Dapagliflozin and metformin sustained-release tablet and preparation method thereof

Abstract

The invention relates to a dapagliflozin and metformin sustained-release tablet and a preparation method thereof, corresponding anti-spallation stabilizers are respectively added into dapagliflozin and metformin layer materials in a prescription, and the problems of temperature, humidity and spallation generated in the storage process can be reduced.

Description

Technical Field

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

[0002] Currently, the combination of dapagliflozin and metformin is indicated as an adjunct to diet and exercise to improve blood sugar control in adults with type 2 diabetes, but is not indicated for patients with type 1 diabetes or diabetic ketoacidosis. Following oral administration, dapagliflozin is rapidly absorbed, reaching peak plasma concentrations within 2 hours and having an elimination half-life of approximately 12.9 hours. The extended-release layer of metformin hydrochloride is released slowly, reaching peak plasma concentrations in approximately 4 to 8 hours, and is primarily eliminated unchanged in the urine.

[0003] CN116370430A discloses a dapagliflozin metformin sustained-release tablet, which comprises, from the inside to the outside, a metformin hydrochloride sustained-release micro-pellet core, an isolation layer, a dapagliflozin layer and a film coating layer; wherein the metformin hydrochloride sustained-release micro-pellet core comprises metformin hydrochloride, an adhesive I, a sustained-release material, a lubricant I and a filler; and the dapagliflozin layer comprises dapagliflozin propylene glycol monohydrate, an adhesive II and a lubricant II. CN116473934A discloses dapagliflozin metformin sustained-release tablets, comprising a metformin sustained-release tablet core, an isolation layer, a dapagliflozin top layer, and a film coating layer. Dapagliflozin is coated on the outside of the metformin tablet core using a coating method. The dapagliflozin content can be easily controlled by weight gain, which helps to improve the uniformity of the drug content. At the same time, an isolation layer is provided between the metformin sustained-release tablet core and the dapagliflozin top layer, and the dapagliflozin layer is coated on the surface of the isolation layer. CN102711739A discloses a method for preparing a double-layer tablet, comprising a first layer of a metformin hydrochloride sustained-release preparation, a second layer of an SGLT2 inhibitor preparation, and a film coating, to achieve long-lasting sustained-release and zero-order release effects. CN106924208A discloses a compound dapagliflozin metformin sustained-release tablet and its preparation method, wherein metformin hydrochloride is first prepared into a sustained-release tablet core, and then dapagliflozin and an adhesive are prepared into a solution or suspension for drug coating, and finally film coating is performed. CN113398097A discloses a dapagliflozin metformin sustained-release preparation consisting of a metformin hydrochloride sustained-release micro-pellet core, an isolation layer, a dapagliflozin immediate-release layer and a protective layer. However, the process flow of the above method is cumbersome and complicated, and has high requirements for the fluidity and compressibility of the particles. A dry granulator and a double-layer tablet press are required for scale-up production, and industrial production is difficult and has poor reproducibility. Alternatively, due to the use of tablet core drug coating, the requirements for the tablet core are high, and the tablet core needs to have a certain strength. However, since the tablet core is too large, it will cause wear on the edges and corners during the coating process, and it is necessary to coat slowly, which requires high requirements for the setting of the coating process and parameters.

[0004] In addition, layer cracking of double-layer tablets is the most common problem in the process. Due to the different compositions between the two layers and the elastic mismatch between the excipients, the interfaces of adjacent layers of the double-layer tablets lack sufficient coarse adhesion, forming interfacial cracks, which will eventually lead to layer cracking. Especially in the coating process after double-layer tableting, the double-layer tablets are affected by temperature and humidity at the same time, and are constantly tumbling in the coating machine, causing layer cracking. Summary of the Invention

[0005] To solve the above technical problems, the present invention provides a dapagliflozin metformin sustained-release tablet and a preparation method thereof, which can reduce the temperature, humidity and delamination of the double-layer tablet during storage, and can quickly release dapagliflozin and slowly release metformin. At the same time, the double-layer tablet has storage stability.

[0006] The present invention provides a double-layer tablet of dapagliflozin and metformin, wherein the double-layer tablet comprises a metformin sustained-release layer core, a dapagliflozin immediate-release layer core, and a coating covering the double-layer core, wherein the dapagliflozin immediate-release layer is compressed on the metformin sustained-release layer core.

