hemifumarate, preferably tenofovir alafenamide hemifumarate; similarly, emtricitabine may be present in a solvated or non-solvated form, preferably in the form of a free emtricitabine base.

[0022] It should be noted that, unless otherwise specified, the dosages mentioned in this application refer to the amount of the active ingredient tenofovir alafenamide or emtricitabine. For example, 25 mg of tenofovir alafenamide or 28 mg of tenofovir alafenamide hemifumarate has the same active ingredient. The mannitol mentioned in this application is manufactured by Roquette, France, under the trade name PEARLITOL, model 50C.

[0023] Effect of the proportion of FTC added in the first particle of Experiment Example 1 on the stability and angle of repose of the mixture

[0024] Increasing the drug loading of tenofovir alafenamide improves its stability. Based on bioequivalence studies, the dosage of tenofovir alafenamide in tablets was determined to be 25 mg. Although emtricitabine affects the stability of tenofovir alafenamide, especially under high temperature and humidity conditions, the process of dry granulation and compression of emtricitabine and tenofovir alafenamide is simple and meets the requirements for tablet production.

[0025] Because emtricitabine has poor compressibility and flowability, and its total content is as high as 64%, direct compression for tablet core preparation yields extremely poor results. Furthermore, tenofovir alafenamide is sensitive to water, making wet granulation for tablet preparation currently impractical. Therefore, the applicant prepared large-diameter first granules and conducted the following experiments on the dosage of emtricitabine in the first granules:

[0026] 280g of tenofovir alafenamide hemifumarate, 280g of croscarmellose sodium, 880g of microcrystalline cellulose, 25g of magnesium stearate, and a certain amount of emtricitabine were dry granulated. Specific process parameters were: feed rate 9Hz, roller pressure 0.8MPa, roller speed 16Hz, and granulation speed 15Hz to obtain the first granules. 90 The particle size was 200 μm. The first particle, the remaining emtricitabine, and magnesium stearate were mixed, and the angle of repose of the material was measured. At the same time, a portion of the material was stored at 40℃ / 75%RH for one month to measure the total amount of degradation products of tenofovir alafenamide hemifumarate in the material. The results are shown in Table 1.

[0027] Table 1. Effects of Emtricitabine Dosage in the First Particle on Material Stability and Compressibility

[0028]

[0029]

[0030] Take 50g of the prepared mixture and slowly add it from the top funnel, allowing the excipients to gradually accumulate on the base plate through the funnel's buffer, forming a cone, until the highest cone is obtained. Measure the height H of the cone and calculate the angle of repose using the following formula: α = arctg(H / R), where α is the angle of repose and R is the radius of the base plate. When the angle of repose is ≤30°, the material exhibits excellent flowability; when the angle of repose is 36-40°, the material has good flowability; and when the angle of repose is 42-45°, the material may still have some flowability. The detection methods for the corresponding degradation products or total impurities of tenofovir alafenamide are existing technologies and will not be elaborated here.

[0031] As shown in the table above, the first particle (particle size D) 90 The smallest material unit is 200 μm. Reducing the amount of emtricitabine can increase the relative content of tenofovir alafenamide in the first granule, which is beneficial to improving its storage stability. However, emtricitabine without dry granulation will change the compressibility of the material. When the amount of emtricitabine in the first granule accounts for 60-80% of the total amount, the stability of the mixture for preparing the tablet core is good and can meet the tableting requirements. In fact, when the amount of emtricitabine in the first granule is less than 50% of the total amount, not only the angle of repose parameter is lost, but the mixed material cannot be used for tableting at all.

[0032] In the initial stage of the experiment, the applicant attempted to dry granulate only tenofovir alafenamide, and then mix it with emtricitabine and lubricant for tableting and coating. However, the poor compressibility of the mixture resulted in large differences in tablet weight, which made it difficult to meet production requirements. After dry granulating tenofovir alafenamide with microcrystalline cellulose, a second dry granulation was performed with emtricitabine. Due to the change in material properties, the uniformity of the second dry granulation was not up to standard, the process was relatively complicated, and the stability was significantly poor.

