Highly effective ethylamine pyrazine rifamycin tablet and its preparation method

Abstract

The application discloses a preparation method of high-efficiency ethambutol-pyrazine-rifampicin-isoniazid tablets, which comprises the following steps: (1) preparing isoniazid granules by mixing isoniazid, pyrazine amide, microcrystalline cellulose and pregelatinized starch; and preparing ethambutol hydrochloride granules by mixing ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch; (2) adding an aqueous solution of povidone K30 into the isoniazid granules to obtain isoniazid soft material, and adding a mixed aqueous solution of povidone K30 and sodium dodecyl sulfate into the ethambutol hydrochloride granules to prepare ethambutol hydrochloride soft material; granulating, drying and whole-granulating to obtain ethambutol hydrochloride dry granules; (3) mixing the ethambutol hydrochloride dry granules, talc and rifampicin, stirring, then adding corn starch, isoniazid dry granules, crosslinked povidone and magnesium stearate, uniformly mixing, tabletting, coating and obtaining finished products. The preparation method is optimized, the disintegration time of the tablets is shortened, the dissolution of the active ingredients of the medicine is accelerated, and the drug efficacy is improved. In addition, the solubility of rifampicin is significantly improved by preparing a rifampicin inclusion compound, and the drug efficacy is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of ethylamine pyrazine rifampicin isoniazid tablet production and processing, and particularly relates to a high-efficiency ethylamine pyrazine rifampicin isoniazid tablet and a preparation method thereof. BACKGROUND

[0002] Tuberculosis is an infectious disease caused by the bacillus Mycobacterium tuberculosis. It usually affects the lungs, but can also affect other sites. According to the WHO, about one-third of the world's population is infected with the disease. The occurrence of drug-resistant tuberculosis is a major public health problem because it threatens the future development of tuberculosis control. Drug resistance in tuberculosis patients is mainly due to poor compliance of patients with treatment. When using a single drug composition, patients need to take 6-8 tablets on an empty stomach once a day. Incomplete compliance with treatment leads to the development of multi-drug resistant strains of tuberculosis. SUMMARY

[0003] To this end, the present application provides a preparation method of a high-efficiency ethylamine pyrazine rifampicin isoniazid tablet, steps comprising:

[0004] (1) The sieved isoniazid, pyrazinamide and ethambutol hydrochloride are weighed according to the prescription amount, then the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch are mixed and stirred uniformly to obtain isoniazid granules; the ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch are mixed and stirred uniformly to obtain ethambutol granules;

[0005] (2) A mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is configured, and an aqueous solution of povidone K30 is configured; the aqueous solution of povidone K30 is added to the isoniazid granules under stirring to obtain isoniazid soft material, and then granulation, drying and whole granulation are performed to obtain isoniazid dry granules; the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is added to the ethambutol granules under stirring to obtain ethambutol soft material, and then granulation, drying and whole granulation are performed to obtain ethambutol dry granules;

[0006] (3) The ethambutol dry granules, talc and rifampicin are mixed and stirred uniformly to obtain a first mixture, then corn starch, the isoniazid dry granules, cross-linked povidone and magnesium stearate are added to the first mixture under stirring, and after the addition is completed, the mixture is stirred uniformly, tabletting is performed, and coating is performed to obtain the ethylamine pyrazine rifampicin isoniazid tablet.

[0007] Further, in the step (1), the isoniazid granule raw material comprises, by mass fraction: isoniazid 8-10 parts, pyrazinamide 45-50 parts, microcrystalline cellulose 2-3 parts and pregelatinized starch 1-1.5 parts; and the ethambutol granule raw material comprises, by mass fraction: ethambutol hydrochloride 30-35 parts, microcrystalline cellulose 1.2-1.5 parts and pregelatinized starch 3-5 parts.

[0008] Further, the isoniazid is a powder with a mesh size of 40 mesh or more, the pyrazinamide is a powder with a mesh size of 100 mesh or more, and the ethambutol hydrochloride is a powder with a mesh size of 120 mesh or more.

[0009] Further, in the step (2), the mass percentage of the povidone K30 in the mixed aqueous solution of the povidone K30 and sodium dodecyl sulfate is 14%-16%, and the mass percentage of the sodium dodecyl sulfate is 2%-4%; the mixed aqueous solution of the povidone K30 and sodium dodecyl sulfate is sprayed into the ethambutol granules so that the mass ratio of the ethambutol hydrochloride to the povidone K30 is ethambutol hydrochloride:povidone K30=30-35:0.5-0.7; the mass percentage of the povidone K30 in the aqueous solution of the povidone K30 is 14%-16%; and the aqueous solution of the povidone K30 is sprayed into the isoniazid granules so that the mass ratio of the isoniazid to the povidone K30 is isoniazid:povidone K30=8-10:1-1.4.

[0010] Further, in the step (3), the mass ratio of the isoniazid to the talc, rifampicin, corn starch, cross-linked povidone and magnesium stearate is isoniazid:talc:rifampicin:corn starch:cross-linked povidone:magnesium stearate=8-10:1-1.4:16-20:2-2.3:2-2.3:0.8-1.2.

[0011] Further, the rifampicin is mixed with the olive leaf-kelp enzymatic hydrolysate, hydroxypropyl-β-cyclodextrin and soybean enzymatic hydrolysate before feeding, to obtain a rifampicin inclusion compound, and then the rifampicin inclusion compound is mixed with the ethambutol dry granules and talc; and the preparation method of the rifampicin inclusion compound is as follows:

[0012] Step one, mixing the dry powder of olive leaves and dry powder of kelp to form a mixed powder, adding the mixed powder into a cellulase enzymatic hydrolysate, adjusting the pH to 5-5.5 with hydrochloric acid, then heating in a water bath to 55-60℃, constant temperature extraction for more than 5h, then enzyme inactivation treatment, solid-liquid separation, liquid phase vacuum concentration, freeze-drying to obtain the olive leaf-kelp enzymatic hydrolysate;

[0013] Step two, preparing an aqueous solution of acetic acid, adding soybeans into the aqueous solution of acetic acid, soaking at room temperature for more than 5h, then filtering, washing the soybeans with deionized water for more than 3 times, then using a beater to beat into soy milk, filtering the soy milk with nylon cloth to remove soybean dregs, adding neutral protease to the filtrate, heating in a water bath to 50±3℃ after adding enzyme, enzymatic hydrolysis for more than 2h, then enzyme inactivation treatment, centrifugal separation, vacuum concentration of the supernatant, freeze-drying to obtain the soybean enzymatic hydrolysate;

[0014] Step three, mixing rifampicin, the olive leaf-kelp enzymatic hydrolysate, hydroxypropyl-beta-cyclodextrin and soybean enzymatic hydrolysate, stirring the mixture for more than 10 minutes, and then grinding for more than 30 minutes to obtain the rifampicin inclusion compound.

[0015] Further, in the step one, the mass ratio of the olive leaf dry powder and the kelp dry powder is olive leaf dry powder:kelp dry powder=10:2-10; the concentration of the cellulase in the cellulase enzymatic hydrolysate is 80-100 mg / 100 mL, the solvent is water, and the amount ratio of the mixed powder to the cellulase enzymatic hydrolysate is mixed powder:cellulase enzymatic hydrolysate=1 g:50-80 mL; the mass percentage of the solute in the hydrochloric acid is 10%.

