Ethambutol hydrochloride tablet and preparation method thereof

Abstract

This invention proposes an ethambutol hydrochloride tablet and its preparation method. The ethambutol hydrochloride tablet is composed of the following components by weight percentage: 63-65.5% ethambutol hydrochloride, 16-19% anhydrous calcium hydrogen phosphate, 8-9.5% mannitol, 3-5% corn starch, 0.5-1% PVP K30, 2-5% low-substituted hydroxypropyl cellulose, 0.5-1.0% colloidal silica, and 0.5-1.0% magnesium stearate. The ethambutol hydrochloride tablet effectively solves the problems of difficult molding and disintegration / dissolution contradictions through the synergistic effect of an optimized excipient system and precise process parameters, reducing the crystal form transformation and degradation of the active pharmaceutical ingredient. Its stability is significantly better than existing products, and all quality indicators meet the relevant pharmacopoeia regulations, ensuring greater safety and efficacy for clinical use.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to an ethambutol hydrochloride tablet and its preparation method. Background Technology

[0002] Ethambutol hydrochloride is a commonly used antibacterial anti-tuberculosis drug in clinical practice. It inhibits arabinosyltransferase in Mycobacterium tuberculosis, preventing cell wall synthesis, and is widely used in the combined treatment of pulmonary and extrapulmonary tuberculosis. However, there are significant technical bottlenecks when using it as the main drug to prepare tablets: First, ethambutol hydrochloride raw material has poor compressibility, and its crystal morphology is mainly needle-like / rod-like crystals, accounting for more than 60% of the formulation. This makes tablet forming difficult and prone to cracking and loosening. Second, the granulation process window is narrow. Over-agglomerated particles will seriously affect disintegration and dissolution performance, while over-loose particles will lead to poor flowability and excessive tablet weight variation during compression. Third, existing processes mostly use a single filler or binder, which makes it difficult to balance the contradiction between formability and disintegration and dissolution. Some products have quality problems such as substandard dissolution and insufficient stability.

[0003] In existing technologies, for example, a method for preparing ethambutol hydrochloride tablets disclosed in the 2006 Guangzhou Pharmaceutical Cross-Strait Pharmaceutical Forum / Salon uses pregelatinized starch and low-substituted hydroxypropyl cellulose as fillers and 15% corn starch paste as a single binder. The resulting product has a hardness of only 8-9 kg, a dissolution rate of approximately 85% after 45 minutes, and after accelerated testing (40℃±2℃, RH 75%±5%) for 6 months, a 3% decrease in content and an increase in total related substances to 0.8%. Furthermore, it exhibits problems such as excessive tablet weight variation (±3.0% or more) and a tablet breakage rate of up to 5%. In addition, this literature does not specify key process parameters such as mixing time and granulation equipment, resulting in poor product quality reproducibility and difficulty in meeting the needs of industrial production.

[0004] It is necessary to overcome the above-mentioned defects in the existing ethambutol hydrochloride tablet formulation technology, solve the problems of difficult molding, disintegration and dissolution contradictions and insufficient stability, improve the overall performance of the formulation, and provide a quality-controllable ethambutol hydrochloride tablet suitable for industrial production and its preparation method. Summary of the Invention

[0005] This invention proposes an ethambutol hydrochloride tablet and its preparation method, which solves the problems of difficult molding, disintegration and dissolution contradictions, and insufficient stability in the prior art.

[0006] The technical solution of this invention is implemented as follows:

[0007] The first aspect of the present invention is to provide an ethambutol hydrochloride tablet, which is composed of the following components by weight percentage: 63-65.5% ethambutol hydrochloride, 16-19% anhydrous dicalcium phosphate, 8-9.5% mannitol, 3-5% corn starch, 0.5-1% PVP K30, 2-5% low-substituted hydroxypropyl cellulose, 0.5-1.0% colloidal silica, and 0.5-1.0% magnesium stearate.

[0008] Furthermore, the ethambutol hydrochloride tablets are prepared in batches of 1000 tablets, with a total feed amount of 630g, each tablet containing 0.4g of ethambutol hydrochloride and a total weight of 0.63g; the composition is as follows: 400g of ethambutol hydrochloride, 105-115g of anhydrous dicalcium phosphate, 52-58g of mannitol, 22-25.2g of corn starch, 5g of PVP K30, 18-25g of low-substituted hydroxypropyl cellulose, 5-6g of colloidal silica, and 5-6g of magnesium stearate.

