A trimetazidine hydrochloride tablet and a preparation process thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and discloses a trimetazidine hydrochloride tablet and a preparation process thereof.The trimetazidine hydrochloride tablet is composed of trimetazidine hydrochloride, lactose, microcrystalline cellulose, sodium crosslinked carboxymethyl cellulose and other auxiliary materials, and specific auxiliary components are added simultaneously.The preparation process comprises the following steps in sequence: pretreatment of core components, inclusion and dispersion, mixing of soft materials, granulation, drying, total mixing and tablet pressing, and the solubility and dispersibility of the drug are effectively improved.The trimetazidine hydrochloride tablet can realize rapid and sufficient release of the drug, has excellent content uniformity, provides precise and stable dose guarantee for clinical medication, and meets the clinical treatment requirements.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a trimetazidine hydrochloride tablet and its preparation process. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Trimetazidine hydrochloride (chemical name: 1-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride) is a drug of significant clinical value. Its core mechanism of action is to ensure energy metabolism in ischemic and hypoxic cardiomyocytes, prevent a decline in intracellular ATP levels, maintain intracellular homeostasis, and ensure the proper functioning of ion pumps and normal transmembrane sodium-potassium pump transport. Clinically, this drug is widely used as an adjunct therapy for the symptomatic treatment of stable angina in adult patients who have poor or intolerable control of angina with first-line antianginal therapy. It can also be used as an adjunct symptomatic treatment for dizziness and tinnitus. It effectively increases coronary flow reserve, reduces the frequency of angina attacks, and lowers the dosage of nitroglycerin, without producing significant direct hemodynamic effects, thus occupying an important position in the treatment of cardiovascular diseases.

[0004] With the increasing clinical demand, the formulation development and process optimization of trimetazidine hydrochloride have become a research hotspot in the pharmaceutical field. Tablets, due to their advantages such as convenient administration, precise dosage, and good stability, have become one of the main formulation forms. However, existing trimetazidine hydrochloride tablet preparation technologies and related processes still have many problems that urgently need to be solved, restricting the improvement of product quality and the optimization of clinical application effects. Clinical applications have shown that trimetazidine hydrochloride formulations may cause adverse reactions such as dizziness, lightheadedness, and gastrointestinal discomfort. Some existing formulations, due to inappropriate drug release rates, may lead to excessive fluctuations in blood drug concentration, further increasing the risk of adverse reactions. Furthermore, current research on optimizing the drug release characteristics of trimetazidine hydrochloride tablets is relatively scarce, making it difficult to achieve stable control of blood drug concentration through formulation process improvements to reduce the incidence of adverse reactions.

[0005] Chinese patent CN110279666A discloses a trimetazidine hydrochloride tablet and its preparation method. The method uses a solvent method to mix trimetazidine hydrochloride raw material with a porous carrier, magnesium aluminum silicate, to form a solid dispersion, improving the drug's flowability and compressibility, and is used for direct compression of the powder into tablets. Although existing technologies have provided a certain technical foundation for the preparation of trimetazidine hydrochloride and its pharmaceutical salts, current trimetazidine hydrochloride tablets still have shortcomings in terms of the rationality of the original formulation, the stability of the molding process, and the optimization of drug release characteristics. Therefore, developing a trimetazidine hydrochloride tablet with good dissolution performance and stability, and its preparation process, has become an urgent technical problem to be solved in this field, and has significant clinical and industrial value. Summary of the Invention

[0006] To address the technical problems of existing trimetazidine hydrochloride tablets, such as poor dissolution performance and poor content uniformity, this invention provides a trimetazidine hydrochloride tablet and its preparation process, aiming to achieve rapid and full drug release, improve content uniformity, reduce the risk of adverse clinical reactions, and meet clinical medication needs.

[0007] The specific formulation of the trimetazidine hydrochloride tablets of the present invention is as follows: The ingredients, by weight, are: 20 parts trimetazidine hydrochloride, 30-100 parts lactose, 10-60 parts microcrystalline cellulose, 2-6 parts croscarmellose sodium, 1-5 parts hydroxypropyl methylcellulose, 0.3-1.8 parts magnesium stearate, 0.2-1.0 parts micronized silica gel, 1-3 parts β-cyclodextrin, 0.5-1.5 parts eugenol diglucoside, and 0.3-0.8 parts dithiothreitol. Preferred formulation (by weight): 20 parts trimetazidine hydrochloride, 40-60 parts lactose, 20-35 parts microcrystalline cellulose, 3-5 parts croscarmellose sodium, 2-4 parts hydroxypropyl methylcellulose, 1.0-1.3 parts magnesium stearate, 0.5-0.7 parts micronized silica gel, 1.8-2.2 parts β-cyclodextrin, 0.9-1.1 parts eugenol diglucoside, 0.45-0.55 parts dithiothreitol. Most preferred formulation (by weight): 20 parts trimetazidine hydrochloride, 50 parts lactose, 25 parts microcrystalline cellulose, 4 parts croscarmellose sodium, 3 parts hydroxypropyl methylcellulose, 1.2 parts magnesium stearate, 0.6 parts micronized silica gel, 2 parts β-cyclodextrin, 1.0 part eugenol diglucoside, 0.5 parts dithiothreitol.

[0008] The preparation process steps of the trimetazidine hydrochloride tablets of the present invention are as follows: (1) Pretreatment of core components: Trimetazidine hydrochloride, β-cyclodextrin, eugenol diglucoside and dithiothreitol were pulverized and sieved respectively; the pulverized β-cyclodextrin was taken and added to 5 to 8 times its weight of purified water, and stirred and dissolved in a water bath at 60 to 70°C to prepare a saturated β-cyclodextrin solution for later use.