[0016] Further, in the step two, the mass percentage of the solute in the acetic acid aqueous solution is 5-6%, and the solvent is water; the mass ratio of the soybean to the acetic acid aqueous solution is soybean:acetic acid aqueous solution=1:5-10; the cleaned soybean is added into deionized water for beating at a mass ratio of soybean:water=1:8-10; the mass ratio of the added neutral protease to the volume of the filtrate is neutral protease:filtrate=3-4 g:100 mL.

[0017] Further, in the step three, the mass ratio of rifampicin, the olive leaf-kelp enzymatic hydrolysate, hydroxypropyl-beta-cyclodextrin and soybean enzymatic hydrolysate is rifampicin:olive leaf-kelp enzymatic hydrolysate:hydroxypropyl-beta-cyclodextrin:soybean enzymatic hydrolysate=10:1-2:16-18:2-6.

[0018] The added adjuvant functions as:

[0019] Microcrystalline cellulose: stable in nature, good in safety, mainly used as a binder or a filler, and better than starch in disintegration performance and compressibility, has precedents for use in foreign FDC formulations, and can reduce the risks possibly caused by use in a prescription;

[0020] Cross-linked polyvinylpyrrolidone: stable in nature, good in safety, and very strong in disintegration capacity, has precedents for use in foreign FDC formulations, and can reduce the risks possibly caused by use in a prescription;

[0021] Polyvinylpyrrolidone K30: usually used as a binder for tablets and capsules, needs to be used as a binder, has precedents for use in foreign FDC formulations, and can reduce the risks possibly caused by use in a prescription;

[0022] Sodium dodecyl sulfate: an anionic surfactant, which plays a role in wetting and promoting dissolution;

[0023] Corn starch: corn starch is used as a binder in the prescription of the product, and the moisture content of corn starch is close to the upper limit. Direct feeding may affect the disintegration of the self-made product and affect the subsequent pre-experimental prescription judgment. It can be used after drying;

[0024] Talc: used as a glidant in the product to lubricate between particles, combined with magnesium stearate to reduce the risk of uneven mixing and tablet sticking.

[0025] Magnesium stearate: lubricant, can avoid sticking phenomenon in the tabletting process, ensure the smoothness of the tablet.

[0026] The beneficial effects of the present application are: the present application optimizes the preparation process, reduces the disintegration time of the tablet, accelerates the dissolution of the active ingredient of the drug, and improves the drug efficacy. In addition, due to the low solubility of rifampicin, the drug efficacy is further improved. The present application can significantly improve the solubility of rifampicin by preparing rifampicin inclusion compound, and improve the drug resistance. DETAILED DESCRIPTION

[0027] The present application will be further described below in conjunction with examples.

[0028] Example 1

[0029] A preparation method of high-efficiency ethylamine pyrazine rifampicin isethionic acid tablet, comprising the following steps:

[0030] (1) The sieved isoniazid, pyrazinamide and ethylamine butanol hydrochloride are weighed according to the prescription amount, wherein the isoniazid is a powder with a mesh size of 40 mesh, the pyrazinamide is a powder with a mesh size of 100 mesh, and the ethylamine butanol hydrochloride is a powder with a mesh size of 120 mesh; then the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch are mixed, stirred for 10 min to mix uniformly, to obtain isoniazid granules; the ethylamine butanol hydrochloride, microcrystalline cellulose and pregelatinized starch are mixed, stirred for 10 min to mix uniformly, to obtain ethylamine granules; the isoniazid granule raw material is 9 parts of isoniazid, 48 parts of pyrazinamide, 2.16 parts of microcrystalline cellulose and 1.2 parts of pregelatinized starch by mass fraction; the ethylamine granule raw material is 33 parts of ethylamine butanol hydrochloride, 1.44 parts of microcrystalline cellulose and 3.6 parts of pregelatinized starch by mass fraction;

[0031] (2) prepare a mixed aqueous solution of povidone K30 and sodium dodecyl sulfate, the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is 15%, and the mass percentage of sodium dodecyl sulfate is 3%; prepare an aqueous solution of povidone K30, the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; under stirring, add the aqueous solution of povidone K30 to the isoniazid granules (add for 5 min, and then mix and stir for 5 min) to obtain isoniazid soft material, the addition of the aqueous solution of povidone K30 to the isoniazid granules is such that the mass ratio of isoniazid to povidone K30 is isoniazid: povidone K30 = 9:1.2; then granulate, dry, and size the granules to obtain isoniazid dry granules; under stirring, add the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate to the ethambutol hydrochloride granules (add for 5 min, and then mix and stir for 5 min) to obtain ethambutol hydrochloride soft material, the addition of the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate to the ethambutol hydrochloride granules is such that the mass ratio of ethambutol hydrochloride to povidone K30 is ethambutol hydrochloride: povidone K30 = 33:0.6; then granulate, dry, and size the granules to obtain ethambutol hydrochloride dry granules;

[0032] (3) mix the ethambutol hydrochloride dry granules, talc, and rifampicin, stir for 10 min to mix uniformly to obtain a first mixture, then under stirring, add corn starch, the isoniazid dry granules, cross-linked povidone, and magnesium stearate to the first mixture, the mass ratio of isoniazid to talc to rifampicin to corn starch to cross-linked povidone to magnesium stearate is isoniazid: talc: rifampicin: corn starch: cross-linked povidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96; after the addition is completed, stir for 10 min to mix uniformly, tablet (tablet hardness is 10 kg, which is the same in all examples and comparative examples), coat, and obtain the ethambutol hydrochloride pyrazinamide rifampicin isoniazid tablets.

[0033] Example 2

[0034] A preparation method of high-efficiency ethambutol hydrochloride pyrazinamide rifampicin isoniazid tablets, the steps comprising:

[0035] (1) according to the formula, the screened isoniazid, pyrazinamide and ethambutol hydrochloride, wherein the isoniazid is the powder of 40 mesh screen, the pyrazinamide is the powder of 100 mesh screen, the ethambutol hydrochloride is the powder of 120 mesh screen; then the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch are mixed, stirred for 10 min, the mixture is uniform, obtain isoniazid granules; the ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch are mixed, stirred for 10 min, the mixture is uniform, obtain ethambutol granules; the isoniazid granules raw material is calculated by mass fraction: isoniazid 9 parts, pyrazinamide 48 parts, microcrystalline cellulose 2.16 parts, pregelatinized starch 1.2 parts; the ethambutol granules raw material is calculated by mass fraction: ethambutol hydrochloride 33 parts, microcrystalline cellulose 1.44 parts, pregelatinized starch 3.6 parts;