[0009] A second aspect of the present invention is to provide a method for preparing the ethambutol hydrochloride tablets described in the first aspect, comprising the steps of:

[0010] S1. Add ethylamine butanol hydrochloride, colloidal silica, anhydrous dicalcium phosphate, and mannitol to a wet mixing granulator and mix well; add corn starch slurry and PVP K30 solution, stir and cut to form soft material, sieve and granulate;

[0011] S2. Dry the wet granules with hot air circulation, controlling the granule moisture content to 2-5%;

[0012] S3. The dried particles are granulated to achieve a particle size distribution of D10=80-100μm, D50=150-200μm, and D90=300-350μm;

[0013] S4. Add the dry granules, low-substituted hydroxypropyl cellulose, and colloidal silica to a wet granulation mixer, mix well, and then add magnesium stearate and mix until the uniformity RSD ≤ 2.0%;

[0014] S5. Compress the material obtained in S4 to obtain ethambutol hydrochloride tablets.

[0015] Furthermore, the ethylamine hydrochloride passes through a 100-mesh sieve; and / or, the colloidal silica passes through a 60-mesh sieve; and / or, the low-substituted hydroxypropyl cellulose and magnesium stearate both pass through an 80-mesh sieve.

[0016] Further, the concentration of the corn starch slurry is 15-20 wt%; and / or, the concentration of the PVP K30 solution is 15-20 wt%.

[0017] Further, in step S1, the stirring and cutting process is carried out at a stirring speed of 130-150 rpm and a cutting speed of 2000-2500 rpm; and / or, the granulation is passed through a 12-mesh sieve.

[0018] Furthermore, in step S1, the corn starch slurry is added while stirring during the soft material preparation process.

[0019] Furthermore, in step S2, the moisture content of the particles is 3-4%.

[0020] Furthermore, the quality indicators of the ethylamine hydrochloride tablets are as follows: hardness 6-9 kg, friability 0.3-0.7%, disintegration time 10-14 minutes, dissolution rate >94% at 45 minutes, content 99.50%-101.00%, content uniformity RSD ≤2.0%, and aminobutanol impurity content ≤0.11%.

[0021] A third aspect of the present invention is the application of the ethambutol hydrochloride tablets described in the first aspect, or the ethambutol hydrochloride tablets prepared by the method described in the second aspect, in the preparation of drugs for treating pulmonary tuberculosis, extrapulmonary tuberculosis, and atypical tuberculosis infections.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0023] The ethambutol hydrochloride tablets of this invention use a composite filler composed of anhydrous dicalcium phosphate and mannitol to synergistically improve the compressibility and particle flowability of ethambutol hydrochloride, effectively avoiding tablet cracking and loosening problems; and use a composite binder system of corn starch and PVPK30 to synergistically regulate particle strength, which not only avoids excessive particle agglomeration affecting disintegration, but also prevents excessively loose particles from causing poor molding, effectively solving the problems of difficult molding and disintegration dissolution contradiction.

[0024] The ethambutol hydrochloride tablets of this invention reduce the crystal form transformation and degradation of the active pharmaceutical ingredient through the synergistic effect of an optimized excipient system and precise process parameters. After accelerated testing (40℃±2℃, RH75%±5%) for 6 months and long-term testing (30℃±2℃, RH65%±10%) for 6 months, the dissolution rate decreased by less than 5%, the content retention rate was ≥98.09%, and the impurity (aminobutol) was ≤0.11%, demonstrating significantly better stability than existing products.