[0033] Experiment Example 2: The Effect of Fillers on Material Stability

[0034] The applicant was able to improve stability by increasing the particle size of the first particle while reducing the proportion of emtricitabine in the first particle, but this improvement is still needed compared to other drugs. Moisture is generally considered to be an important factor affecting the stability of tenofovir alafenamide, while fillers are generally considered to have no effect on stability.

[0035] Due to the different types of excipients, their performance varies slightly. Specifically, the particle size and bulk density of different types of microcrystalline cellulose differ, resulting in variations in their physicochemical properties. Consequently, the applicant unexpectedly discovered that tablets prepared with Avicel PH113 exhibit significantly greater stability than those prepared with conventional Avicel PH101 and Avicel PH102. The applicant prepared first granules using different types and grades of fillers, each containing 80% emtricitabine. These first granules were then mixed with the remaining emtricitabine and a lubricant. The mixture was stored at 40°C / 75% RH for one month for stability testing, and the results are shown in Table 2.

[0036] Table 2. Effects of different fillers on material stability

[0037] AvicelPH102 0.63％ AvicelPH113 0.52％ AvicelPH301 0.67％ Colloidal silica 0.76％ Mannitol 0.78％ Sodium chloride 0.59％ Lactose monohydrate: AvicelPH113 = 1:1 0.81％ Sodium chloride: AvicelPH113 = 1:1 0.47％ Colloidal silica: Avicel PH113 = 1:1 0.79％ Mannitol:AvicelPH113 = 1:1 0.82％ Sodium chloride: AvicelPH113 = 1:2 0.42％ Sodium chloride: AvicelPH113 = 1:3 0.38％ Sodium chloride: AvicelPH113 = 1:4 0.47％ Sodium chloride: AvicelPH113 = 1:5 0.54％

[0038] As shown in the table above, common fillers do not affect the stability of tenofovir alafenamide. However, compared to the common Avicel PH102, the microcrystalline cellulose Avicel PH113 can further improve the stability of tenofovir alafenamide. The inventors unexpectedly discovered that when the ratio of sodium chloride to Avicel PH113 is 1:3, the degradation rate of tenofovir alafenamide can be reduced to as low as 0.38%, and the stability of tenofovir alafenamide can be significantly improved in long-term accelerated tests. This may be because sodium chloride is a very stable neutral compound with excellent compatibility; it does not react chemically with emtricitabine or tenofovir alafenamide. Furthermore, sodium chloride is readily soluble in water, which is beneficial for the dissolution and release of the active ingredient after process improvement. Additionally, sodium chloride has a very low water content and very low hygroscopicity in production environments with relative humidity below 70%. Moreover, sodium chloride is a cubic crystal with excellent compressibility, which is beneficial for tableting under lower pressure after process improvement.

[0039] Experimental Example 3: Effect of Particle Size on Tablet Preparation

[0040] The applicant discovered that when the above excipients were used to prepare tablets, the increased particle size of the first particles obtained by dry granulation affected the uniformity of the final mixture. Therefore, the applicant used sodium chloride:Avicel PH113 = 1:3 as a filler to dry granulate 80% of emtricitabine and tenofovir alafenamide to prepare first particles of different sizes. The remaining emtricitabine was micronized, and the content uniformity under different particle sizes was measured. The material was stored at 40℃ / 75%RH for 1 month to determine the total impurity content of tenofovir alafenamide. The results are shown in Table 3.

[0041] The content uniformity was determined according to the content uniformity test method (General Rule 0941) of Part IV of the 2020 edition of the Chinese Pharmacopoeia. After mixing the materials for each parameter condition for 10 min, 10 samples were taken and the relative content Xi of tenofovir alafenamide with a labeled amount of 100 was determined. The average value and standard deviation S of the relative content and the absolute value A of the difference between the labeled amount and the average index were calculated. A+2.2S was used as the content uniformity index of the test sample.

