Sustained release tablet containing empagliflozin and metformin hydrochloride and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a sustained release preparation containing empagliflozin and metformin hydrochloride and a preparation method of the sustained release preparation. The method comprises the following steps: (1) preparing a sustained-release bulk drug, a sustained-release skeleton auxiliary material A, a sustained-release skeleton auxiliary material B, a lubricant and purified water into a tablet core; (2) preparing a coating spacer fluid from a film-forming agent, a thickening agent, a plasticizer, an opacifying agent and purified water; (3) preparing a coating liquid medicine from the quick-release bulk drug, a film-forming agent, a thickening agent, a plasticizer, an opacifying agent and purified water; (4) preparing a sealing solution from a film-forming agent, a plasticizer, an opacifying agent, a color lake and purified water; and (5) sequentially treating the tablet core with a spacer fluid, a coating liquid medicine and a sealing fluid to prepare the empagliflozin and metformin hydrochloride sustained release tablet. Under the condition of ensuring similar dissolution curves, polyoxyethylene is replaced, and the risk of high-temperature burst release of a large amount of metformin hydrochloride is avoided; and the coating process and the process flow are simplified, and the material consumption is reduced.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a sustained-release preparation containing empagliflozin and metformin hydrochloride and a preparation method thereof. Background Art

[0002] Empagliflozin, also known as empagliflozin, was approved by the FDA for marketing on August 1, 2014. It is a sodium glucose co-transporter type 2 (SGLT-2) inhibitor jointly developed by Boehringer Ingelheim and Eli Lilly. Under physiological conditions, the kidneys filter and reabsorb glucose into the circulatory system to maintain blood sugar balance in the body. Glucose enters the blood through the lumen of the renal tubules, which must be coordinated with glucose co-transporters. The SGLT-2 inhibitor empagliflozin blocks the reabsorption of glucose by the proximal tubules, reduces the reabsorption of glucose by the kidneys, and increases the excretion of glucose in the urine, thereby reducing plasma glucose levels. Moreover, the hypoglycemic effect does not depend on β-cell function and is not affected by insulin resistance. Empagliflozin has good efficacy, low risk of hypoglycemia, and weight loss effects. It is an effective orally administered drug with good market prospects.

[0003] Metformin Hydrochloride (Metformin for short) belongs to the biguanide hypoglycemic drug, which can reduce liver glucose production, inhibit intestinal absorption of glucose, and increase the uptake and utilization of glucose by peripheral tissues. It can improve insulin sensitivity by increasing the uptake and utilization of peripheral sugar. It does not cause insulin resistance caused by increased serum insulin concentration caused by sulfonylurea and insulin treatment, and has a direct or indirect effect on insulin resistance. In addition, metformin can reduce the incidence of cardiovascular disease and mortality in patients with type 2 diabetes accompanied by obesity. It also has effects other than hypoglycemia, such as reducing weight and improving blood lipids, and has therefore been widely used.

[0004] In 2015, Boehringer Ingelheim launched Synjardy (combination of empagliflozin and metformin immediate-release tablets) which also received FDA approval. However, the preparation faces the problem of inconvenience in taking and the possible increase in the risk of hypoglycemia in actual use. To solve this problem, the combination of empagliflozin and metformin extended-release tablets came into being. This combination ensures rapid onset of drug effect while achieving sustained action, maintaining a stable blood drug concentration, effectively reducing the incidence of adverse reactions, and significantly improving patients' medication compliance.

[0005] In view of the superiority of empagliflozin and metformin sustained-release tablets over immediate-release tablets, in addition to the original developer Boehringer Ingelheim, many institutions are engaged in the research of sustained-release tablets. For example, the invention name of patent CN113616624A is "An empagliflozin metformin sustained-release preparation and its preparation method". The invention specifically relates to an empagliflozin metformin sustained-release preparation and its preparation method, wherein the empagliflozin micro-pellet core is the immediate-release part, and the metformin hydrochloride micro-pellet core is the sustained-release part. The two parts of the pellet core are coated with an isolation layer respectively, and then the two parts of the drug-loaded micro-pellets are mixed and filled into capsules. The preparation method of the empagliflozin metformin sustained-release preparation is also disclosed: ① Extrusion spheronization process is used to make metformin hydrochloride sustained-release pellet cores; ② Extrusion spheronization process is used to make empagliflozin immediate-release pellet cores; ③ Separately coat the two drug-loaded pellet cores with an isolation layer; ④ Fill the capsules with the two drug-loaded micro-pellets according to a certain ratio. In this compound preparation, metformin has a large specification, and it needs to be packaged into pellets, which requires the addition of more auxiliary materials. The pellet coating process is demanding, the process steps are complicated, and the scale-up process brings defects such as low production efficiency, energy consumption, and low yield.

[0006] Patent CN107432869A discloses a double-layer tablet containing metformin hydrochloride and empagliflozin and a preparation method thereof, wherein metformin hydrochloride is first prepared into sustained-release granules, and then empagliflozin is prepared into immediate-release granules, which are compressed using a double-layer tablet press, and finally film-coated. The process is complicated, and since a double-layer tablet press is required for tablet compression, relatively high requirements are placed on the fluidity and compressibility of the granules. Since the tablet core is a double-layer tablet, cracks will be formed at the joints of the double-layer tablet during the coating process, and slow coating is required, which places high requirements on the setting of the coating process and parameters, leading to an increase in the overall production cost.

[0007] Patent CN107432869A discloses a controlled-release tablet of metformin hydrochloride and empagliflozin, characterized in that: the controlled-release tablets include 300-600 parts of metformin hydrochloride as the main drug component, 10-12 parts of empagliflozin, 18-22 parts of sodium carboxymethylcellulose, 11-16 parts of lactose, 8-12 parts of corn starch, 40-80 parts of a 4.4-5% hydroxypropyl methylcellulose aqueous solution, 3-8 parts of magnesium stearate, 80-90 parts of 95% ethanol by mass, 5-7 parts of cellulose acetate, 1.6-1.8 parts of polyvinylpyrrolidone K30, and 0.8-0.9 parts of polyethylene glycol 6000, according to weight parts. The patent indicates that there are many filling excipients, and the process has high requirements for solution preparation, which is not conducive to operation during the production scale-up process, has a high storage risk, and has poor scale-up operability.