[0025] The ethambutol hydrochloride tablets of this invention use fewer types of excipients, all of which are commonly used and safe excipients in the pharmaceutical field, reducing potential risks. This ensures that the final product meets the requirements for molding and disintegration, including a hardness of 6-9 kg, friability <0.9%, and disintegration time <15 minutes. In addition, the content is controlled at 98.09%-101.00%, the content uniformity RSD is ≤2.0%, and the impurity (aminobutol) is ≤0.11%. All quality indicators comply with the relevant provisions of the 2025 edition of the Chinese Pharmacopoeia, thus ensuring greater safety and efficacy for clinical use. Detailed Implementation

[0026] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0027] This invention proposes an ethambutol hydrochloride tablet, comprising the active ingredient ethambutol hydrochloride, as well as fillers, binders, and additives. The fillers are anhydrous dicalcium phosphate and mannitol; the binders are corn starch and PVP K30; and the additives are low-substituted hydroxypropyl cellulose, colloidal silica, and magnesium stearate. The composition by weight percentage is: ethambutol hydrochloride 63-65.5%, anhydrous dicalcium phosphate 16-19%, mannitol 8-9.5%, corn starch 3-5%, PVP K30 0.5-1%, low-substituted hydroxypropyl cellulose 2-5%, colloidal silica 0.5-1.0%, and magnesium stearate 0.5-1.0%.

[0028] In this invention, anhydrous dicalcium phosphate possesses good rigidity and compressibility, providing structural support for tablets; mannitol exhibits excellent plastic deformation capabilities, reducing the risk of tablet breakage during compression. The two work synergistically to improve the compressibility of the active pharmaceutical ingredient and particle flowability, solving the molding problem of high-proportion, difficult-to-compress raw materials. Corn starch is a natural binder, low in cost and ensuring basic particle adhesion; PVP K30 is a synthetic binder, providing stable bonding strength and enhancing particle anti-aging capabilities. The combination of these two allows for precise control of particle strength, balancing moldability and disintegration / dissolution performance; low-substituted hydroxypropyl cellulose enhances tablet disintegration performance through water absorption and swelling; colloidal silica reduces inter-particle friction and improves particle flowability; magnesium stearate acts as a lubricant, reducing sticking and impaction during compression. The three work synergistically to ensure the stability of the formulation production process and its clinical effectiveness.

[0029] In a preferred embodiment, the ethambutol hydrochloride tablets are prepared in batches of 1000 tablets, with a total feed amount of 630g. Each tablet contains 0.4g of ethambutol hydrochloride, and each tablet weighs 0.63g. The active ingredient is 400g of ethambutol hydrochloride, 105-115g of anhydrous calcium hydrogen phosphate, 52-58g of mannitol, 22-25.2g of corn starch, and 5g of PVP K30, along with 18-25g of low-substituted hydroxypropyl cellulose, 5-6g of colloidal silica, and 5-6g of magnesium stearate.

[0030] This invention proposes a method for preparing the above-mentioned ethambutol hydrochloride tablets, the specific steps of which are as follows:

[0031] 1. Material pretreatment: Ethylaminobutanol hydrochloride is passed through a 100-mesh sieve (particle size ≤150μm), colloidal silica is passed through a 60-mesh sieve (particle size ≤250μm), and anhydrous dicalcium phosphate, mannitol, low-substituted hydroxypropyl cellulose, and magnesium stearate are all passed through an 80-mesh sieve (particle size ≤180μm) for later use.

[0032] 2. Adhesive preparation: Prepare 18% corn starch slurry: Add 18g of corn starch to 100mL of purified water, heat to boiling and stir until transparent, then cool; Prepare 20% PVP K30 solution: Add 20g of PVP K30 to 100mL of purified water, stir to dissolve until clear, and set aside.

[0033] 3. Mixing and granulation: Add ethambutol hydrochloride, anhydrous dicalcium phosphate, and mannitol to a wet mixing granulator, set the speed to 120 rpm, and mix for 5 minutes until homogeneous (mixing uniformity RSD ≤ 2.0%); add 18% corn starch slurry and 20% PVP K30 solution according to the prescription, stir at 100-150 rpm, and cut at 2000-2500 rpm to make a soft material that "can be formed into a ball when squeezed by hand but crumbles easily when touched"; granulate through a 12-mesh sieve (particle size ≤ 1400 μm) using a gyratory granulator to obtain wet granules; this operation can avoid local over-clumping or over-loosening of granules and ensure granule uniformity;

[0034] 4. Drying: Place the wet granules in a hot air circulating drying oven and dry at 60℃ for 2.5 hours. Turn the granules over every 30 minutes during the drying process to control the moisture content of the dried granules to 2%-5% (preferably 3-4%). ​​These temperature and time parameters can ensure that the granules are completely dried while avoiding degradation of the active pharmaceutical ingredient due to high temperature (degradation rate of active pharmaceutical ingredient ≤0.1%).

