Saxagliptin metformin sustained release tablet and preparation method thereof

Abstract

The invention discloses a saxagliptin and metformin sustained-release tablet and a preparation method thereof.The saxagliptin and metformin sustained-release tablet is composed of a core layer, a first coating layer, a second coating layer and a third coating layer, the sustained-release tablet achieves the staged release effect of saxagliptin quick release and metformin hydrochloride slow release through the multi-layer coating design, the hypoglycemic curative effect is synergistically enhanced, the medication frequency is reduced, and the preparation method is simple and convenient. The compliance of a patient is improved, and good clinical application value is achieved.

Description

Technical Field

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

[0002] Diabetes is a common chronic metabolic disease that seriously affects the quality of life and health of patients. Metformin is a first-line drug for the treatment of type 2 diabetes. It inhibits hepatic gluconeogenesis, reduces hepatic glucose output, and increases the uptake and utilization of glucose by peripheral tissues, thereby lowering blood sugar levels. Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that can inhibit DPP-4 enzyme activity, increase the concentration of endogenous glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), promote insulin secretion, and lower blood sugar. Combining the two to form a compound preparation can exert a synergistic hypoglycemic effect and improve the therapeutic effect.

[0003] However, existing metformin and saxagliptin combination preparations present several challenges in terms of dosage form and formulation. For example, conventional tablets cannot achieve sustained drug release, requiring multiple dosing and resulting in poor patient compliance. Furthermore, some sustained-release preparations still require improvement in terms of drug release characteristics and stability, making it difficult to ensure sustained and stable drug effects in the body. Therefore, the development of a saxagliptin and metformin sustained-release tablet with superior formulation and release characteristics is of great clinical significance. Summary of the Invention

[0004] The purpose of the present invention is to provide a saxagliptin metformin sustained-release tablet and a preparation method thereof. By screening and optimizing the prescription, a compound sustained-release tablet is prepared that can achieve slow release of metformin and rapid release of saxagliptin, and has good stability and high bioavailability, thereby improving the therapeutic effect of the drug and the patient's medication compliance.

[0005] A saxagliptin metformin sustained-release tablet comprising a core layer, a first coating layer, a second coating layer and a third coating layer, wherein:

[0006] The core layer is composed of 900-1100 parts of metformin hydrochloride, 4-10 parts of magnesium stearate, 40-60 parts of sodium carboxymethylcellulose and 350-450 parts of hypromellose in parts by weight;

[0007] The first coating layer is formed by a gastric soluble film coating premix solution with a mass percentage concentration of 13-17%, and the coating weight gain on the basis of the plain tablet is 9-11%±0.5%;

[0008] The second coating layer is formed by a solution having a mass percentage concentration of 11-14.5% based on the gastric-soluble film coating premix, wherein the solution comprises 4-6 parts of saxagliptin and 15-25 parts of the gastric-soluble film coating premix;

[0009] The third coating layer is formed by a gastric soluble film coating premix solution with a mass percentage concentration of 13-17%, and the coating weight gain is 2-4%±0.5% based on the plain tablet.

[0010] The coating weight gain of the first coating layer is 10%±0.5% based on the plain tablet; the coating weight gain of the third coating layer is 3%±0.5% based on the plain tablet.

[0011] The magnesium stearate is in the core layer, 4-6 parts of magnesium stearate are mixed and ground with metformin hydrochloride, and the remaining magnesium stearate is added when the dry granules after granulation are mixed with hypromellose.

[0012] The preparation method of the saxagliptin metformin sustained-release tablets comprises the following steps:

[0013] Preparation of the core layer: 900-1100 parts of metformin hydrochloride and 4-6 parts of magnesium stearate are uniformly mixed and then pulverized to obtain a pulverized mixture; the pulverized mixture is mixed with 40-60 parts of sodium carboxymethylcellulose, granulated by a wet method, dried and granulated, and then mixed with 350-450 parts of hypromellose and the remaining magnesium stearate, and tableted to obtain the core layer;

[0014] Preparation of the first coating layer: Prepare a gastric-soluble film coating premix to form a first coating solution with a mass concentration of 13-17%; spray the first coating solution evenly on the surface of the core layer tablets to achieve a coating weight gain of 9-11%, thereby forming the first coating layer;

[0015] Preparation of the second coating layer: 4-6 parts of saxagliptin and 15-25 parts of a gastric-soluble film coating premix are prepared to form a second coating solution having a concentration of 11-14.5% by mass of the gastric-soluble film coating premix; the second coating solution is sprayed on the surface of the first coating layer to form a second coating layer;

[0016] Preparation of the third coating layer: A gastric-soluble third coating solution with a mass percentage concentration of 13-17% is prepared as a film coating premix; the third coating solution is evenly sprayed on the surface of the second coated tablet to make the coating weight gain reach 2-4% to form a third coating layer, thereby preparing saxagliptin metformin sustained-release tablets.

