Dolutegravir, tenofovir and lamivudine compound tablet

Abstract

The present invention relates to a dolutegravir-tenofovir-lamivudine combination tablet. Specifically, the present invention provides a dolutegravir-tenofovir-lamivudine combination bilayer tablet, comprising a first immediate-release tablet and a second immediate-release tablet; the first immediate-release tablet comprising dolutegravir, lamivudine, a diluent, optionally a binder, and optionally a disintegrant; and the second immediate-release tablet comprising tenofovir disoproxil, a diluent, optionally a binder, and optionally a disintegrant. The dolutegravir-tenofovir-lamivudine combination tablet of the present invention has a fast dissolution rate and high stability, thereby having excellent bioequivalence and shelf life.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, in particular to a dolutegravir-tenofovir-lamivudine compound tablet. Background Art

[0002] Tenofovir disoproxil fumarate (TDF), lamivudine (3TC) and dolutegravir sodium (DTG) are antiviral compounds that can be used to treat AIDS;

[0003] The integrase inhibitor dolutegravir sodium (DTG) combined with the nucleoside analogues tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) is the first choice HIV regimen recommended by the WHO and is widely used in the treatment of HIV.

[0004] Although DTG, TDF, and 3TC combination preparations have been reported in the prior art, these preparations struggle to ensure that DTG, TDF, and 3TC simultaneously have excellent dissolution rates, making it difficult to achieve the rapid therapeutic effects of DTG, TDF, and 3TC. Furthermore, these preparations suffer from poor stability and are prone to degradation during storage, leading to an increase in impurities and toxic side effects. Furthermore, the tablet weight of these preparations often exceeds 1 gram, making them difficult to swallow and resulting in poor patient compliance.

[0005] Therefore, there is a need in the art to develop a compound preparation of DTG, TDF and 3TC with a fast dissolution rate and high stability, thereby improving the therapeutic effect and stability of DTG, TDF and 3TC drugs. Summary of the Invention

[0006] The object of the present invention is to provide a dolutegravir, tenofovir and lamivudine compound double-layer tablet with fast dissolution rate and high stability.

[0007] In a first aspect, the present invention provides a dolutegravir, tenofovir and lamivudine compound double-layer tablet, wherein the compound double-layer tablet comprises a first immediate-release tablet and a second immediate-release tablet;

[0008] The first immediate-release tablet comprises dolutegravir, lamivudine, a diluent, optionally a binder, and optionally a disintegrant; and

[0009] The second immediate-release tablet comprises tenofovir disoproxil, a diluent, optionally a binder, and optionally a disintegrant.

[0010] In another preferred embodiment, the dolutegravir comprises dolutegravir sodium.

[0011] In another preferred embodiment, the tenofovir disoproxil fumarate includes tenofovir disoproxil fumarate.

[0012] In another preferred embodiment, the particle size D90 of the dolutegravir is ≤15 μm.

[0013] In another preferred embodiment, the particle size of the lamivudine is 100 μm ≤ D90 ≤ 300 μm.

[0014] In another preferred embodiment, the particle size D90 of the tenofovir disoproxil is ≤15 μm.

[0015] In another preferred embodiment, the first immediate-release tablet and the second immediate-release tablet are stacked together to form a compound double-layer tablet.

[0016] In another preferred embodiment, the first immediate-release tablet is a round or oval tablet.

[0017] In another preferred embodiment, the second immediate-release tablet is a round or oval tablet.

[0018] In another preferred embodiment, the compound double-layer tablet is a round or oval tablet.

[0019] In another preferred embodiment, the first immediate-release tablet further comprises a lubricant.

[0020] In another preferred embodiment, the second immediate-release tablet further comprises a lubricant.

[0021] In another preferred embodiment, the diluent is selected from the group consisting of lactose, mannitol, microcrystalline cellulose, pregelatinized starch, or a combination thereof.

[0022] In another preferred embodiment, the binder is selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, or a combination thereof.

[0023] In another preferred embodiment, the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, or a combination thereof.

[0024] In another preferred embodiment, the microcrystalline cellulose is selected from the following group: microcrystalline cellulose PH101, microcrystalline cellulose PH102, microcrystalline cellulose PH112, or a combination thereof.

[0025] In another preferred embodiment, the povidone includes povidone K30.

[0026] In another preferred embodiment, the lubricant is selected from the following group: magnesium stearate, sodium stearyl fumarate, or a combination thereof.

[0027] In another preferred embodiment, the compound double-layer tablet is a coated tablet.

[0028] In another preferred embodiment, the coating material of the compound double-layer tablet is Opadry.

[0029] In another preferred embodiment, the coating weight gain is 1.5-3.0%.

[0030] In another preferred embodiment, the tablet weight of the first immediate-release tablet is 450-600 mg, preferably 500-550 mg.

[0031] In another preferred embodiment, the tablet weight of the second immediate-release tablet is 300-400 mg, preferably 320-380 mg.

[0032] In another preferred embodiment, the weight of the dolutegravir, tenofovir and lamivudine compound double-layer tablet is 800-1000 mg, preferably 850-950 mg.

[0033] In another preferred embodiment, the weight ratio of the first immediate-release tablet to the second immediate-release tablet is 450-600:300-400, preferably 500-550:320-380.

[0034] In another preferred embodiment, the hardness of the first rapid-release tablet is ≤3.0 kg.

[0035] In another preferred embodiment, the hardness of the compound double-layer tablet is 12 to 18 kg.

[0036] In another preferred embodiment, the cumulative dissolution rate of the dolutegravir, tenofovir and lamivudine compound double-layer tablets is greater than 85% in 15 minutes under the following dissolution conditions;

[0037] The dissolution conditions are:

[0038] Stirring: paddle method 75 rpm;

[0039] Temperature: 37 ± 0.5°C;

[0040] Dissolution medium: 0.5% sodium lauryl sulfate 900 ml pH 6.8 phosphate buffer.

[0041] In another preferred embodiment, the compound double-layer tablet is prepared by compressing dolutegravir and lamivudine granules and tenofovir granules into two layers;

[0042] The dolutegravir and lamivudine granules include dolutegravir granules and lamivudine powder.

[0043] In another preferred embodiment, the dolutegravir and lamivudine particles are the first layer.

[0044] In another preferred embodiment, the tenofovir particles are the first layer.

[0045] In another preferred embodiment, the dolutegravir-lamivudine granules are obtained by mixing dolutegravir granules with lamivudine powder.

[0046] In another preferred embodiment, the dolutegravir granules comprise:

[0047] dolutegravir, a first diluent, a first binder, and a first disintegrant;

[0048] The first diluent is selected from the group consisting of microcrystalline cellulose, mannitol, or a combination thereof;

[0049] The first adhesive comprises povidone;

[0050] The first disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, or a combination thereof.

[0051] In another preferred embodiment, the first diluent is selected from the following group: microcrystalline cellulose, mannitol, or a combination thereof.

[0052] In another preferred embodiment, the first disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, or a combination thereof.

[0053] In another preferred embodiment, the amount of dolutegravir is 40-60 parts by weight, preferably 45-57 parts by weight.

[0054] In another preferred embodiment, the microcrystalline fiber is 5-150 parts by weight, preferably 10-130 parts by weight.

[0055] In another preferred embodiment, the amount of the microcrystalline cellulose is 10-30 parts by weight.

[0056] In another preferred embodiment, the amount of the microcrystalline cellulose is 100-130 parts by weight.

[0057] In another preferred embodiment, the microcrystalline cellulose is 30-50 parts by weight.

