Efficient ethylamine pyrazine rifosinate tobacco flakes and preparation method thereof

Abstract

The invention discloses a preparation method of an efficient ethylamine pyrazine rifo tablet. The preparation method comprises the following steps: (1) preparing isoniazide, pyrazinamide, microcrystalline cellulose and pregelatinized starch into isoniazide particles; mixing ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch to prepare ethylamine particles; (2) spraying and adding an aqueous solution of povidone K30 into the iso-tobacco particles to obtain an iso-tobacco soft material, spraying and adding a mixed aqueous solution of povidone K30 and lauryl sodium sulfate into ethylamine particles to prepare an ethylamine soft material, granulating, drying and finishing the particles to obtain dry ethylamine particles; and (3) mixing and stirring the ethylamine dry granules, talcum powder and rifampicin, then adding corn starch, the iso-tobacco dry granules, polyvinylpolypyrrolidone and magnesium stearate, uniformly mixing, tabletting and coating to obtain a finished product. By optimizing the preparation process, the disintegration time of the tablet is shortened, the dissolution of active ingredients of the medicine is accelerated, and the medicine effect of the medicine is improved. In addition, by preparing the rifampicin clathrate compound, the solubility of rifampicin can be remarkably improved, and the drug property is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of production and processing of ethylamine, pyrazine, and rifampicin tobacco tablets, and in particular to a high-efficiency ethylamine, pyrazine, and rifampicin tobacco tablet and a preparation method thereof. Background Art

[0002] Tuberculosis is an infectious disease caused by the bacillus Mycobacterium tuberculosis. It usually affects the lungs, but can also affect other parts of the body. According to the WHO, approximately one-third of the world's population is infected with the disease. The development of drug-resistant tuberculosis is a major public health concern because it threatens the future of tuberculosis control. Drug resistance in tuberculosis patients is mainly due to poor patient compliance with treatment. When using a single drug combination, patients need to take 6-8 tablets once a day on an empty stomach. Failure to fully comply with treatment leads to the development of multidrug-resistant strains of tuberculosis. Summary of the Invention

[0003] To this end, the present invention provides a method for preparing high-efficiency ethamidine pyrazine and rifampicin tobacco tablets, the steps comprising: (1) Weighing the sieved isoniazid, pyrazinamide, and ethambutol hydrochloride according to the formula amount, then mixing the isoniazid, pyrazinamide, microcrystalline cellulose, and pregelatinized starch, stirring evenly to obtain isoniazid particles; mixing the ethambutol hydrochloride, microcrystalline cellulose, and pregelatinized starch, stirring evenly to obtain ethambutol particles; (2) preparing a mixed aqueous solution of povidone K30 and sodium lauryl sulfate to prepare an aqueous solution of povidone K30; spraying the aqueous solution of povidone K30 into the iso-yan granules under stirring to obtain an iso-yan soft material, and then granulating, drying, and sizing to obtain iso-yan dry granules; spraying the mixed aqueous solution of povidone K30 and sodium lauryl sulfate into the ethylamine granules under stirring to obtain an ethylamine soft material, and then granulating, drying, and sizing to obtain ethylamine dry granules; (3) The ethylamine dry particles are mixed with talc and rifampicin, and stirred evenly to obtain a first mixture. Then, corn starch, the isoflavone dry particles, cross-linked polyvinylpyrrolidone and magnesium stearate are added to the first mixture under stirring. After the addition is completed, the mixture is stirred evenly, tableted, and coated to obtain the ethylamine pyrazine rifampicin tablets.

[0004] Furthermore, in step (1), the raw materials of the isoniazid particles are calculated by weight as follows: 8 to 10 parts of isoniazid, 45 to 50 parts of pyrazinamide, 2 to 3 parts of microcrystalline cellulose, and 1 to 1.5 parts of pregelatinized starch; the raw materials of the ethylamine particles are calculated by weight as follows: 30 to 35 parts of ethambutol hydrochloride, 1.2 to 1.5 parts of microcrystalline cellulose, and 3 to 5 parts of pregelatinized starch.

[0005] Furthermore, the isoniazid is a powder that can pass through a sieve with a mesh number of 40 or more, the pyrazinamide is a powder that can pass through a sieve with a mesh number of 100 or more, and the ethambutol hydrochloride is a powder that can pass through a sieve with a mesh number of 120 or more.

[0006] Furthermore, in the step (2), in the mixed aqueous solution of povidone K30 and sodium lauryl sulfate, the mass percentage of povidone K30 is 14% to 16%, and the mass percentage of sodium lauryl sulfate is 2% to 4%; the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine particles so that the mass ratio of ethambutol hydrochloride and povidone K30 is ethambutol hydrochloride: povidone K30 = 30 to 35: 0.5 to 0.7; in the aqueous solution of povidone K30, the mass percentage of povidone K30 is 14% to 16%; the aqueous solution of povidone K30 is sprayed into the isoniazid particles so that the mass ratio of isoniazid and povidone K30 is isoniazid: povidone K30 = 8 to 10: 1 to 1.4.

[0007] Furthermore, in step (3), the mass ratio of the amounts of talc, rifampicin, corn starch, cross-linked polyvinylpyrrolidone and magnesium stearate to the amount of isoniazid in step (1) is isoniazid: talc: rifampicin: corn starch: cross-linked polyvinylpyrrolidone: magnesium stearate = 8-10: 1-1.4: 16-20: 2-2.3: 2-2.3: 0.8-1.2.

[0008] Furthermore, the rifampicin is first mixed evenly with the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate before adding the materials to obtain a rifampicin inclusion complex, and then the rifampicin inclusion complex is mixed with the ethylamine dry particles and talc. The preparation method of the rifampicin inclusion complex is: Step 1: Mix olive leaf dry powder and kelp dry powder to form a mixed powder, add the mixed powder to a cellulase hydrolyzate, adjust the pH to 5-5.5 with hydrochloric acid, then heat in a water bath to 55-60° C., extract at a constant temperature for more than 5 hours, then inactivate the enzyme, separate the solid and liquid, concentrate the liquid phase under reduced pressure, and freeze-dry to obtain an olive leaf-kelp hydrolyzate; Step 2: preparing an aqueous solution of acetic acid, adding soybeans to the aqueous solution of acetic acid, soaking at room temperature for more than 5 hours, then filtering, washing the soybeans with deionized water for more than 3 times, adding deionized water, and beating with a beater to make soy milk, filtering the soy milk with nylon cloth to remove bean dregs, adding neutral protease to the filtrate, heating to 50±3° C. in a water bath after adding the enzyme, keeping the temperature for enzymatic hydrolysis for more than 2 hours, then inactivating the enzyme, centrifuging, concentrating the supernatant under reduced pressure, and freeze-drying to obtain the soybean hydrolyzate; Step 3: Mix rifampicin, the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate, stir the mixture for more than 10 minutes, and then grind it for more than 30 minutes to obtain the rifampicin inclusion complex.