[0007] The metformin sustained-release layer tablet core comprises an active ingredient, metformin or its salt, a skeleton agent, hydroxypropyl cellulose, and an anti-lamination stabilizer A, wherein the anti-lamination stabilizer A is carnauba wax and glyceryl monostearate;

[0008] The dapagliflozin rapid-release layer tablet core comprises the active ingredient dapagliflozin or its salt or hydrate thereof, fillers lactose and microcrystalline cellulose, a disintegrant crospovidone and an anti-lamination stabilizer B, wherein the anti-lamination stabilizer B is methylcellulose.

[0009] The metformin sustained-release layer tablet core is formed by wet granulation and compression, and the dapagliflozin immediate-release layer tablet is formed by dry granulation and then compressed onto the metformin sustained-release layer tablet core.

[0010] The metformin sustained-release layer tablet core comprises active ingredients metformin or its salt, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, carnauba wax, glyceryl monostearate, silicon dioxide and magnesium stearate.

[0011] The dapagliflozin immediate-release layer tablet core comprises the active ingredient dapagliflozin or its salt or hydrate, lactose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, methylcellulose, silicon dioxide and magnesium stearate.

[0012] The metformin sustained-release layer tablet core comprises 800-1200 parts by weight of the active ingredient metformin or its salt (preferably 900, 1000, 1100, 1200 parts by weight), 40-60 parts by weight of sodium carboxymethylcellulose (preferably 40, 45, 50, 55, 60 parts by weight), 200-250 parts by weight of hydroxypropyl methylcellulose (preferably 200, 210, 220, 230, 240, 250 parts by weight), 2-10 parts by weight of carnauba wax (preferably 2, 4, 5, 6, 8, 10 parts by weight), 1-4 parts by weight of glyceryl monostearate (preferably 1, 2, 3, 4 parts by weight), 10-15 parts by weight of silicon dioxide (preferably 10, 11, 12, 13, 14, 15 parts by weight) and 3-9 parts by weight of magnesium stearate (preferably 4, 5, 6, 7, 8, 9 parts by weight).

[0013] The preferred metformin sustained-release layer tablet core is prepared by wet granulation of the active ingredient metformin, sodium carboxymethylcellulose and magnesium stearate, drying, adding hydroxypropyl methylcellulose, carnauba wax, glyceryl monostearate and silicon dioxide, mixing evenly and then tableting.

[0014] In parts by weight, the dapagliflozin immediate-release layer core comprises 5-10 parts by weight of the active ingredient dapagliflozin or its salt or hydrate thereof (preferably 5, 6, 7, 8, 9 parts by weight), 20-45 parts by weight of lactose (preferably 21, 22, 23, 24, 25, 27, 30, 32, 33, 35, 36, 38, 40, 42 parts by weight), 150-200 parts by weight of microcrystalline cellulose (preferably 155, 160, 165, 170, 180, 190, 195 parts by weight), 10-15 parts by weight of cross-linked polyvinylpyrrolidone (preferably 11, 12, 13, 14, 15 parts by weight), 40-60 parts by weight of methylcellulose (preferably 42, 44, 45, 46, 48, 50, 52, 54, 55, 56, 58 parts by weight), 3-10 parts by weight of silicon dioxide and 1-6 parts by weight of magnesium stearate.

[0015] The dapagliflozin immediate-release layer tablet core is prepared by the following method: the dapagliflozin active ingredient, lactose, microcrystalline cellulose, methylcellulose, 1 / 3-1 / 2 of the prescription amount of cross-linked polyvinylpyrrolidone, 3 / 4 of the prescription amount of silicon dioxide, and 1 / 2 of the prescription amount of magnesium stearate are mixed and then dry-powdered to granulate, and then the remaining amount of cross-linked polyvinylpyrrolidone, silicon dioxide, and magnesium stearate are added and mixed.

[0016] The hydroxypropyl methylcellulose is selected from K100M, and the microcrystalline cellulose is microcrystalline cellulose PH302.

[0017] The weight ratio of the anti-lamination stabilizer A to hydroxypropyl methylcellulose is (5-15):230, and the weight ratio of carnauba wax to glyceryl monostearate is (3-8):(1-3).