[0058] In another preferred embodiment, the mannitol is 50-80 parts by weight, preferably 60-70 parts by weight.

[0059] In another preferred embodiment, the mannitol is 30-60 parts by weight, preferably 40-50 parts by weight.

[0060] In another preferred embodiment, the amount of the polyvidone is 2-10 parts by weight, preferably 4-8 parts by weight.

[0061] In another preferred embodiment, the sodium starch glycolate is 1-10 parts by weight, preferably 3-8 parts by weight.

[0062] In another preferred embodiment, the amount of the cross-linked sodium carboxymethyl cellulose is 1-10 parts by weight, preferably 3-8 parts by weight.

[0063] In another preferred embodiment, the dolutegravir granules comprise:

[0064] Dolutegravir 45-57 parts by weight microcrystalline cellulose 15-25 parts by weight Mannitol 60-70 parts by weight Povidone 4-8 parts by weight Sodium starch glycolate 3-7 parts by weight.

[0065] In another preferred embodiment, the dolutegravir granules comprise:

[0066] Dolutegravir sodium 45-57 parts by weight microcrystalline cellulose 100-130 parts by weight Povidone 4-8 parts by weight Croscarmellose sodium 4-8 parts by weight.

[0067] In another preferred embodiment, the dolutegravir granules comprise:

[0068] Dolutegravir sodium 45-57 parts by weight microcrystalline cellulose 30-50 parts by weight Mannitol 40-50 parts by weight Povidone 4-8 parts by weight Sodium starch glycolate 4-8 parts by weight.

[0069] In another preferred embodiment, the dolutegravir granules are prepared by wet granulation and / or fluidized bed granulation.

[0070] In another preferred embodiment, the dolutegravir granules are prepared by the following method:

[0071] (i-1) preparing a suspension by mixing a first binder, dolutegravir and water;

[0072] (i-2) placing a first diluent and a first disintegrant in a fluidized bed, and spraying the suspension obtained in step (i) into the fluidized first diluent and the first disintegrant to obtain dolutegravir granules.

[0073] In another preferred embodiment, in the step (i-1), the content of dolutegravir is 15-40 wt%, preferably 20-30 wt%, based on the total weight of the suspension.

[0074] In another preferred embodiment, in the step (i-2), the fluidized bed comprises the following parameters:

[0075] Inlet air temperature is 60±10℃; and / or

[0076] Adjust the air volume to 30~60m 3 / h.

[0077] In another preferred embodiment, the spray includes the following parameters:

[0078] Liquid supply pump speed 30~60rp;

[0079] Atomization pressure 1.0~2.5Pa; and / or

[0080] Suspension feed rate: 5-10g / min.

[0081] In another preferred embodiment, in the step (i-2), the moisture content of the obtained dolutegravir granules is ≤3.0%.

[0082] In another preferred embodiment, in the step (i-2), the obtained dolutegravir granules are sieved through a 20-40 mesh sieve for dry granulation.

[0083] In another preferred embodiment, the dolutegravir granules are prepared by the following method:

[0084] (ii-1) preparing a first binder and water to form a binder solution;

[0085] (ii-2) placing dolutegravir, a first diluent, and a first disintegrant in a fluidized bed, and spraying the binder solution obtained in step (ii-1) onto the dolutegravir, the first diluent, and the first disintegrant in the fluidized state to obtain dolutegravir granules.

[0086] In another preferred embodiment, in the step (ii-1), the content of the first binder is 0.5-6 wt %, preferably 1.5-3.5 wt %, based on the total weight of the binder solution.

[0087] In another preferred embodiment, in the step (ii-2), the fluidized bed comprises the following parameters:

[0088] Inlet air temperature is 60±10℃; and / or

[0089] Adjust the air volume to 30~60m 3 / h.

[0090] In another preferred embodiment, the spray includes the following parameters:

[0091] Liquid supply pump speed 30-60rp; and / or

[0092] Suspension feed rate: 5-10g / min.

[0093] In another preferred embodiment, in the step (ii-2), the moisture content of the obtained dolutegravir granules is ≤3.0%.

[0094] In another preferred embodiment, in the step (ii-2), the obtained dolutegravir granules are sieved through a 20-40 mesh sieve to dry granulate.

[0095] In another preferred embodiment, the lamivudine powder comprises:

[0096] lamivudine, a second diluent, and a second disintegrant;

[0097] The second diluent comprises microcrystalline cellulose;

[0098] The second disintegrant is selected from the group consisting of sodium starch glycolate, croscarmellose sodium, or a combination thereof.

[0099] In another preferred embodiment, the amount of lamivudine is 200-400 parts by weight, preferably 250-350 parts by weight.

[0100] In another preferred embodiment, the microcrystalline cellulose is 20-80 parts by weight, preferably 30-65 parts by weight.

[0101] In another preferred embodiment, the amount of the microcrystalline cellulose is 30-40 parts by weight.

[0102] In another preferred embodiment, the microcrystalline cellulose is 55-65 parts by weight.

[0103] In another preferred embodiment, the sodium starch glycolate is 5-20, preferably 8-12 parts by weight.

[0104] In another preferred embodiment, the amount of the cross-linked sodium carboxymethyl cellulose is 1-15, preferably 4-8 parts by weight.

[0105] In another preferred embodiment, the lamivudine powder further comprises a first lubricant.

[0106] In another preferred embodiment, the first lubricant includes magnesium stearate.

[0107] In another preferred embodiment, the magnesium stearate is 1-10, preferably 3-8 parts by weight.

[0108] In another preferred embodiment, the lamivudine powder comprises:

[0109] Lamivudine 250-350 parts by weight microcrystalline cellulose 30-40 parts by weight Sodium starch glycolate 8-12 parts by weight magnesium stearate 3-8 parts by weight.

[0110] In another preferred embodiment, the lamivudine powder comprises:

[0111] Lamivudine 250-350 parts by weight microcrystalline cellulose 55-65 parts by weight Croscarmellose sodium 4-8 parts by weight magnesium stearate 3-8 parts by weight.

[0112] In another preferred embodiment, the lamivudine powder is prepared by direct mixing and / or wet granulation process.

[0113] In another preferred embodiment, the lamivudine powder is obtained by mixing lamivudine, a second diluent, a second disintegrant and optionally a first lubricant.

[0114] In another preferred embodiment, the tenofovir granules include:

[0115] tenofovir disoproxil, a third diluent, and a third disintegrant;

[0116] The third diluent includes lactose, microcrystalline cellulose, pregelatinized starch,

[0117] The third disintegrant is selected from the group consisting of sodium starch glycolate, croscarmellose sodium, or a combination thereof.

[0118] In another preferred embodiment, the amount of tenofovir disoproxil fumarate is 200-400 parts by weight, preferably 250-350 parts by weight, and more preferably 280-320 parts by weight.

[0119] In another preferred embodiment, the lactose is 5-30 parts by weight, preferably 10-20 parts by weight.

[0120] In another preferred embodiment, the microcrystalline cellulose is 5-50 parts by weight, preferably 10-35 parts by weight.

[0121] In another preferred embodiment, the amount of the microcrystalline cellulose is 10-20 parts by weight.

[0122] In another preferred embodiment, the microcrystalline cellulose is 25-35 parts by weight.

[0123] In another preferred embodiment, the amount of the microcrystalline cellulose is 20-30 parts by weight.

[0124] In another preferred embodiment, the pregelatinized starch is 2-20 parts by weight, preferably 3-15 parts by weight.