[0035] 5. Granulation: Granulation is carried out using a gyratory granulator with a 16-mesh nylon screen (particle size ≤1000μm). After granulation, the particle size distribution is D10=80-100μm, D50=150-200μm, and D90=300-350μm, ensuring uniform particle size and further improving the fluidity of subsequent tableting.

[0036] 6. Final Mixing: Add the dry granules, low-substituted hydroxypropyl cellulose, and colloidal silica to a wet granulation mixer, set the speed to 120 rpm, and mix for 10 minutes; then add magnesium stearate and continue mixing for 5 minutes until homogeneous (mixing uniformity RSD≤2.0%). Using a step-by-step mixing method can avoid the problem of "over-lubrication" or uneven mixing caused by adding magnesium stearate too early, and ensure its uniform lubrication effect.

[0037] 7. Tableting: A rotary tablet press is used, with the tableting pressure controlled at 15-20 MPa. The resulting tablets have a hardness of 6-9 kg, a friability of 0.3-0.7%, a disintegration time of 10-14 minutes, a dissolution rate of >94% at 45 minutes, a content of 99.50%-101.00%, a content uniformity RSD of ≤2.0%, and impurities (aminobutanol) of ≤0.11%, which comply with the relevant provisions of Part IV and Part II of the 2025 edition of the Chinese Pharmacopoeia.

[0038] The ethambutol hydrochloride tablets of the present invention, or the ethambutol hydrochloride tablets prepared by the preparation method of the present invention, can effectively exert the anti-tuberculosis effect of ethambutol hydrochloride. They are suitable for preparing drugs to treat infections caused by Mycobacterium tuberculosis, especially for the combined treatment of pulmonary tuberculosis and extrapulmonary tuberculosis, and can also be used for the treatment of atypical Mycobacterium tuberculosis infection, and have important clinical application value.

[0039] Example 1

[0040] The prescription composition of 1000 tablets of ethambutol hydrochloride is as follows:

[0041] 400g of ethambutol hydrochloride, 105g of anhydrous dicalcium phosphate, 55g of mannitol, 160g of 18% corn starch paste, 30g of 20% PVPK30 solution, 20g of low-substituted hydroxypropyl cellulose, 5g of colloidal silica, and 5g of magnesium stearate.

[0042] Preparation method:

[0043] 1. Preparation and material pretreatment: Take ethylamine hydrochloride and pass it through a 100-mesh sieve, colloidal silica through a 60-mesh sieve, and anhydrous dicalcium phosphate, mannitol, low-substituted hydroxypropyl cellulose, and magnesium stearate through an 80-mesh sieve. Weigh them according to the prescription and set them aside.

[0044] 2. Adhesive preparation: Prepare 18% corn starch paste (18g corn starch + 100mL purified water, heat to boiling until transparent and then cool) and 20% PVP K30 solution (20g PVP K30 + 100mL purified water, stir to dissolve until clear), and take 160g and 30g respectively for later use;

[0045] 3. Mixing and granulation: Add ethambutol hydrochloride, anhydrous dicalcium phosphate, and mannitol to a wet mixing granulator, mix at 120 rpm for 5 minutes; add 18% corn starch slurry and 20% PVP K30 solution, stir at 150 rpm, cut at 2500 rpm, and pass through a 12-mesh sieve to form wet granules.

[0046] 4. Drying: Place the wet granules in a hot air circulating drying oven and dry at 60℃ for 2.5 hours, turning them over every 30 minutes. The moisture content of the dried granules is 3.5%.

[0047] 5. Granulation: Uniform dry granules (D10=90μm, D50=170μm, D90=320μm) are obtained by passing through a 16-mesh oscillating granulator.

[0048] 6. Final Mixing: First, add low-substituted hydroxypropyl cellulose and colloidal silica, and mix for 10 minutes using a wet granulator at 120 rpm; then add magnesium stearate and continue mixing for 5 minutes, with a mixing uniformity RSD of 1.5%.

[0049] 7. Tableting: A rotary tablet press is used, with a tableting pressure of 15 MPa, a tablet hardness of 7.5 kg, and a friability of 0.5%.