[0008] From the original FDA approval information and patent US2022105043A1, it can be seen that the original empagliflozin and metformin sustained-release tablets contain polyethylene oxide in their cores, which has a low melting point. Using polyethylene oxide as the skeleton of the sustained-release tablet core makes the sustained-release tablet core have the risk of high-temperature burst release, and the cost is high and the availability is poor (currently there is only one company with CDE registration A status, and it is imported). At the same time, the original tablet coating has a total of four layers of coating and printing, which is a relatively complicated process, and the coating time cost and material cost are high.

[0009] Therefore, it is very necessary to provide a sustained-release tablet core that does not release suddenly at high temperature, has good stability, low cost, and good availability, and a coating method that has a simple coating process and saves coating time and material costs. Summary of the invention

[0010] The technical solution of the present invention aims to solve the technical problems of the existing disclosed technical solutions, such as burst release at high temperature, low stability, high cost, and difficulty in obtaining, and provides a sustained-release tablet containing empagliflozin and metformin hydrochloride and a preparation method thereof.

[0011] The main purposes of the present invention are: 1. By optimizing both the process and the ingredients, the sustained-release tablet core has good release stability without using polyethylene oxide, and will not cause a sudden release under high temperature; 2. Simplifying the coating process, saving the process and reducing the material cost.

[0012] To achieve the above object, the present invention adopts the following technical scheme: a method for preparing a sustained-release tablet containing empagliflozin and metformin hydrochloride, the method comprising: (1) Weighing the sustained-release API, sustained-release matrix excipient A, sustained-release matrix excipient B, lubricant and purified water in proportion, wet granulating the sustained-release API, sustained-release matrix excipient A and purified water, drying the whole granules, adding the sustained-release matrix excipient B and the lubricant, mixing, and tableting to prepare tablet cores; (2) Mix the film-forming agent, thickener, plasticizer, sunscreen and purified water in proportion to prepare a coating isolation solution; (3) Mix the immediate-release API, film-forming agent, thickener, plasticizer, opacifier and purified water in appropriate proportions to prepare a coating solution; (4) Mix the film-forming agent, plasticizer, sunscreen, lake and purified water in proportion to prepare a sealing liquid; (5) The tablet cores are treated with an isolating liquid, a coating solution and a sealing liquid in sequence to prepare sustained-release tablets containing empagliflozin and metformin hydrochloride.

[0013] As a preference, The sustained-release API in step (1) is metformin hydrochloride; The sustained-release matrix excipient A in step (1) is hypromellose; The sustained-release matrix excipient B in step (1) is hydroxypropyl cellulose; The lubricant in step (1) is magnesium stearate; The purified water in step (1) is distilled water and / or deionized water; The sustained-release API, sustained-release matrix excipient A, sustained-release matrix excipient B, lubricant and purified water in step (1) are weighed in a mass ratio of 125: (26-30): (26-30): (1-2): (20-26).

[0014] As a preference, The wet granulation in step (1) is performed by adding the sustained-release API, sustained-release matrix excipient A and purified water and stirring and granulating for 3 to 5 minutes at a temperature of 15 to 25°C; The drying in step (1) is performed at a temperature of 60°C for 0.5 to 1 h; The granulation in step (1) uses a sieve with an aperture of 0.6 to 1.2 mm and a granulation rotation speed of 400 to 600 rpm; The tablet pressing in step (1) uses a pressure of 15 to 25 kN and controls the tablet core hardness to be 150 to 200 N.

[0015] As a preference, The film-forming agent in step (2) is hypromellose; The thickener in step (2) is polydextrose; The plasticizer in step (2) is polyethylene glycol; The sunscreen in step (2) is titanium dioxide; The purified water in step (2) is distilled water and / or deionized water; Step (2) The film-forming agent, thickener, plasticizer, sunscreen and purified water are uniformly mixed in a mass ratio of 1: (0.6-1): (0.3-0.5): (0.01-0.02): (10-14); The step (2) of preparing the isolation liquid is to stir for 1 h in an environment with a temperature of 15 to 25 °C.

[0016] As a preference, The rapid-release raw material in step (3) is empagliflozin; The film-forming agent in step (3) is hypromellose; The thickener in step (3) is polydextrose; The plasticizer in step (3) is polyethylene glycol; The sunscreen in step (3) is titanium dioxide; The purified water in step (3) is distilled water and / or deionized water; The quick-release raw material, film-forming agent, thickener, plasticizer, sunscreen and purified water in step (3) are uniformly mixed in a mass ratio of 3:1: (0.6-1): (0.3-0.5): (0.01-0.02): (10-14); The step (3) of preparing the coating solution is to stir for 1 hour in an environment with a temperature of 15 to 25 °C.

[0017] As a preference, The film-forming agent of step (4) is hypromellose; The plasticizer in step (4) is polyethylene glycol; The sunscreen in step (4) is titanium dioxide; The color lake in step (4) is a light green color lake; The purified water in step (4) is distilled water and / or deionized water; Step (4) The film-forming agent, plasticizer, sunscreen, lake and purified water are uniformly mixed in a mass ratio of 1: (0.3-0.7): (0.01-0.02): (0.02-0.04): (10-14); The sealing liquid is prepared in step (4) by stirring for 1 h in an environment with a temperature of 15 to 25 °C.

[0018] As a preference, Step (5) the tablet core is sequentially isolated, coated and sealed; The isolation is performed in an environment where the fan frequency is 1000-1300 Hz, the atomization pressure is 0.10-0.20 MPa, the isolation liquid is supplied at a liquid supply rate of 5-15 rpm, and the temperature is 38-42° C. to prepare the isolation layer of the core; The coating is performed in an environment where the fan frequency is 1000-1300 Hz, the atomization pressure is 0.10-0.20 MPa, the coating liquid is supplied at a liquid supply rate of 5-15 rpm, and the temperature is 33-37°C. The sealing treatment is to perform sealing coating in an environment with a fan frequency of 1000-1300 Hz, an atomization pressure of 0.10-0.20 MPa, a sealing liquid supply rate of 5-15 rpm, and a temperature of 38-42° C. to prepare a sealing layer of the tablet core.

[0019] The core of the technical solution of the present invention is to replace the polyethylene oxide in the original tablet core auxiliary material, use the sustained-release skeleton material with high melting point, low cost and good availability - hydroxypropyl cellulose, and simplify the coating process to three-layer coating. This can effectively avoid the sudden release of metformin hydrochloride, the sustained-release raw material of the tablet core, under high temperature conditions. It also reduces the consumption of coating materials and shortens the coating process time.