[0009] Furthermore, in the step one, the mass ratio of the olive leaf powder and the kelp powder is olive leaf powder: kelp powder = 10:2-10; the concentration of cellulase in the cellulase hydrolysate is 80-100 mg / 100 mL, the solvent is water, and the amount ratio of the mixed powder added to the cellulase hydrolysate is mixed powder: cellulase hydrolysate = 1 g: 50-80 mL; the mass percentage of the solute in the hydrochloric acid is 10%.

[0010] Furthermore, in step 2, the mass percentage of the solute in the aqueous solution of acetic acid is 5% to 6%, and the solvent is water; the mass ratio of the soybeans added to the aqueous solution of acetic acid is soybeans: acetic acid aqueous solution = 1:5 to 10; the washed soybeans are added to deionized water at a mass ratio of soybeans: water = 1:8 to 10 for pulping; the volume ratio of the added mass of neutral protease to the filtrate is neutral protease: filtrate = 3 to 4 g: 100 mL.

[0011] Furthermore, in the step three, the mass ratio of rifampicin, the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate is rifampicin: olive leaf-kelp hydrolysate: hydroxypropyl-β-cyclodextrin: soybean hydrolysate = 10:1~2:16~18:2~6.

[0012] The auxiliary materials added in the present invention have the following functions: Microcrystalline cellulose: It has stable properties and good safety. It is mainly used as a binder or filler. Its disintegration and compressibility are better than starch. It has been used in FDC preparations abroad and can reduce the risks that may arise from its use in prescriptions. Cross-linked polyvinylpyrrolidone: It has stable properties, good safety, and strong disintegration ability. It has been used in foreign FDC preparations and can reduce the risks that may arise from its use in prescriptions. Povidone K30: Usually used as a binder for tablets and capsules. It is required as a binder and has been used in foreign FDC preparations. It can reduce the risks that may arise from its use in prescriptions. Sodium lauryl sulfate: an anionic surfactant that plays a role in wetting and promoting dissolution; Corn starch: In this product’s formulation, corn starch is used as a binder. The moisture content of corn starch is close to the upper limit of control. Direct addition of corn starch may affect the disintegration of the self-made product and affect the subsequent pre-experimental formulation judgment. It can be used after drying. Talc: It is used as a glidant in this product to lubricate particles. It is used in combination with magnesium stearate to reduce the risk of uneven mixing and tableting. Magnesium stearate: Lubricant, can avoid sticking during tableting and ensure smooth tablet surface.

[0013] The present invention has the beneficial effects of reducing the disintegration time of the tablets, accelerating the dissolution of the active pharmaceutical ingredient, and improving the efficacy of the drug by optimizing the preparation process. Furthermore, the low solubility of rifampicin restricts its further efficacy. By preparing a rifampicin inclusion complex, the present invention can significantly increase the solubility of rifampicin and enhance its medicinal properties. DETAILED DESCRIPTION

[0014] The present invention will be further described below with reference to the embodiments.

[0015] Example 1 A method for preparing high-efficiency ethamidine pyrazine and rifampicin tobacco tablets, comprising the following steps: (1) Weighing the sieved isoniazid, pyrazinamide and ethambutol hydrochloride according to the formula amount, wherein the isoniazid is a powder with a mesh number of 40 mesh, the pyrazinamide is a powder with a mesh number of 100 mesh, and the ethambutol hydrochloride is a powder with a mesh number of 120 mesh; then mixing the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain isoniazid particles; mixing the ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain ethylamine particles; the raw materials of the isoniazid particles are calculated by weight: 9 parts of isoniazid, 48 parts of pyrazinamide, 2.16 parts of microcrystalline cellulose, and 1.2 parts of pregelatinized starch; the raw materials of the ethylamine particles are calculated by weight: 33 parts of ethambutol hydrochloride, 1.44 parts of microcrystalline cellulose, and 3.6 parts of pregelatinized starch; (2) preparing a mixed aqueous solution of povidone K30 and sodium lauryl sulfate, wherein the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is 15% and the mass percentage of sodium lauryl sulfate is 3%; preparing an aqueous solution of povidone K30, wherein the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; spraying the aqueous solution of povidone K30 into the iso-smoke particles under stirring (adding for 5 minutes, then mixing and stirring for 5 minutes) to obtain an iso-smoke soft material, spraying the aqueous solution of povidone K30 into the iso-smoke particles to make the iso-smoke soft material The mass ratio of niacinhydrazide to povidone K30 is 9:1.2; granulation, drying, and sizing are then performed to obtain isoniazid dry granules; a mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules under stirring (adding for 5 minutes, followed by mixing and stirring for 5 minutes) to obtain an ethylamine soft material; the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules so that the mass ratio of ethambutol hydrochloride to povidone K30 is 33:0.6; granulation, drying, and sizing are then performed to obtain ethylamine dry granules; (3) The ethylamine dry particles are mixed with talcum powder and rifampicin, and the mixture is stirred for 10 minutes to be uniformly mixed to obtain a first mixture. Then, corn starch, the isoniazid dry particles, cross-linked polyvinylpyrrolidone and magnesium stearate are added to the first mixture under stirring. The mass ratio of the talcum powder, rifampicin, corn starch, cross-linked polyvinylpyrrolidone and magnesium stearate to the amount of isoniazid in step (1) is isoniazid: talcum powder: rifampicin: corn starch: cross-linked polyvinylpyrrolidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96; after the addition is completed, the mixture is stirred for 10 minutes to be uniformly mixed, tableted (tableting hardness is 10 kg, the same for each embodiment and comparative example), and coated to obtain the ethylamine pyrazine rifampicin tablets.

[0016] Example 2 A method for preparing high-efficiency ethamidine pyrazine and rifampicin tobacco tablets, comprising the following steps: (1) Weighing the sieved isoniazid, pyrazinamide and ethambutol hydrochloride according to the formula amount, wherein the isoniazid is a powder with a mesh number of 40 mesh, the pyrazinamide is a powder with a mesh number of 100 mesh, and the ethambutol hydrochloride is a powder with a mesh number of 120 mesh; then mixing the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain isoniazid particles; mixing the ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain ethylamine particles; the raw materials of the isoniazid particles are calculated by weight: 9 parts of isoniazid, 48 parts of pyrazinamide, 2.16 parts of microcrystalline cellulose, and 1.2 parts of pregelatinized starch; the raw materials of the ethylamine particles are calculated by weight: 33 parts of ethambutol hydrochloride, 1.44 parts of microcrystalline cellulose, and 3.6 parts of pregelatinized starch; (2) preparing a mixed aqueous solution of povidone K30 and sodium lauryl sulfate, wherein the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is 15% and the mass percentage of sodium lauryl sulfate is 3%; preparing an aqueous solution of povidone K30, wherein the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; spraying the aqueous solution of povidone K30 into the iso-smoke particles under stirring (adding for 5 minutes, then mixing and stirring for 5 minutes) to obtain an iso-smoke soft material, spraying the aqueous solution of povidone K30 into the iso-smoke particles to make the iso-smoke soft material The mass ratio of niacinhydrazide to povidone K30 is 9:1.2; granulation, drying, and sizing are then performed to obtain isoniazid dry granules; a mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules under stirring (adding for 5 minutes, followed by mixing and stirring for 5 minutes) to obtain an ethylamine soft material; the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules so that the mass ratio of ethambutol hydrochloride to povidone K30 is 33:0.6; granulation, drying, and sizing are then performed to obtain ethylamine dry granules; (3) The ethylamine dry particles are mixed with talcum powder and rifampicin inclusion compound, and the mixture is stirred for 10 minutes to be uniformly mixed to obtain a first mixture. Then, corn starch, the isoniazid dry particles, cross-linked polyvinylpyrrolidone and magnesium stearate are added to the first mixture under stirring. The mass ratio of the talcum powder, rifampicin used to prepare the rifampicin inclusion compound, corn starch, cross-linked polyvinylpyrrolidone and magnesium stearate to the amount of isoniazid in step (1) is isoniazid: talcum powder: rifampicin: corn starch: cross-linked polyvinylpyrrolidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96; after the addition is completed, the mixture is stirred for 10 minutes to be uniformly mixed, tableted, and coated to obtain the ethylamine pyrazine rifampicin tablets.