[0050] 8. Quality inspection and packaging: After testing, the tablets have a disintegration time of 12 minutes, a dissolution rate of 94.27% at 45 minutes, a content of 100.25%, a content uniformity RSD of 1.5%, and an impurity (aminobutanol) of 0.08%, which meet the requirements. After passing the test, the tablets are packaged.

[0051] Example 2

[0052] The prescription composition of 1000 tablets of ethambutol hydrochloride is as follows:

[0053] 400g of ethambutol hydrochloride, 110g of anhydrous dicalcium phosphate, 58g of mannitol, 160g of 18% corn starch paste, 30g of 20% PVPK30 solution, 25g of low-substituted hydroxypropyl cellulose, 6g of colloidal silica, and 6g of magnesium stearate.

[0054] Preparation method:

[0055] 1. The preparation and material pretreatment, and adhesive preparation are the same as in Example 1;

[0056] 2. Mixing and granulation: Add ethambutol hydrochloride, anhydrous dicalcium phosphate, and mannitol to a wet mixing granulator and mix at 120 rpm for 5 minutes; add 18% corn starch slurry and 20% PVP K30 solution, stir at 130 rpm, cut at 2000 rpm, and pass through a 12-mesh sieve to form wet granules.

[0057] 3. Drying: Dry at 60℃ for 2.5 hours, turning the granules every 30 minutes. The moisture content of the dried granules is 2.8%.

[0058] 4. Granulation: Uniform dry granules (D10=85μm, D50=160μm, D90=310μm) are obtained by passing through a 16-mesh oscillating granulator.

[0059] 5. Final mixing: First, add low-substituted hydroxypropyl cellulose and colloidal silica, and mix for 10 minutes; then add magnesium stearate and mix for 5 minutes, with a mixing uniformity RSD of 1.4%.

[0060] 6. Tableting: Compression pressure 15MPa, tablet hardness 6.2kg, friability 0.3%;

[0061] 7. Quality inspection and packaging: After testing, the tablets have a disintegration time of 10 minutes, a dissolution rate of 95.39% at 45 minutes, a content of 100.32% ± 0.15%, a content uniformity RSD of 1.3%, and an impurity (aminobutanol) of 0.09%, which meet the requirements. After passing the test, the tablets are packaged.

[0062] Example 3

[0063] The prescription composition of 1000 tablets of ethambutol hydrochloride is as follows:

[0064] 400g of ethambutol hydrochloride, 115g of anhydrous dicalcium phosphate, 52g of mannitol, 160g of 18% corn starch paste, 30g of 20% PVPK30 solution, 18g of low-substituted hydroxypropyl cellulose, 5g of colloidal silica, and 5g of magnesium stearate.

[0065] Preparation method:

[0066] 1. The preparation and material pretreatment, and adhesive preparation are the same as in Example 1;

[0067] 2. Mixing and granulation: Add ethambutol hydrochloride, anhydrous dicalcium phosphate, and mannitol to a wet mixing granulator and mix at 120 rpm for 5 minutes; add 18% corn starch slurry and 20% PVP K30 solution, stir at 140 rpm, cut at 2300 rpm, and pass through a 12-mesh sieve to form wet granules.

[0068] 3. Drying: Dry at 60℃ for 2.5 hours, turning the granules every 30 minutes. The moisture content of the dried granules is 4.2%.

[0069] 4. Granulation: Uniform dry granules (D10=95μm, D50=190μm, D90=340μm) are obtained by passing through a 16-mesh oscillating granulator.

[0070] 5. Final mixing: First, add low-substituted hydroxypropyl cellulose and colloidal silica, and mix for 10 minutes; then add magnesium stearate and mix for 5 minutes, with a mixing uniformity RSD of 1.6%.

[0071] 6. Tableting: Compression pressure 20MPa, tablet hardness 8.8kg, friability 0.7%;

[0072] 7. Quality inspection and packaging: After testing, the tablets have a disintegration time of 14 minutes, a dissolution rate of 94.89% at 45 minutes, a content of 100.18%, a content uniformity RSD of 1.6%, and an impurity (aminobutanol) of 0.07%, which meet the requirements. After passing the test, the tablets are packaged.