[0017] The solvents of the first coating liquid, the second coating liquid and the third coating liquid are all hydrochloric acid aqueous solution. The mass percentage concentration of the first hydrochloric acid aqueous solution is 0.016%; the mass percentage concentration of the second hydrochloric acid aqueous solution is 1.00%; and the mass percentage concentration of the third hydrochloric acid aqueous solution is 0.10%.

[0018] The present invention achieves the slow release of metformin hydrochloride and prolongs the drug action time by screening the core layer prescription and rationally matching metformin hydrochloride, a disintegrant, a filler and a sustained-release skeleton material.

[0019] The three-layer coating has a unique design. The first coating layer plays an isolation and initial sustained-release role. The second coating layer realizes the rapid release of saxagliptin, forming a synergistic hypoglycemic effect with the sustained-release metformin hydrochloride. The third coating layer further regulates the overall drug release rate, improves the rationality and stability of drug release, and realizes "rapid release + sustained release" synergistic hypoglycemic effect.

[0020] It reduces the number of times patients take medication, improves medication compliance, and is beneficial to blood sugar control in diabetic patients.

[0021] The gastric-soluble film coating premix described in the present invention is sourced from Shanghai Colorcon Coating Technology Co., Ltd. and was purchased on April 14, 2023. DETAILED DESCRIPTION

[0022] Example 1

[0023] Preparation of the core layer: 1000 mg of metformin hydrochloride and 5 mg of magnesium stearate were mixed uniformly and pulverized to obtain a metformin hydrochloride / magnesium stearate pulverized mixture; the metformin hydrochloride / magnesium stearate pulverized mixture was mixed with 50 mg of sodium carboxymethyl cellulose, granulated by a wet method, and dried to obtain dry granules; the granulated dry granules were mixed with 393 mg of hypromellose, and 2 mg of magnesium stearate was added, the mixture was continued to mix, and tableted to obtain the core layer;

[0024] Preparation of the first coating layer: Add hydrochloric acid aqueous solution to a container and start stirring. Slowly add the gastric soluble film coating premix during stirring. Continue stirring after addition to form a first coating solution with a concentration of 15%. Spray the first coating solution evenly onto the surface of the core layer tablets to a coating weight gain of 10.0% ± 0.5% (based on the plain tablets) to form the first coating layer.

[0025] Preparation of the second coating layer: Add 200 g of hydrochloric acid aqueous solution to a container and start stirring. Slowly add 5 g of saxagliptin and 20 g of gastric-soluble film coating premix during stirring. Continue stirring to mix evenly after addition to prepare a second coating solution with a concentration of 10% of the gastric-soluble film coating premix. Spray the second coating solution on the surface of the first coating layer to form a second coating layer.

[0026] Preparation of the third coating layer: Add an appropriate amount of hydrochloric acid aqueous solution to a container and start stirring. Slowly add the gastric-soluble film coating premix during stirring. Continue stirring evenly after addition to form a third coating solution with a concentration of 15%; use a high-efficiency coating machine to evenly spray the coating solution on the surface of the second-layer coated tablets, and the coating weight gain is 3.0% ± 0.5% (based on the plain tablets) to form a third coating layer, thereby obtaining saxagliptin metformin sustained-release tablets.

[0027] Example 2

[0028] Core layer preparation: Core layer: 1000 mg of metformin hydrochloride and 6 mg of magnesium stearate were mixed uniformly and pulverized to obtain a metformin hydrochloride / magnesium stearate pulverized mixture; the metformin hydrochloride / magnesium stearate pulverized mixture was mixed with 50 mg of sodium carboxymethyl cellulose, granulated by wet method, and dried to obtain dry granules; the granulated dry granules were mixed with 400 mg of hypromellose, and 2 mg of magnesium stearate was added, the mixture was continued to mix, and tableted to obtain the core layer;

[0029] Preparation of the first coating layer: Add hydrochloric acid aqueous solution to a container and start stirring. Slowly add the gastric soluble film coating premix during stirring. Continue stirring after addition to form a first coating solution with a concentration of 13%. Spray the first coating solution evenly onto the surface of the core layer tablets to a coating weight gain of 9.0% ± 0.5% (based on the original tablets) to form the first coating layer.