[0017] Wherein, the rifampicin is first mixed evenly with the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate before adding the materials to obtain a rifampicin inclusion complex; the preparation method of the rifampicin inclusion complex is: Step 1, mixing olive leaf dry powder and kelp dry powder to form a mixed powder, the mass ratio of the olive leaf dry powder and the kelp dry powder is olive leaf dry powder: kelp dry powder = 10:2; the mixed powder is added to a cellulase hydrolyzate, the concentration of cellulase in the cellulase hydrolyzate is 80 mg / 100 mL, the solvent is water, and the amount ratio of the mixed powder added to the cellulase hydrolyzate is mixed powder: cellulase hydrolyzate = 1 g: 50 mL; using hydrochloric acid (the mass percentage of solute in hydrochloric acid is 10%) to adjust the pH to 5.5, then heating to 60°C in a water bath, constant temperature extraction for 5h, and then inactivating the enzyme at 90°C for 10min, solid-liquid separation, and concentrating the liquid phase under reduced pressure to 1 / 4 of the volume before concentration, freeze-drying to obtain an olive leaf-kelp hydrolyzate; Step 2: prepare an aqueous solution of acetic acid, wherein the mass percentage of the solute in the aqueous solution of acetic acid is 5% and the solvent is water; add soybeans to the aqueous solution of acetic acid and soak at room temperature for 5 hours, wherein the mass ratio of the soybeans added to the aqueous solution of acetic acid is soybeans: acetic acid aqueous solution = 1:5; then filter, wash the soybeans with deionized water 3 times, add deionized water, and beat into soy milk with a beater, and add the washed soybeans to deionized water at a mass ratio of soybeans: water = 1:9 for bean pulping; filter the soy milk with nylon cloth to remove bean dregs, add neutral protease to the filtrate, and the volume ratio of the added mass of neutral protease to the filtrate is neutral protease: filtrate = 3g:100mL; after adding the enzyme, heat in a water bath to 50°C, keep enzymolysis for 2 hours, then inactivate the enzyme at 90°C for 10 minutes, centrifuge, concentrate the supernatant under reduced pressure to 1 / 2 of the volume before concentration, and freeze-dry to obtain the soybean hydrolysate; Step three, mixing rifampicin, the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate, the mass ratio of rifampicin, the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate is rifampicin: olive leaf-kelp hydrolysate: hydroxypropyl-β-cyclodextrin: soybean hydrolysate = 10:1:16:2; stirring the mixture for 10 minutes, and then grinding for 30 minutes to obtain the rifampicin inclusion complex.

[0018] Example 3 A method for preparing high-efficiency ethamidine pyrazine and rifampicin tobacco tablets, comprising the following steps: (1) Weighing the sieved isoniazid, pyrazinamide and ethambutol hydrochloride according to the formula amount, wherein the isoniazid is a powder with a mesh number of 40 mesh, the pyrazinamide is a powder with a mesh number of 100 mesh, and the ethambutol hydrochloride is a powder with a mesh number of 120 mesh; then mixing the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain isoniazid particles; mixing the ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain ethylamine particles; the raw materials of the isoniazid particles are calculated by weight: 9 parts of isoniazid, 48 parts of pyrazinamide, 2.16 parts of microcrystalline cellulose, and 1.2 parts of pregelatinized starch; the raw materials of the ethylamine particles are calculated by weight: 33 parts of ethambutol hydrochloride, 1.44 parts of microcrystalline cellulose, and 3.6 parts of pregelatinized starch; (2) preparing a mixed aqueous solution of povidone K30 and sodium lauryl sulfate, wherein the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is 15% and the mass percentage of sodium lauryl sulfate is 3%; preparing an aqueous solution of povidone K30, wherein the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; spraying the aqueous solution of povidone K30 into the iso-smoke particles under stirring (adding for 5 minutes, then mixing and stirring for 5 minutes) to obtain an iso-smoke soft material, spraying the aqueous solution of povidone K30 into the iso-smoke particles to make the iso-smoke soft material The mass ratio of niacinhydrazide to povidone K30 is 9:1.2; granulation, drying, and sizing are then performed to obtain isoniazid dry granules; a mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules under stirring (adding for 5 minutes, followed by mixing and stirring for 5 minutes) to obtain an ethylamine soft material; the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules so that the mass ratio of ethambutol hydrochloride to povidone K30 is 33:0.6; granulation, drying, and sizing are then performed to obtain ethylamine dry granules; (3) The ethylamine dry particles are mixed with talcum powder and rifampicin inclusion compound, and the mixture is stirred for 10 minutes to be uniformly mixed to obtain a first mixture. Then, corn starch, the isoniazid dry particles, cross-linked polyvinylpyrrolidone and magnesium stearate are added to the first mixture under stirring. The mass ratio of the talcum powder, rifampicin used to prepare the rifampicin inclusion compound, corn starch, cross-linked polyvinylpyrrolidone and magnesium stearate to the amount of isoniazid in step (1) is isoniazid: talcum powder: rifampicin: corn starch: cross-linked polyvinylpyrrolidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96; after the addition is completed, the mixture is stirred for 10 minutes to be uniformly mixed, tableted, and coated to obtain the ethylamine pyrazine rifampicin tablets.