[0073] Comparative Example 1: Ethamibutanol Hydrochloride Tablets with Single Filler

[0074] The prescription of 1000 tablets consists of:

[0075] 400g of ethambutol hydrochloride, 160g of anhydrous dicalcium phosphate (single filler), 160g of 18% corn starch paste, 30g of 20% PVP K30 solution, 20g of low-substituted hydroxypropyl cellulose, 5g of colloidal silica, and 5g of magnesium stearate.

[0076] Preparation method: Except for the use of anhydrous calcium hydrogen phosphate as filler, the other steps are the same as in Example 1.

[0077] Comparative Example 2: Ethamibutanol Hydrochloride Tablets with a Single Adhesive

[0078] The prescription of 1000 tablets consists of:

[0079] 400g ethambutol hydrochloride, 105g anhydrous dicalcium phosphate, 55g mannitol, 193g 18% corn starch paste (single binder), 20g low-substituted hydroxypropyl cellulose, 5g colloidal silica, and 5g magnesium stearate.

[0080] Preparation method: Except for the use of anhydrous calcium hydrogen phosphate as filler, the other steps are the same as in Example 1.

[0081] Comparative Example 3: Ethamibutanol Hydrochloride Tablets were reconstituted based on existing literature.

[0082] Composition of a 1000-tablet prescription (calculated based on publicly available literature):

[0083] 400g of ethambutol hydrochloride, 85g of pregelatinized starch, 85g of low-substituted hydroxypropyl cellulose, 200g of 15% starch paste solution (single binder), 25g of sodium carboxymethyl starch, and 5g of magnesium stearate.

[0084] Preparation method: Following the process disclosed in this literature, the raw and auxiliary materials were passed through an 80-mesh sieve, dried to a moisture content of less than 2%, and granulated to a 16-mesh sieve. The remaining steps were the same as in Example 1.

[0085] Comparative Example 4: Filler Replacement

[0086] The anhydrous dicalcium phosphate in the formulation of Example 1 was replaced with an equal mass of microcrystalline cellulose, while other components and amounts remained unchanged. The preparation method was the same as in Example 1.

[0087] Comparative Example 5: Adhesive Replacement

[0088] The 20% PVP K30 solution in the formulation of Example 1 was replaced with an equal mass of 20% CMC-Na solution (prepared at 20g / 100ml water), while other components and amounts remained unchanged. The preparation method was the same as in Example 1.

[0089] Comparative Example 6: Replacement of Additives

[0090] In Example 1, the colloidal silica was replaced with an equal mass of talc powder, while other components and amounts remained unchanged. The preparation method was the same as in Example 1.

[0091] Experimental Example 1: Formulation Formulation Study

[0092] The tablets of Examples 1-3 and Comparative Examples 1-6 were evaluated for formability, and indicators such as hardness, tablet weight difference, cracking rate, and particle flowability were examined. The results are shown in Table 1.

[0093] Table 1:

[0094] sample Hardness (kg) Tablet weight difference (%) Fragmentation rate (%) Friability (%) Particle flowability (angle of repose °) Mixing uniformity RSD (%) Example 1 7.5 ±2.1 0 0.5 31.2 1.5 Example 2 6.2 ±2.3 0 0.3 32.5 1.4 Example 3 8.8 ±1.9 0 0.7 30.8 1.6 Comparative Example 1 4.3 ±3.5 8.6 1.8 38.7 2.8 Comparative Example 2 5.1 ±3.2 5.3 1.5 35.4 2.5 Comparative Example 3 4.8 ±2.8 4.7 0.9 34.9 2.6 Comparative Example 4 4.1 ±3.6 9.2 1.9 37.5 3.0 Comparative Example 5 4.5 ±3.4 7.8 1.7 36.8 2.4 Comparative Example 6 5.2 ±3.1 6.3 1.5 35.9 2.6

[0095] Experimental results show that the tablets of Examples 1-3 have a hardness range of 6-9 kg, a tablet weight difference of ≤±2.3%, no tablet cracking, a friability of <0.9%, a particle repose angle of ≤32.5°, and a mixing uniformity RSD of ≤2.0%, exhibiting excellent formability and flowability. In contrast, Comparative Example 1 (single filler) lacks the plastic synergistic effect of mannitol, resulting in insufficient hardness and a high cracking rate. Comparative Example 2 (single binder) has poor formability due to uneven particle strength. The formability of Comparative Examples 3-6 is inferior to that of the embodiments of the present invention, indicating that the composite filler and binder system of the present invention can effectively solve the forming problem of high proportion of difficult-to-compress raw materials.