[0030] Preparation of the second coating layer: Add hydrochloric acid aqueous solution to a container and start stirring. Slowly add 5g of saxagliptin and 20g of gastric-soluble film coating premix during stirring. Continue stirring after addition to prepare a second coating solution with a concentration of 10% based on the gastric-soluble film coating premix. Spray the second coating solution on the surface of the first coating layer to form a second coating layer.

[0031] Preparation of the third coating layer: Add appropriate amounts of purified water and hydrochloric acid to a container and start stirring. Slowly add the gastric-soluble film coating premix during stirring. Continue stirring after addition to form a third coating solution with a concentration of 17%. Use a high-efficiency coating machine to evenly spray the coating solution on the surface of the second-layer coated tablets, and the coating weight gain is 4.0% ± 0.5% (based on the plain tablets) to form a third coating layer, thereby obtaining saxagliptin metformin sustained-release tablets.

[0032] Example 3

[0033] Preparation of the core layer: 900 mg of metformin hydrochloride and 4 mg of magnesium stearate were mixed uniformly and pulverized to obtain a metformin hydrochloride / magnesium stearate pulverized mixture; the metformin hydrochloride / magnesium stearate pulverized mixture was mixed with 40 mg of sodium carboxymethyl cellulose, granulated by a wet method, and dried to obtain dry granules; the granulated dry granules were mixed with 350 mg of hypromellose, and 1 mg of magnesium stearate was added, the mixture was continued to mix, and tableting was performed to obtain the core layer;

[0034] Preparation of the first coating layer: Add appropriate amounts of purified water and hydrochloric acid to a container and start stirring. Slowly add the gastric-soluble film coating premix during stirring. Continue stirring after addition to form a first coating solution with a concentration of 14%. Spray the first coating solution evenly onto the surface of the core layer tablets to a coating weight gain of 9.0% ± 0.5% (based on the original tablets) to form the first coating layer.

[0035] Preparation of the second coating layer: Add hydrochloric acid aqueous solution to a container and start stirring. Slowly add 5g of saxagliptin and 20g of gastric-soluble film coating premix during stirring. Continue stirring after addition to prepare a second coating solution with a concentration of 10% based on the gastric-soluble film coating premix. Spray the second coating solution on the surface of the first coating layer to form a second coating layer.

[0036] Preparation of the third coating layer: Add appropriate amounts of purified water and hydrochloric acid to a container and start stirring. Slowly add the gastric-soluble film coating premix during stirring. Continue stirring evenly after addition to form a third coating solution with a concentration of 13%. Use a high-efficiency coating machine to evenly spray the coating solution on the surface of the second-layer coated tablets, and the coating weight gain is 2.0% ± 0.5% (based on the plain tablets) to form a third coating layer, thereby obtaining saxagliptin metformin sustained-release tablets.

[0037] Example 4

[0038] Preparation of the core layer: 1100 mg of metformin hydrochloride and 6 mg of magnesium stearate were mixed uniformly and pulverized to obtain a metformin hydrochloride / magnesium stearate pulverized mixture; the metformin hydrochloride / magnesium stearate pulverized mixture was mixed with 60 mg of sodium carboxymethyl cellulose, granulated by a wet method, and dried to obtain dry granules; the granulated dry granules were mixed with 450 mg of hypromellose, and 2 mg of magnesium stearate was added, the mixture was continued to mix, and tableting was performed to obtain the core layer;

[0039] 2. Coating Layer Preparation

[0040] Preparation of the first coating layer: Add appropriate amounts of purified water and hydrochloric acid to a container and start stirring. Slowly add the gastric-soluble film coating premix during stirring. Continue stirring after addition to form a first coating solution with a concentration of 17%. Spray the first coating solution evenly onto the surface of the core layer tablets to a coating weight gain of 11.0% ± 0.5% (based on the original tablet) to form the first coating layer.

[0041] Preparation of the second coating layer: Add hydrochloric acid aqueous solution to a container and start stirring. Slowly add 5g of saxagliptin and 20g of gastric-soluble film coating premix during stirring. Continue stirring after addition to prepare a second coating solution with a concentration of 10% based on the gastric-soluble film coating premix. Spray the second coating solution on the surface of the first coating layer to form a second coating layer.