[0019] Wherein, the rifampicin is first mixed evenly with the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate before adding the materials to obtain a rifampicin inclusion complex; the preparation method of the rifampicin inclusion complex is: Step 1, mixing olive leaf dry powder and kelp dry powder to form a mixed powder, the mass ratio of the olive leaf dry powder and the kelp dry powder is olive leaf dry powder: kelp dry powder = 10:6; the mixed powder is added to a cellulase hydrolyzate, the concentration of cellulase in the cellulase hydrolyzate is 90 mg / 100 mL, the solvent is water, and the amount ratio of the mixed powder added to the cellulase hydrolyzate is mixed powder: cellulase hydrolyzate = 1 g: 50 mL; using hydrochloric acid (the mass percentage of solute in hydrochloric acid is 10%) to adjust the pH to 5.5, then heating to 60°C in a water bath, constant temperature extraction for 5h, and then inactivating the enzyme at 90°C for 10min, solid-liquid separation, and concentrating the liquid phase under reduced pressure to 1 / 4 of the volume before concentration, freeze-drying, and obtaining an olive leaf-kelp hydrolyzate; Step 2: prepare an aqueous solution of acetic acid, wherein the mass percentage of the solute in the aqueous solution of acetic acid is 5% and the solvent is water; add soybeans to the aqueous solution of acetic acid and soak at room temperature for 5 hours, wherein the mass ratio of the soybeans added to the aqueous solution of acetic acid is soybeans: acetic acid aqueous solution = 1:5; then filter, wash the soybeans with deionized water 3 times, add deionized water, and beat into soy milk with a beater, and add the washed soybeans to deionized water at a mass ratio of soybeans: water = 1:9 for bean pulping; filter the soy milk with nylon cloth to remove bean dregs, add neutral protease to the filtrate, and the volume ratio of the added mass of neutral protease to the filtrate is neutral protease: filtrate = 3g:100mL; after adding the enzyme, heat in a water bath to 50°C, keep enzymolysis for 2 hours, then inactivate the enzyme at 90°C for 10 minutes, centrifuge, concentrate the supernatant under reduced pressure to 1 / 2 of the volume before concentration, and freeze-dry to obtain the soybean hydrolysate; Step three, mixing rifampicin, the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate, the mass ratio of rifampicin, the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate is rifampicin: olive leaf-kelp hydrolysate: hydroxypropyl-β-cyclodextrin: soybean hydrolysate = 10:1:17:4; stirring the mixture for 10 minutes, and then grinding for 30 minutes to obtain the rifampicin inclusion complex.

[0020] Example 4 A method for preparing high-efficiency ethamidine pyrazine and rifampicin tobacco tablets, comprising the following steps: (1) Weighing the sieved isoniazid, pyrazinamide and ethambutol hydrochloride according to the formula amount, wherein the isoniazid is a powder with a mesh number of 40 mesh, the pyrazinamide is a powder with a mesh number of 100 mesh, and the ethambutol hydrochloride is a powder with a mesh number of 120 mesh; then mixing the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain isoniazid particles; mixing the ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain ethylamine particles; the raw materials of the isoniazid particles are calculated by weight: 9 parts of isoniazid, 48 parts of pyrazinamide, 2.16 parts of microcrystalline cellulose, and 1.2 parts of pregelatinized starch; the raw materials of the ethylamine particles are calculated by weight: 33 parts of ethambutol hydrochloride, 1.44 parts of microcrystalline cellulose, and 3.6 parts of pregelatinized starch; (2) preparing a mixed aqueous solution of povidone K30 and sodium lauryl sulfate, wherein the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is 15% and the mass percentage of sodium lauryl sulfate is 3%; preparing an aqueous solution of povidone K30, wherein the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; spraying the aqueous solution of povidone K30 into the iso-smoke particles under stirring (adding for 5 minutes, then mixing and stirring for 5 minutes) to obtain an iso-smoke soft material, spraying the aqueous solution of povidone K30 into the iso-smoke particles to make the iso-smoke soft material The mass ratio of niacinhydrazide to povidone K30 is 9:1.2; granulation, drying, and sizing are then performed to obtain isoniazid dry granules; a mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules under stirring (adding for 5 minutes, followed by mixing and stirring for 5 minutes) to obtain an ethylamine soft material; the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules so that the mass ratio of ethambutol hydrochloride to povidone K30 is 33:0.6; granulation, drying, and sizing are then performed to obtain ethylamine dry granules; (3) The ethylamine dry particles are mixed with talcum powder and rifampicin inclusion compound, and the mixture is stirred for 10 minutes to be uniformly mixed to obtain a first mixture. Then, corn starch, the isoniazid dry particles, cross-linked polyvinylpyrrolidone and magnesium stearate are added to the first mixture under stirring. The mass ratio of the talcum powder, rifampicin used to prepare the rifampicin inclusion compound, corn starch, cross-linked polyvinylpyrrolidone and magnesium stearate to the amount of isoniazid in step (1) is isoniazid: talcum powder: rifampicin: corn starch: cross-linked polyvinylpyrrolidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96; after the addition is completed, the mixture is stirred for 10 minutes to be uniformly mixed, tableted, and coated to obtain the ethylamine pyrazine rifampicin tablets.

[0021] Wherein, the rifampicin is first mixed evenly with the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate before adding the materials to obtain a rifampicin inclusion complex; the preparation method of the rifampicin inclusion complex is: Step 1, mixing olive leaf dry powder and kelp dry powder to form a mixed powder, the mass ratio of the olive leaf dry powder and the kelp dry powder is olive leaf dry powder: kelp dry powder = 10:10; the mixed powder is added to a cellulase hydrolyzate, the concentration of cellulase in the cellulase hydrolyzate is 100 mg / 100 mL, the solvent is water, and the amount ratio of the mixed powder added to the cellulase hydrolyzate is mixed powder: cellulase hydrolyzate = 1 g: 50 mL; using hydrochloric acid (the mass percentage of solute in hydrochloric acid is 10%) to adjust the pH to 5.5, then heating to 60°C in a water bath, constant temperature extraction for 5h, and then inactivating the enzyme at 90°C for 10min, solid-liquid separation, and concentrating the liquid phase under reduced pressure to 1 / 4 of the volume before concentration, freeze-drying to obtain an olive leaf-kelp hydrolyzate; Step 2: preparing an aqueous solution of acetic acid, wherein the mass percentage of the solute in the aqueous solution of acetic acid is 6% and the solvent is water; adding soybeans to the aqueous solution of acetic acid and soaking them at room temperature for 5 hours, wherein the mass ratio of the soybeans added to the aqueous solution of acetic acid is soybeans: the aqueous solution of acetic acid = 1:5; then filtering, washing the soybeans with deionized water 3 times, adding deionized water, and beating them into soy milk with a beater, and beating the washed soybeans with deionized water at a mass ratio of soybeans: water = 1:9; filtering the soy milk with nylon cloth to remove bean dregs, adding neutral protease to the filtrate, and the volume ratio of the added mass of neutral protease to the filtrate is neutral protease: filtrate = 4g:100mL; heating in a water bath to 50°C after adding the enzyme, keeping the enzyme hydrolyzed for 2 hours, then inactivating the enzyme at 90°C for 10 minutes, centrifuging, concentrating the supernatant under reduced pressure to 1 / 2 of the volume before concentration, and freeze-drying to obtain the soybean hydrolyzate; Step three, mixing rifampicin, the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate, the mass ratio of rifampicin, the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate is rifampicin: olive leaf-kelp hydrolysate: hydroxypropyl-β-cyclodextrin: soybean hydrolysate = 10:2:18:6; stirring the mixture for 10 minutes, and then grinding for 30 minutes to obtain the rifampicin inclusion complex.