[0042] Table 3. Effects of different particle sizes on the mixing uniformity and stability of materials.

[0043]

[0044]

[0045] Table 3 shows that the total impurity content of tenofovir alafenamide is generally proportional to the particle size of the first particle. This may be because this application reduced the emtricitabine content in the first particle, thereby increasing the amount of tenofovir alafenamide within this local micro-unit and improving overall stability. Table 3 also shows the influence of the particle size of the first particle and the emtricitabine directly compressed on the uniformity of the material content. The inventors unexpectedly discovered that when the particle size D of the first particle... 90 =250μm, emtricitabine particle size D 90 When the particle size is 150 μm, the mixing uniformity of the material is better. At the same time, the dissolution rate of tenofovir alafenamide and emtricitabine in the prepared tablets reaches more than 90% within 20 minutes. The possible reason is that the relative content of disintegrant and filler in the first particle increases, which leads to changes in the material properties. By controlling the particle size of the first particle and emtricitabine used directly for tableting, the flowability of the material is significantly improved. The inventors conducted preliminary experiments to further increase the particle size of the first particle. At this time, the dissolution performance of the prepared tablets obviously cannot meet the requirements, and there is a clear lack of bioequivalence with the original drug.

[0046] Example 1

[0047] An emtricitabine-propofol-tenofovir combination tablet, with a prescription composition of 1000 tablets, is as follows:

[0048]

[0049]

[0050] The following preparation process is adopted:

[0051] S1. Tenofovir disoproxil fumarate and emtricitabine are pulverized and the particle size D is controlled. 90 It is 150μm;

[0052] S2. Mix the prescribed amounts of tenofovir alafenamide hemifumarate, emtricitabine, microcrystalline cellulose (Avicel PH113), sodium chloride, croscarmellose sodium, and magnesium stearate, and dry granulate using a dry granulator. After granulation, the particle size D of the first granules is obtained. 90 The particle size is 250 μm; the process parameters for dry granulation are: feeding speed 9 Hz, roller pressure 0.8 MPa, and roller speed 16 Hz.

[0053] S2. Mix the first particle and the remaining emtricitabine and magnesium stearate using a three-dimensional mixer for 10 minutes.

[0054] S3. Press the material into 350mg tablet cores, a total of 1000 tablets, and then perform film coating.

[0055] Example 2

[0056] An emtricitabine-propofol-tenofovir combination tablet, with a prescription composition of 1000 tablets, is as follows:

[0057]

[0058]

[0059] The following preparation process is adopted:

[0060] S1. Tenofovir disoproxil fumarate and emtricitabine are pulverized and the particle size D is controlled. 90 It is 150μm;

[0061] S2. Mix the prescribed amounts of tenofovir alafenamide hemifumarate, emtricitabine, microcrystalline cellulose (Avicel PH113), sodium chloride, croscarmellose sodium, and magnesium stearate, and dry granulate using a dry granulator. After granulation, the particle size D of the first granules is obtained. 90 The particle size is 250 μm; the process parameters for dry granulation are: feeding speed 8 Hz, roller pressure 0.9 MPa, and roller speed 12 Hz.

[0062] S2. Mix the first particle and the remaining emtricitabine and magnesium stearate using a three-dimensional mixer for 8 minutes.

[0063] S3. Press the material into 350mg tablet cores, a total of 1000 tablets, and then perform film coating.

[0064] Example 3

[0065] An emtricitabine-propofol-tenofovir combination tablet, with a prescription composition of 1000 tablets, is as follows:

[0066]

[0067]

[0068] The following preparation process is adopted:

[0069] S1. Tenofovir disoproxil fumarate and emtricitabine are pulverized and the particle size D is controlled. 90 It is 150μm;

[0070] S2. Mix the prescribed amounts of tenofovir alafenamide hemifumarate, emtricitabine, microcrystalline cellulose (Avicel PH113), sodium chloride, croscarmellose sodium, and magnesium stearate, and dry granulate using a dry granulator. After granulation, the particle size D of the first granules is obtained. 90 The particle size is 250 μm; the process parameters for dry granulation are: feeding speed 10 Hz, roller pressure 0.7 MPa, and roller speed 14 Hz.