[0020] The hydrophilic gel skeleton materials hydroxypropyl methylcellulose and hydroxypropyl cellulose involved in this technical solution act as a barrier layer for drugs, preventing water from penetrating into the interior of metformin and preventing metformin from diffusing outwards. Its drug release mechanism is the synergistic effect of drug metformin diffusion and skeleton dissolution. Hydrophilic gel skeleton sustained-release preparations have the characteristics of small drug release variation, high safety, low human irritation, wide application range and mature technology.

[0021] In the technical solution of the present invention, the empagliflozin and metformin hydrochloride sustained-release tablets adopt a three-layer coating design, the first layer is an isolation layer with hydroxypropyl methylcellulose, polydextrose and polyethylene glycol as the main components, which aims to isolate the core sustained-release drug metformin hydrochloride from the external environment; the second layer is mainly composed of empagliflozin and assisted by other pharmaceutical excipients, forming an empagliflozin rapid-release coating layer to accelerate the release rate of the coating drug empagliflozin; the third layer is a sealing layer with hydroxypropyl methylcellulose and polyethylene glycol as the main components, which further enhances the integrity of the coating and the stability of the drug.

[0022] The present invention is beneficial in that: (1) the present invention avoids the use of polyoxyethylene. Since polyoxyethylene has a low melting point, the sustained-release tablet core has the risk of high-temperature burst release, and polyoxyethylene has high cost and poor availability. The present invention replaces polyoxyethylene with other materials and achieves effective preparation, which greatly reduces the hidden danger of high-temperature burst release of the sustained-release tablet core, so that the tablet core has good and stable release ability, reduces costs, and ensures the supply of key auxiliary materials. (2) The present invention greatly simplifies the coating process, and the use of three layers of coating effectively realizes the final encapsulation preparation of the sustained-release tablet, ensuring that the obtained sustained-release tablet has good stability while reducing the coating process, greatly reducing time and material costs. DETAILED DESCRIPTION

[0023] The present invention is further described in detail below in conjunction with specific embodiments. Those of ordinary skill in the art will be able to implement the present invention based on these descriptions. In addition, the embodiments of the present invention involved in the following description are generally only embodiments of a part of the present invention, rather than all embodiments. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work should fall within the scope of protection of the present invention.

[0024] Unless otherwise specified, the raw materials used in the examples of the present invention are all commercially available or available to those skilled in the art; unless otherwise specified, the methods used in the examples of the present invention are all methods known to those skilled in the art.

[0025] Example 1 A method for preparing a sustained-release tablet comprising empagliflozin and metformin hydrochloride, The method comprises: (1) The metformin hydrochloride, hydroxypropyl methylcellulose, hydroxypropyl cellulose, magnesium stearate and purified water are weighed in a mass ratio of 125:26:26:1:20. At 20°C, metformin hydrochloride, hydroxypropyl methylcellulose and purified water are added and stirred for granulation for 5 min for wet granulation. At 60°C, the wet granules are dried for 0.5 h. The sieve aperture used is 0.6 mm and the granulation speed is 400 rpm. After granulation, hydroxypropyl cellulose and magnesium stearate are added to the granules for mixing. A pressure of 15 kN is used to control the tablet core hardness to 150 N for tableting to prepare a tablet core; (2) Mix hydroxypropyl methylcellulose, polydextrose, polyethylene glycol, titanium dioxide and distilled water in a mass ratio of 1:0.6:0.3:0.01:10 and stir at 20 °C for 1 h to prepare an isolation solution; (3) Empagliflozin, hypromellose, polydextrose, polyethylene glycol, titanium dioxide, and distilled water were mixed evenly in a mass ratio of 3:1:0.6:0.3:0.01:10 and stirred at 20°C for 1 h to prepare a coating solution; (4) Mix hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, light green lake, and distilled water in a mass ratio of 1:0.3:0.01:0.02:10 and stir at 20 °C for 1 h to prepare a sealing liquid; (5) The tablet cores were subjected to isolation coating in an environment with a fan frequency of 1000 Hz, an atomization pressure of 0.10 MPa, an isolation liquid supplied at a liquid supply rate of 5 rpm, and a temperature of 38°C to prepare an isolation layer for the tablet cores; the tablet cores with an isolation layer were coated with an empagliflozin upper drug layer in an environment with a fan frequency of 1000 Hz, an atomization pressure of 0.10 MPa, a coating upper drug solution supplied at a liquid supply rate of 5 rpm, and a temperature of 33°C to prepare an empagliflozin immediate-release coating layer for the tablet cores; the tablet cores with an empagliflozin immediate-release coating layer were sealed in an environment with a fan frequency of 1000 Hz, an atomization pressure of 0.10 MPa, a sealing liquid supplied at a liquid supply rate of 5 rpm, and a temperature of 38°C to prepare a sealing layer for the tablet cores, thereby obtaining sustained-release tablets containing empagliflozin and metformin hydrochloride.

[0026] Dissolution tests were performed on samples of the sustained-release tablets containing empagliflozin and metformin hydrochloride prepared in Example 1 at 0 day and at 60° C. for 30 days, and the characterization results are as follows.

[0027] Dissolution test of 0-day samples: Referring to the provisions of the "Guidelines for Sustained-Release, Controlled-Release and Delayed-Release Preparations", the basket method was used in an environment with a rotation speed of 100 rpm and a temperature of 37°C, in deionized water, hydrochloric acid solution with a pH value of 1.2, acetate buffer with a pH value of 4.5, and phosphate buffer with a pH value of 6.8. Samples were taken at different time points, and high performance liquid chromatography was used to detect the dissolution of metformin hydrochloride in each medium. The results are as follows.

[0028]

[0029] 0-day sample ethanol dose dumping test: The sustained-release tablets prepared in the example were subjected to a dumping test in accordance with the provisions of the "Technical Guidelines for Pharmaceutical Research of Ethanol Dose Dumping Tests for Oral Modified-Release Preparations of Generic Chemical Drugs" at a speed of 100 rpm, a temperature of 37°C, and a medium of pH 1.2 ethanol solution. Samples were taken at different time points, and the solubility of metformin hydrochloride in each medium was detected by high performance liquid chromatography. The results are as follows.