[0018] The weight ratio of the anti-spacing stabilizer B to the microcrystalline cellulose is (40-60): (170-190).

[0019] The present invention also provides a method for preparing the above-mentioned double-layer tablet: the method comprises the following steps:

[0020] (1) Preparation of metformin hydrochloride sustained-release layer: Metformin hydrochloride is crushed and sieved, sodium carboxymethyl cellulose and magnesium stearate are added, and high-shear wet granulation is performed with water as a wetting agent. The granules are dried and ground into whole pieces. Hydroxypropyl methylcellulose, carnauba wax, glyceryl monostearate, and silicon dioxide are added, mixed evenly, and tableted to prepare metformin hydrochloride sustained-release layer tablet cores.

[0021] (2) Preparation of dapagliflozin immediate-release layer total mixed powder: Dapagliflozin active ingredient, lactose, microcrystalline cellulose, methylcellulose, 1 / 3-1 / 2 of the prescribed amount of cross-linked polyvinylpyrrolidone, and 3 / 4 of the prescribed amount of silicon dioxide are added to a mixer and mixed, and then 1 / 2 of the prescribed amount of magnesium stearate is added and continued to mix, followed by dry granulation, and then the remaining amount of cross-linked polyvinylpyrrolidone, silicon dioxide, and magnesium stearate are added and mixed to prepare the dapagliflozin immediate-release layer total mixed powder;

[0022] (3) Add the dapagliflozin immediate-release layer powder mixture from step (2) onto the metformin sustained-release layer tablet core from step (1) above, and compress the mixture into a double-layer tablet.

[0023] After step (3), it is preferred to further coat the double-layer tablet using a gastric-soluble film coating premix.

[0024] Beneficial technical effects:

[0025] 1. The present invention addresses the problem of delamination that is prone to occur in double-layer tablets of dapagliflozin and metformin. It is found that adding corresponding anti-delamination stabilizers to the dapagliflozin and metformin layer materials in the prescription can solve the delamination problem caused by temperature, humidity and storage process.

[0026] 2. The dapagliflozin and metformin bilayer tablets of the present invention can also rapidly release dapagliflozin and slowly release metformin, and the bilayer tablets are storage stable. DETAILED DESCRIPTION

[0027] Example 1

[0028] Metformin hydrochloride sustained-release layer tablet core

[0029] In the granules: Metformin hydrochloride 1000g

[0030] Sodium carboxymethyl cellulose 50g

[0031] Magnesium stearate 5g

[0032] Extragranular:

[0033] Dapagliflozin immediate-release layer core tablet

[0034] Intragranular:

[0035] Extragranular: Cross-linked polyvinylpyrrolidone 6.9g

[0036] Silicon dioxide 1.1g

[0037] Magnesium stearate 1.475g

[0038] Coating: 40g of gastric soluble film coating premix.

[0039] Preparation method:

[0040] 1. Preparation of the metformin hydrochloride sustained-release layer: Metformin hydrochloride is crushed and sieved, sodium carboxymethylcellulose and magnesium stearate are added, and high-shear wet granulation is performed with water as a wetting agent. The granules are dried and ground into a whole. Hydroxypropyl methylcellulose K100M, carnauba wax, glyceryl monostearate, and silicon dioxide are added. The mixture is uniformly mixed and then tableted to prepare the metformin hydrochloride sustained-release layer tablet core.

[0041] 2. Preparation of dapagliflozin immediate-release layer: Add the prescribed amount of dapagliflozin propylene glycol monohydrate, microcrystalline cellulose, anhydrous lactose, methylcellulose, silicon dioxide (internal addition) and cross-linked polyvinylpyrrolidone (internal addition) into a mixer and mix for 15 minutes. Add magnesium stearate (internal addition) and continue mixing for 10 minutes. Then, dry granulate is performed. Continue mixing silicon dioxide (external addition), cross-linked polyvinylpyrrolidone (external addition) and magnesium stearate (external addition) for 25 minutes to prepare the dapagliflozin immediate-release layer total mixed powder.

[0042] 3. Add the dapagliflozin immediate-release layer powder mix to the metformin sustained-release layer core prepared in step 1 above, and compress the tablets into double-layer tablets. The weight range of the metformin layer tablets is controlled within ±5.0%, and the weight range of the double-layer tablets is controlled within ±5.0%.