[0125] In another preferred embodiment, the amount of the pregelatinized starch is 2-8 parts by weight.

[0126] In another preferred embodiment, the amount of the pregelatinized starch is 5-15 parts by weight.

[0127] In another preferred embodiment, the cross-linked sodium carboxymethyl cellulose is 5-15 parts by weight, preferably 5-10 parts by weight.

[0128] In another preferred embodiment, the tenofovir particles further include a second binder and / or a second lubricant.

[0129] In another preferred embodiment, the second adhesive includes povidone.

[0130] In another preferred embodiment, the amount of the povidone is 0.5-6 parts by weight, preferably 1-5 parts by weight.

[0131] In another preferred embodiment, the second lubricant includes magnesium stearate.

[0132] In another preferred embodiment, the magnesium stearate is 1-10, preferably 2-8 parts by weight.

[0133] In another preferred embodiment, the tenofovir granules include:

[0134] Tenofovir disoproxil fumarate 280-320 parts by weight lactose 10-20 parts by weight Croscarmellose sodium 5-15 parts by weight microcrystalline cellulose 10-20 parts by weight Pregelatinized starch 2-8 parts by weight magnesium stearate 2-8 parts by weight.

[0135] In another preferred embodiment, the tenofovir particles are prepared by centrifugal granulation and / or extrusion spheronization pelleting process.

[0136] In another preferred embodiment, the tenofovir granules are prepared by the following method:

[0137] Tenofovir disoproxil fumarate, lactose, and cross-linked sodium carboxymethyl cellulose are mixed to prepare a soft material, which is then extruded and spheronized to obtain tenofovir disoproxil fumarate micropellets. The tenofovir disoproxil fumarate micropellets are then mixed with microcrystalline cellulose, pregelatinized starch, and magnesium stearate to obtain tenofovir disoproxil fumarate layered granules.

[0138] In another preferred embodiment, water is used as a binder in the process of making the soft material.

[0139] In another preferred embodiment, the tenofovir granules include:

[0140] Tenofovir disoproxil fumarate 280-320 parts by weight microcrystalline cellulose 25-35 parts by weight Croscarmellose sodium 5-10 parts by weight Povidone 1-5 parts by weight Pregelatinized starch 2-8 parts by weight magnesium stearate 2-8 parts by weight.

[0141] In another preferred embodiment, the tenofovir granules are prepared by the following method:

[0142] Tenofovir disoproxil fumarate, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose were mixed, and a soft material was prepared using a polyvidone aqueous solution as a binder. The soft material was extruded and spheronized to obtain tenofovir disoproxil fumarate micropellets. The tenofovir disoproxil fumarate micropellets were mixed with pregelatinized starch and magnesium stearate to obtain tenofovir disoproxil fumarate layered granules.

[0143] In another preferred embodiment, the content of povidone in the povidone aqueous solution is 0.5-6 wt %.

[0144] In another preferred embodiment, the tenofovir granules include:

[0145] Tenofovir disoproxil fumarate 280-320 parts by weight Microcrystalline cellulose PH101 20-30 parts by weight Croscarmellose sodium 5-10 parts by weight Povidone 1-5 parts by weight Pregelatinized starch 5-15 parts by weight magnesium stearate 2-8 parts by weight.

[0146] In another preferred embodiment, the tenofovir granules are prepared by the following method:

[0147] Tenofovir disoproxil fumarate, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose were mixed, and a soft material was prepared using a polyvidone aqueous solution as a binder. The soft material was extruded and spheronized to obtain tenofovir disoproxil fumarate micropellets. The tenofovir disoproxil fumarate micropellets were mixed with pregelatinized starch and magnesium stearate to obtain tenofovir disoproxil fumarate layered granules.

[0148] In another preferred embodiment, the content of povidone in the povidone aqueous solution is 0.5-6 wt %.

[0149] The second aspect of the present invention provides a use of the dolutegravir, tenofovir and lamivudine compound double-layer tablets as described in the first aspect of the present invention for preparing antiviral drugs.

[0150] In another preferred embodiment, the virus includes HIV virus.

[0151] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0152] After extensive and in-depth research, the inventors unexpectedly developed a bilayer compound tablet comprising dolutegravir, tenofovir, and lamivudine. The compound bilayer tablet comprises a first immediate-release tablet and a second immediate-release tablet. The compound bilayer tablets described herein enable rapid release, exhibit excellent stability, bioequivalence, and high patient compliance. Based on this, the inventors completed the present invention.

[0153] the term

[0154] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0155] As used herein, the terms "comprise," "include," and "contain" are used interchangeably to include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of," "consisting essentially of."

[0156] As used herein, the term "other pharmaceutically acceptable carriers or excipients" refers to substances that are suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), that is, substances with a reasonable benefit / risk ratio.

[0157] As used herein, the term "parts by weight" can be any fixed weight expressed in milligrams, grams, or kilograms (e.g., 1 mg, 1 g, 2 g, or 1 kg, etc.). For example, a composition consisting of 1 part by weight of component a and 9 parts by weight of component b can be composed of 1 gram of component a + 9 grams of component b, or 10 grams of component a + 90 grams of component b, etc. In such a composition, the percentage content of a component = (parts by weight of the component / sum of the parts by weight of all components) × 100%. Therefore, in a composition consisting of 1 part by weight of component a and 9 parts by weight of component b, the content of component a is 10%, and the content of component b is 90%.

[0158] The term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention with an acid or base that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred salt type is a salt formed by a compound of the present invention with an acid. Suitable acids for forming salts include (but are not limited to): inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid. A preferred salt type is a metal salt formed by a compound of the present invention with a base. Suitable bases for forming salts include (but are not limited to): inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate; and organic bases such as ammonia, triethylamine, and diethylamine.

[0159] Active ingredient

[0160] The dolutegravir, tenofovir and lamivudine compound double-layer tablets of the present invention contain dolutegravir, lamivudine and tenofovir disoproxil as active ingredients.

[0161] In the present invention, it should be understood that the dolutegravir includes dolutegravir, a pharmaceutically acceptable salt of dolutegravir, or a mixture thereof.

[0162] In a preferred embodiment of the present invention, the particle size D90 of the dolutegravir is ≤15 μm.

[0163] Typically, the dolutegravir is dolutegravir sodium, which has the following structure:

[0164]

[0165] In the present invention, it should be understood that the lamivudine includes lamivudine, a pharmaceutically acceptable salt of lamivudine, or a mixture thereof.

[0166] In a preferred embodiment of the present invention, the particle size of the dolutegravir is 100 μm ≤ D90 ≤ 300 μm.

[0167] Typically, the dolutegravir is the free form of lamivudine, having the following structure:

[0168]

[0169] In the present invention, it should be understood that the tenofovir disoproxil includes tenofovir disoproxil, dolutegravir pharmaceutically acceptable salts, or a mixture of the two.

[0170] In a preferred embodiment of the present invention, the particle size D90 of tenofovir disoproxil is ≤15 μm.

[0171] Typically, the tenofovir disoproxil fumarate is tenofovir disoproxil fumarate, and the structure is as follows:

[0172]

[0173] Tenofovir disoproxil fumarate and lamivudine are Class III drugs in the BCS classification. After extremely rapid dissolution, their in vivo absorption is no longer affected by dissolution. Dolutegravir sodium is a Class II drug (low-solubility, high-permeability drug) in the BCS classification. Therefore, the tablet disintegration and dissolution process is the rate-limiting step for drug absorption. Dissolution rate significantly influences bioavailability. Increasing the dissolution rate of dolutegravir sodium can enhance gastrointestinal absorption, thereby improving bioavailability.