[0030]

[0031] Influencing factors 60 ℃ 30 days sample dissolution test: The sustained-release tablets prepared in the example were tested in an environment with a rotation speed of 100 rpm and a temperature of 37 ℃ with reference to the "Technical Guidelines for Stability Studies of Chemical Drugs (APIs and Preparations)". Samples were taken at different time points, and the dissolution of metformin hydrochloride in each medium was tested using high performance liquid chromatography. The results are as follows.

[0032]

[0033] Influencing factors 60 ℃ 30-day sample ethanol dose dumping test: The 60 ℃ 30-day sample of the sustained-release tablets prepared in the example was placed in an environment with a rotation speed of 100 rpm, a temperature of 37 ℃, and a medium of pH 1.2 ethanol solution for dumping test according to the provisions of the "Technical Guidelines for Pharmaceutical Research on Ethanol Dose Dumping Test of Oral Modified Release Preparations of Chemical Generic Drugs". Samples were taken at different time points, and the solubility of metformin hydrochloride in each medium was detected by high performance liquid chromatography. The results are as follows.

[0034]

[0035] Example 2 A method for preparing a sustained-release tablet comprising empagliflozin and metformin hydrochloride, The method comprises: (1) The metformin hydrochloride, hydroxypropyl methylcellulose, hydroxypropyl cellulose, magnesium stearate and purified water are weighed in a mass ratio of 125:28:28:1.5:22. At 23°C, metformin hydrochloride, hydroxypropyl methylcellulose and purified water are added and stirred for granulation for 4 min for wet granulation. At 60°C, the wet granules are dried for 0.75 h. The sieve aperture used is 0.8 mm and the granulation speed is 500 rpm. After granulation, hydroxypropyl cellulose and magnesium stearate are added to the granules for mixing. A pressure of 20 kN is used to control the tablet core hardness to 180 N for tableting to prepare a tablet core. (2) Mix hydroxypropyl methylcellulose, polydextrose, polyethylene glycol, titanium dioxide and distilled water in a mass ratio of 1:0.8:0.4:0.01:12 and stir at 23 °C for 1 h to prepare an isolation solution; (3) Empagliflozin, hypromellose, polydextrose, polyethylene glycol, titanium dioxide, and distilled water were mixed uniformly in a mass ratio of 3:1:0.8:0.4:0.01:12 and stirred at 23°C for 1 h to prepare a coating solution; (4) Mix hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, light green lake, and distilled water in a mass ratio of 1:0.4:0.01:0.03:12, and stir at 23 °C for 1 h to prepare a sealing liquid; (5) The tablet cores were isolated and coated in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.15 MPa, an isolation liquid supplied at a liquid supply rate of 7 rpm, and a temperature of 40°C to prepare an isolation layer for the tablet core; the tablet cores with an isolation layer were coated with an empagliflozin upper drug layer in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.15 MPa, a coating liquid supplied at a liquid supply rate of 7 rpm, and a temperature of 35°C to prepare an empagliflozin immediate-release coating layer for the tablet core; the tablet cores with an empagliflozin immediate-release coating layer were seal-coated in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.15 MPa, a sealing liquid supplied at a liquid supply rate of 7 rpm, and a temperature of 40°C to prepare a sealing layer for the tablet core, thereby obtaining sustained-release tablets containing empagliflozin and metformin hydrochloride.

[0036] Dissolution tests were performed on samples of the sustained-release tablets containing empagliflozin and metformin hydrochloride prepared in Example 2 at 0 days and at 60° C. for 30 days, and the results are as follows.

[0037] Dissolution test of 0-day samples: Referring to the Guiding Principles for Sustained-Release, Controlled-Release and Delayed-Release Preparations, the basket method was used in an environment with a rotation speed of 100 rpm and a temperature of 37°C, using deionized water, hydrochloric acid solution with a pH value of 1.2, acetate buffer with a pH value of 4.5, and phosphate buffer with a pH value of 6.8. Samples were taken at different time points, and high performance liquid chromatography was used to detect the solubility of metformin hydrochloride and empagliflozin in each medium. The results are as follows.

[0038]

[0039]

[0040] 0-day sample ethanol dose dumping test: The sustained-release tablets prepared in the example were subjected to a dumping test in an environment of 100 rpm, 37 °C, and pH 1.2 ethanol solution as the medium, with reference to the "Technical Guidelines for Pharmaceutical Research on Ethanol Dose Dumping Tests of Oral Modified-Release Preparations of Generic Chemical Drugs". Samples were taken at different time points, and the solubility of metformin hydrochloride in each medium was detected by high performance liquid chromatography. The results are as follows.

[0041]

[0042] Influencing factors 60 ℃ 30-day sample dissolution test: The 60 ℃ 30-day sample of the sustained-release tablets prepared in the example was tested in an environment of a rotation speed of 100 rpm, a temperature of 37 ℃, and a pH 6.8 phosphate buffer solution with reference to the "Technical Guidelines for Stability Studies of Chemical Drugs (APIs and Preparations)". Samples were taken at different time points, and high performance liquid chromatography was used to detect the solubility of metformin hydrochloride and empagliflozin in each medium. The results are as follows.

[0043]

[0044]

[0045] Influencing factors 60 ℃ 30-day sample ethanol dose dumping test: The 60 ℃ 30-day sample of the sustained-release tablets prepared in the example was placed in an environment with a rotation speed of 100 rpm, a temperature of 37 ℃, and a medium of pH 1.2 ethanol solution for dumping test according to the provisions of the "Technical Guidelines for Pharmaceutical Research on Ethanol Dose Dumping Test of Oral Modified Release Preparations of Chemical Generic Drugs". Samples were taken at different time points, and the solubility of metformin hydrochloride in each medium was detected by high performance liquid chromatography. The results are as follows.