[0036] (2) the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is configured, the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is 15%, the mass percentage of sodium dodecyl sulfate is 3%; the aqueous solution of povidone K30 is configured, the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; under the stirring state, the aqueous solution of povidone K30 is added to the isoniazid granules (add 5 min, then mix and stir for 5 min), obtain isoniazid soft material, the aqueous solution of povidone K30 is added to the isoniazid granules, so that the mass ratio of isoniazid and povidone K30 is isoniazid: povidone K30 = 9:1.2; then granulation, drying, whole granule, obtain isoniazid dry granules; under the stirring state, the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is added to the ethambutol granules (add 5 min, then mix and stir for 5 min), obtain ethambutol soft material, the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is added to the ethambutol granules, so that the mass ratio of ethambutol hydrochloride and povidone K30 is ethambutol hydrochloride: povidone K30 = 33:0.6; then granulation, drying, whole granule, obtain ethambutol dry granules;

[0037] (3) the ethambutol dry granules, talc and rifampicin inclusion compound are mixed, stirred for 10 min, the mixture is uniform, obtain the first mixture, then under the stirring state, the corn starch, isoniazid dry granules, crosslinked povidone and magnesium stearate are added to the first mixture, the amount of talc, rifampicin used to prepare rifampicin inclusion compound, corn starch, crosslinked povidone and magnesium stearate is isoniazid: talc: rifampicin: corn starch: crosslinked povidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96 by mass ratio of isoniazid; after the completion of the addition, stir for 10 min, mix uniformly, press the tablet, coating, obtain the ethambutol pyrazine rifampicin isoniazid tablet.

[0038] The rifampicin is mixed with the olive leaf-kelp enzymatic hydrolysate, the hydroxypropyl-beta-cyclodextrin and the soybean enzymatic hydrolysate uniformly before charging to obtain a rifampicin inclusion compound; the preparation method of the rifampicin inclusion compound is as follows:

[0039] Step one, the dry powder of olive leaves and the dry powder of kelp are mixed to form a mixed powder, the mass ratio of the dry powder of olive leaves to the dry powder of kelp is 10:2; the mixed powder is added into a cellulase enzymatic hydrolysate, the concentration of cellulase in the cellulase enzymatic hydrolysate is 80 mg / 100 mL, the solvent is water, the amount of the mixed powder added into the cellulase enzymatic hydrolysate is 1 g:50 mL; hydrochloric acid (the mass percentage of solute in the hydrochloric acid is 10%) is used to adjust the pH to 5.5, then water bath heating is performed to 60℃, constant temperature extraction is performed for 5 h, then enzyme inactivation treatment is performed at 90℃ for 10 min, solid-liquid separation is performed, the liquid phase is concentrated to 1 / 4 of the original volume under reduced pressure, and freeze-drying is performed to obtain the olive leaf-kelp enzymatic hydrolysate;

[0040] Step two, an aqueous acetic acid solution is configured, the mass percentage of solute in the aqueous acetic acid solution is 5%, and the solvent is water; the soybean is added into the aqueous acetic acid solution, soaked at room temperature for 5 h, the mass ratio of the soybean added into the aqueous acetic acid solution is 1:5; then filtration is performed, the soybean is washed with deionized water for 3 times, the soybean after washing is added into deionized water to be beaten into soy milk at a mass ratio of 1:9; the soy milk is filtered to remove soybean dregs with nylon cloth, the filtrate is added with neutral protease, the mass ratio of the neutral protease to the volume of the filtrate is 3 g:100 mL; enzyme hydrolysis is performed after adding the neutral protease, water bath heating is performed to 50℃, and constant temperature enzyme hydrolysis is performed for 2 h, then enzyme inactivation treatment is performed at 90℃ for 10 min, centrifugal separation is performed, the supernatant is concentrated to 1 / 2 of the original volume under reduced pressure, and freeze-drying is performed to obtain the soybean enzymatic hydrolysate;

[0041] Step three, rifampicin, the olive leaf-kelp enzymatic hydrolysate, the hydroxypropyl-beta-cyclodextrin and the soybean enzymatic hydrolysate are mixed, the mass ratio of rifampicin, the olive leaf-kelp enzymatic hydrolysate, the hydroxypropyl-beta-cyclodextrin and the soybean enzymatic hydrolysate is 10:1:16:2; the mixture is stirred for 10 min, then ground for 30 min to obtain the rifampicin inclusion compound.

[0042] Example 3

[0043] A preparation method of high-efficiency ethylamine pyrazine rifampicin ism is provided, which comprises the following steps:

[0044] (1) according to the formula, the screened isoniazid, pyrazinamide and ethambutol hydrochloride, wherein the isoniazid is the powder of 40 mesh screen, the pyrazinamide is the powder of 100 mesh screen, the ethambutol hydrochloride is the powder of 120 mesh screen; then the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch are mixed, stirred for 10 min, the mixture is uniform, and isoniazid granules are obtained; the ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch are mixed, stirred for 10 min, the mixture is uniform, and ethambutol granules are obtained; the isoniazid granules raw material is calculated by mass fraction: isoniazid 9 parts, pyrazinamide 48 parts, microcrystalline cellulose 2.16 parts, and pregelatinized starch 1.2 parts; the ethambutol granules raw material is calculated by mass fraction: ethambutol hydrochloride 33 parts, microcrystalline cellulose 1.44 parts, and pregelatinized starch 3.6 parts;

[0045] (2) the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is configured, the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is 15%, and the mass percentage of sodium dodecyl sulfate is 3%; the aqueous solution of povidone K30 is configured, the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; the aqueous solution of povidone K30 is sprayed and added to the isoniazid granules under stirring (add for 5 min, and then mix and stir for 5 min), and isoniazid soft material is obtained, the aqueous solution of povidone K30 is sprayed and added to the isoniazid granules, so that the mass ratio of isoniazid and povidone K30 is isoniazid: povidone K30 = 9:1.2; then granulation, drying and whole granulation are carried out, and isoniazid dry granules are obtained; the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is sprayed and added to the ethambutol granules under stirring (add for 5 min, and then mix and stir for 5 min), and ethambutol soft material is obtained, the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is sprayed and added to the ethambutol granules, so that the mass ratio of ethambutol hydrochloride and povidone K30 is ethambutol hydrochloride: povidone K30 = 33:0.6; then granulation, drying and whole granulation are carried out, and ethambutol dry granules are obtained;

[0046] (3) the ethambutol dry granules, talc and rifampicin inclusion compound are mixed, stirred for 10 min, the mixture is uniform, a first mixture is obtained, then corn starch, the isoniazid dry granules, crosslinked povidone and magnesium stearate are added to the first mixture under stirring, the amount of talc, rifampicin used for preparing rifampicin inclusion compound, corn starch, crosslinked povidone and magnesium stearate is 9:1.2:18:2.16:2.16:0.96, the mass ratio of isoniazid in step (1); after the addition is completed, the mixture is stirred for 10 min, the tablet is pressed, and the coating is obtained. The ethambutol pyrazinamide rifampicin isoniazid tablet.