[0009] (2) Inclusion and dispersion: The sieved trimetazidine hydrochloride, eugenol diglucoside and dithiothreitol were mixed evenly, and the above β-cyclodextrin saturated solution was added. The mixture was stirred at a constant temperature of 60~70℃ and 200~300r / min for 30~40min to form a dispersion. The dispersion was dried in a vacuum drying oven at 55℃ for 4~6h until constant weight, pulverized and sieved to obtain the inclusion micro powder.

[0010] (3) Mixing to prepare soft material: Mix the encapsulated micro powder with lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose evenly, add 4%~6% hydroxypropyl methyl cellulose aqueous solution, and stir to prepare a suitable soft material.

[0011] (4) Granulation and drying: After granulating the soft material, dry it at 45~55℃ for 2~3h, control the moisture content of the particles to be 2.0%~3.0%, and then granulate it after drying.

[0012] (5) Total mixing and tableting: Mix the granulated particles with magnesium stearate and micronized silica gel evenly, and then compress the mixture into tablets using a tablet press to obtain trimetazidine hydrochloride tablets.

[0013] It should be noted that the long-term stability of trimetazidine hydrochloride tablets in Examples 1-5 of this invention is qualified.

[0014] Compared with the prior art, the technical advantages of the present invention are as follows: (1) Significantly improved dissolution performance, achieving rapid and sufficient drug release: The trimetazidine hydrochloride tablets of the present invention have a dissolution rate of not less than 90% in 0.05 mol / L hydrochloric acid solution for 30 minutes, which is superior to commercially available formulations and comparative examples 1-8. The present invention effectively improves the solubility and dispersibility of the drug, solves the technical pain points of poor dissolution rate and insufficient release of trimetazidine hydrochloride tablets in the prior art, and ensures that the drug takes effect quickly and exerts a sustained therapeutic effect.

[0015] (2) Excellent content uniformity, ensuring accurate and stable dosage: The relative standard deviation (RSD) of the content uniformity of the trimetazidine hydrochloride tablets prepared by this invention is ≤0.5%, which is better than that of comparative examples 1-8 and commercially available formulations. Through the synergistic optimization of the pretreatment of core components, inclusion dispersion process and subsequent mixing and granulation steps, the problem of drug particle aggregation or uneven distribution is effectively avoided, so that trimetazidine hydrochloride is uniformly dispersed in the tablets, providing accurate dosage assurance for clinical use. Attached Figure Description

[0016] Figure 1 Dissolution curve of trimetazidine hydrochloride tablets. Detailed Implementation

[0017] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0018] Example 1: Trimetazidine Hydrochloride Tablets formula: Trimetazidine hydrochloride 20g, lactose 50g, microcrystalline cellulose 25g, croscarmellose sodium 4g, hydroxypropyl methylcellulose 3g, magnesium stearate 1.2g, micronized silica gel 0.6g, β-cyclodextrin 2g, eugenol diglucoside 1.0g, dithiothreitol 0.5g.

[0019] Preparation process: (1) Special treatment of core components: Take the prescribed amount of trimetazidine hydrochloride, β-cyclodextrin, eugenol diglucoside and dithiothreitol, pulverize them separately and pass them through a 100-mesh sieve. Add the pulverized β-cyclodextrin to 6 times its weight of purified water and place it in a 65°C water bath and stir until completely dissolved to prepare a saturated β-cyclodextrin solution for later use.

[0020] (2) Inclusion and dispersion treatment: The sieved trimetazidine hydrochloride, eugenol diglucoside and dithiothreitol were mixed evenly and slowly added to the above β-cyclodextrin saturated solution. The mixture was kept in a 65°C water bath and stirred for 35 min at a constant temperature, with the stirring rate controlled at 250 r / min during the process, to form a dispersion. The dispersion was placed in a vacuum drying oven and dried at 55°C to constant weight. After being removed, it was pulverized and passed through a 120-mesh sieve to obtain the inclusion micro powder.

[0021] (3) Mixing treatment: Place the above-mentioned encapsulated micro powder, lactose, microcrystalline cellulose and croscarmellose sodium in a three-dimensional mixer and mix for 18 minutes. After mixing evenly, add 5% aqueous solution of hydroxypropyl methylcellulose prepared according to the prescription amount and stir to make a suitable soft material.

[0022] (4) Granulation and drying: The soft material is granulated through an 18-mesh sieve. The wet granules are placed in a fluidized bed dryer and dried at 50°C until the moisture content of the granules is 2.0%-3.0%. After drying, the granules are sized by passing them through a 16-mesh sieve.

[0023] (5) Total mixing and tableting: The granulated particles, magnesium stearate and micronized silica gel of the prescription amount are placed in a three-dimensional mixer and mixed for 9 minutes. The uniformly mixed particles are then compressed into tablets using a tableting machine to make trimetazidine hydrochloride tablets.

[0024] Example 2 Trimetazidine Hydrochloride Tablets formula: Trimetazidine hydrochloride 20g, lactose 40g, microcrystalline cellulose 20g, croscarmellose sodium 3g, hydroxypropyl methylcellulose 2g, magnesium stearate 1.0g, micronized silica gel 0.5g, β-cyclodextrin 1.8g, eugenol diglucoside 0.9g, dithiothreitol 0.45g.