[0046]

[0047] Example 3 A method for preparing a sustained-release tablet comprising empagliflozin and metformin hydrochloride, The method comprises: (1) The metformin hydrochloride, hydroxypropyl methylcellulose, hydroxypropyl cellulose, magnesium stearate and purified water are weighed in a mass ratio of 125:29:29:2:24. At 24°C, metformin hydrochloride, hydroxypropyl methylcellulose and purified water are added and stirred for granulation for 5 min for wet granulation. At 60°C, the wet granules are dried for 0.75 h. The sieve aperture used is 1.0 mm and the granulation speed is 500 rpm. After granulation, hydroxypropyl cellulose and magnesium stearate are added to the granules for mixing. A pressure of 20 kN is used to control the tablet core hardness to 180 N for tableting to prepare a tablet core. (2) Mix hydroxypropyl methylcellulose, polydextrose, polyethylene glycol, titanium dioxide and distilled water in a mass ratio of 1:0.8:0.4:0.02:13 and stir at 24 °C for 1 h to prepare an isolation solution; (3) Mix empagliflozin, hypromellose, polydextrose, polyethylene glycol, titanium dioxide and distilled water in a mass ratio of 3:1:0.8:0.4:0.02:13 and stir at 24 °C for 1 h to prepare a coating solution; (4) Mix hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, light green lake, and distilled water in a mass ratio of 1:0.5:0.02:0.03:13, and stir at 24 °C for 1 h to prepare a sealing liquid; (5) The tablet cores were isolated and coated in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.10 MPa, an isolation liquid supplied at a rate of 8 rpm, and a temperature of 40°C to prepare an isolation layer for the tablet cores; the tablet cores with an isolation layer were coated with an empagliflozin upper drug layer in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.10 MPa, a coating liquid supplied at a rate of 8 rpm, and a temperature of 35°C to prepare an empagliflozin immediate-release coating layer for the tablet cores; the tablet cores with an empagliflozin immediate-release coating layer were seal-coated in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.10 MPa, a sealing liquid supplied at a rate of 8 rpm, and a temperature of 40°C to prepare a sealing layer for the tablet cores, and sustained-release tablets containing empagliflozin and metformin hydrochloride were obtained.

[0048] Dissolution tests were performed on the 0-day and 60° C. 30-day samples of the sustained-release tablets containing empagliflozin and metformin hydrochloride prepared in Example 3, and the results are as follows.

[0049] Dissolution test of 0-day samples: Referring to the Guiding Principles for Sustained-Release, Controlled-Release and Delayed-Release Preparations, the basket method was used at a speed of 100 rpm and a temperature of 37°C in deionized water, hydrochloric acid solution with a pH value of 1.2, acetate buffer with a pH value of 4.5, and phosphate buffer with a pH value of 6.8. Samples were taken at different time points, and high performance liquid chromatography was used to detect the dissolution of metformin hydrochloride in each medium. The results are as follows.

[0050]

[0051] 0-day sample ethanol dose dumping test: The sustained-release tablets prepared in the example were subjected to a dumping test in accordance with the provisions of the "Technical Guidelines for Pharmaceutical Research of Ethanol Dose Dumping Tests for Oral Modified-Release Preparations of Generic Chemical Drugs" at a speed of 100 rpm, a temperature of 37°C, and a medium of pH 1.2 ethanol solution. Samples were taken at different time points, and the solubility of metformin hydrochloride in each medium was detected by high performance liquid chromatography. The results are as follows.

[0052]

[0053] Influencing factors 60 ℃ 30-day sample dissolution test: The 60 ℃ 30-day sample of the sustained-release tablets prepared in the example was tested in an environment with a rotation speed of 100 rpm and a temperature of 37 ℃ with reference to the "Technical Guidelines for Stability Studies of Chemical Drugs (APIs and Preparations)". Samples were taken at different time points, and the dissolution of metformin hydrochloride in each medium was detected by high performance liquid chromatography. The results are as follows.

[0054]

[0055] Influencing factors 60 ℃ 30-day sample ethanol dose dumping test: The 60 ℃ 30-day sample of the sustained-release tablets prepared in the example was placed in an environment with a rotation speed of 100 rpm, a temperature of 37 ℃, and a medium of pH 1.2 ethanol solution for dumping test according to the provisions of the "Technical Guidelines for Pharmaceutical Research on Ethanol Dose Dumping Test of Oral Modified Release Preparations of Chemical Generic Drugs". Samples were taken at different time points, and the solubility of metformin hydrochloride in each medium was detected by high performance liquid chromatography. The results are as follows.

[0056]

[0057] Example 4 A method for preparing a sustained-release tablet comprising empagliflozin and metformin hydrochloride, The method comprises: (1) The metformin hydrochloride, hydroxypropyl methylcellulose, hydroxypropyl cellulose, magnesium stearate and purified water are weighed in a mass ratio of 125:30:30:2:26. At 25°C, metformin hydrochloride, hydroxypropyl methylcellulose and purified water are added and stirred for granulation for 5 min for wet granulation. At 60°C, the wet granules are dried for 1 h. The sieve aperture used is 1.2 mm and the granulation speed is 600 rpm. After granulation, hydroxypropyl cellulose and magnesium stearate are added to the granules for mixing. A pressure of 25 kN is used to control the tablet core hardness to 200 N for tableting to prepare a tablet core. (2) Mix hydroxypropyl methylcellulose, polydextrose, polyethylene glycol, titanium dioxide and distilled water in a mass ratio of 1:1:0.5:0.02:14 and stir at 25 °C for 1 h to prepare an isolation solution; (3) Empagliflozin, hypromellose, polydextrose, polyethylene glycol, titanium dioxide, and distilled water were mixed evenly in a mass ratio of 3:1:1:0.5:0.02:14 and stirred at 25°C for 1 h to prepare a coating solution; (4) Mix hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, light green lake, and distilled water in a mass ratio of 1:0.7:0.02:0.04:14 and stir at 25 °C for 1 h to prepare a sealing liquid; (5) The tablet cores were isolated and coated in an environment with a fan frequency of 1300 Hz, an atomization pressure of 0.20 MPa, an isolation liquid supplied at a rate of 15 rpm, and a temperature of 42°C to prepare an isolation layer for the tablet cores; the tablet cores with an isolation layer were coated with an empagliflozin upper drug layer in an environment with a fan frequency of 1300 Hz, an atomization pressure of 0.20 MPa, a coating liquid supplied at a rate of 15 rpm, and a temperature of 37°C to prepare an empagliflozin immediate-release coating layer for the tablet cores; the tablet cores with an empagliflozin immediate-release coating layer were seal-coated in an environment with a fan frequency of 130 Hz, an atomization pressure of 0.20 MPa, a sealing liquid supplied at a rate of 15 rpm, and a temperature of 42°C to prepare a sealing layer for the tablet cores, thereby obtaining sustained-release tablets containing empagliflozin and metformin hydrochloride.

[0058] Dissolution tests were performed on samples of the sustained-release tablets containing empagliflozin and metformin hydrochloride prepared in Example 4 at 0 day and 60° C. for 30 days, and the results are as follows.