[0174] Dolutegravir, tenofovir and lamivudine combination double-layer tablets

[0175] The present invention provides a dolutegravir, tenofovir and lamivudine compound double-layer tablet, wherein the compound double-layer tablet comprises a first rapid-release tablet and a second rapid-release tablet;

[0176] The first immediate-release tablet comprises dolutegravir, lamivudine, a diluent, optionally a binder, and optionally a disintegrant; and

[0177] The second immediate-release tablet comprises tenofovir disoproxil, a diluent, optionally a binder, and optionally a disintegrant.

[0178] In a preferred embodiment of the present invention, the first immediate-release tablet and the second immediate-release tablet are stacked together to form a compound double-layer tablet.

[0179] The shape of the tablet of the present invention is not particularly limited. Typically, the compound double-layer tablet can be a round or oval tablet.

[0180] In another preferred embodiment of the present invention, the first immediate-release tablet further comprises a lubricant.

[0181] The second immediate-release tablet further comprises a lubricant.

[0182] In another preferred embodiment, the diluent is selected from the group consisting of lactose, mannitol, microcrystalline cellulose, pregelatinized starch, or a combination thereof.

[0183] In another preferred embodiment, the microcrystalline cellulose is selected from the following group: microcrystalline cellulose PH101, microcrystalline cellulose PH102, microcrystalline cellulose PH112, or a combination thereof.

[0184] In another preferred embodiment, the binder is selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, or a combination thereof.

[0185] In another preferred embodiment, the povidone includes povidone K30.

[0186] In another preferred embodiment, the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, or a combination thereof.

[0187] In another preferred embodiment, the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, or a combination thereof.

[0188] The tablet weight of the tablet of the present invention is not particularly limited. Typically, the tablet weight of the dolutegravir, tenofovir and lamivudine compound double-layer tablet is 800-1000 mg, preferably 850-950 mg.

[0189] In another preferred embodiment, the hardness of the first rapid-release tablet is ≤3.0 kg.

[0190] In another preferred embodiment, the hardness of the compound double-layer tablet is 12 to 18 kg.

[0191] In another preferred embodiment, the cumulative dissolution rate of the dolutegravir, tenofovir and lamivudine compound double-layer tablets is greater than 85% in 15 minutes under the following dissolution conditions;

[0192] The dissolution conditions are:

[0193] Stirring: paddle method 75 rpm;

[0194] Temperature: 37 ± 0.5°C;

[0195] Dissolution medium: 0.5% sodium lauryl sulfate 900 ml pH 6.8 phosphate buffer.

[0196] In a preferred embodiment of the present invention, the compound double-layer tablet is prepared by compressing dolutegravir and lamivudine granules and tenofovir granules into two layers.

[0197] Preferably, the dolutegravir and lamivudine particles are the first layer.

[0198] Preferably, the tenofovir particles are the first layer.

[0199] Dolutegravir and Lamivudine Granules

[0200] In a preferred embodiment of the present invention, the dolutegravir / lamivudine granules comprise dolutegravir granules and lamivudine powder.

[0201] Preferably, the dolutegravir and lamivudine granules are obtained by mixing dolutegravir granules with lamivudine powder.

[0202] Dolutegravir granules and preparation method

[0203] In a preferred embodiment of the present invention, the dolutegravir granules comprise:

[0204] dolutegravir, a first diluent, a first binder, and a first disintegrant;

[0205] The first diluent includes (but is not limited to): microcrystalline cellulose, mannitol, or a combination thereof;

[0206] The first adhesive comprises povidone;

[0207] The first disintegrant includes (but is not limited to): croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, or a combination thereof.

[0208] In a preferred embodiment, the first diluent includes (but is not limited to): microcrystalline cellulose, mannitol, or a combination thereof.

[0209] In another preferred embodiment, the first disintegrant includes (but is not limited to): croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, or a combination thereof.

[0210] In another preferred embodiment, the amount of dolutegravir is 40-60 parts by weight, preferably 45-57 parts by weight.

[0211] In another preferred embodiment, the microcrystalline fiber is 5-150 parts by weight, preferably 10-130 parts by weight.

[0212] In another preferred embodiment, the amount of the microcrystalline cellulose is 10-30 parts by weight.

[0213] In another preferred embodiment, the amount of the microcrystalline cellulose is 100-130 parts by weight.

[0214] In another preferred embodiment, the microcrystalline cellulose is 30-50 parts by weight.

[0215] In another preferred embodiment, the mannitol is 50-80 parts by weight, preferably 60-70 parts by weight.

[0216] In another preferred embodiment, the mannitol is 30-60 parts by weight, preferably 40-50 parts by weight.

[0217] In another preferred embodiment, the amount of the polyvidone is 2-10 parts by weight, preferably 4-8 parts by weight.

[0218] In another preferred embodiment, the sodium starch glycolate is 1-10 parts by weight, preferably 3-8 parts by weight.

[0219] In another preferred embodiment, the amount of the cross-linked sodium carboxymethyl cellulose is 1-10 parts by weight, preferably 3-8 parts by weight.

[0220] Typically, the dolutegravir granules include:

[0221] Dolutegravir 45-57 parts by weight microcrystalline cellulose 15-25 parts by weight Mannitol 60-70 parts by weight Povidone 4-8 parts by weight Sodium starch glycolate 3-7 parts by weight.

[0222] Typically, the dolutegravir granules include:

[0223] Dolutegravir sodium 45-57 parts by weight microcrystalline cellulose 100-130 parts by weight Povidone 4-8 parts by weight Croscarmellose sodium 4-8 parts by weight.

[0224] Typically, the dolutegravir granules include:

[0225] Dolutegravir sodium 45-57 parts by weight microcrystalline cellulose 30-50 parts by weight Mannitol 40-50 parts by weight Povidone 4-8 parts by weight Sodium starch glycolate 4-8 parts by weight.

[0226] In a preferred embodiment of the present invention, the dolutegravir granules are prepared by wet granulation and / or fluidized bed granulation.

[0227] Typically, the dolutegravir granules are prepared by the following method:

[0228] (i-1) preparing a suspension by mixing a first binder, dolutegravir and water;

[0229] (i-2) placing a first diluent and a first disintegrant in a fluidized bed, and spraying the suspension obtained in step (i) into the fluidized first diluent and the first disintegrant to obtain dolutegravir granules.

[0230] In another preferred embodiment, in the step (i-1), the content of dolutegravir is 15-40 wt%, preferably 20-30 wt%, based on the total weight of the suspension.

[0231] In another preferred embodiment, in the step (i-2), the fluidized bed comprises the following parameters:

[0232] Inlet air temperature is 60±10℃; and / or

[0233] Adjust the air volume to 30~60m 3 / h.

[0234] In another preferred embodiment, the spray includes the following parameters:

[0235] Liquid supply pump speed 30~60rp;

[0236] Atomization pressure 1.0~2.5Pa; and / or

[0237] Suspension feed rate: 5-10g / min.

[0238] In another preferred embodiment, in the step (i-2), the moisture content of the obtained dolutegravir granules is ≤3.0%.

[0239] In another preferred embodiment, in the step (i-2), the obtained dolutegravir granules are sieved through a 20-40 mesh sieve for dry granulation.