[0042] Preparation of the third coating layer: Add appropriate amounts of purified water and hydrochloric acid to a container and start stirring. Slowly add the gastric-soluble film coating premix during stirring. Continue stirring evenly after addition to form a third coating solution with a concentration of 16%. Use a high-efficiency coating machine to evenly spray the coating solution on the surface of the second-layer coated tablets, and the coating weight gain is 3.5.0% ± 0.5% (based on the plain tablets) to form a third coating layer, thereby obtaining saxagliptin metformin sustained-release tablets.

[0043] Example 5

[0044] Preparation of the core layer: 950 mg of metformin hydrochloride and 3 mg of magnesium stearate were mixed uniformly and pulverized to obtain a metformin hydrochloride / magnesium stearate pulverized mixture; the metformin hydrochloride / magnesium stearate pulverized mixture was mixed with 45 mg of sodium carboxymethyl cellulose, granulated by a wet method, and dried to obtain dry granules; the granulated dry granules were mixed with 380 mg of hypromellose, and 2 mg of magnesium stearate was added, the mixture was continued to mix, and tableted to obtain the core layer;

[0045] Preparation of the first coating layer: Add appropriate amounts of purified water and hydrochloric acid to a container and start stirring. Slowly add the gastric-soluble film coating premix during stirring. Continue stirring after addition to form a first coating solution with a concentration of 14%. Spray the first coating solution evenly onto the surface of the core layer tablets to a coating weight gain of 9.5% ± 0.5% (based on the original tablets) to form the first coating layer.

[0046] Preparation of the second coating layer: Add hydrochloric acid aqueous solution to a container and start stirring. Slowly add 5g of saxagliptin and 20g of gastric-soluble film coating premix during stirring. Continue stirring after addition to prepare a second coating solution with a concentration of 10% based on the gastric-soluble film coating premix. Spray the second coating solution on the surface of the first coating layer to form a second coating layer.

[0047] Preparation of the third coating layer: Add appropriate amounts of purified water and hydrochloric acid to a container and start stirring. Slowly add the gastric-soluble film coating premix during stirring. Continue stirring evenly after addition to form a third coating solution with a concentration of 14%. Use a high-efficiency coating machine to evenly spray the coating solution on the surface of the second-layer coated tablets, and the coating weight gain is 2.0% ± 0.5% (based on the plain tablets) to form a third coating layer, thereby obtaining saxagliptin metformin sustained-release tablets.

[0048] The above-mentioned concentrations are all mass percentage concentrations.

[0049] The solvents of the first coating layer, the second coating layer and the third coating layer are all hydrochloric acid aqueous solution. The mass percentage concentration of the first layer of hydrochloric acid aqueous solution is 0.016%; the mass percentage concentration of the second layer of hydrochloric acid aqueous solution is 1.00%; and the mass percentage concentration of the third layer of hydrochloric acid aqueous solution is 0.10%.

[0050] Test Example 1: Screening test data of weight gain formula for the first and third coating layers

[0051] The effects of different coating weight gains of the first coating layer and the third coating layer on the drug release behavior, stability and comprehensive performance of saxagliptin and metformin sustained-release tablets were investigated, the superiority of a 10% weight gain in the first coating layer and a 3% weight gain in the third coating layer were verified, and the optimal coating process parameters were determined.

[0052] 1. Experimental Grouping

[0053] The core layer and the second coating layer formulation and process (Example 1) were fixed, and only the coating weight gain of the first coating layer and the third coating layer was changed. The following experimental groups were set:

[0054] Table 1

[0055]

[0056]

[0057] 2. Test methods

[0058] Tablet preparation: Saxagliptin metformin sustained-release tablets were prepared according to the parameters of each test group. The core layer and the second coating layer process were referred to Example 1. The coating process was carried out in the same high-efficiency coating machine with the inlet air temperature controlled at 45-65°C, the exhaust air temperature at 35-55°C, and the coating pan speed at 10-30 rpm.

[0059] Release determination: The paddle method was used with 900 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium at a rotation speed of 50 rpm. Samples were taken at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 12 h to determine the cumulative release of saxagliptin and metformin hydrochloride.

[0060] Stability study: The prepared tablets were placed under accelerated conditions (temperature 40°C ± 2°C, relative humidity 75% ± 5%) for 6 months. Samples were taken at 0, 1, 2, 3, and 6 months to examine the appearance, tablet weight, content, and release rate.