[0059] Dissolution test of 0-day samples: Referring to the Guiding Principles for Sustained-Release, Controlled-Release and Delayed-Release Preparations, the basket method was used at a speed of 100 rpm and a temperature of 37°C in deionized water, hydrochloric acid solution with a pH value of 1.2, acetate buffer with a pH value of 4.5, and phosphate buffer with a pH value of 6.8. Samples were taken at different time points, and high performance liquid chromatography was used to detect the dissolution of metformin hydrochloride in each medium. The results are as follows.

[0060]

[0061] 0-day sample ethanol dose dumping test: The sustained-release tablets prepared in the example were subjected to a dumping test in accordance with the provisions of the "Technical Guidelines for Pharmaceutical Research of Ethanol Dose Dumping Tests for Oral Modified-Release Preparations of Generic Chemical Drugs" at a speed of 100 rpm, a temperature of 37°C, and a medium of pH 1.2 ethanol solution. Samples were taken at different time points, and the solubility of metformin hydrochloride in each medium was detected by high performance liquid chromatography. The results are as follows.

[0062]

[0063] Influencing factors 60 ° C 30-day dissolution test: The 60 ° C 30-day sample of the sustained-release tablets prepared in the example was tested at a speed of 100 rpm and a temperature of 37 ° C in accordance with the "Technical Guidelines for Stability Studies of Chemical Drugs (APIs and Preparations)". Samples were taken at different time points, and the dissolution of metformin hydrochloride in each medium was detected by high performance liquid chromatography. The results are as follows.

[0064]

[0065] Influencing factors 60 ℃ 30-day sample ethanol dose dumping test: The 60 ℃ 30-day sample of the sustained-release tablets prepared in the example was placed in an environment with a rotation speed of 100 rpm, a temperature of 37 ℃, and a medium of pH 1.2 ethanol solution for dumping test according to the provisions of the "Technical Guidelines for Pharmaceutical Research on Ethanol Dose Dumping Test of Oral Modified Release Preparations of Chemical Generic Drugs". Samples were taken at different time points, and the solubility of metformin hydrochloride in each medium was detected by high performance liquid chromatography. The results are as follows.

[0066]

[0067] Comparative Example 1 A method for preparing a sustained-release tablet containing empagliflozin and metformin hydrochloride, wherein the specific preparation method is the same as that of Example 2. Only in the granulation of the tablet core, another sustained-release skeleton, namely, polyethylene oxide, is added at a higher ratio, and hydroxypropyl cellulose is removed to prepare empagliflozin metformin sustained-release tablets, that is, polyethylene oxide is used to replace hydroxypropyl cellulose to simulate the original formulation for comparison. The dissolution curve of metformin hydrochloride in Comparative Example 1 is investigated, and the dissolution curve of metformin hydrochloride in Comparative Example 1 is compared with that in Example 2. The specific operation is as follows: A method for preparing a sustained-release tablet comprising empagliflozin and metformin hydrochloride, The method comprises: (1) Weigh metformin hydrochloride, hydroxypropyl methylcellulose, polyoxyethylene, magnesium stearate and distilled water in a mass ratio of 125:28:28:1:22. Add metformin hydrochloride, hydroxypropyl methylcellulose, polyoxyethylene and distilled water and stir for 4 min at 23 °C for wet granulation. Dry at 60 °C for 0.75 h. Use a sieve with a mesh size of 0.8 mm and a granulation speed of 500 rpm for granulation. Only magnesium stearate is added and mixed. Use a pressure of 20 kN and control the tablet core hardness to 180 N for tableting to prepare tablet cores. (2) Mix hydroxypropyl methylcellulose, polydextrose, polyethylene glycol, titanium dioxide and distilled water in a mass ratio of 1:0.8:0.4:0.01:12 and stir at 23 °C for 1 h to prepare an isolation solution; (3) Empagliflozin, hypromellose, polydextrose, polyethylene glycol, titanium dioxide, and distilled water were mixed uniformly in a mass ratio of 3:1:0.8:0.4:0.01:12 and stirred at 23°C for 1 h to prepare a coating solution; (4) Mix hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, light green lake, and distilled water in a mass ratio of 1:0.4:0.01:0.03:12, and stir at 23 °C for 1 h to prepare a sealing liquid; (5) The tablet cores were isolated and coated in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.15 MPa, an isolation liquid supplied at a liquid supply rate of 7 rpm, and a temperature of 40°C to prepare an isolation layer for the tablet core; the tablet cores with an isolation layer were coated with an empagliflozin upper drug layer in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.15 MPa, a coating liquid supplied at a liquid supply rate of 7 rpm, and a temperature of 35°C to prepare an empagliflozin immediate-release coating layer for the tablet core; the tablet cores with an empagliflozin immediate-release coating layer were seal-coated in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.15 MPa, a sealing liquid supplied at a liquid supply rate of 7 rpm, and a temperature of 40°C to prepare a sealing layer for the tablet core, thereby obtaining sustained-release tablets containing empagliflozin and metformin hydrochloride.

[0068] The sustained-release tablets containing empagliflozin and metformin hydrochloride prepared in Comparative Example 1 were subjected to dissolution testing in the same manner as in Example 2, and the results are as follows.

[0069]

[0070] The ethanol dose dumping test for the day 0 sample showed the following results.

[0071]

[0072] The dissolution rate of the samples influencing the factors at 60 ℃ for 30 days was tested, and the results are as follows.

[0073]

[0074] The influencing factors were tested by ethanol dosage dumping on samples at 60 °C for 30 days, and the results are as follows.

[0075]

[0076] Comparing the dissolution test results of the comparative example 1 with those of the example 2, it can be seen that after a higher proportion of polyethylene oxide is added to the tablet core, the release rate of metformin hydrochloride is too fast under high temperature conditions.