[0043] 4. Use gastric soluble film coating premix to coat the above double-layer tablets.

[0044] Example 2

[0045] Metformin hydrochloride sustained-release layer tablet core

[0046] In the granules: Metformin hydrochloride 1000g

[0047] Sodium carboxymethyl cellulose 60g

[0048] Magnesium stearate 5g Extragranular: Dapagliflozin immediate-release layer core tablet

[0049] Intragranular: Extragranular: Cross-linked polyvinylpyrrolidone 5.9g

[0050] Silicon dioxide 1.1g

[0051] Magnesium stearate 1.475g Coating: 35g of gastric soluble film coating premix. The preparation method is the same as that of Example 1.

[0052] Example 3

[0053] Metformin hydrochloride sustained-release layer tablet core In the granules: Metformin hydrochloride 1000g

[0054] Sodium carboxymethyl cellulose 50g

[0055] Magnesium stearate 5g Extragranular: Dapagliflozin immediate-release layer core tablet

[0056] Intragranular:

[0058] Extragranular: Crospovidone 4.9g

[0059] Silicon dioxide 1.1g

[0060] Magnesium stearate 1.475g Coating: 40g of gastric soluble film coating premix. The preparation method is the same as that of Example 1.

[0061] Example 4

[0062] Metformin hydrochloride sustained-release layer tablet core In the granules: Metformin hydrochloride 1000g

[0063] Sodium carboxymethyl cellulose 45g

[0064] Magnesium stearate 5g Extragranular: Dapagliflozin immediate-release layer core tablet

[0065] Intragranular: Extragranular: Cross-linked polyvinylpyrrolidone 8.9g

[0066] Silicon dioxide 1.1g

[0067] Magnesium stearate 1.475g

[0068] Coating: 40g of gastric soluble film coating premix.

[0069] The preparation method is the same as that of Example 1.

[0070] Comparative Example 1

[0071] Metformin hydrochloride sustained-release layer tablet core

[0072] In the granules: Metformin hydrochloride 1000g

[0073] Sodium carboxymethyl cellulose 50g

[0074] Magnesium stearate 5g

[0075] Extragranular: Hydroxypropyl methylcellulose K100M 235g

[0076] Magnesium stearate 2g

[0077] Silicon dioxide 13g

[0078] Dapagliflozin immediate-release layer core tablet

[0079] Intragranular:

[0080] Extragranular: Cross-linked polyvinylpyrrolidone 5.9g

[0081] Silicon dioxide 1.1g

[0082] Magnesium stearate 1.475g

[0083] Coating: 40g of gastric soluble film coating premix.

[0084] Preparation method:

[0085] 1. Preparation of the metformin hydrochloride sustained-release layer: Metformin hydrochloride is crushed and sieved, sodium carboxymethylcellulose and magnesium stearate are added, and high-shear wet granulation is performed with water as a wetting agent. The granules are dried and ground into a whole, and hydroxypropyl methylcellulose K100M, magnesium stearate, and silicon dioxide are added. The mixture is uniformly mixed and then tableted to prepare the metformin hydrochloride sustained-release layer tablet core;

[0086] 2. Preparation of dapagliflozin immediate-release layer: Add the prescribed amount of dapagliflozin propylene glycol monohydrate, microcrystalline cellulose, anhydrous lactose, silicon dioxide (internal addition) and cross-linked polyvinylpyrrolidone (internal addition) into a mixer and mix for 15 minutes. Add magnesium stearate (internal addition) and continue mixing for 10 minutes. Then, dry granulate is performed. Continue mixing silicon dioxide (external addition), cross-linked polyvinylpyrrolidone (external addition) and magnesium stearate (external addition) for 25 minutes to prepare the dapagliflozin immediate-release layer total mixed powder.

[0087] 3. Add the dapagliflozin immediate-release layer powder mix to the metformin sustained-release layer core prepared in step 1 above, and compress the tablets into double-layer tablets. The weight range of the metformin layer tablets is controlled within ±5.0%, and the weight range of the double-layer tablets is controlled within ±5.0%.

[0088] 4. Use gastric soluble film coating premix to coat the above double-layer tablets.