[0061] Table 2 Release data

[0062]

[0063] The table above shows that in Group 3 (10% weight gain for the first coating layer and 3% weight gain for the third coating layer), the release of saxagliptin reached 80.3% at 0.5 h, meeting the requirement for rapid release. The cumulative release of metformin hydrochloride over 12 h was 90.1%, demonstrating optimal sustained-release efficacy. However, due to the thin coating layer in Groups 1 and 2, early release of metformin hydrochloride was too rapid. The overly thick coating layer in Groups 4 and 5 resulted in delayed drug release, impacting the overall synergistic hypoglycemic effect.

[0064] Table 3 Stability data (release rate change of metformin hydrochloride over 12 hours)

[0065]

[0066] As shown in the table above, Group 3 maintained a generally normal appearance over the six-month accelerated test, with minimal change in release (only -3.8%). This demonstrates that the film structure is stable despite the increased weight of the coating, effectively protecting the drug. Groups 1 and 5 exhibited poor stability. Group 1, due to its thin coating, was susceptible to adhesion and breakage due to environmental influences, while Group 5, due to its overly thick coating, exhibited discoloration and deformation in high-humidity environments.

[0067] In summary, the combination of a first coating layer weight gain of 10% and a third coating layer weight gain of 3% can ensure the rapid release of saxagliptin and the ideal sustained-release effect of metformin hydrochloride while also having good stability. This is the optimal coating layer thickness parameter for saxagliptin metformin sustained-release tablets, verifying the scientificity and practicality of the preferred coating weight gain of the present invention.

[0068] Test Example 2: Accelerated Stability Test Comparison

[0069] Experimental Design: Tablets prepared in Example 1 of the present invention (inventive group) and tablets prepared in Example 2 of the reference document (CN119185227A) (control group) were placed in an accelerated testing chamber at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months. Samples were collected at the end of 0, 1, 2, 3, and 6 months, and the total impurity content and the maximum single impurity content were determined by HPLC.

[0070] 2. Detection Method

[0071] Saxagliptin was determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0072] Test solution: Take 10 sustained-release tablets of Example 1 and the comparative document, place them in a beaker, accurately add 50 ml of 0.1 mol hydrochloric acid solution, and stir with an electromagnetic stirrer (about 300 rpm) for at least 15 minutes to completely dissolve the saxagliptin coating layer (the tablet core does not dissolve). Take an appropriate amount of the mixed solution, centrifuge it, filter the supernatant, and take the filtrate.

[0073] Reference solution: Take an appropriate amount of saxagliptin reference substance, accurately weigh it, and use 0.1 mol / L hydrochloric acid solution to prepare a solution containing approximately 4.0 μg of saxagliptin per 1 ml.

[0074] System suitability solution: Weigh appropriate amounts of saxagliptin, impurity A, impurity B, impurity D, and impurity U respectively, and use 0.1 mol / L hydrochloric acid solution to prepare a mixed solution containing approximately 1.0 mg of saxagliptin, 10.0 μg of impurity A, 4.0 μg of impurity B, 4.0 μg of impurity D, and 10.0 μg of impurity U per 1 ml.

[0075] Accurately measure an appropriate amount of the reference solution and add 0.1 mol hydrochloric acid solution to prepare a solution containing approximately 0.5 μg of saxagliptin sensitivity solution F per 1 mL.

[0076] Chromatographic conditions: Octadecylsilane bonded silica gel as the packing material (Ultimate XB-C18, 4.6 mm x 250 mm, 5 μm or equivalent performance column); mobile phase A: phosphoric acid solution (1.0 ml of phosphoric acid, add 950 ml of water, and adjust the pH to 4.4 with 2 mol / L sodium hydroxide solution)-acetonitrile (95:5); mobile phase B: acetonitrile-water-phosphoric acid (90:10:0.1); flow rate: 1.0 ml / min, gradient elution according to the table below; detection wavelength: 210 nm; column temperature: 30°C; injection volume: 40 μl.

[0077] Table 4

[0078] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 13 100 0 20 90 10 40 50 50 60 20 80 61 100 0

[0079] System suitability requirements: In the system suitability solution chromatogram, the peak order is impurity D, impurity A, saxagliptin, impurity B, and impurity U. The resolution between the saxagliptin peak and the impurity B peak should be greater than 2.0. In the sensitivity solution chromatogram, the signal-to-noise ratio of the saxagliptin peak should be greater than 10.

[0080] Determination: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph, and record the chromatogram. The correction factors for impurities A and D are 0.5 and 1.3, respectively. The correction factors for other impurities are calculated as 1.0.