[0077] Comparative Example 2 A method for preparing a sustained-release tablet containing empagliflozin and metformin hydrochloride, wherein the specific preparation method is the same as that in Example 2. Compared with Comparative Example 1, only the proportion of polyethylene oxide in the tablet core is reduced to prepare empagliflozin metformin hydrochloride sustained-release tablets. The dissolution curve of metformin hydrochloride in Comparative Example 2 is investigated, and the dissolution curve of metformin hydrochloride in Comparative Example 2 is compared with that in Example 2. The specific operation is as follows: A method for preparing a sustained-release tablet comprising empagliflozin and metformin hydrochloride, The method comprises: (1) Metformin hydrochloride, hydroxypropyl methylcellulose, polyoxyethylene, magnesium stearate and distilled water were mixed uniformly in a mass ratio of 125:42:14:1:22. Metformin hydrochloride, hydroxypropyl methylcellulose, polyoxyethylene and distilled water were added and stirred for 4 min at 23°C for wet granulation. The mixture was dried at 60°C for 0.75 h. The sieve size was 0.8 mm and the granulation speed was 500 rpm. Only magnesium stearate was added and mixed. The tablet core was compressed at a pressure of 20 kN and the tablet core hardness was controlled to be 180 N to prepare the tablet core. (2) Mix hydroxypropyl methylcellulose, polydextrose, polyethylene glycol, titanium dioxide and distilled water in a mass ratio of 1:0.8:0.4:0.01:12 and stir at 23 °C for 1 h to prepare an isolation solution; (3) Empagliflozin, hypromellose, polydextrose, polyethylene glycol, titanium dioxide, and distilled water were mixed uniformly in a mass ratio of 3:1:0.8:0.4:0.01:12 and stirred at 23°C for 1 h to prepare a coating solution; (4) Mix hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, light green lake, and distilled water in a mass ratio of 1:0.4:0.01:0.03:12, and stir at 23 °C for 1 h to prepare a sealing liquid; (5) The tablet cores were isolated and coated in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.15 MPa, an isolation liquid supplied at a liquid supply rate of 7 rpm, and a temperature of 40°C to prepare an isolation layer for the tablet core; the tablet cores with an isolation layer were coated with an empagliflozin upper drug layer in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.15 MPa, a coating liquid supplied at a liquid supply rate of 7 rpm, and a temperature of 35°C to prepare an empagliflozin immediate-release coating layer for the tablet core; the tablet cores with an empagliflozin immediate-release coating layer were seal-coated in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.15 MPa, a sealing liquid supplied at a liquid supply rate of 7 rpm, and a temperature of 40°C to prepare a sealing layer for the tablet core, thereby obtaining sustained-release tablets containing empagliflozin and metformin hydrochloride.

[0078] The sustained-release tablets containing empagliflozin and metformin hydrochloride prepared in Comparative Example 2 were subjected to dissolution testing in the same manner as in Example 2, and the results are as follows.

[0079]

[0080] The ethanol dose dumping test for the day 0 sample showed the following results.

[0081]

[0082] The dissolution rate of the samples influencing the factors at 60 ℃ for 30 days was tested, and the results are as follows.

[0083]

[0084] The influencing factors were tested by ethanol dosage dumping on samples at 60 °C for 30 days, and the results are as follows.

[0085]

[0086] Comparing the dissolution test results of the comparative example 2 with those of the example 2, it can be seen that after the dosage of the core polyethylene oxide is reduced relative to that of the comparative example 1, the release of metformin hydrochloride at 60°C for 30 days is slowed down. However, compared with the example 2, the dissolution rate is still too fast.

[0087] Comparative Example 3 According to the original FDA approval information and the preparation method of metformin hydrochloride sustained-release tablets published in US2022105043A1 in the existing public technical scheme, empagliflozin metformin sustained-release tablets were prepared. The dissolution curves of metformin hydrochloride and empagliflozin in comparative example 3 were investigated, and the dissolution curves of metformin hydrochloride and empagliflozin in comparative example 3 were compared with those in Example 2. The specific operation is as follows: A method for preparing a sustained-release tablet comprising empagliflozin and metformin hydrochloride, The method comprises: (1) The metformin hydrochloride, hydroxypropyl methylcellulose, hydroxypropyl cellulose, magnesium stearate and purified water are weighed in a mass ratio of 125:28:28:1:22. At 23°C, metformin hydrochloride, hydroxypropyl methylcellulose and purified water are added and stirred for granulation for 4 minutes for wet granulation. At 60°C, the wet granules are dried for 0.75 hours. The sieve aperture used is 0.8 mm and the granulation speed is 500 rpm. After granulation, the granules are added with the converted hydroxypropyl cellulose and magnesium stearate for mixing. The tablets are compressed using a pressure of 20 kN and the tablet hardness is controlled to be 180 N to prepare tablet cores. (2) Mix hydroxypropyl methylcellulose, polydextrose, polyethylene glycol, titanium dioxide and distilled water in a mass ratio of 1:0.8:0.4:0.01:12 and stir at 23 °C for 1 h to prepare an isolation solution; (3) Empagliflozin, hypromellose, polydextrose, polyethylene glycol, titanium dioxide, and distilled water were mixed uniformly in a mass ratio of 3:1:0.8:0.4:0.01:12 and stirred at 23°C for 1 h to prepare a coating solution; (4) Mix hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, light green lake, and distilled water in a mass ratio of 1:0.4:0.01:0.03:12, and stir at 23 °C for 1 h to prepare a sealing liquid; (5) Mix hydroxypropyl methylcellulose, carnauba wax and distilled water in a mass ratio of 1.5:0.3:12 and stir at 23 °C for 1 h to prepare a wax layer liquid; (6) Mix medical black ink and isopropyl alcohol in a mass ratio of 1:6 and stir at 23 °C for 1 h to prepare a printing layer liquid; (7) The tablet cores were isolated and coated in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.15 MPa, an isolation liquid supply rate of 7 rpm, and a temperature of 40°C to prepare an isolation layer for the tablet cores; the tablet cores with an isolation layer were coated with empagliflozin in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.15 MPa, a coating liquid supply rate of 7 rpm, and a temperature of 35°C to prepare an empagliflozin immediate-release coating layer for the tablet cores; the tablet cores with an empagliflozin immediate-release coating layer were sealed and coated in an environment with a fan frequency of 1200 Hz, an atomization pressure of 0.15 MPa, a sealing liquid supply rate of 7 rpm, and a temperature of 40°C to prepare a sealing layer for the tablet core; the wax layer liquid was supplied at a fan frequency of 1200 Hz, an atomization pressure of 0.15 MPa, a coating liquid supply rate of 7 rpm, and a temperature of 40 The core tablets with the sealing layer were coated with a wax layer in an environment of ℃; the core tablets with the wax layer were hand-printed with ink using a printing layer liquid and placed in a 45 ℃ oven for drying. Sustained-release tablets containing empagliflozin and metformin hydrochloride were obtained.