[0071] S2. Mix the first particle and the remaining emtricitabine and magnesium stearate using a three-dimensional mixer for 9 minutes.

[0072] S3. Press the material into 350mg tablet cores, a total of 1000 tablets, and then perform film coating.

[0073] Example 4

[0074] An emtricitabine-propofol-tenofovir combination tablet, with a prescription composition of 1000 tablets, is as follows:

[0075]

[0076] The following preparation process is adopted:

[0077] S1. Tenofovir disoproxil fumarate and emtricitabine are pulverized and the particle size D is controlled. 90 It is 150μm;

[0078] S2. Mix the prescribed amounts of tenofovir alafenamide hemifumarate, emtricitabine, microcrystalline cellulose (Avicel PH113), sodium chloride, croscarmellose sodium, and hydrogenated vegetable oil, and dry granulate using a dry granulator. After granulation, the first particle size D is obtained. 90 The particle size is 250 μm; the process parameters for dry granulation are: feeding speed 9 Hz, roller pressure 0.8 MPa, and roller speed 14 Hz.

[0079] S2. Mix the first particle, the remaining emtricitabine, and the hydrogenated vegetable oil using a three-dimensional mixer for 9 minutes.

[0080] S3. Press the material into 350mg tablet cores, a total of 1000 tablets, and then perform film coating.

[0081] Comparative Example 1

[0082] Commercially available tablets, brand name: Descovy.

[0083] Comparative Example 2

[0084] Using the same formulation as in Example 1, the specific preparation process is as follows: S1, tenofovir alafenamide hemifumarate and emtricitabine are pulverized and the particle size D is controlled. 90 The particle size is 50μm; S2, the prescribed amounts of tenofovir alafenamide hemifumarate, microcrystalline cellulose (model Avicel PH113), mannitol, and croscarmellose sodium are dry granulated using a dry granulator. The process parameters are: feed speed 15rpm, roller pressure 38bar, roller gap 0.6mm. After granulation, the particle size D of the first particle is obtained. 90 It is 150μm;

[0085] S2. Mix the first particle with emtricitabine, croscarmellose sodium, and magnesium stearate using a three-dimensional mixer for 9 minutes.

[0086] S3. Press the material into 350mg tablet cores, a total of 1000 tablets, and then perform film coating.

[0087] Comparative Example 3

[0088] The same formulation and preparation process as in Example 1 were used, with the only difference being that the dry granulation process parameters were: feeding speed 18 rpm, roller pressure 28 bar, and roller gap 0.9 mm.

[0089] Comparative Example 4

[0090] Using the same components and process as published by CN107847450A, the difference is that microcrystalline cellulose (model Avicel PH113) is used in a ratio of 3:1 to replace the commonly used microcrystalline cellulose Avicel PH102.

[0091] Three samples of tablets prepared in Examples 1-4 and Comparative Examples 1-3 were placed under light (5000 lx) for 10 days and under accelerated conditions (40℃-RH75%) for 1 and 3 months, respectively. The total impurity content of tenofovir alafenamide hemifumarate was detected and the average value was calculated. The results are shown in Table 4.

[0092] Table 4 Stability Data

[0093]

[0094] As shown in Table 4, Examples 1-4 of this application innovatively adjusted the preparation process of emtricitabine-propofol-tenofovir combination tablets and optimized the components accordingly. The prepared tablets do not require the addition of a desiccant and exhibit better stability than commercially available formulations under light and accelerated testing conditions. Emtricitabine also showed good stability during the experiment. Generally, hydrogenated vegetable oil and magnesium stearate are both hydrophobic lubricants. Although they have better adhesive properties and weaker hydrophobicity, they can effectively reduce the force required to push the tablet out of the die orifice to improve compressibility. However, this application unexpectedly discovered that, compared to weakly alkaline magnesium stearate, hydrogenated vegetable oil as a lubricant can improve the stability of tenofovir alafenamide hemifumarate in the tablets prepared in this application under light conditions.