[0025] Preparation process: (1) Special treatment of core components: Take the prescribed amount of trimetazidine hydrochloride, β-cyclodextrin, eugenol diglucoside and dithiothreitol, pulverize them separately and pass them through a 100-mesh sieve. Add the pulverized β-cyclodextrin to 6 times its weight of purified water and place it in a 65°C water bath and stir until completely dissolved to prepare a saturated β-cyclodextrin solution for later use.

[0026] (2) Inclusion and dispersion treatment: The sieved trimetazidine hydrochloride, eugenol diglucoside and dithiothreitol were mixed evenly and slowly added to the above β-cyclodextrin saturated solution. The mixture was kept in a 65°C water bath and stirred for 35 min at a constant temperature, with the stirring rate controlled at 250 r / min during the process, to form a dispersion. The dispersion was placed in a vacuum drying oven and dried at 55°C to constant weight. After being removed, it was pulverized and passed through a 120-mesh sieve to obtain the inclusion micro powder.

[0027] (3) Mixing treatment: Place the above-mentioned encapsulated micro powder, lactose, microcrystalline cellulose and croscarmellose sodium in a three-dimensional mixer and mix for 18 minutes. After mixing evenly, add 5% aqueous solution of hydroxypropyl methylcellulose prepared according to the prescription amount and stir to make a suitable soft material.

[0028] (4) Granulation and drying: The soft material is granulated through an 18-mesh sieve. The wet granules are placed in a fluidized bed dryer and dried at 50°C until the moisture content of the granules is 2.0%-3.0%. After drying, the granules are sized by passing them through a 16-mesh sieve.

[0029] (5) Total mixing and tableting: The granulated particles, magnesium stearate and micronized silica gel of the prescription amount are placed in a three-dimensional mixer and mixed for 9 minutes. The uniformly mixed particles are then compressed into tablets using a tableting machine to make trimetazidine hydrochloride tablets.

[0030] Example 3 Trimetazidine Hydrochloride Tablets formula: Trimetazidine hydrochloride 20g, lactose 60g, microcrystalline cellulose 35g, croscarmellose sodium cellulose 5g, hydroxypropyl methylcellulose 4g, magnesium stearate 1.3g, micronized silica gel 0.7g, β-cyclodextrin 2.2g, eugenol diglucoside 1.1g, dithiothreitol 0.55g.

[0031] Preparation process: (1) Special treatment of core components: Take the prescribed amount of trimetazidine hydrochloride, β-cyclodextrin, eugenol diglucoside and dithiothreitol, pulverize them separately and pass them through a 100-mesh sieve. Add the pulverized β-cyclodextrin to 6 times its weight of purified water and place it in a 65°C water bath and stir until completely dissolved to prepare a saturated β-cyclodextrin solution for later use.

[0032] (2) Inclusion and dispersion treatment: The sieved trimetazidine hydrochloride, eugenol diglucoside and dithiothreitol were mixed evenly and slowly added to the above β-cyclodextrin saturated solution. The mixture was kept in a 65°C water bath and stirred for 35 min at a constant temperature, with the stirring rate controlled at 250 r / min during the process, to form a dispersion. The dispersion was placed in a vacuum drying oven and dried at 55°C to constant weight. After being removed, it was pulverized and passed through a 120-mesh sieve to obtain the inclusion micro powder.

[0033] (3) Mixing treatment: Place the above-mentioned encapsulated micro powder, lactose, microcrystalline cellulose and croscarmellose sodium in a three-dimensional mixer and mix for 18 minutes. After mixing evenly, add 5% aqueous solution of hydroxypropyl methylcellulose prepared according to the prescription amount and stir to make a suitable soft material.

[0034] (4) Granulation and drying: The soft material is granulated through an 18-mesh sieve. The wet granules are placed in a fluidized bed dryer and dried at 50°C until the moisture content of the granules is 2.0%-3.0%. After drying, the granules are sized by passing them through a 16-mesh sieve.

[0035] (5) Total mixing and tableting: The granulated particles, magnesium stearate and micronized silica gel of the prescription amount are placed in a three-dimensional mixer and mixed for 9 minutes. The uniformly mixed particles are then compressed into tablets using a tableting machine to make trimetazidine hydrochloride tablets.

[0036] Example 4 Trimetazidine Hydrochloride Tablets formula: Trimetazidine hydrochloride 20g, lactose 30g, microcrystalline cellulose 10g, croscarmellose sodium cellulose 2g, hydroxypropyl methylcellulose 1g, magnesium stearate 0.3g, micronized silica gel 0.2g, β-cyclodextrin 1g, eugenol diglucoside 0.5g, dithiothreitol 0.3g.

[0037] Preparation process: (1) Special treatment of core components: Take the prescribed amount of trimetazidine hydrochloride, β-cyclodextrin, eugenol diglucoside and dithiothreitol, pulverize them separately and pass them through a 100-mesh sieve. Add the pulverized β-cyclodextrin to 5 times its weight of purified water, place it in a 60℃ water bath and stir until completely dissolved to prepare a saturated β-cyclodextrin solution for later use.

[0038] (2) Inclusion and dispersion treatment: The sieved trimetazidine hydrochloride, eugenol diglucoside and dithiothreitol were mixed evenly and slowly added to the above β-cyclodextrin saturated solution. The mixture was kept in a 60°C water bath and stirred for 30 min at a constant temperature, with the stirring rate controlled at 200 r / min during the process, to form a dispersion. The dispersion was placed in a vacuum drying oven and dried at 50°C to constant weight. After being removed, it was pulverized and passed through a 120-mesh sieve to obtain the inclusion micro powder.

[0039] (3) Mixing treatment: Place the above-mentioned encapsulated micro powder, lactose, microcrystalline cellulose and croscarmellose sodium in a three-dimensional mixer and mix for 15 minutes. After mixing evenly, add 4% aqueous solution of hydroxypropyl methylcellulose prepared in the prescription amount and stir to make a suitable soft material.