[0088] The sustained-release tablets containing empagliflozin and metformin hydrochloride prepared in Comparative Example 3 were subjected to dissolution testing in the same manner as in Example 2, and the results are as follows.

[0089]

[0090]

[0091] Comparing the dissolution data of empagliflozin in comparative example 3 with the data of example 2, it can be seen that the dissolution of comparative example 3 shows a similar trend to that of example 2, and the dissolution values ​​are similar, and the release characteristics of empagliflozin do not show obvious differences between the two. And there is no obvious difference in the release of metformin hydrochloride. This result effectively proves that the three-layer coating technology introduced in the present invention can be regarded as an effective alternative to the published four-layer coating plus printing technology in terms of function, aiming to simplify the coating steps and optimize the overall preparation process to improve process efficiency.

Claims

1. A method for preparing a sustained-release tablet containing empagliflozin and metformin hydrochloride, characterized in that: The method comprises: (1) Weighing the sustained-release API, sustained-release matrix excipient A, sustained-release matrix excipient B, lubricant and purified water in proportion, wet granulating the sustained-release API, sustained-release matrix excipient A and purified water, drying the whole granules, adding the sustained-release matrix excipient B and the lubricant, mixing, and tableting to prepare tablet cores; (2) Mix the film-forming agent, thickener, plasticizer, sunscreen and purified water in proportion to prepare a coating isolation liquid; (3) Mix the immediate-release API, film-forming agent, thickener, plasticizer, opacifier and purified water in appropriate proportions to prepare a coating solution; (4) Mix the film-forming agent, plasticizer, sunscreen, lake and purified water in proportion to prepare a sealing liquid; (5) The tablet cores are treated with an isolating liquid, a coating solution and a sealing liquid in sequence to prepare sustained-release tablets containing empagliflozin and metformin hydrochloride.

2. The method for preparing a sustained-release tablet containing empagliflozin and metformin hydrochloride according to claim 1, characterized in that: The sustained-release API in step (1) is metformin hydrochloride; The sustained-release matrix excipient A in step (1) is hypromellose; The sustained-release matrix excipient B in step (1) is hydroxypropyl cellulose; The lubricant in step (1) is magnesium stearate; The purified water in step (1) is distilled water and / or deionized water; The sustained-release API, sustained-release matrix excipient A, sustained-release matrix excipient B, lubricant and purified water in step (1) are weighed in a mass ratio of 125: (26-30): (26-30): (1-2): (20-26).

3. The method for preparing a sustained-release tablet containing empagliflozin and metformin hydrochloride according to claim 1 or 2, characterized in that: The wet granulation in step (1) is performed by adding the sustained-release API, sustained-release matrix excipient A and purified water and stirring and granulating for 3 to 5 minutes at a temperature of 15 to 25°C; The drying in step (1) is performed at a temperature of 60°C for 0.5 to 1 h; The granulation in step (1) uses a sieve with an aperture of 0.6 to 1.2 mm and a granulation rotation speed of 400 to 600 rpm; The tablet pressing in step (1) uses a pressure of 15 to 25 kN and controls the tablet core hardness to be 150 to 200 N.

4. The method for preparing a sustained-release tablet containing empagliflozin and metformin hydrochloride according to claim 1, characterized in that: The film-forming agent in step (2) is hypromellose; The thickener in step (2) is polydextrose; The plasticizer in step (2) is polyethylene glycol; The sunscreen in step (2) is titanium dioxide; The purified water in step (2) is distilled water and / or deionized water; Step (2) The film-forming agent, thickener, plasticizer, sunscreen and purified water are uniformly mixed in a mass ratio of 1: (0.6-1): (0.3-0.5): (0.01-0.02): (10-14); The step (2) of preparing the isolation liquid is to stir for 1 h in an environment with a temperature of 15 to 25 °C.

5. The method for preparing a sustained-release tablet containing empagliflozin and metformin hydrochloride according to claim 1, characterized in that: The rapid-release raw material in step (3) is empagliflozin; The film-forming agent in step (3) is hypromellose; The thickener in step (3) is polydextrose; The plasticizer in step (3) is polyethylene glycol; The sunscreen in step (3) is titanium dioxide; The purified water in step (3) is distilled water and / or deionized water; The quick-release raw material, film-forming agent, thickener, plasticizer, sunscreen and purified water in step (3) are uniformly mixed in a mass ratio of 3:1: (0.6-1): (0.3-0.5): (0.01-0.02): (10-14); The step (3) of preparing the coating solution is to stir for 1 hour in an environment with a temperature of 15 to 25 °C.

6. The method for preparing a sustained-release tablet containing empagliflozin and metformin hydrochloride according to claim 1, characterized in that: The film-forming agent of step (4) is hypromellose; The plasticizer in step (4) is polyethylene glycol; The sunscreen in step (4) is titanium dioxide; The color lake in step (4) is a light green color lake; The purified water in step (4) is distilled water and / or deionized water; Step (4) The film-forming agent, plasticizer, sunscreen, lake and purified water are uniformly mixed in a mass ratio of 1: (0.3-0.7): (0.01-0.02): (0.02-0.04): (10-14); The sealing liquid is prepared in step (4) by stirring for 1 h in an environment with a temperature of 15 to 25 °C.

7. The method for preparing a sustained-release tablet containing empagliflozin and metformin hydrochloride according to claim 1, characterized in that: Step (5) the core tablets are sequentially isolated, coated with drugs and sealed; The isolation is performed in an environment where the fan frequency is 1000-1300 Hz, the atomization pressure is 0.10-0.20 MPa, the isolation liquid is supplied at a liquid supply rate of 5-15 rpm, and the temperature is 38-42° C. to prepare the isolation layer of the core; The coating is performed in an environment where the fan frequency is 1000-1300 Hz, the atomization pressure is 0.10-0.20 MPa, the coating liquid is supplied at a liquid supply rate of 5-15 rpm, and the temperature is 33-37°C. The sealing treatment is to perform sealing coating in an environment with a fan frequency of 1000-1300 Hz, an atomization pressure of 0.10-0.20 MPa, a sealing liquid supply rate of 5-15 rpm, and a temperature of 38-42° C. to prepare a sealing layer of the tablet core.

8. A sustained-release tablet containing empagliflozin and metformin hydrochloride prepared by the method of any one of claims 1 to 7.

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