[0047] The rifampicin is mixed with the olive leaf-kelp enzymatic hydrolysate, the hydroxypropyl-beta-cyclodextrin and the soybean enzymatic hydrolysate uniformly before charging to obtain a rifampicin inclusion compound; the preparation method of the rifampicin inclusion compound is as follows:

[0048] Step one, the dry powder of olive leaves and the dry powder of kelp are mixed to form a mixed powder, the mass ratio of the dry powder of olive leaves to the dry powder of kelp is 10:6; the mixed powder is added into a cellulase enzymatic hydrolysate, the concentration of cellulase in the cellulase enzymatic hydrolysate is 90 mg / 100 mL, the solvent is water, the amount of the mixed powder added into the cellulase enzymatic hydrolysate is 1 g:50 mL; hydrochloric acid (the mass percentage of solute in the hydrochloric acid is 10%) is used to adjust the pH to 5.5, then water bath heating is performed to 60℃, constant temperature extraction is performed for 5 h, then enzyme inactivation treatment is performed at 90℃ for 10 min, solid-liquid separation is performed, the liquid phase is concentrated to 1 / 4 of the original volume under reduced pressure, and freeze-drying is performed to obtain the olive leaf-kelp enzymatic hydrolysate;

[0049] Step two, an aqueous acetic acid solution is configured, the mass percentage of solute in the aqueous acetic acid solution is 5%, and the solvent is water; soybeans are added into the aqueous acetic acid solution, soaked at room temperature for 5 h, the mass ratio of the soybeans added into the aqueous acetic acid solution is 1:5; then filtration is performed, the soybeans are washed with deionized water for 3 times, the soybeans after washing are added into deionized water to be beaten into soy milk at a mass ratio of 1:9; the soy milk is filtered to remove soybean dregs with nylon cloth, and the filtrate is added with neutral protease, the mass ratio of the neutral protease to the volume of the filtrate is 3 g:100 mL; enzyme hydrolysis is performed after adding the neutral protease, water bath heating is performed to 50℃, and constant temperature enzyme hydrolysis is performed for 2 h, then enzyme inactivation treatment is performed at 90℃ for 10 min, centrifugal separation is performed, the supernatant is concentrated to 1 / 2 of the original volume under reduced pressure, and freeze-drying is performed to obtain the soybean enzymatic hydrolysate;

[0050] Step three, rifampicin, the olive leaf-kelp enzymatic hydrolysate, the hydroxypropyl-beta-cyclodextrin and the soybean enzymatic hydrolysate are mixed, the mass ratio of rifampicin, the olive leaf-kelp enzymatic hydrolysate, the hydroxypropyl-beta-cyclodextrin and the soybean enzymatic hydrolysate is 10:1:17:4; the mixture is stirred for 10 min, and then ground for 30 min to obtain the rifampicin inclusion compound.

[0051] Example 4

[0052] A preparation method of high-efficiency ethylamine pyrazine rifampicin ism is disclosed, which comprises the following steps:

[0053] (1) The isoniazid, pyrazinamide and ethambutol hydrochloride after sieving are weighed according to the formula amount, wherein the isoniazid is powder with a mesh size of 40 mesh, the pyrazinamide is powder with a mesh size of 100 mesh, and the ethambutol hydrochloride is powder with a mesh size of 120 mesh; then the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch are mixed, and stirred for 10 min to mix uniformly to obtain isoniazid granules; the ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch are mixed, and stirred for 10 min to mix uniformly to obtain ethambutol granules; the isoniazid granules are prepared according to the following mass fractions: isoniazid 9 parts, pyrazinamide 48 parts, microcrystalline cellulose 2.16 parts, and pregelatinized starch 1.2 parts; the ethambutol granules are prepared according to the following mass fractions: ethambutol hydrochloride 33 parts, microcrystalline cellulose 1.44 parts, and pregelatinized starch 3.6 parts;

[0054] (2) A mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is configured, wherein the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is 15%, and the mass percentage of sodium dodecyl sulfate is 3%; an aqueous solution of povidone K30 is configured, wherein the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; under stirring, the aqueous solution of povidone K30 is added to the isoniazid granules by spraying (add for 5 min, and then mix and stir for 5 min) to obtain isoniazid soft material, and the mass ratio of isoniazid to povidone K30 is isoniazid: povidone K30 = 9:1.2; then granulation, drying and granulation are performed to obtain isoniazid dry granules; under stirring, the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is added to the ethambutol granules by spraying (add for 5 min, and then mix and stir for 5 min) to obtain ethambutol soft material, and the mass ratio of ethambutol hydrochloride to povidone K30 is ethambutol hydrochloride: povidone K30 = 33:0.6; then granulation, drying and granulation are performed to obtain ethambutol dry granules;

[0055] (3) The ethambutol dry granules, talc and rifampicin inclusion compound are mixed under stirring for 10 min to mix uniformly to obtain a first mixture, and then corn starch, the isoniazid dry granules, crosslinked povidone and magnesium stearate are added to the first mixture under stirring, and the mass ratio of isoniazid to talc to rifampicin to corn starch to crosslinked povidone to magnesium stearate is isoniazid: talc: rifampicin: corn starch: crosslinked povidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96; after the addition is completed, the mixture is stirred for 10 min to mix uniformly, tabletting is performed, and coating is performed to obtain the ethambutol pyrazinamide rifampicin isoniazid tablets.

[0056] The rifampicin is mixed with the olive leaf-kelp enzymatic hydrolysate, the hydroxypropyl-beta-cyclodextrin and the soybean enzymatic hydrolysate uniformly before charging to obtain a rifampicin inclusion compound; the preparation method of the rifampicin inclusion compound is as follows:

[0057] Step one, the dry powder of olive leaves and the dry powder of kelp are mixed to form a mixed powder, the mass ratio of the dry powder of olive leaves to the dry powder of kelp is 10:10; the mixed powder is added into a cellulase enzymatic hydrolysate, the concentration of cellulase in the cellulase enzymatic hydrolysate is 100 mg / 100 mL, the solvent is water, the amount of the mixed powder added into the cellulase enzymatic hydrolysate is 1 g:50 mL; hydrochloric acid (the mass percentage of solute in the hydrochloric acid is 10%) is used to adjust the pH to 5.5, then water bath heating is performed to 60℃, constant temperature extraction is performed for 5 h, then enzyme inactivation treatment is performed at 90℃ for 10 min, solid-liquid separation is performed, the liquid phase is concentrated to 1 / 4 of the original volume under reduced pressure, and freeze-drying is performed to obtain the olive leaf-kelp enzymatic hydrolysate;

[0058] Step two, an aqueous acetic acid solution is configured, the mass percentage of solute in the aqueous acetic acid solution is 6%, and the solvent is water; soybeans are added into the aqueous acetic acid solution, soaked at room temperature for 5 h, the mass ratio of the soybeans added into the aqueous acetic acid solution is 1:5; then filtration is performed, the soybeans are washed with deionized water for 3 times, the soybeans after washing are added into deionized water to be beaten into soy milk at a mass ratio of 1:9; the soy milk is filtered with nylon cloth to remove soybean dregs, and the filtrate is added with neutral protease, the mass ratio of the neutral protease to the volume of the filtrate is 4 g:100 mL; after the enzyme is added, water bath heating is performed to 50℃, and enzyme hydrolysis is performed for 2 h, then enzyme inactivation treatment is performed at 90℃ for 10 min, centrifugal separation is performed, and the supernatant is concentrated to 1 / 2 of the original volume under reduced pressure, and freeze-drying is performed to obtain the soybean enzymatic hydrolysate;

[0059] Step three, rifampicin, the olive leaf-kelp enzymatic hydrolysate, the hydroxypropyl-beta-cyclodextrin and the soybean enzymatic hydrolysate are mixed, the mass ratio of rifampicin, the olive leaf-kelp enzymatic hydrolysate, the hydroxypropyl-beta-cyclodextrin and the soybean enzymatic hydrolysate is 10:2:18:6; the mixture is stirred for 10 min, and then ground for 30 min to obtain the rifampicin inclusion compound.