[0081] Limit: If impurity peaks are evident in the chromatogram of the test solution, excluding the solvent, metformin hydrochloride and its related impurity peaks (chromatographic peaks with relative retention times less than 0.25), calculate according to the following formula. The results are shown in Table 5.

[0082] Impurity % = (fxAxC R xD) / (A R xnxL)x100%

[0083] Where f is the correction factor for impurities;

[0084] A x is the peak area of ​​the impurity peak in the test solution;

[0085] A R is the peak area of ​​the reference solution saxagliptin;

[0086] C R is the concentration of saxagliptin in the reference solution;

[0087] D is the dilution factor of the test sample;

[0088] n is the number of test sample pieces;

[0089] L is the nominal amount.

[0090] Table 5 Comparison results of accelerated stability test

[0091]

[0092]

[0093] Conclusion: After 6 months of accelerated storage, the total impurity content in the inventive group was only 0.65%, significantly lower than the 3.58% in the control group. This indicates that the three-layer coating structure of the present invention provides improved stability. In summary, the multi-layer coating structure of the present invention not only effectively controls impurities during storage but also reduces the formation of degradation products during drug release, ensuring the safety and efficacy of the drug in vivo.

Claims

1. A saxagliptin metformin sustained-release tablet, characterized in that: The invention comprises a core layer, a first coating layer, a second coating layer and a third coating layer, wherein: The core layer is composed of 900-1100 parts of metformin hydrochloride, 4-10 parts of magnesium stearate, 40-60 parts of sodium carboxymethylcellulose and 350-450 parts of hypromellose in parts by weight; The first coating layer is formed by a gastric soluble film coating premix solution with a mass percentage concentration of 13-17%, and the coating weight gain on the basis of the plain tablet is 9-11%±0.5%; The second coating layer is formed by a solution having a mass percentage concentration of 11-14.5% based on the gastric-soluble film coating premix, wherein the solution comprises 4-6 parts of saxagliptin and 15-25 parts of the gastric-soluble film coating premix; The third coating layer is formed by a gastric soluble film coating premix solution with a mass percentage concentration of 13-17%, and the coating weight gain is 2-4%±0.5% based on the plain tablet.

2. The saxagliptin metformin sustained-release tablets according to claim 1, characterized in that The coating weight gain of the first coating layer is 10%±0.5% based on the plain tablet; the coating weight gain of the third coating layer is 3%±0.5% based on the plain tablet.

3. The saxagliptin metformin sustained-release tablets according to claim 1, characterized in that The magnesium stearate is in the core layer, 4-6 parts of magnesium stearate are mixed and ground with metformin hydrochloride, and the remaining magnesium stearate is added when the dry granules after granulation are mixed with hypromellose.

4. A method for preparing the saxagliptin metformin sustained-release tablets according to any one of claims 1 to 3, characterized in that: The following steps are involved: Preparation of the core layer: 900-1100 parts of metformin hydrochloride and 4-6 parts of magnesium stearate are uniformly mixed and then pulverized to obtain a pulverized mixture; the pulverized mixture is mixed with 40-60 parts of sodium carboxymethylcellulose, granulated by a wet method, dried and granulated, and then mixed with 350-450 parts of hypromellose and the remaining magnesium stearate, and tableted to obtain the core layer; Preparation of the first coating layer: Prepare a gastric-soluble film coating premix to form a first coating solution with a mass concentration of 13-17%; spray the first coating solution evenly on the surface of the core layer tablets to achieve a coating weight gain of 9-11%, thereby forming the first coating layer; Preparation of the second coating layer: 4-6 parts of saxagliptin and 15-25 parts of a gastric-soluble film coating premix are prepared into a second coating solution having a concentration of 11-14.5% by mass based on the gastric-soluble film coating premix; the second coating solution is sprayed on the surface of the first coating layer to form the second coating layer; Preparation of the third coating layer: A gastric-soluble third coating solution with a mass percentage concentration of 13-17% is prepared as a film coating premix; the third coating solution is evenly sprayed on the surface of the second coated tablet to make the coating weight gain reach 2-4% to form a third coating layer, thereby preparing saxagliptin metformin sustained-release tablets.

5. The preparation method according to claim 4, characterized in that The solvents of the first coating liquid, the second coating liquid and the third coating liquid are all hydrochloric acid aqueous solution, and the mass percentage concentration of the first layer of hydrochloric acid aqueous solution is 0.016%; The mass percentage concentration of the second layer of hydrochloric acid aqueous solution is 1.00%; the mass percentage concentration of the third layer of hydrochloric acid aqueous solution is 0.10%.

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