[0089] Comparative Example 2

[0090] The order of compressing the double-layer tablets in Example 1 was adjusted to compress the dapagliflozin immediate-release layer core tablet first, and then compress the metformin sustained-release layer thereon.

[0091] Comparative Example 3

[0092] The carnauba wax in Example 1 was replaced with insect wax, and the rest was the same as in Example 1.

[0093] Comparative Example 4

[0094] The methylcellulose in the dapagliflozin layer in Example 1 was replaced with hydroxypropyl cellulose, and the rest was the same as in Example 1.

[0095] Comparative Example 5

[0096] In Example 1, the glyceryl monostearate in the metformin layer was replaced with polyethylene glycol, and the methylcellulose in the dapagliflozin layer was replaced with hydroxypropyl cellulose. The rest was the same as in Example 1.

[0097] Experimental Example 1

[0098] Double layer crack evaluation

[0099] The bilayer tablets of Example 1 and Comparative Examples 1-5 were subjected to temperature, humidity, and tumble tests. In the temperature test, 1000 samples of Example 1 and Comparative Examples 1-5 were heated at 60°C for 4 hours, taken out and cooled, and then observed for obvious cracks at the interface between the two layers, and the number of cracked tablets was recorded. In the humidity test, 1000 samples were placed at room temperature and 75% humidity for 4 hours, and counted using the same method as above. In the tumble test, 100 samples were placed in a friability tester, set for a test time of 30 minutes, observed after the test, and counted using the same method as above to investigate the risk of bilayer tablet cracking.

[0100] Table 1 Effect of double tablet delamination

[0101]

[0102] The above results indicate that the formulation of Example 1 of the present invention can effectively reduce the number of delaminations of double-layer tablets. The present invention can enhance the delamination effect between the double-layer tablets by adding carnauba wax and glyceryl monostearate to the metformin sustained-release layer and simultaneously adding part of methylcellulose to the dapagliflozin immediate-release layer.

[0103] Experimental Example 2

[0104] Dissolution test

[0105] The dissolution curves were measured using a basket method at 100 rpm and a 20-mesh basket using pH 6.8 phosphate buffer, pH 4.5 acetate buffer, pH 1.2 hydrochloric acid solution, and purified water as dissolution media. The dissolution rates of Examples 1 and 2 and Comparative Examples 1 and 2 were measured respectively.

[0106] Table 2 Cumulative dissolution of metformin

[0107]

[0108]

[0109] Table 3 Cumulative dissolution of dapagliflozin

[0110]

[0111] The above results show that after adding carnauba wax and glyceryl monostearate to the metformin sustained-release layer and adding part of methylcellulose to the dapagliflozin immediate-release layer, the dissolution rate does not change significantly, and the dissolution effect is still considerable.

[0112] Experimental Example 3

[0113] Stability test

[0114] The dapagliflozin hydrochloride metformin bilayer tablets prepared in Example 1 were placed under high temperature (60°C) and humid heat (40°C / RH75%) conditions, and samples were taken on the 10th and 30th days, respectively. The inspection indicators were: properties and related substances (including NMDA).

[0115] Table 4 Stability test results

[0116]

[0117]

[0118] The above experimental results show that the double-layer tablet of Example 1 has excellent stability under high temperature and high humidity environment.

Claims

1. A double-layer tablet of dapagliflozin and metformin, characterized in that: The double-layer tablet comprises a metformin sustained-release layer core, a dapagliflozin immediate-release layer core, and a coating covering the double-layer core, wherein the dapagliflozin immediate-release layer is compressed on the metformin sustained-release layer core; The metformin sustained-release layer tablet core comprises an active ingredient, metformin or its salt, a skeleton agent, hydroxypropyl cellulose, and an anti-lamination stabilizer A, wherein the anti-lamination stabilizer A is carnauba wax and glyceryl monostearate; The dapagliflozin rapid-release layer tablet core comprises the active ingredient dapagliflozin or its salt or hydrate thereof, fillers lactose and microcrystalline cellulose, a disintegrant crospovidone and an anti-lamination stabilizer B, wherein the anti-lamination stabilizer B is methylcellulose.

2. The bilayer tablet according to claim 1, characterized in that: The metformin sustained-release layer tablet core is formed by wet granulation and compression, and the dapagliflozin immediate-release layer tablet is formed by dry granulation and then compressed onto the metformin sustained-release layer tablet core.