[0095] Ten samples of tablets prepared in Examples 1-4 and Comparative Examples 1-3 were taken respectively to detect the percentage content of tenofovir alafenamide hemifumarate and emtricitabine. The average content and standard deviation were calculated, and the coefficient of variation (CV) representing the mixing uniformity was calculated as follows: CV = (standard deviation SD / average value M) × 100%. The results are shown in Table 5. The detection method of tenofovir alafenamide hemifumarate and emtricitabine is existing technology and will not be described in detail here.

[0096] Table 5 Mixture homogeneity data

[0097]

[0098] Uneven mixing of antiviral drugs can lead to concentration fluctuations, potentially causing viral resistance, especially in combination formulations where tablet mixing uniformity is crucial. As shown in the table above, the tablets prepared in Examples 1-4 of this application, after modifying the preparation process and optimizing the components and particle size, achieved a content uniformity essentially consistent with Comparative Example 1. Comparative Example 2, using a different preparation process, resulted in poorer mixing uniformity of the active pharmaceutical ingredient (API). Comparative Example 3 demonstrates that the process parameters of dry granulation affect the content uniformity of the API in the tablets, similarly worsening the mixing uniformity. Compared to Comparative Example 1, even changing the composition of the filler in Comparative Example 4 affects mixing uniformity. In the tablets prepared in Examples 1-4 of this application, the dissolution rates of tenofovir alafenamide hemifumarate and emtricitabine within 20 minutes were all above 90%, essentially consistent with Comparative Example 1.

[0099] While the present invention has been disclosed above, it is not limited thereto. Any person skilled in the art can make various modifications and alterations without departing from the spirit and scope of the invention; therefore, the scope of protection of the present invention should be determined by the scope defined in the claims.

Claims

1. An emtricitabine-propionol-tenofovir combination tablet, characterized in that, The tablet core comprises 300-330 parts by weight of a first particle, 20-40 parts by weight of emtricitabine, and 3-5 parts by weight of a lubricant. The first particle is composed of 28 parts by weight of tenofovir alafenamide hemifumarate, 160-180 parts by weight of emtricitabine, 85-90 parts by weight of a filler, 25-30 parts by weight of a disintegrant, and 3-5 parts by weight of a lubricant, with a particle size D. 90 The particle size is 100-300 μm; the particle size D of the first particle is... 90 The particle size D of the emtricitabine is 250 μm. 90 The thickness is 150 μm. The lubricant is magnesium stearate or hydrogenated vegetable oil. The disintegrant is croscarmellose sodium. The filler is composed of sodium chloride and microcrystalline cellulose in a weight ratio of 1:0.5-1:3, wherein the microcrystalline cellulose is of type Avicel PH113 and is prepared by the following method: S1. Tenofovir disoproxil fumarate and emtricitabine are pulverized and the particle size D is controlled. 90 It is 150μm, ready for use; S2. Mix the prescribed amounts of tenofovir alafenamide hemifumarate, emtricitabine, filler, disintegrant, and lubricant, and then dry granulate them using a dry granulator to obtain the first granules. S3. Mix the first granules, the remaining emtricitabine, and the lubricant using a three-dimensional mixer for 5-10 minutes. Press the material into 350mg tablet cores, making a total of 1000 tablets, and then perform film coating.

2. The emtricitabine-propionol-tenofovir combination tablets according to claim 1, characterized in that, Emtricitabine-Propionate-Tenofovir Combination Tablets consist of 307-327 parts by weight of the first tablet, 20-40 parts by weight of emtricitabine, and 3-5 parts by weight of lubricant. The first tablet consists of 28 parts by weight of tenofovir alafenamide hemifumarate, 160-180 parts by weight of emtricitabine, 88 parts by weight of filler, and 28 parts by weight of disintegrant.

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