[0060] Comparative Example 1

[0061] A preparation method of an ethylamine pyrazine rifampicin isoniazid tablet, the steps comprising:

[0062] (1) according to the formula, the amount of sieved isoniazid, pyrazinamide and ethambutol hydrochloride, wherein the isoniazid is a powder with a mesh size of 40 mesh, the pyrazinamide is a powder with a mesh size of 100 mesh, and the ethambutol hydrochloride is a powder with a mesh size of 120 mesh; then the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch are mixed, stirred for 10 min to mix evenly, and isoniazid granules are obtained; the ethambutol hydrochloride, microcrystalline cellulose and pregelatinized starch are mixed, stirred for 10 min to mix evenly, and ethambutol granules are obtained; the isoniazid granules raw material is 9 parts of isoniazid, 48 parts of pyrazinamide, 2.16 parts of microcrystalline cellulose and 1.2 parts of pregelatinized starch according to the mass fraction; the ethambutol granules raw material is 33 parts of ethambutol hydrochloride, 1.44 parts of microcrystalline cellulose and 3.6 parts of pregelatinized starch according to the mass fraction;

[0063] (2) a mixed aqueous solution of povidone K30 and sodium lauryl sulfate is configured, 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%; an aqueous solution of povidone K30 is configured, the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; under stirring, the aqueous solution of povidone K30 is added to the isoniazid granules (add for 5 min, and then mix and stir for 5 min) to obtain isoniazid soft material, the mass ratio of isoniazid to povidone K30 is isoniazid: povidone K30 = 9:1.2, and the aqueous solution of povidone K30 is added to the isoniazid granules; then granulation, drying and granulation are performed to obtain isoniazid dry granules; under stirring, the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is added to the ethambutol granules (add for 5 min, and then mix and stir for 5 min) to obtain ethambutol soft material, the mass ratio of ethambutol hydrochloride to povidone K30 is ethambutol hydrochloride: povidone K30 = 33:0.6, and the mixed aqueous solution of povidone K30 and sodium lauryl sulfate is added to the ethambutol granules; then granulation, drying and granulation are performed to obtain ethambutol dry granules;

[0064] (3) the ethambutol dry granules, talc and rifampicin inclusion compound are mixed, stirred for 10 min to mix evenly to obtain a first mixture, then corn starch, the isoniazid dry granules, cross-linked povidone and magnesium stearate are added to the first mixture under stirring, the mass ratio of isoniazid to talc, rifampicin, corn starch, cross-linked povidone and magnesium stearate is isoniazid: talc: rifampicin: corn starch: cross-linked povidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96, and the amount of rifampicin used to prepare the rifampicin inclusion compound; after the addition is completed, stirring is performed for 10 min to mix evenly, tabletting is performed, and coating is performed to obtain the ethambutol pyrazinamide rifampicin isoniazid tablets.

[0065] The rifampicin is mixed with hydroxypropyl-β-cyclodextrin and soybean enzymatic product before feeding to obtain the rifampicin inclusion compound of the present comparative example; the preparation method of the rifampicin inclusion compound is as follows:

[0066] Step one, prepare an acetic acid aqueous solution, the mass percentage of solute in the acetic acid aqueous solution is 5%, and water is used as solvent; add soybean into the acetic acid aqueous solution, soak at room temperature for 5 h, the mass ratio of the soybean added into the acetic acid aqueous solution is soybean: acetic acid aqueous solution = 1:5; then filter, wash the soybean with deionized water for 3 times, add deionized water, and beat into soy milk with a beater; the washed soybean is added into deionized water to beat into soy milk at a mass ratio of soybean: water = 1:9; filter the soy milk with nylon cloth to remove soybean residue, add neutral protease, the mass ratio of the added neutral protease to the volume of the filtrate is neutral protease: filtrate = 3 g: 100 mL; after adding the enzyme, heat to 50℃ in a water bath, and keep the temperature for 2 h of enzymatic hydrolysis, then treat at 90℃ for 10 min to inactivate the enzyme, centrifugal separation, concentrate the supernatant to 1 / 2 of the original volume under reduced pressure, and freeze-dry to obtain the soybean enzymatic product;

[0067] Step two, mix rifampicin, hydroxypropyl-β-cyclodextrin and soybean enzymatic product, the mass ratio of rifampicin, hydroxypropyl-β-cyclodextrin and soybean enzymatic product is rifampicin: hydroxypropyl-β-cyclodextrin: soybean enzymatic product = 10:17:4; stir and mix the mixture for 10 min, then grind for 30 min to obtain the rifampicin inclusion compound of the present comparative example.

[0068] Comparative Example 2

[0069] A preparation method of an ethylamine pyrazine rifampicin isoniazid tablet, the steps comprising:

[0070] (1) weigh the sieved isoniazid, pyrazinamide and ethylamine butanol hydrochloride according to the formula amount, wherein the isoniazid is a powder with a mesh size of 40 mesh sieve, the pyrazinamide is a powder with a mesh size of 100 mesh sieve, and the ethylamine butanol hydrochloride is a powder with a mesh size of 120 mesh sieve; then mix the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch, stir for 10 min to mix uniformly to obtain isoniazid granules; mix the ethylamine butanol hydrochloride, microcrystalline cellulose and pregelatinized starch, stir for 10 min to mix uniformly to obtain ethylamine granules; the isoniazid granule raw material is 9 parts of isoniazid, 48 parts of pyrazinamide, 2.16 parts of microcrystalline cellulose and 1.2 parts of pregelatinized starch in terms of mass fraction; the ethylamine granule raw material is 33 parts of ethylamine butanol hydrochloride, 1.44 parts of microcrystalline cellulose and 3.6 parts of pregelatinized starch in terms of mass fraction;

[0071] (2) configuring a mixed aqueous solution of povidone K30 and sodium dodecyl sulfate, the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is 15%, the mass percentage of sodium dodecyl sulfate is 3%; configuring an aqueous solution of povidone K30, the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; under the state of stirring, the aqueous solution of povidone K30 is added to the isoniazid granules by spraying (add for 5 min, then mix and stir for 5 min), to obtain isoniazid soft material, the aqueous solution of povidone K30 is added to the isoniazid granules by spraying so that the mass ratio of isoniazid to povidone K30 is isoniazid: povidone K30 = 9:1.2; then granulating, drying, and whole-granulating to obtain isoniazid dry granules; under the state of stirring, the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is added to the ethambutol hydrochloride granules by spraying (add for 5 min, then mix and stir for 5 min), to obtain ethambutol hydrochloride soft material, the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is added to the ethambutol hydrochloride granules by spraying so that the mass ratio of ethambutol hydrochloride to povidone K30 is ethambutol hydrochloride: povidone K30 = 33:0.6; then granulating, drying, and whole-granulating to obtain ethambutol hydrochloride dry granules;

[0072] (3) mixing the ethambutol hydrochloride dry granules, talc, and rifampicin inclusion compound, stirring for 10 min to mix uniformly, to obtain a first mixture, then under the state of stirring, adding corn starch, the isoniazid dry granules, crosslinked povidone, and magnesium stearate to the first mixture, the use amount of the talc, rifampicin used for preparing the rifampicin inclusion compound, corn starch, crosslinked povidone, and magnesium stearate, and the use amount of isoniazid in step (1) have a mass ratio of isoniazid: talc: rifampicin: corn starch: crosslinked povidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96; after the completion of adding, stirring for 10 min to mix uniformly, tabletting, coating, to obtain the ethambutol hydrochloride pyrazine rifampicin isoniazid tablets.