[0096] Experimental Example 2: Disintegration and Dissolution Investigation

[0097] The tablets of Examples 1-3 and Comparative Examples 1-6 were tested according to the General Chapter 0921 Disintegration Time Test and 0931 Dissolution and Release Determination Method in Part IV of the 2025 edition of the Chinese Pharmacopoeia. The results are shown in Table 2.

[0098] Table 2:

[0099] sample Disintegration timeout (minutes) Dissolution rate at 45 minutes (%) Example 1 12 94.27 Example 2 10 95.39 Example 3 14 94.89 Comparative Example 1 18 85.68 Comparative Example 2 25 81.25 Comparative Example 3 16 88.95 Comparative Example 4 22 78.36 Comparative Example 5 28 72.45 Comparative Example 6 19 83.62

[0100] Experimental results show that the tablets of Examples 1-3 have a disintegration time of less than 15 minutes and a dissolution rate of >94% at 45 minutes, with stable and excellent dissolution performance. Comparative Example 1 has uneven dissolution due to poor particle flowability, and Comparative Example 2 has slow disintegration and low dissolution rate due to excessive particle agglomeration. Although the dissolution performance of Comparative Example 3 is better than the former two, it is still significantly inferior to the examples of the present invention. This indicates that the composite excipient system and precise process of the present invention can effectively balance disintegration and dissolution performance.

[0101] Experiment Example 3: Stability Assessment

[0102] Samples from Examples 1-3 (batch numbers: 20250701-20250703) and Comparative Example 3 were subjected to accelerated testing (40℃±2℃, RH75%±5%) at 0 months, 1 month, 2 months, 3 months, and 6 months, and long-term testing (30℃±2℃, RH65%±10%) at 0 months, 3 months, and 6 months. Dissolution rate, content, and related substances were determined, and the results are shown in Table 3.

[0103] Table 3:

[0104] Example batch number Types of Examination Inspection period (months) Dissolution rate (%) content(%) Impurities (aminobutanol) (%) Example 1 20250701 accelerate 0 94.27 100.25 0.08 Example 1 20250701 accelerate 1 93.28 100.21 0.08 Example 1 20250701 accelerate 2 92.75 99.63 0.09 Example 1 20250701 accelerate 3 92.22 99.16 0.09 Example 1 20250701 accelerate 6 90.19 98.09 0.10 Example 1 20250701 long 3 94.66 100.22 0.08 Example 1 20250701 long 6 93.54 100.20 0.08 Example 2 20250702 accelerate 0 95.39 99.75 0.09 Example 2 20250702 accelerate 1 95.72 100.17 0.07 Example 2 20250702 accelerate 2 94.3 99.82 0.07 Example 2 20250702 accelerate 3 92.27 99.27 0.08 Example 2 20250702 accelerate 6 91.64 98.39 0.08 Example 2 20250702 long 3 94.31 99.96 0.09 Example 2 20250702 long 6 92.69 99.74 0.07 Example 3 20250703 accelerate 0 94.89 100.25 0.07 Example 3 20250703 accelerate 1 94.69 100.20 0.08 Example 3 20250703 accelerate 2 92.97 99.52 0.09 Example 3 20250703 accelerate 3 92.24 99.03 0.09 Example 3 20250703 accelerate 6 90.38 98.48 0.10 Example 3 20250703 long 3 94.78 100.13 0.10 Example 3 20250703 long 6 93.96 99.29 0.11 Comparative Example 3 Reference Sample accelerate 0 88.72 99.85 0.09 Comparative Example 3 Reference Sample accelerate 1 85.96 99.21 0.13 Comparative Example 3 Reference Sample accelerate 2 83.97 98.76 0.25 Comparative Example 3 Reference Sample accelerate 3 82.5 96.99 0.39 Comparative Example 3 Reference Sample accelerate 6 81.23 95.27 0.72 Comparative Example 3 Reference Sample long 3 85.34 99.53 0.21 Comparative Example 3 Reference Sample long 6 84.68 98.88 0.24