[0040] (4) Granulation and drying: The soft material is granulated through an 18-mesh sieve. The wet granules are placed in a fluidized bed dryer and dried at 45°C until the moisture content of the granules is 2.0%-3.0%. After drying, the granules are sized by passing them through a 16-mesh sieve.

[0041] (5) Total mixing and tableting: The granulated particles, magnesium stearate and micronized silica gel of the prescription amount are placed in a three-dimensional mixer and mixed for 8 minutes. The uniformly mixed particles are then compressed into tablets using a tableting machine to make trimetazidine hydrochloride tablets.

[0042] Example 5 Trimetazidine Hydrochloride Tablets formula: Trimetazidine hydrochloride 20g, lactose 100g, microcrystalline cellulose 60g, croscarmellose sodium cellulose 6g, hydroxypropyl methylcellulose 5g, magnesium stearate 1.8g, micronized silica gel 1.0g, β-cyclodextrin 3g, eugenol diglucoside 1.5g, dithiothreitol 0.8g.

[0043] Preparation process: (1) Special treatment of core components: Take the prescribed amount of trimetazidine hydrochloride, β-cyclodextrin, eugenol diglucoside and dithiothreitol, pulverize them separately and pass them through a 100-mesh sieve. Add the pulverized β-cyclodextrin to 8 times its weight of purified water, place it in a 70℃ water bath and stir until completely dissolved to prepare a saturated β-cyclodextrin solution for later use.

[0044] (2) Inclusion and dispersion treatment: The sieved trimetazidine hydrochloride, eugenol diglucoside and dithiothreitol were mixed evenly and slowly added to the above β-cyclodextrin saturated solution. The mixture was kept in a 70°C water bath and stirred for 40 min at a constant temperature, with the stirring rate controlled at 300 r / min during the process, to form a dispersion. The dispersion was placed in a vacuum drying oven and dried at 60°C under vacuum until constant weight. After removal, it was pulverized and passed through a 120-mesh sieve to obtain the inclusion micro powder.

[0045] (3) Mixing treatment: Place the above-mentioned encapsulated micro powder, lactose, microcrystalline cellulose and croscarmellose sodium in a three-dimensional mixer and mix for 20 minutes. After mixing evenly, add 6% aqueous solution of hydroxypropyl methylcellulose prepared according to the prescription amount and stir to make a suitable soft material.

[0046] (4) Granulation and drying: The soft material is granulated through an 18-mesh sieve. The wet granules are placed in a fluidized bed dryer and dried at 55°C until the moisture content of the granules is 2.0%-3.0%. After drying, the granules are sized by passing them through a 16-mesh sieve.

[0047] (5) Total mixing and tableting: The granulated particles, magnesium stearate and micronized silica gel of the prescription amount are placed in a three-dimensional mixer and mixed for 10 minutes. The uniformly mixed particles are taken and tableted using a tableting machine to make trimetazidine hydrochloride tablets.

[0048] Comparative Example 1: Trimetazidine Hydrochloride Tablets formula: Trimetazidine hydrochloride 20g, lactose 50g, microcrystalline cellulose 25g, croscarmellose sodium 4g, hydroxypropyl methylcellulose 3g, magnesium stearate 1.2g, micronized silica gel 0.6g, eugenol diglucoside 1.0g, dithiothreitol 0.5g.

[0049] Preparation process: (1) Pretreatment: Take the prescribed amount of trimetazidine hydrochloride, eugenol diglucoside and dithiothreitol, pulverize them and pass them through a 100-mesh sieve.

[0050] (2) Dispersion treatment: Mix trimetazidine hydrochloride, eugenol diglucoside and dithiothreitol after sieving evenly, add them to the aqueous solution, keep the water bath at 65℃ and stir for 35 min at a constant temperature, during which the stirring rate is controlled at 250 r / min to form a dispersion; place the dispersion in a vacuum drying oven and dry it at 55℃ to constant weight, take it out and pulverize it, pass it through a 120 mesh sieve to obtain micro powder.

[0051] (3) Mixing treatment: Place the above-mentioned micro powder with the prescribed amount of lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose in a three-dimensional mixer and mix for 18 minutes. After mixing evenly, add the prescribed amount of hydroxypropyl methylcellulose in a 5% aqueous solution and stir to prepare a suitable soft material.

[0052] (4) Granulation and drying: The soft material is granulated through an 18-mesh sieve. The wet granules are placed in a fluidized bed dryer and dried at 50°C until the moisture content of the granules is 2.0%-3.0%. After drying, the granules are sized by passing them through a 16-mesh sieve.

[0053] (5) Total mixing and tableting: The granulated particles, magnesium stearate and micronized silica gel of the prescription amount are placed in a three-dimensional mixer and mixed for 9 minutes. The uniformly mixed particles are then compressed into tablets using a tableting machine to make trimetazidine hydrochloride tablets.

[0054] Comparative Example 2: Trimetazidine Hydrochloride Tablets formula: Trimetazidine hydrochloride 20g, lactose 50g, microcrystalline cellulose 25g, croscarmellose sodium 4g, hydroxypropyl methylcellulose 3g, magnesium stearate 1.2g, micronized silica gel 0.6g, β-cyclodextrin 2g, dithiothreitol 0.5g.