[0073] The rifampicin is mixed uniformly with olive leaf enzymatic product, hydroxypropyl-beta-cyclodextrin, and soybean enzymatic product before adding, to obtain the rifampicin inclusion compound of the present comparative example; the preparation method of the rifampicin inclusion compound is as follows:

[0074] Step one, adding dry olive leaf powder to cellulase enzymatic solution, the concentration of cellulase in the cellulase enzymatic solution is 90 mg / 100 mL, the solvent is water, the amount ratio of the dry olive leaf powder added to the cellulase enzymatic solution is dry olive leaf powder: cellulase enzymatic solution = 1 g: 50 mL; adjusting pH to 5.5 with hydrochloric acid (the mass percentage of solute in the hydrochloric acid is 10%), then heating to 60°C in a water bath, constant-temperature extraction for 5 h, then enzyme inactivation treatment at 90°C for 10 min, solid-liquid separation, liquid phase concentration to 1 / 4 of the original volume under reduced pressure, freeze-drying, to obtain olive leaf enzymatic product;

[0075] Step two, configure the acetic acid aqueous solution, the mass percentage of solute in the acetic acid aqueous solution is 5%, and the solvent is water; soybeans are added into the acetic acid aqueous solution, soaked at room temperature for 5h, and the mass ratio of the soybeans added into the acetic acid aqueous solution is soybeans: acetic acid aqueous solution = 1:5; then filtered, washed the soybeans with deionized water for 3 times, and then added into deionized water to be beaten into soy milk by a beater according to the mass ratio of soybeans: water = 1:9; the soy milk is filtered to remove soybean dregs by a nylon cloth, and the filtrate is added with neutral protease, and the mass ratio of the neutral protease to the volume of the filtrate is neutral protease: filtrate = 3g: 100mL; after the addition of the enzyme, heated to 50℃ in a water bath, and then treated by enzyme inactivation at 90℃ for 10min, centrifuged, and the supernatant is concentrated to 1 / 2 of the original volume under reduced pressure, and then freeze-dried to obtain the soybean enzyme hydrolysate;

[0076] Step three, mix rifampicin, the olive leaf enzyme hydrolysate, hydroxypropyl-β-cyclodextrin and the soybean enzyme hydrolysate, and the mass ratio of rifampicin, the olive leaf enzyme hydrolysate, hydroxypropyl-β-cyclodextrin and the soybean enzyme hydrolysate is rifampicin: olive leaf enzyme hydrolysate: hydroxypropyl-β-cyclodextrin: soybean enzyme hydrolysate = 10: 1: 17: 4; the mixture is stirred for 10min, and then ground for 30min to obtain the rifampicin inclusion compound of the present comparative example.

[0077] Comparative Example 3

[0078] A preparation method of an ethylamine pyrazine rifampicin isoniazid tablet, the steps comprising:

[0079] (1) The sieved isoniazid, pyrazinamide and ethylamine butanol hydrochloride are weighed according to the formula amount, wherein the isoniazid is a powder with a mesh size of 40 mesh, the pyrazinamide is a powder with a mesh size of 100 mesh, and the ethylamine butanol hydrochloride is a powder with a mesh size of 120 mesh; then the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch are mixed, stirred for 10min, and uniformly mixed to obtain isoniazid granules; the ethylamine butanol hydrochloride, microcrystalline cellulose and pregelatinized starch are mixed, stirred for 10min, and uniformly mixed to obtain ethylamine granules; the isoniazid granule raw material is 9 parts of isoniazid, 48 parts of pyrazinamide, 2.16 parts of microcrystalline cellulose and 1.2 parts of pregelatinized starch according to the mass fraction; the ethylamine granule raw material is 33 parts of ethylamine butanol hydrochloride, 1.44 parts of microcrystalline cellulose and 3.6 parts of pregelatinized starch according to the mass fraction;

[0080] (2) configuring a mixed aqueous solution of povidone K30 and sodium dodecyl sulfate, the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is 15%, and the mass percentage of sodium dodecyl sulfate is 3%; configuring an aqueous solution of povidone K30, the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; under the stirring state, the aqueous solution of povidone K30 is added to the isoniazid granules by spraying (add for 5 min, and then mix and stir for 5 min) to obtain isoniazid soft material, the aqueous solution of povidone K30 is added to the isoniazid granules by spraying so that the mass ratio of isoniazid to povidone K30 is isoniazid: povidone K30 = 9:1.2; then granulating, drying, and whole-granulating to obtain isoniazid dry granules; under the stirring state, the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is added to the ethambutol hydrochloride granules by spraying (add for 5 min, and then mix and stir for 5 min) to obtain ethambutol soft material, the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is added to the ethambutol hydrochloride granules by spraying so that the mass ratio of ethambutol hydrochloride to povidone K30 is ethambutol hydrochloride: povidone K30 = 33:0.6; then granulating, drying, and whole-granulating to obtain ethambutol dry granules;

[0081] (3) mixing the ethambutol dry granules, talc, and rifampicin inclusion compound, stirring for 10 min to mix uniformly to obtain a first mixture, then adding corn starch, the isoniazid dry granules, crosslinked povidone, and magnesium stearate to the first mixture under the stirring state, the use amount of the talc, rifampicin used for preparing the rifampicin inclusion compound, corn starch, crosslinked povidone, and magnesium stearate, and the use amount of isoniazid in step (1) have a mass ratio of isoniazid: talc: rifampicin: corn starch: crosslinked povidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96; after the addition is completed, stirring for 10 min to mix uniformly, tabletting, coating, and obtaining the ethambutol pyrazine rifampicin isoniazid tablets.