[0240] Typically, the dolutegravir granules are prepared by the following method:

[0241] (ii-1) preparing a first binder and water to form a binder solution;

[0242] (ii-2) placing dolutegravir, a first diluent, and a first disintegrant in a fluidized bed, and spraying the binder solution obtained in step (ii-1) onto the dolutegravir, the first diluent, and the first disintegrant in the fluidized state to obtain dolutegravir granules.

[0243] In another preferred embodiment, in the step (ii-1), the content of the first binder is 0.5-6 wt %, preferably 1.5-3.5 wt %, based on the total weight of the binder solution.

[0244] In another preferred embodiment, in the step (ii-2), the fluidized bed comprises the following parameters:

[0245] Inlet air temperature is 60±10℃; and / or

[0246] Adjust the air volume to 30~60m 3 / h.

[0247] In another preferred embodiment, the spray includes the following parameters:

[0248] Liquid supply pump speed 30-60rp; and / or

[0249] Suspension feed rate: 5-10g / min.

[0250] In another preferred embodiment, in the step (ii-2), the moisture content of the obtained dolutegravir granules is ≤3.0%.

[0251] In another preferred embodiment, in the step (ii-2), the obtained dolutegravir granules are sieved through a 20-40 mesh sieve to dry granulate.

[0252] Lamivudine powder and preparation method

[0253] In a preferred embodiment of the present invention, the lamivudine powder comprises:

[0254] lamivudine, a second diluent, and a second disintegrant;

[0255] The second diluent comprises microcrystalline cellulose;

[0256] The second disintegrant includes (but is not limited to): sodium starch glycolate, croscarmellose sodium, or a combination thereof.

[0257] In another preferred embodiment, the amount of lamivudine is 200-400 parts by weight, preferably 250-350 parts by weight.

[0258] In another preferred embodiment, the microcrystalline cellulose is 20-80 parts by weight, preferably 30-65 parts by weight.

[0259] In another preferred embodiment, the amount of the microcrystalline cellulose is 30-40 parts by weight.

[0260] In another preferred embodiment, the microcrystalline cellulose is 55-65 parts by weight.

[0261] In another preferred embodiment, the sodium starch glycolate is 5-20, preferably 8-12 parts by weight.

[0262] In another preferred embodiment, the amount of the cross-linked sodium carboxymethyl cellulose is 1-15, preferably 4-8 parts by weight.

[0263] In another preferred embodiment, the lamivudine powder further comprises a first lubricant.

[0264] In another preferred embodiment, the first lubricant includes magnesium stearate.

[0265] In another preferred embodiment, the magnesium stearate is 1-10, preferably 3-8 parts by weight.

[0266] Typically, the lamivudine powder comprises:

[0267] Lamivudine 250-350 parts by weight microcrystalline cellulose 30-40 parts by weight Sodium starch glycolate 8-12 parts by weight magnesium stearate 3-8 parts by weight.

[0268] Typically, the lamivudine powder comprises:

[0269] Lamivudine 250-350 parts by weight microcrystalline cellulose 55-65 parts by weight Croscarmellose sodium 4-8 parts by weight magnesium stearate 3-8 parts by weight.

[0270] In a preferred embodiment of the present invention, the lamivudine powder is prepared by direct mixing and / or wet granulation process.

[0271] In another preferred embodiment, the lamivudine powder is obtained by mixing lamivudine, a second diluent, a second disintegrant and optionally a first lubricant.

[0272] Tenofovir granules and preparation method

[0273] In a preferred embodiment of the present invention, the tenofovir granules include:

[0274] tenofovir disoproxil, a third diluent, and a third disintegrant;

[0275] The third diluent includes lactose, microcrystalline cellulose, pregelatinized starch,

[0276] The third disintegrant includes (but is not limited to): sodium starch glycolate, croscarmellose sodium, or a combination thereof.

[0277] In another preferred embodiment, the amount of tenofovir disoproxil fumarate is 200-400 parts by weight, preferably 250-350 parts by weight, and more preferably 280-320 parts by weight.

[0278] In another preferred embodiment, the lactose is 5-30 parts by weight, preferably 10-20 parts by weight.

[0279] In another preferred embodiment, the microcrystalline cellulose is 5-50 parts by weight, preferably 10-35 parts by weight.

[0280] In another preferred embodiment, the amount of the microcrystalline cellulose is 10-20 parts by weight.

[0281] In another preferred embodiment, the microcrystalline cellulose is 25-35 parts by weight.

[0282] In another preferred embodiment, the amount of the microcrystalline cellulose is 20-30 parts by weight.

[0283] In another preferred embodiment, the pregelatinized starch is 2-20 parts by weight, preferably 3-15 parts by weight.

[0284] In another preferred embodiment, the amount of the pregelatinized starch is 2-8 parts by weight.

[0285] In another preferred embodiment, the amount of the pregelatinized starch is 5-15 parts by weight.

[0286] In another preferred embodiment, the cross-linked sodium carboxymethyl cellulose is 5-15 parts by weight, preferably 5-10 parts by weight.

[0287] In another preferred embodiment, the tenofovir particles further include a second binder and / or a second lubricant.

[0288] In another preferred embodiment, the second adhesive includes povidone.

[0289] In another preferred embodiment, the amount of the povidone is 0.5-6 parts by weight, preferably 1-5 parts by weight.

[0290] In another preferred embodiment, the second lubricant includes magnesium stearate.

[0291] In another preferred embodiment, the magnesium stearate is 1-10, preferably 2-8 parts by weight.

[0292] Typically, the tenofovir granules include:

[0293] Tenofovir disoproxil fumarate 280-320 parts by weight lactose 10-20 parts by weight Croscarmellose sodium 5-15 parts by weight microcrystalline cellulose 10-20 parts by weight Pregelatinized starch 2-8 parts by weight magnesium stearate 2-8 parts by weight.

[0294] In another preferred embodiment, the tenofovir particles are prepared by centrifugal granulation and / or extrusion spheronization pelleting process.

[0295] In another preferred embodiment, the tenofovir granules are prepared by the following method:

[0296] Tenofovir disoproxil fumarate, lactose, and cross-linked sodium carboxymethyl cellulose are mixed to prepare a soft material, which is then extruded and spheronized to obtain tenofovir disoproxil fumarate micropellets. The tenofovir disoproxil fumarate micropellets are then mixed with microcrystalline cellulose, pregelatinized starch, and magnesium stearate to obtain tenofovir disoproxil fumarate layered granules.

[0297] In another preferred embodiment, water is used as a binder in the process of making the soft material.

[0298] Typically, the tenofovir granules include:

[0299] Tenofovir disoproxil fumarate 280-320 parts by weight microcrystalline cellulose 25-35 parts by weight Croscarmellose sodium 5-10 parts by weight Povidone 1-5 parts by weight Pregelatinized starch 2-8 parts by weight magnesium stearate 2-8 parts by weight.

[0300] In another preferred embodiment, the tenofovir granules are prepared by the following method:

[0301] Tenofovir disoproxil fumarate, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose were mixed, and a soft material was prepared using a polyvidone aqueous solution as a binder. The soft material was extruded and spheronized to obtain tenofovir disoproxil fumarate micropellets. The tenofovir disoproxil fumarate micropellets were mixed with pregelatinized starch and magnesium stearate to obtain tenofovir disoproxil fumarate layered granules.

[0302] In another preferred embodiment, the content of povidone in the povidone aqueous solution is 0.5-6 wt %.

[0303] Typically, the tenofovir granules include:

[0304] Tenofovir disoproxil fumarate 280-320 parts by weight Microcrystalline cellulose PH101 20-30 parts by weight Croscarmellose sodium 5-10 parts by weight Povidone 1-5 parts by weight Pregelatinized starch 5-15 parts by weight magnesium stearate 2-8 parts by weight.