[0055] Preparation process: (1) Special treatment of core components: Take the prescribed amount of trimetazidine hydrochloride, β-cyclodextrin and dithiothreitol, pulverize them separately and pass them through a 100-mesh sieve. Add the pulverized β-cyclodextrin to 6 times its weight of purified water, place it in a 65℃ water bath and stir until completely dissolved to prepare a saturated β-cyclodextrin solution for later use.

[0056] (2) Inclusion and dispersion treatment: The sieved trimetazidine hydrochloride and dithiothreitol were mixed evenly and slowly added to the above β-cyclodextrin saturated solution. The mixture was kept in a 65°C water bath and stirred for 35 min at a constant temperature, with the stirring rate controlled at 250 r / min during the process, to form a dispersion. The dispersion was placed in a vacuum drying oven and dried at 55°C under vacuum until constant weight. After removal, it was pulverized and passed through a 120-mesh sieve to obtain the inclusion micro powder.

[0057] (3) Mixing treatment: Place the above-mentioned encapsulated micro powder, lactose, microcrystalline cellulose and croscarmellose sodium in a three-dimensional mixer and mix for 18 minutes. After mixing evenly, add 5% aqueous solution of hydroxypropyl methylcellulose prepared according to the prescription amount and stir to make a suitable soft material.

[0058] (4) Granulation and drying: The soft material is granulated through an 18-mesh sieve. The wet granules are placed in a fluidized bed dryer and dried at 50°C until the moisture content of the granules is 2.0%-3.0%. After drying, the granules are sized by passing them through a 16-mesh sieve.

[0059] (5) Total mixing and tableting: The granulated particles, magnesium stearate and micronized silica gel of the prescription amount are placed in a three-dimensional mixer and mixed for 9 minutes. The uniformly mixed particles are then compressed into tablets using a tableting machine to make trimetazidine hydrochloride tablets.

[0060] Comparative Example 3: Trimetazidine Hydrochloride Tablets formula: Trimetazidine hydrochloride 20g, lactose 50g, microcrystalline cellulose 25g, croscarmellose sodium 4g, hydroxypropyl methylcellulose 3g, magnesium stearate 1.2g, micronized silica gel 0.6g, β-cyclodextrin 2g, eugenol diglucoside 1.0g.

[0061] Preparation process: (1) Special treatment of core components: Take the prescribed amount of trimetazidine hydrochloride, β-cyclodextrin, and eugenol diglucoside, pulverize them separately and pass them through a 100-mesh sieve. Add the pulverized β-cyclodextrin to 6 times its weight of purified water, place it in a 65°C water bath and stir until completely dissolved to prepare a saturated β-cyclodextrin solution for later use.

[0062] (2) Inclusion and dispersion treatment: The sieved trimetazidine hydrochloride and eugenol diglucoside were mixed evenly and slowly added to the above β-cyclodextrin saturated solution. The mixture was kept in a 65°C water bath and stirred for 35 min at a constant temperature, with the stirring rate controlled at 250 r / min during the process, to form a dispersion. The dispersion was placed in a vacuum drying oven and dried at 55°C under vacuum until constant weight. After removal, it was pulverized and passed through a 120-mesh sieve to obtain the inclusion micro powder.

[0063] (3) Mixing treatment: Place the above-mentioned encapsulated micro powder, lactose, microcrystalline cellulose and croscarmellose sodium in a three-dimensional mixer and mix for 18 minutes. After mixing evenly, add 5% aqueous solution of hydroxypropyl methylcellulose prepared according to the prescription amount and stir to make a suitable soft material.

[0064] (4) Granulation and drying: The soft material is granulated through an 18-mesh sieve. The wet granules are placed in a fluidized bed dryer and dried at 50°C until the moisture content of the granules is 2.0%-3.0%. After drying, the granules are sized by passing them through a 16-mesh sieve.

[0065] (5) Total mixing and tableting: The granulated particles, magnesium stearate and micronized silica gel of the prescription amount are placed in a three-dimensional mixer and mixed for 9 minutes. The uniformly mixed particles are then compressed into tablets using a tableting machine to make trimetazidine hydrochloride tablets.

[0066] Comparative Example 4: Trimetazidine Hydrochloride Tablets formula: Trimetazidine hydrochloride 20g, lactose 50g, microcrystalline cellulose 25g, croscarmellose sodium 4g, hydroxypropyl methylcellulose 3g, magnesium stearate 1.2g, micronized silica gel 0.6g, β-cyclodextrin 2g, pinoresinol diglucoside 1.0g, dithiothreitol 0.5g.

[0067] Preparation process: (1) Special treatment of core components: Take the prescribed amount of trimetazidine hydrochloride, β-cyclodextrin, pinoresinol diglucoside and dithiothreitol, pulverize them separately and pass them through a 100-mesh sieve. Add the pulverized β-cyclodextrin to 6 times its weight of purified water, place it in a 65℃ water bath and stir until completely dissolved to prepare a saturated β-cyclodextrin solution for later use.

[0068] (2) Inclusion and dispersion treatment: The sieved trimetazidine hydrochloride, pinoresinol diglucoside and dithiothreitol were mixed evenly and slowly added to the above β-cyclodextrin saturated solution. The mixture was kept in a 65°C water bath and stirred for 35 min at a constant temperature, with the stirring rate controlled at 250 r / min during the process, to form a dispersion. The dispersion was placed in a vacuum drying oven and dried at 55°C under vacuum until constant weight. After being removed, it was pulverized and passed through a 120-mesh sieve to obtain the inclusion micro powder.

[0069] (3) Mixing treatment: Place the above-mentioned encapsulated micro powder, lactose, microcrystalline cellulose and croscarmellose sodium in a three-dimensional mixer and mix for 18 minutes. After mixing evenly, add 5% aqueous solution of hydroxypropyl methylcellulose prepared according to the prescription amount and stir to make a suitable soft material.