[0082] In the formula, the rifampicin is first mixed uniformly with kelp enzymatic hydrolysate, hydroxypropyl-beta-cyclodextrin, and soybean enzymatic hydrolysate before addition, to obtain the rifampicin inclusion compound of the present comparative example; the preparation method of the rifampicin inclusion compound is as follows:

[0083] Step one, adding kelp dry powder into cellulase enzymatic hydrolysate, the concentration of cellulase in the cellulase enzymatic hydrolysate is 90 mg / 100 mL, the solvent is water, and the amount ratio of the kelp dry powder added into the cellulase enzymatic hydrolysate is kelp dry powder: cellulase enzymatic hydrolysate = 1 g: 50 mL; adjusting pH to 5.5 with hydrochloric acid (the mass percentage of solute in the hydrochloric acid is 10%), then heating to 60 ℃ in a water bath, constant-temperature extraction for 5 h, then enzyme inactivation treatment at 90 ℃ for 10 min, solid-liquid separation, liquid phase concentration to 1 / 4 of the original volume under reduced pressure, freeze-drying to obtain kelp enzymatic hydrolysate;

[0084] Step two, configure the acetic acid aqueous solution, the mass percentage of solute in the acetic acid aqueous solution is 5%, and the solvent is water; soybeans are added into the acetic acid aqueous solution, soaked at room temperature for 5h, and the mass ratio of the soybeans added into the acetic acid aqueous solution is soybeans: acetic acid aqueous solution = 1:5; then filtered, washed the soybeans with deionized water for 3 times, and then added into deionized water to be beaten into soy milk by a beater according to the mass ratio of soybeans: water = 1:9; the soy milk is filtered to remove soybean dregs by nylon cloth, and the filtrate is added with neutral protease, and the mass ratio of the neutral protease to the volume of the filtrate is neutral protease: filtrate = 3g: 100mL; after adding the enzyme, heated to 50℃ in a water bath, and then treated at 90℃ for 10min to inactivate the enzyme, centrifuged, and the supernatant is concentrated to 1 / 2 of the original volume under reduced pressure, and then freeze-dried to obtain the soybean enzyme hydrolysate;

[0085] Step three, mix rifampicin, the kelp enzyme hydrolysate, hydroxypropyl-β-cyclodextrin and the soybean enzyme hydrolysate, and the mass ratio of rifampicin, the kelp enzyme hydrolysate, hydroxypropyl-β-cyclodextrin and the soybean enzyme hydrolysate is rifampicin: kelp enzyme hydrolysate: hydroxypropyl-β-cyclodextrin: soybean enzyme hydrolysate = 10: 1: 17: 4; the mixture is stirred for 10min, and then ground for 30min to obtain the rifampicin inclusion compound of the present comparative example.

[0086] Comparative Example 4

[0087] A preparation method of an ethylamine pyrazine rifampicin isoniazid tablet, the steps comprising:

[0088] (1) The sieved isoniazid, pyrazinamide and ethylamine butanol hydrochloride are weighed according to the formula amount, wherein the isoniazid is a powder with a mesh size of 40 mesh, the pyrazinamide is a powder with a mesh size of 100 mesh, and the ethylamine butanol hydrochloride is a powder with a mesh size of 120 mesh; then the isoniazid, pyrazinamide, microcrystalline cellulose and pregelatinized starch are mixed, stirred for 10min to mix uniformly, and the isoniazid granules are obtained; the ethylamine butanol hydrochloride, microcrystalline cellulose and pregelatinized starch are mixed, stirred for 10min to mix uniformly, and the ethylamine granules are obtained; the isoniazid granule raw material is 9 parts of isoniazid, 48 parts of pyrazinamide, 2.16 parts of microcrystalline cellulose and 1.2 parts of pregelatinized starch according to the mass fraction; and the ethylamine granule raw material is 33 parts of ethylamine butanol hydrochloride, 1.44 parts of microcrystalline cellulose and 3.6 parts of pregelatinized starch according to the mass fraction;

[0089] (2) configuring a mixed aqueous solution of povidone K30 and sodium dodecyl sulfate, the mass percentage of povidone K30 in the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is 15%, and the mass percentage of sodium dodecyl sulfate is 3%; configuring an aqueous solution of povidone K30, the mass percentage of povidone K30 in the aqueous solution of povidone K30 is 15%; under the stirring state, the aqueous solution of povidone K30 is added to the isoniazid granules by spraying (add for 5 min, and then mix and stir for 5 min) to obtain isoniazid soft material, the aqueous solution of povidone K30 is added to the isoniazid granules by spraying so that the mass ratio of isoniazid to povidone K30 is isoniazid: povidone K30 = 9:1.2; then granulating, drying, and whole-granulating to obtain isoniazid dry granules; under the stirring state, the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is added to the ethambutol hydrochloride granules by spraying (add for 5 min, and then mix and stir for 5 min) to obtain ethambutol hydrochloride soft material, the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is added to the ethambutol hydrochloride granules by spraying so that the mass ratio of ethambutol hydrochloride to povidone K30 is ethambutol hydrochloride: povidone K30 = 33:0.6; then granulating, drying, and whole-granulating to obtain ethambutol hydrochloride dry granules;

[0090] (3) mixing the ethambutol hydrochloride dry granules, talc, and rifampicin inclusion compound, stirring for 10 min to mix uniformly to obtain a first mixture, then adding corn starch, the isoniazid dry granules, crosslinked povidone, and magnesium stearate to the first mixture under the stirring state, the mass ratio of isoniazid to talc, rifampicin, corn starch, crosslinked povidone, and magnesium stearate is isoniazid: talc: rifampicin: corn starch: crosslinked povidone: magnesium stearate = 9:1.2:18:2.16:2.16:0.96; after the addition is completed, stirring for 10 min to mix uniformly, tabletting, coating, and obtaining the ethambutol hydrochloride pyrazinamide rifampicin isoniazid tablets.

[0091] In the formula, the rifampicin is first mixed uniformly with olive leaf and kelp enzymatic hydrolysate and hydroxypropyl-β-cyclodextrin before being added, to obtain the rifampicin inclusion compound of the present comparative example; the preparation method of the rifampicin inclusion compound is as follows:

[0092] Step one, mixing dry olive leaf powder and dry kelp powder to form a mixed powder, the mass ratio of dry olive leaf powder and dry kelp powder is dry olive leaf powder: dry kelp powder = 10:6; the mixed powder is added into a cellulase enzyme hydrolysis liquid, the concentration of cellulase in the cellulase enzyme hydrolysis liquid is 90 mg / 100 mL, the solvent is water, the amount of the mixed powder added into the cellulase enzyme hydrolysis liquid is mixed powder: cellulase enzyme hydrolysis liquid = 1 g: 50 mL; hydrochloric acid (the mass percentage of solute in the hydrochloric acid is 10%) is used to adjust the pH to 5.5, then water bath heating is performed to 60℃, constant temperature extraction is performed for 5 h, then enzyme inactivation treatment is performed at 90℃ for 10 min, solid-liquid separation is performed, the liquid phase is concentrated to 1 / 4 of the original volume under reduced pressure, freeze-drying is performed, and an olive leaf-kelp enzyme hydrolysate is obtained;

[0093] Step two, mixing rifampicin, the olive leaf-kelp enzyme hydrolysate, and hydroxypropyl-β-cyclodextrin, the mass ratio of rifampicin, the olive leaf-kelp enzyme hydrolysate, and hydroxypropyl-β-cyclodextrin is rifampicin: olive leaf-kelp enzyme hydrolysate: hydroxypropyl-β-cyclodextrin = 10:1:17; the mixture is stirred for 10 min, then grinding is performed for 30 min, and the rifampicin inclusion compound of the present comparative example is obtained.