[0305] In another preferred embodiment, the tenofovir granules are prepared by the following method:

[0306] Tenofovir disoproxil fumarate, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose were mixed, and a soft material was prepared using a polyvidone aqueous solution as a binder. The soft material was extruded and spheronized to obtain tenofovir disoproxil fumarate micropellets. The tenofovir disoproxil fumarate micropellets were mixed with pregelatinized starch and magnesium stearate to obtain tenofovir disoproxil fumarate layered granules.

[0307] The main advantages of the present invention include:

[0308] 1. The present invention develops a dolutegravir, tenofovir and lamivudine compound double-layer tablet, which has a rapid dissolution rate, thereby quickly achieving pharmacodynamic effects, and is bioequivalent to the compound preparations of Viread, Epivir and Tivicay.

[0309] 2. The dolutegravir, tenofovir and lamivudine compound double-layer tablets of the present invention have excellent stability and thus have excellent quality stability during storage.

[0310] 3. The dolutegravir, tenofovir and lamivudine compound double-layer tablets of the present invention can weigh less than 1 gram and are easy to swallow, thereby improving patient compliance.

[0311] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0312] Example 1

[0313] This embodiment 1 provides a dolutegravir, tenofovir and lamivudine compound double-layer tablet, the prescription composition of which is shown in Table 1 below:

[0314] Table 1 Dolutegravir, Tenofovir and Lamivudine Compound Double-layer Tablets Prescription (1000 tablets) of Example 1

[0315]

[0316]

[0317] Preparation method:

[0318] 6 g of povidone K30 and 52.8 g of dolutegravir sodium were weighed and added to purified water to prepare a dolutegravir sodium suspension with a solid content of about 30 wt%; 20 g of microcrystalline cellulose PH101, 65.2 g of mannitol and 5 g of sodium starch glycolate were weighed and placed in a fluidized bed, and the inlet air temperature was set to 60 ± 10 ° C and the air volume was adjusted to 30-60 m 3 / h, make the material fluidized; start spraying, add dolutegravir sodium suspension, wherein the liquid supply pump speed is 30-60rpm (5-10g / min), the atomization pressure is 1.0-2.5pa, and observe the material temperature and fluidization state during the process. After the spraying is completed, enter the drying stage, adjust the air volume to 40-60m 3 / h, dried to a moisture content of ≤3.0%, and sieved through a 30-mesh sieve to obtain dolutegravir sodium granules. 300 g of lamivudine, 36 g of microcrystalline cellulose PH102, 10 g of sodium starch glycolate, and 5 g of magnesium stearate were added to the dolutegravir sodium granules and mixed uniformly to obtain dolutegravir sodium and lamivudine-layered granules.

[0319] 300 g of tenofovir disoproxil fumarate, 15 g of lactose, and 10 g of croscarmellose sodium were weighed and mixed evenly. Purified water was used as a wetting agent to prepare a soft material, which was placed in an extrusion spheronizer to prepare tenofovir disoproxil fumarate micropellets and dried to a moisture content of ≤3.0%. 15 g of microcrystalline cellulose PH112, 5 g of pregelatinized starch, and 5 g of magnesium stearate were added to the tenofovir disoproxil fumarate micropellets and mixed evenly to obtain tenofovir disoproxil fumarate layered granules.

[0320] A double-layer tablet press is used to compress tablets (18.5*9.6mm oval tablets), wherein the dolutegravir and lamivudine granules are the first layer, the first layer tablet weight is 500mg, and the hardness is ≤3.0kg; the tenofovir disoproxil fumarate granules are the second layer, the total tablet weight is about 850mg; the hardness is 12-18kg; and the disintegration time is ≤10 minutes.

[0321] The plain tablets were coated with a 15 wt % Opadry aqueous suspension solution, and the coating weight gain was about 1.5-3.0%; and the dolutegravir, tenofovir and lamivudine compound double-layer tablets were obtained.

[0322] Example 2

[0323] This embodiment 2 provides a dolutegravir, tenofovir and lamivudine compound double-layer tablet, the prescription composition of which is shown in Table 2 below:

[0324] Table 2 Dolutegravir, Tenofovir and Lamivudine Compound Double-layer Tablets Prescription (1000 tablets) of Example 2

[0325]

[0326]

[0327] Preparation method:

[0328] Weigh 6 g of povidone K30 and 52.8 g of dolutegravir sodium and add purified water to prepare a dolutegravir sodium suspension with a solid content of about 20 wt%; weigh 115.2 g of microcrystalline cellulose pH 101 and 6 g of croscarmellose sodium and place them in a fluidized bed, set the inlet air temperature to 60 ± 10 ° C, and adjust the air volume to 30-60 m 3 / h, so that the material is in a fluidized state; start spraying, add dolutegravir sodium suspension, wherein the liquid supply pump speed is 30-60rpm, the atomization pressure is 1.0-2.5pa, and observe the material temperature and fluidization state during the process. After the spraying is completed, enter the drying stage, adjust the air volume to 40-60m 3 / h, dried to a moisture content of ≤3.0%, and granulated into 30 mesh pieces to obtain dolutegravir sodium granules. 300g of lamivudine, 59g of microcrystalline cellulose PH102, 6g of croscarmellose sodium, and 5g of magnesium stearate were added to the dolutegravir sodium granules and mixed evenly to obtain dolutegravir and lamivudine layer granules.

[0329] 300 g of tenofovir disoproxil fumarate, 30 g of microcrystalline cellulose pH 101, and 7.5 g of croscarmellose sodium were weighed and mixed evenly. A 2 wt % povidone K30 (containing 2.5 g of povidone K30) solution was used as a binder to prepare a soft material, which was placed in an extrusion spheronizer to prepare tenofovir disoproxil fumarate micropellets. The pellets were dried to a moisture content of ≤3.0%. 5 g of pregelatinized starch and 5 g of magnesium stearate were added according to the pellet core yield and mixed evenly to obtain tenofovir disoproxil fumarate layered granules.

[0330] A double-layer tablet press is used to compress tablets (18.5*9.6mm oval tablets), wherein the dolutegravir and lamivudine granules are the first layer, the first layer tablet weight is 550mg, and the hardness is ≤3.0kg; the tenofovir disoproxil fumarate granules are the second layer, the total tablet weight is approximately 900mg; the hardness is 14-22kg; and the disintegration time is ≤10 minutes.