[0022] Comparative Example 1 A method for preparing ethamidine pyrazine and rifampicin tobacco tablets, comprising the following steps: (1) Weighing the sieved isoniazid, pyrazinamide and ethambutol hydrochloride according to the formula amount, wherein the isoniazid is a powder with a mesh number of 40 mesh, the pyrazinamide is a powder with a mesh number of 100 mesh, and the ethambutol hydrochloride is a powder with a mesh number of 120 mesh; then mixing the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain isoniazid particles; mixing the ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain ethylamine particles; the raw materials of the isoniazid particles are calculated by weight: 9 parts of isoniazid, 48 parts of pyrazinamide, 2.16 parts of microcrystalline cellulose, and 1.2 parts of pregelatinized starch; the raw materials of the ethylamine particles are calculated by weight: 33 parts of ethambutol hydrochloride, 1.44 parts of microcrystalline cellulose, and 3.6 parts of pregelatinized starch; (2) preparing a mixed aqueous solution of povidone K30 and sodium lauryl sulfate, wherein the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is 15% and the mass percentage of sodium lauryl sulfate is 3%; preparing an aqueous solution of povidone K30, wherein the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; spraying the aqueous solution of povidone K30 into the iso-smoke particles under stirring (adding for 5 minutes, then mixing and stirring for 5 minutes) to obtain an iso-smoke soft material, spraying the aqueous solution of povidone K30 into the iso-smoke particles to make the iso-smoke soft material The mass ratio of niacinhydrazide to povidone K30 is 9:1.2; granulation, drying, and sizing are then performed to obtain isoniazid dry granules; a mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules under stirring (adding for 5 minutes, followed by mixing and stirring for 5 minutes) to obtain an ethylamine soft material; the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules so that the mass ratio of ethambutol hydrochloride to povidone K30 is 33:0.6; granulation, drying, and sizing are then performed to obtain ethylamine dry granules; (3) The ethylamine dry particles are mixed with talcum powder and rifampicin inclusion compound, and the mixture is stirred for 10 minutes to be uniformly mixed to obtain a first mixture. Then, corn starch, the isoniazid dry particles, cross-linked polyvinylpyrrolidone and magnesium stearate are added to the first mixture under stirring. The mass ratio of the talcum powder, rifampicin used to prepare the rifampicin inclusion compound, corn starch, cross-linked polyvinylpyrrolidone and magnesium stearate to the amount of isoniazid in step (1) is isoniazid: talcum powder: rifampicin: corn starch: cross-linked polyvinylpyrrolidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96; after the addition is completed, the mixture is stirred for 10 minutes to be uniformly mixed, tableted, and coated to obtain the ethylamine pyrazine rifampicin tablets.

[0023] Wherein, the rifampicin is first mixed evenly with hydroxypropyl-β-cyclodextrin and soybean hydrolysate before adding the materials to obtain the rifampicin inclusion compound of this comparative example; the preparation method of the rifampicin inclusion compound is: Step 1, preparing an aqueous solution of acetic acid, wherein the mass percentage of the solute in the aqueous solution of acetic acid is 5%, and the solvent is water; adding soybeans to the aqueous solution of acetic acid and soaking them at room temperature for 5 hours, wherein the mass ratio of the soybeans added to the aqueous solution of acetic acid is soybeans: the aqueous solution of acetic acid = 1:5; then filtering, washing the soybeans with deionized water 3 times, adding deionized water, and beating them into soy milk with a beater, and beating the washed soybeans into deionized water at a mass ratio of soybeans: water = 1:9; filtering the soy milk with nylon cloth to remove bean dregs, adding neutral protease to the filtrate, and the volume ratio of the added mass of neutral protease to the filtrate is neutral protease: filtrate = 3g:100mL; after adding the enzyme, heating to 50°C in a water bath, keeping the enzyme hydrolyzed for 2 hours, then inactivating the enzyme at 90°C for 10 minutes, centrifuging, concentrating the supernatant under reduced pressure to 1 / 2 of the volume before concentration, and freeze-drying to obtain the soybean hydrolyzate; Step 2: Mix rifampicin, hydroxypropyl-β-cyclodextrin and soybean hydrolysate, and the mass ratio of rifampicin, hydroxypropyl-β-cyclodextrin and soybean hydrolysate is rifampicin: hydroxypropyl-β-cyclodextrin: soybean hydrolysate = 10:17:4; stir the mixture for 10 minutes, and then grind for 30 minutes to obtain the rifampicin inclusion complex described in this comparative example.

[0024] Comparative Example 2 A method for preparing ethamidine pyrazine and rifampicin tobacco tablets, comprising the following steps: (1) Weighing the sieved isoniazid, pyrazinamide and ethambutol hydrochloride according to the formula amount, wherein the isoniazid is a powder with a mesh number of 40 mesh, the pyrazinamide is a powder with a mesh number of 100 mesh, and the ethambutol hydrochloride is a powder with a mesh number of 120 mesh; then mixing the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain isoniazid particles; mixing the ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain ethylamine particles; the raw materials of the isoniazid particles are calculated by weight: 9 parts of isoniazid, 48 parts of pyrazinamide, 2.16 parts of microcrystalline cellulose, and 1.2 parts of pregelatinized starch; the raw materials of the ethylamine particles are calculated by weight: 33 parts of ethambutol hydrochloride, 1.44 parts of microcrystalline cellulose, and 3.6 parts of pregelatinized starch; (2) preparing a mixed aqueous solution of povidone K30 and sodium lauryl sulfate, wherein the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is 15% and the mass percentage of sodium lauryl sulfate is 3%; preparing an aqueous solution of povidone K30, wherein the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; spraying the aqueous solution of povidone K30 into the iso-smoke particles under stirring (adding for 5 minutes, then mixing and stirring for 5 minutes) to obtain an iso-smoke soft material, spraying the aqueous solution of povidone K30 into the iso-smoke particles to make the iso-smoke soft material The mass ratio of niacinhydrazide to povidone K30 is 9:1.2; granulation, drying, and sizing are then performed to obtain isoniazid dry granules; a mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules under stirring (adding for 5 minutes, followed by mixing and stirring for 5 minutes) to obtain an ethylamine soft material; the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules so that the mass ratio of ethambutol hydrochloride to povidone K30 is 33:0.6; granulation, drying, and sizing are then performed to obtain ethylamine dry granules; (3) The ethylamine dry particles are mixed with talcum powder and rifampicin inclusion compound, and the mixture is stirred for 10 minutes to be uniformly mixed to obtain a first mixture. Then, corn starch, the isoniazid dry particles, cross-linked polyvinylpyrrolidone and magnesium stearate are added to the first mixture under stirring. The mass ratio of the talcum powder, rifampicin used to prepare the rifampicin inclusion compound, corn starch, cross-linked polyvinylpyrrolidone and magnesium stearate to the amount of isoniazid in step (1) is isoniazid: talcum powder: rifampicin: corn starch: cross-linked polyvinylpyrrolidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96; after the addition is completed, the mixture is stirred for 10 minutes to be uniformly mixed, tableted, and coated to obtain the ethylamine pyrazine rifampicin tablets.