[0070] (4) Granulation and drying: The soft material is granulated through an 18-mesh sieve. The wet granules are placed in a fluidized bed dryer and dried at 50°C until the moisture content of the granules is 2.0%-3.0%. After drying, the granules are sized by passing them through a 16-mesh sieve.

[0071] (5) Total mixing and tableting: The granulated particles, magnesium stearate and micronized silica gel of the prescription amount are placed in a three-dimensional mixer and mixed for 9 minutes. The uniformly mixed particles are then compressed into tablets using a tableting machine to make trimetazidine hydrochloride tablets.

[0072] Comparative Example 5: Trimetazidine Hydrochloride Tablets formula: Trimetazidine hydrochloride 20g, lactose 50g, microcrystalline cellulose 25g, croscarmellose sodium cellulose 4g, hydroxypropyl methylcellulose 3g, magnesium stearate 1.2g, micronized silica gel 0.6g, β-cyclodextrin 2g, trehalose 1.0g, dithiothreitol 0.5g.

[0073] Preparation process: (1) Special treatment of core components: Take the prescribed amount of trimetazidine hydrochloride, β-cyclodextrin, trehalose and dithiothreitol, pulverize them separately and pass them through a 100-mesh sieve. Add the pulverized β-cyclodextrin to 6 times its weight of purified water, place it in a 65℃ water bath and stir until completely dissolved to prepare a saturated β-cyclodextrin solution for later use.

[0074] (2) Inclusion and dispersion treatment: The sieved trimetazidine hydrochloride, trehalose and dithiothreitol were mixed evenly and slowly added to the above β-cyclodextrin saturated solution. The mixture was kept in a 65°C water bath and stirred for 35 min at a constant temperature. During this period, the stirring rate was controlled at 250 r / min to form a dispersion. The dispersion was placed in a vacuum drying oven and dried at 55°C under vacuum until constant weight. After being taken out, it was pulverized and passed through a 120-mesh sieve to obtain the inclusion micro powder.

[0075] (3) Mixing treatment: Place the above-mentioned encapsulated micro powder, lactose, microcrystalline cellulose and croscarmellose sodium in a three-dimensional mixer and mix for 18 minutes. After mixing evenly, add 5% aqueous solution of hydroxypropyl methylcellulose prepared according to the prescription amount and stir to make a suitable soft material.

[0076] (4) Granulation and drying: The soft material is granulated through an 18-mesh sieve. The wet granules are placed in a fluidized bed dryer and dried at 50°C until the moisture content of the granules is 2.0%-3.0%. After drying, the granules are sized by passing them through a 16-mesh sieve.

[0077] (5) Total mixing and tableting: The granulated particles, magnesium stearate and micronized silica gel of the prescription amount are placed in a three-dimensional mixer and mixed for 9 minutes. The uniformly mixed particles are then compressed into tablets using a tableting machine to make trimetazidine hydrochloride tablets.

[0078] Comparative Example 6: Trimetazidine Hydrochloride Tablets formula: Trimetazidine hydrochloride 20g, lactose 50g, microcrystalline cellulose 25g, croscarmellose sodium 4g, hydroxypropyl methylcellulose 3g, magnesium stearate 1.2g, micronized silica gel 0.6g, β-cyclodextrin 2g, eugenol diglucoside 1.0g, L-cysteine ​​0.5g.

[0079] Preparation process: (1) Special treatment of core components: Take the prescribed amount of trimetazidine hydrochloride, β-cyclodextrin, eugenol diglucoside and L-cysteine, pulverize them separately and pass them through a 100-mesh sieve. Add the pulverized β-cyclodextrin to 6 times its weight of purified water, place it in a 65℃ water bath and stir until completely dissolved to prepare a saturated β-cyclodextrin solution for later use.

[0080] (2) Inclusion and dispersion treatment: The sieved trimetazidine hydrochloride, eugenol diglucoside and L-cysteine ​​were mixed evenly and slowly added to the above β-cyclodextrin saturated solution. The mixture was kept in a 65°C water bath and stirred for 35 min at a constant temperature, with the stirring rate controlled at 250 r / min during the process, to form a dispersion. The dispersion was placed in a vacuum drying oven and dried at 55°C to constant weight. After being removed, it was pulverized and passed through a 120-mesh sieve to obtain the inclusion micro powder.

[0081] (3) Mixing treatment: Place the above-mentioned encapsulated micro powder, lactose, microcrystalline cellulose and croscarmellose sodium in a three-dimensional mixer and mix for 18 minutes. After mixing evenly, add 5% aqueous solution of hydroxypropyl methylcellulose prepared according to the prescription amount and stir to make a suitable soft material.

[0082] (4) Granulation and drying: The soft material is granulated through an 18-mesh sieve. The wet granules are placed in a fluidized bed dryer and dried at 50°C until the moisture content of the granules is 2.0%-3.0%. After drying, the granules are sized by passing them through a 16-mesh sieve.

[0083] (5) Total mixing and tableting: The granulated particles, magnesium stearate and micronized silica gel of the prescription amount are placed in a three-dimensional mixer and mixed for 9 minutes. The uniformly mixed particles are then compressed into tablets using a tableting machine to make trimetazidine hydrochloride tablets.

[0084] Comparative Example 7: Trimetazidine Hydrochloride Tablets formula: Trimetazidine hydrochloride 20g, lactose 50g, microcrystalline cellulose 25g, croscarmellose sodium 4g, hydroxypropyl methylcellulose 3g, magnesium stearate 1.2g, micronized silica gel 0.6g, β-cyclodextrin 2g, eugenol diglucoside 1.0g, dithioerythritol 0.5g.