[0331] The plain tablets were coated with 15% Opadry solution, and the coating weight gain was about 1.5-3.0%; Dolutegravir, Tenofovir and Lamivudine combination tablets;

[0332] Example 3

[0333] This embodiment 3 provides a dolutegravir, tenofovir and lamivudine compound double-layer tablet, the prescription composition of which is shown in Table 3 below:

[0334] Table 3 Dolutegravir Tenofovir Lamivudine Compound Double-layer Tablets Prescription (1000 tablets) of Example 3

[0335] Dolutegravir sodium and lamivudine Component (g) Dolutegravir sodium (D90≤15μm) 52.8 Microcrystalline cellulose PH101 40 Mannitol 45.2 Povidone K30 6 Sodium starch glycolate 6 Lamivudine (100 μm ≤ D90 ≤ 300 μm) 300 Microcrystalline cellulose PH102 35 Sodium starch glycolate 10 magnesium stearate 5 Tenofovir disoproxil fumarate layer Component (g) Tenofovir disoproxil fumarate (D90≤100μm) 300 Microcrystalline cellulose PH101 25 Croscarmellose sodium 8 Povidone K30 2 Pregelatinized starch 10 magnesium stearate 5 coating Component (g) Obaday 15～25

[0336] Weigh 6g of povidone K30 to prepare a 2.5wt% povidone K30 aqueous solution; weigh 52.8g of dolutegravir sodium, 40g of microcrystalline cellulose PH101, 45.2g of mannitol and 6g of sodium starch glycolate and place them in a fluidized bed. Set the inlet air temperature to 60±10℃ and adjust the air volume to 30-60m 3 / h, make the material fluidized; start spraying, add 2.5wt% povidone K30 solution (containing 6g povidone K30), wherein the liquid supply pump speed is 30-60rpm, the atomization pressure is 0.5-1.5pa, and observe the material temperature and fluidization state during the process. After the spraying is completed, enter the drying stage, adjust the air volume to 40-60m 3 / h, dried to a moisture content of ≤3.0%, and granulated into 30 mesh pieces to obtain dolutegravir sodium granules. 300g of lamivudine, 35g of microcrystalline cellulose PH102, 10g of sodium starch glycolate, and 5g of magnesium stearate were added to the dolutegravir sodium granules and mixed evenly to obtain dolutegravir and lamivudine layer granules.

[0337] 300g of tenofovir disoproxil fumarate, 25g of microcrystalline cellulose PH101, and 8g of croscarmellose sodium were weighed and mixed uniformly. A 1.5wt% aqueous solution of povidone K30 (containing 2g of povidone K30) was used as a binder to prepare a soft material. The material was placed in an extruder and spheronized to prepare tenofovir disoproxil fumarate pellets. The pellets were dried to a moisture content of ≤3.0%. 10g of pregelatinized starch and 5g of magnesium stearate were added to the tenofovir disoproxil fumarate pellets and mixed uniformly to obtain tenofovir disoproxil fumarate layered granules.

[0338] A double-layer tablet press is used to compress tablets (18.5*9.6mm oval tablets), wherein the dolutegravir and lamivudine granules are the first layer, the first layer tablet weight is 500mg, and the hardness is ≤3.0kg; the tenofovir granules are the second layer, the total tablet weight is about 850mg; the hardness is 12-18kg; and the disintegration time is ≤10 minutes.

[0339] The plain tablets were coated with a 15 wt % Opadry aqueous suspension solution, and the coating weight gain was about 1.5-3.0%; and the dolutegravir, tenofovir and lamivudine compound double-layer tablets were obtained.

[0340] Comparative Example 1

[0341] This comparative example 1 provides a dolutegravir, tenofovir and lamivudine compound double-layer tablet, the prescription composition of which is shown in Table 4 below:

[0342] Table 4 Comparative Example 1 Dolutegravir Tenofovir Lamivudine Compound Double-layer Tablet Prescription (1000 tablets)

[0343]

[0344]

[0345] Weigh 3g of povidone K30 to prepare a 5wt% povidone K30 aqueous solution, weigh 52.8g of dolutegravir sodium, 26.5g of microcrystalline cellulose PH101, 60.2g of mannitol, and 6g of sodium starch glycolate, and place them in a wet granulator. Set the stirring speed to 150rpm to mix evenly; add 5% povidone K30 aqueous solution under stirring, turn on the shear speed to 1500rpm after addition, continue granulation for 1-3 minutes, wet granulate to 20 mesh, and then dry in a fluidized bed; set the inlet air temperature to 60±10℃ and the air volume to 40-60m 3 / h, fluidize the material, dry to a moisture content of ≤3.0%, and granulate through 30 mesh to obtain granules. 1.5 g of magnesium stearate was added to the granules, and the mixture was mixed uniformly to obtain dolutegravir layered granules.

[0346] Weigh 300g of tenofovir disoproxil fumarate, 20g of lactose, 20g of microcrystalline cellulose PH101, and 10g of croscarmellose sodium into a wet granulator and set the stirring speed to 150rpm to mix evenly. Use purified water as a wetting agent to make a soft material under stirring. After the addition, turn on the shear speed to 1500rpm and continue granulating for 1 to 3 minutes. After 20 mesh wet granulation, place it in a fluidized bed for drying. Set the inlet air temperature to 60±10℃ and the air volume to 40 to 60m3. 3 / h, fluidize the material, dry to a moisture content of ≤3.0%, and granulate through 30 mesh to obtain granules. Add 300g of lamivudine, 35g of microcrystalline cellulose PH112, 10g of croscarmellose sodium, and 5g of magnesium stearate into the granules and mix evenly to obtain tenofovir lamivudine-layered granules;

[0347] The tablets were compressed using a double-layer tablet press, with tenofovir and lamivudine granules as the first layer, with a controlled theoretical layer weight of 700 mg and a hardness of ≤3.0 kg; dolutegravir granules as the second layer, with a total tablet weight of approximately 850 mg, a hardness of 12 to 20 kg, and a disintegration time of ≤10 minutes.

[0348] The plain tablets were coated with a 15 wt % Opadry aqueous suspension solution, and the coating weight gain was about 1.5-3.0%; and the dolutegravir, tenofovir and lamivudine compound double-layer tablets were obtained.

[0349] Comparative Example 2

[0350] This comparative example 2 provides a dolutegravir, tenofovir and lamivudine compound tablet, the prescription composition of which is shown in Table 5 below:

[0351] Table 5 Comparative Example 2 Dolutegravir Tenofovir Lamivudine Compound Tablet Prescription (1000 tablets)

[0352] Components Weight (g) Dolutegravir sodium (D90≤15μm) 52.8 Tenofovir disoproxil fumarate (D90≤100μm) 300 Lamivudine (100 μm ≤ D90 ≤ 300 μm) 300 Microcrystalline cellulose PH101 37.2 lactose 50 Povidone K30 10 Croscarmellose sodium 20 Microcrystalline cellulose PH112 50 Croscarmellose sodium 20 magnesium stearate 10 Obaday 15～25

[0353] 10g of povidone K30 was weighed to prepare a 2.5wt% povidone K30 aqueous solution, and 52.8g of dolutegravir sodium, 300g of tenofovir disoproxil fumarate, 300g of lamivudine, 37.2g of microcrystalline cellulose PH101, 50g of lactose, and 20g of croscarmellose sodium were weighed and placed in a wet granulator. The stirring speed was set to 150rpm to mix uniformly. The 2.5wt% povidone K30 aqueous solution was added under stirring. After the addition, the shear speed was turned to 1500rpm and granulation was continued for 1-3 minutes. The granules were wet-finished at 20 mesh and then dried in a fluidized bed. The inlet air temperature was set to 60±10℃ and the air volume was 40-60m 3 / h, fluidize the material and dry to a moisture content of ≤3.0%. 30 mesh dry granules are obtained to obtain granules. 50g of microcrystalline cellulose PH112, 20g of croscarmellose sodium, and 10g of magnesium stearate are added to the granules and mixed uniformly to obtain the total mixed granules. Tablets are compressed to a theoretical tablet weight of approximately 850mg, with a hardness of 12-20kg. Disintegration takes ≤10 minutes. The tablets are coated with 15% Opadry solution, with a coating weight gain of approximately 1.5-3.0%. Dolutegravir, tenofovir, and lamivudine combination tablets are obtained.