[0025] Wherein, the rifampicin is evenly mixed with the olive leaf hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate before adding the materials to obtain the rifampicin inclusion compound of this comparative example; the preparation method of the rifampicin inclusion compound is: Step 1, adding olive leaf powder to a cellulase hydrolysate, wherein the concentration of cellulase in the cellulase hydrolysate is 90 mg / 100 mL, the solvent is water, and the amount ratio of the olive leaf powder to the cellulase hydrolysate is olive leaf powder: cellulase hydrolysate = 1 g: 50 mL; adjusting the pH to 5.5 with hydrochloric acid (the mass percentage of solute in hydrochloric acid is 10%), then heating in a water bath to 60° C., extracting at a constant temperature for 5 hours, then inactivating the enzyme at 90° C. for 10 minutes, separating the solid and liquid, and concentrating the liquid phase under reduced pressure to 1 / 4 of the volume before concentration, and freeze-drying to obtain an olive leaf hydrolysate; Step 2: prepare an aqueous solution of acetic acid, wherein the mass percentage of the solute in the aqueous solution of acetic acid is 5% and the solvent is water; add soybeans to the aqueous solution of acetic acid and soak at room temperature for 5 hours, wherein the mass ratio of the soybeans added to the aqueous solution of acetic acid is soybeans: acetic acid aqueous solution = 1:5; then filter, wash the soybeans with deionized water 3 times, add deionized water, and beat into soy milk with a beater, and add the washed soybeans to deionized water at a mass ratio of soybeans: water = 1:9 for bean pulping; filter the soy milk with nylon cloth to remove bean dregs, add neutral protease to the filtrate, and the volume ratio of the added mass of neutral protease to the filtrate is neutral protease: filtrate = 3g:100mL; after adding the enzyme, heat in a water bath to 50°C, keep enzymolysis for 2 hours, then inactivate the enzyme at 90°C for 10 minutes, centrifuge, concentrate the supernatant under reduced pressure to 1 / 2 of the volume before concentration, and freeze-dry to obtain the soybean hydrolysate; Step three, mixing rifampicin, the olive leaf hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate, the mass ratio of rifampicin, the olive leaf hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate is rifampicin: olive leaf hydrolysate: hydroxypropyl-β-cyclodextrin: soybean hydrolysate = 10:1:17:4; the mixture is stirred for 10 minutes and then ground for 30 minutes to obtain the rifampicin inclusion complex described in this comparative example.

[0026] Comparative Example 3 A method for preparing ethamidine pyrazine and rifampicin tobacco tablets, comprising the following steps: (1) Weighing the sieved isoniazid, pyrazinamide and ethambutol hydrochloride according to the formula amount, wherein the isoniazid is a powder with a mesh number of 40 mesh, the pyrazinamide is a powder with a mesh number of 100 mesh, and the ethambutol hydrochloride is a powder with a mesh number of 120 mesh; then mixing the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain isoniazid particles; mixing the ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain ethylamine particles; the raw materials of the isoniazid particles are calculated by weight: 9 parts of isoniazid, 48 parts of pyrazinamide, 2.16 parts of microcrystalline cellulose, and 1.2 parts of pregelatinized starch; the raw materials of the ethylamine particles are calculated by weight: 33 parts of ethambutol hydrochloride, 1.44 parts of microcrystalline cellulose, and 3.6 parts of pregelatinized starch; (2) preparing a mixed aqueous solution of povidone K30 and sodium lauryl sulfate, wherein the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is 15% and the mass percentage of sodium lauryl sulfate is 3%; preparing an aqueous solution of povidone K30, wherein the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; spraying the aqueous solution of povidone K30 into the iso-smoke particles under stirring (adding for 5 minutes, then mixing and stirring for 5 minutes) to obtain an iso-smoke soft material, spraying the aqueous solution of povidone K30 into the iso-smoke particles to make the iso-smoke soft material The mass ratio of niacinhydrazide to povidone K30 is 9:1.2; granulation, drying, and sizing are then performed to obtain isoniazid dry granules; a mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules under stirring (adding for 5 minutes, followed by mixing and stirring for 5 minutes) to obtain an ethylamine soft material; the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules so that the mass ratio of ethambutol hydrochloride to povidone K30 is 33:0.6; granulation, drying, and sizing are then performed to obtain ethylamine dry granules; (3) The ethylamine dry particles are mixed with talcum powder and rifampicin inclusion compound, and the mixture is stirred for 10 minutes to be uniformly mixed to obtain a first mixture. Then, corn starch, the isoniazid dry particles, cross-linked polyvinylpyrrolidone and magnesium stearate are added to the first mixture under stirring. The mass ratio of the talcum powder, rifampicin used to prepare the rifampicin inclusion compound, corn starch, cross-linked polyvinylpyrrolidone and magnesium stearate to the amount of isoniazid in step (1) is isoniazid: talcum powder: rifampicin: corn starch: cross-linked polyvinylpyrrolidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96; after the addition is completed, the mixture is stirred for 10 minutes to be uniformly mixed, tableted, and coated to obtain the ethylamine pyrazine rifampicin tablets.

[0027] Wherein, the rifampicin is evenly mixed with the kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate before adding the materials to obtain the rifampicin inclusion compound of this comparative example; the preparation method of the rifampicin inclusion compound is: Step 1, adding kelp powder to a cellulase hydrolysate, wherein the concentration of cellulase in the cellulase hydrolysate is 90 mg / 100 mL, the solvent is water, and the amount ratio of the kelp powder to the cellulase hydrolysate is kelp powder: cellulase hydrolysate = 1 g: 50 mL; adjusting the pH to 5.5 with hydrochloric acid (the mass percentage of solute in hydrochloric acid is 10%), then heating in a water bath to 60° C., extracting at a constant temperature for 5 hours, then inactivating the enzyme at 90° C. for 10 minutes, separating the solid and liquid, and concentrating the liquid phase under reduced pressure to 1 / 4 of the volume before concentration, and freeze-drying to obtain a kelp hydrolysate; Step 2: prepare an aqueous solution of acetic acid, wherein the mass percentage of the solute in the aqueous solution of acetic acid is 5% and the solvent is water; add soybeans to the aqueous solution of acetic acid and soak at room temperature for 5 hours, wherein the mass ratio of the soybeans added to the aqueous solution of acetic acid is soybeans: acetic acid aqueous solution = 1:5; then filter, wash the soybeans with deionized water 3 times, add deionized water, and beat into soy milk with a beater, and add the washed soybeans to deionized water at a mass ratio of soybeans: water = 1:9 for bean pulping; filter the soy milk with nylon cloth to remove bean dregs, add neutral protease to the filtrate, and the volume ratio of the added mass of neutral protease to the filtrate is neutral protease: filtrate = 3g:100mL; after adding the enzyme, heat in a water bath to 50°C, keep enzymolysis for 2 hours, then inactivate the enzyme at 90°C for 10 minutes, centrifuge, concentrate the supernatant under reduced pressure to 1 / 2 of the volume before concentration, and freeze-dry to obtain the soybean hydrolysate; Step 3, mixing rifampicin, the kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate, the mass ratio of rifampicin, the kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate is rifampicin: kelp hydrolysate: hydroxypropyl-β-cyclodextrin: soybean hydrolysate = 10:1:17:4; stirring the mixture for 10 minutes, and then grinding for 30 minutes to obtain the rifampicin inclusion complex described in this comparative example.