[0085] Preparation process: (1) Special treatment of core components: Take the prescribed amount of trimetazidine hydrochloride, β-cyclodextrin, eugenol diglucoside and dithioerythritol, pulverize them separately and pass them through a 100-mesh sieve. Add the pulverized β-cyclodextrin to 6 times its weight of purified water, place it in a 65℃ water bath and stir until completely dissolved to prepare a saturated β-cyclodextrin solution for later use.

[0086] (2) Inclusion and dispersion treatment: The sieved trimetazidine hydrochloride, eugenol diglucoside and dithioerythritol were mixed evenly and slowly added to the above β-cyclodextrin saturated solution. The mixture was kept in a 65°C water bath and stirred for 35 min at a constant temperature, with the stirring rate controlled at 250 r / min during the process, to form a dispersion. The dispersion was placed in a vacuum drying oven and dried at 55°C to constant weight. After being removed, it was pulverized and passed through a 120-mesh sieve to obtain the inclusion micro powder.

[0087] (3) Mixing treatment: Place the above-mentioned encapsulated micro powder, lactose, microcrystalline cellulose and croscarmellose sodium in a three-dimensional mixer and mix for 18 minutes. After mixing evenly, add 5% aqueous solution of hydroxypropyl methylcellulose prepared according to the prescription amount and stir to make a suitable soft material.

[0088] (4) Granulation and drying: The soft material is granulated through an 18-mesh sieve. The wet granules are placed in a fluidized bed dryer and dried at 50°C until the moisture content of the granules is 2.0%-3.0%. After drying, the granules are sized by passing them through a 16-mesh sieve.

[0089] (5) Total mixing and tableting: The granulated particles, magnesium stearate and micronized silica gel of the prescription amount are placed in a three-dimensional mixer and mixed for 9 minutes. The uniformly mixed particles are then compressed into tablets using a tableting machine to make trimetazidine hydrochloride tablets.

[0090] Comparative Example 8: Trimetazidine Hydrochloride Tablets formula: Trimetazidine hydrochloride 20g, lactose 50g, microcrystalline cellulose 25g, croscarmellose sodium 4g, hydroxypropyl methylcellulose 3g, magnesium stearate 1.2g, micronized silica gel 0.6g, β-cyclodextrin 2g, eugenol diglucoside 1.0g, dithiothreitol 0.5g.

[0091] Preparation process: (1) Special treatment of core components: Take the prescribed amount of trimetazidine hydrochloride, β-cyclodextrin, eugenol diglucoside and dithiothreitol, pulverize them separately and pass them through a 100-mesh sieve for later use.

[0092] (2) Inclusion and dispersion treatment: The sieved trimetazidine hydrochloride, eugenol diglucoside, dithiothreitol and β-cyclodextrin are mixed, pulverized and passed through a 120-mesh sieve to obtain micro powder.

[0093] (3) Mixing treatment: Place the above-mentioned micro powder with the prescribed amount of lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose in a three-dimensional mixer and mix for 18 minutes. After mixing evenly, add the prescribed amount of hydroxypropyl methylcellulose in a 5% aqueous solution and stir to prepare a suitable soft material.

[0094] (4) Granulation and drying: The soft material is granulated through an 18-mesh sieve. The wet granules are placed in a fluidized bed dryer and dried at 50°C until the moisture content of the granules is 2.0%-3.0%. After drying, the granules are sized by passing them through a 16-mesh sieve.

[0095] (5) Total mixing and tableting: The granulated particles, magnesium stearate and micronized silica gel of the prescription amount are placed in a three-dimensional mixer and mixed for 9 minutes. The uniformly mixed particles are then compressed into tablets using a tableting machine to make trimetazidine hydrochloride tablets.

[0096] Commercially available preparation: Trimetazidine Hydrochloride Tablets (Vancelin).

[0097] Trimetazidine Hydrochloride Tablets Dissolution Dissolution and release were determined according to the method for determination of dissolution and release in the Chinese Pharmacopoeia (General Chapter 0931, Method II). Dissolution conditions: 900 ml of 0.05 mol / L hydrochloric acid solution was used as the dissolution medium, and the rotation speed was 50 rpm. The procedure was followed, and samples were taken after 30 minutes. Test solution: 10 ml of the dissolution solution was taken, filtered, and the filtrate was collected. Reference solution: An appropriate amount of trimetazidine hydrochloride reference standard was accurately weighed, dissolved in the dissolution medium, and quantitatively diluted to prepare a solution containing approximately 20 μg per ml. The solution was shaken well. Assay: The absorbance of the test solution and the reference solution was measured separately at a wavelength of 234 nm using ultraviolet-visible spectrophotometry (General Chapter 0401), and the amount dissolved per tablet was calculated.

[0098] Table 1 Dissolution of Trimetazidine Hydrochloride Tablets Table 1 shows that the trimetazidine hydrochloride tablets of the present invention exhibit significant advantages in dissolution performance. The trimetazidine hydrochloride tablets in Examples 1-5 showed better dissolution efficiencies at all sampling time points than all comparative examples 1-8 and commercially available formulations, reaching over 90% at 30 minutes. Overall, they demonstrated rapid dissolution and a steady improvement, ensuring rapid and complete drug release in vivo. The inclusion effect of β-cyclodextrin, the synergistic effect of eugenol diglucoside and dithiothreitol, and the standardized inclusion process design in the formulation of the present invention are key factors in improving drug dissolution efficiency.