3. The bilayer tablet according to claim 1, wherein: The metformin sustained-release layer tablet core comprises active ingredients metformin or its salt, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, carnauba wax, glyceryl monostearate, silicon dioxide and magnesium stearate.

4. The bilayer tablet according to claim 3, characterized in that: The dapagliflozin immediate-release layer tablet core comprises the active ingredient dapagliflozin or its salt or hydrate, lactose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, methylcellulose, silicon dioxide and magnesium stearate.

5. The bilayer tablet according to claim 3, wherein: In parts by weight, the metformin sustained-release layer tablet core comprises 800-1200 parts by weight of the active ingredient metformin or its salt, 40-60 parts by weight of sodium carboxymethylcellulose, 200-250 parts by weight of hydroxypropyl methylcellulose, 2-10 parts by weight of carnauba wax, 1-4 parts by weight of glyceryl monostearate, 10-15 parts by weight of silicon dioxide and 3-9 parts by weight of magnesium stearate.

6. The bilayer tablet according to claim 4, characterized in that: In parts by weight, the dapagliflozin immediate-release layer core tablet comprises 5-10 parts by weight of the active ingredient dapagliflozin or its salt or hydrate thereof, 20-45 parts by weight of lactose, 150-200 parts by weight of microcrystalline cellulose, 10-15 parts by weight of cross-linked polyvinylpyrrolidone, 40-60 parts by weight of methylcellulose, 3-10 parts by weight of silicon dioxide and 1-6 parts by weight of magnesium stearate.

7. The bilayer tablet according to any one of claims 1 to 6, characterized in that: The hydroxypropyl methylcellulose is selected from K100M.

8. The bilayer tablet according to any one of claims 1 to 6, characterized in that: The microcrystalline cellulose is microcrystalline cellulose PH302.

9. The bilayer tablet according to any one of claims 1 to 6, characterized in that: The weight ratio of the anti-lamination stabilizer A to hydroxypropyl methylcellulose is (5-15):230, and the weight ratio of the carnauba wax to glyceryl monostearate is (3-8):(1-3).

10. The bilayer tablet according to any one of claims 1 to 6, characterized in that: The weight ratio of the anti-lamination stabilizer B to the microcrystalline cellulose is (40-60): (170-190).

11. The bilayer tablet according to claim 6, characterized in that: The dapagliflozin immediate-release layer tablet core is prepared by the following method: the dapagliflozin active ingredient, lactose, microcrystalline cellulose, methylcellulose, 1 / 3-1 / 2 of the prescription amount of cross-linked polyvinylpyrrolidone, 3 / 4 of the prescription amount of silicon dioxide, and 1 / 2 of the prescription amount of magnesium stearate are mixed and then dry-powdered to granulate, and then the remaining amount of cross-linked polyvinylpyrrolidone, silicon dioxide, and magnesium stearate are added and mixed.

12. The method for preparing a double-layer tablet according to claim 4, wherein: It includes the following step (1) Preparation of metformin hydrochloride sustained-release layer: Metformin hydrochloride is crushed and sieved, sodium carboxymethyl cellulose and magnesium stearate are added, and high-shear wet granulation is performed with water as a wetting agent. The granules are dried and ground into whole pieces. Hydroxypropyl methylcellulose, carnauba wax, glyceryl monostearate, and silicon dioxide are added, mixed evenly, and tableted to prepare metformin hydrochloride sustained-release layer tablet cores. (2) Preparation of dapagliflozin immediate-release layer total mixed powder: Dapagliflozin active ingredient, lactose, microcrystalline cellulose, methylcellulose, 1 / 3-1 / 2 of the prescribed amount of cross-linked polyvinylpyrrolidone, and 3 / 4 of the prescribed amount of silicon dioxide are added to a mixer and mixed, and then 1 / 2 of the prescribed amount of magnesium stearate is added and continued to mix, followed by dry granulation, and then the remaining amount of cross-linked polyvinylpyrrolidone, silicon dioxide, and magnesium stearate are added and mixed to prepare the dapagliflozin immediate-release layer total mixed powder; (3) Add the dapagliflozin immediate-release layer powder mixture from step (2) onto the metformin sustained-release layer tablet core from step (1) above, and compress the mixture into a double-layer tablet.

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