[0354] Effect experiment

[0355] Dissolution test

[0356] Dissolution curve tests were performed on Examples 1 to 3 and the comparative example of dolutegravir, tenofovir and lamivudine compound tablets, respectively. The method was based on the 2015 edition of the Pharmacopoeia, using a paddle method at 75 rpm, 37 ± 0.5 ° C., 0.5% sodium lauryl sulfate 900 ml pH 6.8 phosphate buffer, and sampling at 10, 15, 20, 30, 45, and 60 minutes, respectively, and HPLC detection; and compared with the comparative example.

[0357] The dissolution data of the dolutegravir, tenofovir and lamivudine compound tablets prepared in Examples 1-3 and Comparative Examples 1-2 are shown in Table 6.

[0358] Table 6 Cumulative dissolution data of dolutegravir, tenofovir and lamivudine compound tablets prepared in Examples 1-3 and Comparative Examples 1-2 (n=6, M±SD)

[0359]

[0360] Note: DTG is dolutegravir sodium; TDF is tenofovir disoproxil fumarate; 3TC is lamivudine.

[0361] As can be seen from Table 6, the three active ingredients DTG, TDF and 3TC of the dolutegravir, tenofovir and lamivudine compound tablets prepared in Examples 1 to 3 were all dissolved at a rate greater than 85% within 15 minutes, and rapid dissolution and rapid drug efficacy were achieved simultaneously.

[0362] Stability test

[0363] Accelerated tests (40° C., 75%) were carried out on the dolutegravir, tenofovir and lamivudine compound tablets prepared in Examples 1-3 and Comparative Examples 1-2, respectively. The stability test results are shown in Table 7 below:

[0364] Table 7 Stability test results of dolutegravir, tenofovir and lamivudine combination tablets (n=3, mean)

[0365]

[0366] Note: TDF is tenofovir disoproxil fumarate.

[0367] Among them, the chemical structure of impurity A is:

[0368]

[0369] As can be seen from Table 7, in the accelerated test (40°C, 75%) accelerated for 6 months, the impurity A in the example increased slightly compared with time 0, and the content of tenofovir disoproxil fumarate did not show significant difference and met the quality requirements. The impurity A in the comparative example increased significantly, and the content of tenofovir disoproxil fumarate decreased significantly. It can be seen that the stability of the dolutegravir and tenofovir lamivudine compound tablets in the example is significantly stronger than that in the comparative example.

[0370] Bioequivalence studies

[0371] Test preparation (T): dolutegravir, tenofovir and lamivudine combination tablets prepared in Example 1.

[0372] Reference preparation (R):

[0373] Dolutegravir sodium tablets: 50 mg (as dolutegravir) / tablet, Viiv Healthcare BV;

[0374] Lamivudine tablets: 300 mg / tablet, ViiV Healthcare UK Limited;

[0375] Tenofovir disoproxil fumarate tablets: 300 mg / tablet, GlaxoSmithKline (Tianjin) Co., Ltd.

[0376] Experimental methods

[0377] The subjects were given a single dose of the test formulation (T) or the reference formulation (R) in the fasting state. Blood was drawn to measure the plasma drug concentration at different time points. Pharmacokinetic parameters and relative bioavailability were calculated using a non-compartmental model to evaluate bioequivalence between the two. A crossover, randomized study was conducted, with a total of 48 male and female subjects ranging in age from 18 (youngest) to 65 (oldest).

[0378] The pharmacokinetic data of the test preparation (T) or the reference preparation (R) are compared as shown in Table 8 below:

[0379] Table 8 Comparison of pharmacokinetic data of the test preparation (T) or reference preparation (R)

[0380]

[0381] Note: T is the dolutegravir, tenofovir and lamivudine compound tablet prepared in Example 1;

[0382] R is the reference preparation.

[0383] As can be seen from Table 8, the dolutegravir, tenofovir and lamivudine compound tablets prepared in Example 1 have excellent bioequivalence to the reference preparation.

[0384] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A dolutegravir, tenofovir and lamivudine compound double-layer tablet, characterized in that: The compound double-layer tablet comprises a first immediate-release tablet and a second immediate-release tablet; The first immediate-release tablet comprises dolutegravir, lamivudine, a diluent, a binder, a disintegrant, and a lubricant; and The second rapid-release tablet comprises tenofovir disoproxil, a diluent, a binder, a disintegrant and a lubricant; in, The particle size of dolutegravir is D90≤15 μm; the particle size of lamivudine is 100 μm≤D90≤300 μm; the particle size of tenofovir disoproxil is D90≤15 μm; The first immediate-release tablet and the second immediate-release tablet are stacked together to form a compound double-layer tablet; The tablet weight of the dolutegravir, tenofovir and lamivudine compound double-layer tablet is 800-1000 mg; and the weight ratio of the first immediate-release tablet to the second immediate-release tablet is 450-600:300-400; The diluent is selected from the group consisting of lactose, mannitol, microcrystalline cellulose, pregelatinized starch, or a combination thereof; The adhesive is povidone; and / or The disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, or a combination thereof; The lubricant is magnesium stearate; Furthermore, the compound double-layer tablet is prepared by compressing two layers of dolutegravir and lamivudine granules and tenofovir granules; The dolutegravir and lamivudine granules include dolutegravir granules and lamivudine powder; and the dolutegravir and lamivudine granules are obtained by mixing dolutegravir granules and lamivudine powder; in, The dolutegravir granules include: Alternatively, include: Alternatively, include: The lamivudine powder comprises: Alternatively, include: The tenofovir granules include: Alternatively, include: Alternatively, include: 。 2. The compound double-layer tablet according to claim 1, characterized in that: The microcrystalline cellulose is selected from the group consisting of microcrystalline cellulose PH101, microcrystalline cellulose PH102, microcrystalline cellulose PH112, or a combination thereof.

3. The compound double-layer tablet according to claim 1, characterized in that: The povidone is povidone K30.

4. The compound double-layer tablet according to claim 1, characterized in that: In the dolutegravir granules, the microcrystalline cellulose is microcrystalline cellulose PH101, and the povidone is povidone K30.

5. The compound double-layer tablet according to claim 1, characterized in that: The dolutegravir granules are prepared by wet granulation and / or fluidized bed granulation.

6. The compound double-layer tablet according to claim 1, characterized in that: In the lamivudine powder, the microcrystalline cellulose is microcrystalline cellulose PH102.

7. The compound double-layer tablet according to claim 1, characterized in that: The lamivudine powder is prepared by direct mixing and / or wet granulation process.

8. The compound double-layer tablet according to claim 1, characterized in that: The tenofovir granules are prepared by centrifugal granulation and / or extrusion spheronization pelleting process.

9. The compound double-layer tablet according to claim 1, characterized in that: The compound double-layer tablet is a coated tablet, and the coating material is Opadry.

10. The compound double-layer tablet according to claim 1, characterized in that: The dolutegravir, tenofovir and lamivudine compound double-layer tablets have a cumulative dissolution rate of greater than 85% in 15 minutes under the following dissolution conditions; The dissolution conditions are: Stirring: paddle method 75 rpm; Temperature: 37 ± 0.5°C; Dissolution medium: 0.5% sodium lauryl sulfate 900 ml pH 6.8 phosphate buffer.

11. The compound double-layer tablet according to claim 1, characterized in that: The tablet weight of the dolutegravir, tenofovir and lamivudine compound double-layer tablet is 850-950 mg.

12. The use of the dolutegravir, tenofovir and lamivudine compound double-layer tablets according to claim 1, wherein: Used to prepare antiviral drugs.

13. The use according to claim 12, characterized in that The virus is HIV virus.

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