[0094] Example 5

[0095] 1. The disintegration time of the uncoated rifampicin tablet prepared by the method of Example 1 after tablet pressing is tested (20 groups are tested), and the mass percentage of rifampicin released at different dissolution times is tested, and the results are shown in Table 1.

[0096] Table 1

[0097]

[0098] 2. The solubility of rifampicin or the rifampicin inclusion compound in the raw material is investigated (0.5 g of the raw material is added into different volumes of dissolution medium, and the dissolution of the raw material is investigated), and the dissolution medium with different pH values is obtained by adding hydrochloric acid into deionized water. 10 ml of each medium is taken into a 50 ml conical flask, and an excess amount of rifampicin or the rifampicin inclusion compound of Example 3 and each comparative example is added, and placed in a constant temperature shaking water tank, and shaken at 37℃ for 8 h, and sampled, and the solubility of each raw material in different media is determined according to the dissolution determination method, and the results are shown in Table 2.

[0099] Table 2. Solubility of each raw material in different media (37℃)

[0100]

[0101] The solubility of isoniazid raw material has pH dependence, and the solubility is obviously increased with the decrease of pH value, and the low solubility of rifampicin restricts the exertion of drug efficacy. The present application can obviously improve the solubility of rifampicin and improve the drug efficacy by preparing rifampicin inclusion compound.

[0102] The above describes the technical solutions provided by the present application in detail. For those skilled in the art, the specific implementation manners and application ranges can be changed according to the idea of the embodiments of the present application. In conclusion, the content of the present application should not be understood as a limitation.

Claims

1. A process for the preparation of high potency ethambutol pyrazinamide rifampicin isoniazid tablet characterized by the steps of include: (1) Weigh out the sieved isoniazid, pyrazinamide, and ethambutol hydrochloride according to the formula, then mix the isoniazid, pyrazinamide, microcrystalline cellulose, and pregelatinized starch, and stir evenly to obtain isoniazid granules; mix the ethambutol hydrochloride, microcrystalline cellulose, and pregelatinized starch, and stir evenly to obtain ethambutol granules; the raw materials for the isoniazid granules are: 8-10 parts by mass of isoniazid, 45-50 parts by mass of pyrazinamide, 2-3 parts by mass of microcrystalline cellulose, and 1-1.5 parts by mass of pregelatinized starch; the raw materials for the ethambutol granules are: 30-35 parts by mass of ethambutol hydrochloride, 1.2-1.5 parts by mass of microcrystalline cellulose, and 3-5 parts by mass of pregelatinized starch; the isoniazid is a powder that has passed through a sieve with a mesh size of 40 mesh or higher, the pyrazinamide is a powder that has passed through a sieve with a mesh size of 100 mesh or higher, and the ethambutol hydrochloride is a powder that has passed through a sieve with a mesh size of 120 mesh or higher; (2) Prepare a mixed aqueous solution of povidone K30 and sodium dodecyl sulfate, wherein the mass percentage of povidone K30 in the mixed aqueous solution is 14%–16% and the mass percentage of sodium dodecyl sulfate is 2%–4%; prepare an aqueous solution of povidone K30, wherein the mass percentage of povidone K30 in the aqueous solution is 14%–16%; spray the aqueous solution of povidone K30 into the fumes particles under stirring to obtain a fumes soft material, and spray the aqueous solution of povidone K30 into the fumes particles to make the fumes soft material... The mass ratio of isoniazid to povidone K30 is 8-10:1-1.4; then granulation, drying, and sizing are performed to obtain dry isoniazid granules; a mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is sprayed into the ethylamine granules under stirring to obtain ethylamine soft material; the mixed aqueous solution of povidone K30 and sodium dodecyl sulfate is sprayed into the ethylamine granules to make the mass ratio of ethambutol hydrochloride to povidone K30 30-35:0.5-0.7; then granulation, drying, and sizing are performed to obtain dry ethylamine granules. (3) Mix the ethylamine dry granules with talc and rifampicin inclusion complex, stir evenly to obtain a first mixture, and then add corn starch, the isoniazid dry granules, crospovidone and magnesium stearate to the first mixture while stirring. The mass ratio of the amount of talc, rifampicin, corn starch, crospovidone and magnesium stearate to the amount of isoniazid in step (1) is isoniazid: talc: rifampicin: corn starch: crospovidone: magnesium stearate = 8~10: 1~1.4: 16~20: 2~2.3: 2~2.3: 0.8~1.

2. After the addition is completed, stir and mix evenly, compress into tablets, coat, and obtain the ethylamine pyrazine rifampicin isoniazid tablets. The preparation method of the rifampicin inclusion complex is as follows: Step 1: Mix dried olive leaf powder and dried kelp powder to form a mixed powder. The mass ratio of dried olive leaf powder to dried kelp powder is 10:2-10. Add the mixed powder to a cellulase hydrolysate. The concentration of cellulase in the cellulase hydrolysate is 80-100 mg / 100 mL. The solvent is water. The mass ratio of the mixed powder to the cellulase hydrolysate is 1 g:50-80 mL. Adjust the pH to 5-5.5 with hydrochloric acid, then heat in a water bath to 55-60°C and extract at a constant temperature for more than 5 hours. Then, perform enzyme inactivation treatment, solid-liquid separation, liquid-phase concentration under reduced pressure, and freeze-drying to obtain olive leaf-kelp hydrolysate. Step 2: Prepare an aqueous solution of acetic acid, wherein the mass percentage of the solute in the aqueous solution is 5%–6%, and the solvent is water; add soybeans to the aqueous solution of acetic acid, wherein the mass ratio of soybeans to aqueous solution of acetic acid is 1:5–10; soak at room temperature for more than 5 hours, then filter, wash the soybeans with deionized water more than 3 times, add them to deionized water again, and grind them into soy milk using a blender. The washed soybeans are added to deionized water at a mass ratio of soybeans to water of 1:8–10 and blended; filter the soy milk through nylon cloth to remove the soybean residue, add neutral protease to the filtrate, wherein the mass ratio of added neutral protease to the volume of filtrate is 3–4 g:100 mL; after adding the enzyme, heat in a water bath to 50±3℃ and incubate for enzymatic hydrolysis for more than 2 hours, then inactivate the enzyme, centrifuge, concentrate the supernatant under reduced pressure, and freeze-dry to obtain the soybean enzymatic hydrolysate; Step 3: Mix rifampicin, the olive leaf-kelp enzymatic hydrolysate, hydroxypropyl-β-cyclodextrin, and soybean enzymatic hydrolysate. The mass ratio of rifampicin to the mixture is rifampicin: olive leaf-kelp enzymatic hydrolysate: hydroxypropyl-β-cyclodextrin: soybean enzymatic hydrolysate = 10:1~2:16~18:2~6. Stir the mixture for at least 10 minutes, then grind it for at least 30 minutes to obtain the rifampicin inclusion complex.

2. The method for preparing a high-efficiency ethylaminepyrazine-rifa isonicotinic tablet according to claim 1, characterized in that, In step one, the mass percentage of the solute in the hydrochloric acid is 10%.

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