[0105] Experimental results show that the samples in Examples 1-3 exhibited excellent stability after 6 months of accelerated dissolution and 6 months of long-term dissolution, with a dissolution rate of <5%, a content retention rate of ≥98.09%, and an impurity (aminobutanol) content of ≤0.11%. In contrast, Comparative Example 3 showed a 7.49% decrease in dissolution and a 1.99% decrease in content after 6 months of accelerated dissolution, with the impurity (aminobutanol) increasing to 0.72%, indicating significantly inferior stability compared to the examples of this invention. This demonstrates that the formulation and process of this invention can effectively improve the storage stability of the preparation.

[0106] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An ethambutol hydrochloride tablet, characterized in that, The composition by weight percentage is as follows: 63-65.5% ethambutol hydrochloride, 16-19% anhydrous dicalcium phosphate, 8-9.5% mannitol, 3-5% corn starch, 0.5-1% PVP K30, 2-5% low-substituted hydroxypropyl cellulose, 0.5-1.0% colloidal silica, and 0.5-1.0% magnesium stearate.

2. The ethambutol hydrochloride tablets according to claim 1, characterized in that, The ethambutol hydrochloride tablets are prepared in batches of 1000 tablets, with a total feed amount of 630g. Each tablet contains 0.4g of ethambutol hydrochloride and weighs 0.63g. The composition is as follows: 400g of ethambutol hydrochloride, 105-115g of anhydrous dicalcium phosphate, 52-58g of mannitol, 22-25.2g of corn starch, 305g of PVP K, 18-25g of low-substituted hydroxypropyl cellulose, 5-6g of colloidal silica, and 5-6g of magnesium stearate.

3. The method for preparing the ethambutol hydrochloride tablets according to claim 1, characterized in that, step... include: S1. Add ethylamine butanol hydrochloride, colloidal silica, anhydrous dicalcium phosphate, and mannitol to a wet mixing granulator and mix well; add corn starch slurry and PVP K30 solution, stir and cut to form soft material, sieve and granulate; S2. Dry the wet granules with hot air circulation, controlling the granule moisture content to 2-5%; S3. The dried particles are granulated to achieve a particle size distribution of D10=80-100μm, D50=150-200μm, and D90=300-350μm; S4. Add the dry granules, low-substituted hydroxypropyl cellulose, and colloidal silica to a wet granulation mixer, mix well, and then add magnesium stearate and mix until the uniformity RSD ≤ 2.0%; S5. Compress the material obtained in S4 to obtain ethambutol hydrochloride tablets.

4. The preparation method according to claim 3, characterized in that, The ethylamine hydrochloride is passed through a 100-mesh sieve; and / or the colloidal silica is passed through a 60-mesh sieve; and / or the low-substituted hydroxypropyl cellulose and magnesium stearate are both passed through an 80-mesh sieve.

5. The preparation method according to claim 3, characterized in that, The concentration of the corn starch slurry is 15-20 wt%; and / or the concentration of the PVP K30 solution is 15-20 wt%.

6. The preparation method according to claim 3, characterized in that, In step S1, the stirring and cutting process is carried out at a stirring speed of 130-150 rpm and a cutting speed of 2000-2500 rpm; and / or, the granulation is passed through a 12-mesh sieve.

7. The preparation method according to claim 3, characterized in that, In step S1, the corn starch slurry is added while stirring during the soft material preparation process.

8. The preparation method according to claim 3, characterized in that, In step S2, the moisture content of the particles is 3-4%.

9. The preparation method according to claim 3, characterized in that, The quality indicators of the ethylamine butanol hydrochloride tablets are as follows: hardness 6-9 kg, friability 0.3-0.7%, disintegration time 10-14 minutes, dissolution rate >94% at 45 minutes, content 99.50%-101.00%, content uniformity RSD ≤2.0%, and aminobutanol impurity content ≤0.11%.

10. The use of the ethambutol hydrochloride tablets according to claim 1 or 2, or the ethambutol hydrochloride tablets prepared by the preparation method according to any one of claims 3-9, in the preparation of drugs for treating pulmonary tuberculosis, extrapulmonary tuberculosis and atypical tuberculosis mycobacterial infection.