[0028] Comparative Example 4 A method for preparing ethamidine pyrazine and rifampicin tobacco tablets, comprising the following steps: (1) Weighing the sieved isoniazid, pyrazinamide and ethambutol hydrochloride according to the formula amount, wherein the isoniazid is a powder with a mesh number of 40 mesh, the pyrazinamide is a powder with a mesh number of 100 mesh, and the ethambutol hydrochloride is a powder with a mesh number of 120 mesh; then mixing the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain isoniazid particles; mixing the ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch, stirring for 10 minutes to mix evenly, to obtain ethylamine particles; the raw materials of the isoniazid particles are calculated by weight: 9 parts of isoniazid, 48 parts of pyrazinamide, 2.16 parts of microcrystalline cellulose, and 1.2 parts of pregelatinized starch; the raw materials of the ethylamine particles are calculated by weight: 33 parts of ethambutol hydrochloride, 1.44 parts of microcrystalline cellulose, and 3.6 parts of pregelatinized starch; (2) preparing a mixed aqueous solution of povidone K30 and sodium lauryl sulfate, wherein the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is 15% and the mass percentage of sodium lauryl sulfate is 3%; preparing an aqueous solution of povidone K30, wherein the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; spraying the aqueous solution of povidone K30 into the iso-smoke particles under stirring (adding for 5 minutes, then mixing and stirring for 5 minutes) to obtain an iso-smoke soft material, spraying the aqueous solution of povidone K30 into the iso-smoke particles to make the iso-smoke soft material The mass ratio of niacinhydrazide to povidone K30 is 9:1.2; granulation, drying, and sizing are then performed to obtain isoniazid dry granules; a mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules under stirring (adding for 5 minutes, followed by mixing and stirring for 5 minutes) to obtain an ethylamine soft material; the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine granules so that the mass ratio of ethambutol hydrochloride to povidone K30 is 33:0.6; granulation, drying, and sizing are then performed to obtain ethylamine dry granules; (3) The ethylamine dry particles are mixed with talcum powder and rifampicin inclusion compound, and the mixture is stirred for 10 minutes to be uniformly mixed to obtain a first mixture. Then, corn starch, the isoniazid dry particles, cross-linked polyvinylpyrrolidone and magnesium stearate are added to the first mixture under stirring. The mass ratio of the talcum powder, rifampicin used to prepare the rifampicin inclusion compound, corn starch, cross-linked polyvinylpyrrolidone and magnesium stearate to the amount of isoniazid in step (1) is isoniazid: talcum powder: rifampicin: corn starch: cross-linked polyvinylpyrrolidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96; after the addition is completed, the mixture is stirred for 10 minutes to be uniformly mixed, tableted, and coated to obtain the ethylamine pyrazine rifampicin tablets.

[0029] Wherein, the rifampicin is evenly mixed with the olive leaf-kelp enzymatic hydrolysate and hydroxypropyl-β-cyclodextrin before adding the materials to obtain the rifampicin inclusion complex of this comparative example; the preparation method of the rifampicin inclusion complex is: Step 1, mixing olive leaf dry powder and kelp dry powder to form a mixed powder, the mass ratio of the olive leaf dry powder and the kelp dry powder is olive leaf dry powder: kelp dry powder = 10:6; the mixed powder is added to a cellulase hydrolyzate, the concentration of cellulase in the cellulase hydrolyzate is 90 mg / 100 mL, the solvent is water, and the amount ratio of the mixed powder added to the cellulase hydrolyzate is mixed powder: cellulase hydrolyzate = 1 g: 50 mL; using hydrochloric acid (the mass percentage of solute in hydrochloric acid is 10%) to adjust the pH to 5.5, then heating to 60°C in a water bath, constant temperature extraction for 5h, and then inactivating the enzyme at 90°C for 10min, solid-liquid separation, and concentrating the liquid phase under reduced pressure to 1 / 4 of the volume before concentration, freeze-drying, and obtaining an olive leaf-kelp hydrolyzate; Step 2: Mix rifampicin, the olive leaf-kelp hydrolysate, and hydroxypropyl-β-cyclodextrin, and the mass ratio of rifampicin, the olive leaf-kelp hydrolysate, and hydroxypropyl-β-cyclodextrin is rifampicin: olive leaf-kelp hydrolysate: hydroxypropyl-β-cyclodextrin = 10:1:17; stir the mixture for 10 minutes, and then grind for 30 minutes to obtain the rifampicin inclusion complex described in this comparative example.

[0030] Example 5 1. The disintegration time of the uncoated ethylamine pyrazine rifampicin tablets prepared by the method described in Example 1 (20 groups tested) and the mass percentage of rifampicin released at different dissolution times were tested. The results are shown in Table 1.

[0031] Table 1 2. The solubility of rifampicin or rifampicin inclusion complexes in the raw materials was investigated (0.5 g of the raw material was added to different volumes of dissolution medium to investigate the dissolution of the raw material). Dissolution media of varying pH were prepared by adding hydrochloric acid to deionized water. 10 ml of each medium was placed in a 50 ml conical flask, and an excess of rifampicin or the rifampicin inclusion complex raw material described in Example 3 and each comparative example was added. The flask was then placed in a constant temperature shaking water bath and shaken at 37°C for 8 hours. Samples were then collected and the solubility of each raw material in the different media was determined using the dissolution assay method. The results are shown in Table 2.

[0032] Table 2. Solubility of various raw materials in different media (37°C) The solubility of isoniazid raw materials is pH-dependent, with the solubility increasing significantly as the pH decreases. The low solubility of rifampicin restricts its efficacy. The present invention can significantly increase the solubility of rifampicin and improve its medicinal properties by preparing a rifampicin inclusion compound.

[0033] The technical solutions provided by the present invention are described in detail above. For those skilled in the art, according to the ideas of the embodiments of the present invention, there may be changes in the specific implementation methods and application scopes. In summary, the contents of this specification should not be understood as limiting the present invention.