[0099] Trimetazidine Hydrochloride Tablets Content Uniformity The content per tablet, calculated based on the content determination, should comply with the regulations (General Rule 0941). The content should be determined according to the High Performance Liquid Chromatography (HPLC) method in the Chinese Pharmacopoeia (General Rule 0512). Test solution: Take 10 tablets of this product, place them in separate 100ml volumetric flasks, add an appropriate amount of water, sonicate to dissolve trimetazidine hydrochloride, dilute to the mark with water, shake well, centrifuge (at 5000 rpm) for 15 minutes, and collect the supernatant. Reference solution: Accurately weigh an appropriate amount of trimetazidine hydrochloride reference standard, dissolve in water, and quantitatively dilute to prepare a solution containing approximately 0.2mg per ml. Chromatographic conditions: Use octadecylsilane-bonded silica gel as the stationary phase; use mobile phase A-mobile phase B (80:20) as the mobile phase (as described in the Related Substances section); detection wavelength is 231nm; injection volume is 10μl. System suitability requirements: The theoretical plate number, calculated based on the trimetazidine peak, should be no less than 3000, and the resolution between the trimetazidine peak and adjacent impurity peaks should meet the requirements. Assay method: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms.

[0100] Table 2 Uniformity of Trimetazidine Hydrochloride Tablet Content Table 2 shows that the trimetazidine hydrochloride tablets prepared in Examples 1-5 of this invention exhibit excellent uniformity in content. Trimetazidine hydrochloride is evenly distributed in the tablets, providing a stable and reliable dosage guarantee for clinical use. The scientific proportions of the excipients in the formulation of this invention, as well as the importance of the complete process design of "core component inclusion-dispersion-mixing," effectively avoid the problems of drug particle aggregation or uneven distribution.

Claims

1. A trimetazidine hydrochloride tablet, characterized in that, The formula consists of the following components by weight: 20 parts trimetazidine hydrochloride, 30-100 parts lactose, 10-60 parts microcrystalline cellulose, 2-6 parts croscarmellose sodium, 1-5 parts hydroxypropyl methylcellulose, 0.3-1.8 parts magnesium stearate, 0.2-1.0 parts micronized silica, 1-3 parts β-cyclodextrin, 0.5-1.5 parts eugenol diglucoside, and 0.3-0.8 parts dithiothreitol.

2. The trimetazidine hydrochloride tablets according to claim 1, characterized in that, The formula, by weight, is as follows: 20 parts trimetazidine hydrochloride, 40-60 parts lactose, 20-35 parts microcrystalline cellulose, 3-5 parts croscarmellose sodium, 2-4 parts hydroxypropyl methylcellulose, 1.0-1.3 parts magnesium stearate, 0.5-0.7 parts micronized silica gel, 1.8-2.2 parts β-cyclodextrin, 0.9-1.1 parts eugenol diglucoside, and 0.45-0.55 parts dithiothreitol.

3. The trimetazidine hydrochloride tablets according to claim 1, characterized in that, By weight, the ingredients are: 50 parts lactose, 25 parts microcrystalline cellulose, 4 parts croscarmellose sodium cellulose, 3 parts hydroxypropyl methylcellulose, 1.2 parts magnesium stearate, 0.6 parts micronized silica gel, 2 parts β-cyclodextrin, 1.0 part eugenol diglucoside, and 0.5 parts dithiothreitol.

4. A preparation process for trimetazidine hydrochloride tablets as described in any one of claims 1 to 3, characterized in that, Includes the following steps: (1) Pretreatment of core components: Trimetazidine hydrochloride, β-cyclodextrin, eugenol diglucoside and dithiothreitol were pulverized and sieved respectively; β-cyclodextrin was added to 5 to 8 times its weight of purified water and stirred and dissolved in a water bath at 60 to 70°C to prepare a saturated solution of β-cyclodextrin. (2) Inclusion and dispersion: Trimetazidine hydrochloride, eugenol diglucoside and dithiothreitol are mixed evenly, and the above β-cyclodextrin saturated solution is added. The mixture is stirred to form a dispersion, vacuum dried, pulverized and sieved to obtain the inclusion micro powder. (3) Mixing to prepare a soft material: Mix the encapsulated micro powder with lactose, microcrystalline cellulose, and croscarmellose sodium, add an aqueous solution of hydroxypropyl methylcellulose, and stir to prepare a soft material; (4) Granulation and drying: granulation, drying, and sizing; (5) Total mixing and tableting: Mix the granules with magnesium stearate and micronized silica gel, and then compress the mixture into tablets.

5. The preparation process according to claim 4, characterized in that, The stirring conditions in step (2) are: 60~70℃, 200~300r / min constant temperature stirring for 30~40min.

6. The preparation process according to claim 4, characterized in that, The hydroxypropyl methylcellulose aqueous solution has a mass fraction of 4% to 6%.

7. The preparation method according to claim 4, characterized in that, In step (2), the vacuum drying temperature is 50~60℃ and the drying time is 4~6h.

8. The preparation method according to claim 4, characterized in that, In step (4), the drying temperature is 45~55℃ and the drying time is 2~3h.

9. The trimetazidine hydrochloride tablets according to any one of claims 1 to 3, characterized in that, The trimetazidine hydrochloride tablets have a dissolution rate of not less than 90% in 0.05 mol / L hydrochloric acid solution for 30 minutes.

10. The trimetazidine hydrochloride tablets according to any one of claims 1 to 3, characterized in that, The relative standard deviation (RSD) of the uniformity of the content of trimetazidine hydrochloride tablets is ≤0.5%.

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