Claims

1. A method for preparing a highly effective ethamidine pyrazine and rifampicin tobacco tablet, characterized in that the steps include: (1) Weighing the sieved isoniazid, pyrazinamide, and ethambutol hydrochloride according to the formula amount, then mixing the isoniazid, pyrazinamide, microcrystalline cellulose, and pregelatinized starch, stirring evenly to obtain isoniazid particles; mixing the ethambutol hydrochloride, microcrystalline cellulose, and pregelatinized starch, stirring evenly to obtain ethambutol particles; (2) preparing a mixed aqueous solution of povidone K30 and sodium lauryl sulfate to prepare an aqueous solution of povidone K30; spraying the aqueous solution of povidone K30 into the iso-yan granules under stirring to obtain an iso-yan soft material, and then granulating, drying, and sizing to obtain iso-yan dry granules; spraying the mixed aqueous solution of povidone K30 and sodium lauryl sulfate into the ethylamine granules under stirring to obtain an ethylamine soft material, and then granulating, drying, and sizing to obtain ethylamine dry granules; (3) The ethylamine dry particles are mixed with talc and rifampicin, and stirred evenly to obtain a first mixture. Then, corn starch, the isoflavone dry particles, cross-linked polyvinylpyrrolidone and magnesium stearate are added to the first mixture under stirring. After the addition is completed, the mixture is stirred evenly, tableted, and coated to obtain the ethylamine pyrazine rifampicin tablets.

2. The method for preparing a high-efficiency ethamidine pyrazine and rifampicin tobacco tablet according to claim 1, characterized in that: In the step (1), the raw materials of the isoniazid particles are calculated by weight as follows: 8 to 10 parts of isoniazid, 45 to 50 parts of pyrazinamide, 2 to 3 parts of microcrystalline cellulose, and 1 to 1.5 parts of pregelatinized starch; the raw materials of the ethylamine particles are calculated by weight as follows: 30 to 35 parts of ethambutol hydrochloride, 1.2 to 1.5 parts of microcrystalline cellulose, and 3 to 5 parts of pregelatinized starch.

3. The method for preparing a high-efficiency ethamidine pyrazine and rifampicin tobacco tablet according to claim 1, characterized in that: The isoniazid is a powder that can pass through a sieve with a mesh number of 40 or more, the pyrazinamide is a powder that can pass through a sieve with a mesh number of 100 or more, and the ethambutol hydrochloride is a powder that can pass through a sieve with a mesh number of 120 or more.

4. The method for preparing a high-efficiency ethamidine pyrazine and rifampicin tobacco tablet according to claim 1, characterized in that: In the step (2), in the mixed aqueous solution of povidone K30 and sodium lauryl sulfate, the mass percentage of povidone K30 is 14% to 16%, and the mass percentage of sodium lauryl sulfate is 2% to 4%; the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is sprayed into the ethylamine particles so that the mass ratio of ethambutol hydrochloride and povidone K30 is ethambutol hydrochloride: povidone K30 = 30 to 35: 0.5 to 0.7; in the aqueous solution of povidone K30, the mass percentage of povidone K30 is 14% to 16%; the aqueous solution of povidone K30 is sprayed into the isoniazid particles so that the mass ratio of isoniazid and povidone K30 isoniazid: povidone K30 = 8 to 10: 1 to 1.

4.

5. The method for preparing a high-efficiency ethamidine pyrazine and rifampicin tobacco tablet according to claim 1, characterized in that: In the step (3), the mass ratio of the amount of the talc, rifampicin, corn starch, cross-linked polyvinylpyrrolidone and magnesium stearate to the amount of isoniazid in step (1) is isoniazid: talc: rifampicin: corn starch: cross-linked polyvinylpyrrolidone: magnesium stearate = 8-10: 1-1.4: 16-20: 2-2.3: 2-2.3: 0.8-1.

2.

6. The method for preparing a high-efficiency ethamidine pyrazine and rifampicin tobacco tablet according to claim 1, characterized in that: Before adding the ingredients, the rifampicin is evenly mixed with the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate to obtain a rifampicin inclusion complex, and then the rifampicin inclusion complex is mixed with the ethylamine dry particles and talc. The preparation method of the rifampicin inclusion complex is as follows: Step 1: Mix olive leaf dry powder and kelp dry powder to form a mixed powder, add the mixed powder to a cellulase hydrolyzate, adjust the pH to 5-5.5 with hydrochloric acid, then heat in a water bath to 55-60° C., extract at a constant temperature for more than 5 hours, then inactivate the enzyme, separate the solid and liquid, concentrate the liquid phase under reduced pressure, and freeze-dry to obtain an olive leaf-kelp hydrolyzate; Step 2: preparing an aqueous solution of acetic acid, adding soybeans to the aqueous solution of acetic acid, soaking at room temperature for more than 5 hours, then filtering, washing the soybeans with deionized water for more than 3 times, adding deionized water, and beating with a beater to make soy milk, filtering the soy milk with nylon cloth to remove bean dregs, adding neutral protease to the filtrate, heating to 50±3° C. in a water bath after adding the enzyme, keeping the temperature for enzymatic hydrolysis for more than 2 hours, then inactivating the enzyme, centrifuging, concentrating the supernatant under reduced pressure, and freeze-drying to obtain the soybean hydrolyzate; Step 3: Mix rifampicin, the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate, stir the mixture for more than 10 minutes, and then grind it for more than 30 minutes to obtain the rifampicin inclusion complex.

7. The method for preparing a high-efficiency ethamidine pyrazine and rifampicin tobacco tablet according to claim 6, characterized in that: In the step 1, the mass ratio of the olive leaf powder and the kelp powder is olive leaf powder: kelp powder = 10:2-10; the concentration of cellulase in the cellulase hydrolysate is 80-100 mg / 100 mL, the solvent is water, and the amount ratio of the mixed powder added to the cellulase hydrolysate is mixed powder: cellulase hydrolysate = 1 g: 50-80 mL; the mass percentage of the solute in the hydrochloric acid is 10%.

8. The method for preparing a high-efficiency ethamidine pyrazine and rifampicin tobacco tablet according to claim 6, characterized in that: In step 2, the mass percentage of the solute in the aqueous solution of acetic acid is 5% to 6%, and the solvent is water; the mass ratio of the soybeans added to the aqueous solution of acetic acid is soybeans: acetic acid aqueous solution = 1:5 to 10; the washed soybeans are added to deionized water at a mass ratio of soybeans: water = 1:8 to 10 for pulping; the volume ratio of the added mass of neutral protease to the filtrate is neutral protease: filtrate = 3 to 4 g: 100 mL.

9. The method for preparing a high-efficiency ethamidine pyrazine and rifampicin tobacco tablet according to claim 6, characterized in that: In the step three, the mass ratio of rifampicin, the olive leaf-kelp hydrolysate, hydroxypropyl-β-cyclodextrin and soybean hydrolysate is rifampicin: olive leaf-kelp hydrolysate: hydroxypropyl-β-cyclodextrin: soybean hydrolysate = 10:1~2:16~18:2~6.

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