Dapagliflozin sustained release tablet and preparation method thereof

Abstract

The invention discloses a dapagliflozin sustained release tablet and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The invention discloses a dapagliflozin sustained release tablet. The dapagliflozin sustained release tablet comprises an active ingredient and a pharmaceutical adjuvant, the active component is dapagliflozin or a pharmaceutically acceptable salt thereof; the pharmaceutic adjuvants comprise a sustained-release framework material and a pH regulator; the mass ratio of the sustained-release framework material to the pH regulator is (4: 1)-(2: 1); the pH regulator accounts for 8-18% of the mass of the sustained release tablet; the sustained-release framework material is glyceryl behenate, and the pH regulator is one or more of fumaric acid, tartaric acid, maleic acid and citric acid. The sustained-release framework material glyceryl behenate and the pH regulator are combined according to a specific proportion to form a stable release channel, so that stable, uniform and slow release of active ingredients can be realized, and meanwhile, the problem that dapagliflozin is gelatinized when meeting water is solved. According to the method, a twin-screw melting granulation process is adopted, the process is simple, stable and controllable, the production efficiency is improved, and the batch-to-batch difference is reduced.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular, relates to a method for preparing a dapagliflozin sustained-release tablet. Background Art

[0002] Diabetes is a chronic disease characterized by high blood sugar, caused by absolute or relative insufficient secretion of insulin and impaired utilization. The disease is mainly divided into three types: type 1, type 2 and gestational diabetes. The cause is mainly attributed to the combined effects of genetic and environmental factors, including decreased insulin secretion caused by islet cell dysfunction, or the body's insensitivity to insulin, or both, which prevents glucose in the blood from being effectively utilized and stored. Long-term high blood sugar in diabetes leads to chronic damage to various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves. Diabetes has become the third largest non-communicable disease after cardiovascular disease and tumors.

[0003] Dapagliflozin is a sodium-glucose transporter inhibitor, and its structural formula is shown in Formula I below. It mainly uses a non-insulin-dependent mechanism of action to reduce the renal glucose reabsorption through highly selective inhibition, and directly excretes excess sugar in the urine, thereby reducing the blood glucose concentration in patients with type 2 diabetes and achieving the effect of treating diabetes. Dapagliflozin is used as a monotherapy to improve blood glucose control in adult patients with type 2 diabetes, and is not suitable for the treatment of type 1 diabetes or diabetic ketoacidosis.

[0004]

[0005] Studies have shown that dapagliflozin has significant side effects, such as hypotension, pyelonephritis, bladder disease, genital infection, etc. Preparing dapagliflozin into a sustained-release preparation can effectively relieve kidney pressure and reduce the risk of side effects such as pyelonephritis, bladder disease, and genital infection.

[0006] Patent CN111481522 discloses a dapagliflozin microencapsulated sustained-release tablet and its preparation method. The production process is to suspend dapagliflozin in an ethylcellulose ethanol solution and then spray-dry it in a fluidized bed. Since dapagliflozin is soluble in ethanol, it will recrystallize after spray drying, resulting in a change in crystal form. In addition, the API is dispersed in each microcapsule. When the microcapsules come into contact with water, the gelling properties of dapagliflozin in contact with water cause the microcapsules to agglomerate and dissolve incompletely, resulting in an unsatisfactory sustained-release effect. Summary of the invention

[0007] In view of the shortcomings of the dapagliflozin sustained-release preparation in the prior art, the present invention provides a dapagliflozin sustained-release tablet and a preparation method thereof. The dapagliflozin sustained-release tablet forms a stable release channel, can effectively achieve stable release under different pH environments, and the sustained-release tablet does not gel when exposed to water.

[0008] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0009] A dapagliflozin sustained-release tablet comprising an active ingredient and pharmaceutical excipients;

[0010] The active ingredient is dapagliflozin or a pharmaceutically acceptable salt thereof;

[0011] The pharmaceutical excipients include a sustained-release skeleton material and a pH regulator; the mass ratio of the sustained-release skeleton material to the pH regulator is 4:1-2:1; the pH regulator accounts for 8% to 18% of the mass of the sustained-release tablet;

[0012] The sustained-release skeleton material is behenic acid glyceryl, and the pH regulator is one or more of fumaric acid, tartaric acid, maleic acid, and citric acid, preferably fumaric acid. When the behenic acid glyceryl and the pH regulator in the erodible skeleton material are combined in a specific ratio, a stable release channel will be formed, and stable release can be effectively achieved under different pH environments.

[0013] In some embodiments, the pharmaceutical excipients further include pore-forming agents, binders, and lubricants.

[0014] The pore-forming agent is one or a combination of sucrose, D-mannitol, sorbitol, and xylitol, preferably mannitol.

[0015] The binder is selected from one or more of hydroxypropyl cellulose, povidone, hypromellose, sodium carboxymethyl cellulose; preferably sodium carboxymethyl cellulose.

[0016] The lubricant is selected from one or more combinations of magnesium stearate, talc, sodium stearyl fumarate, and micro-powder silica gel; preferably magnesium stearate.

[0017] In some embodiments, the contents of the components of the dapagliflozin sustained-release tablets are as follows by weight percentage:

[0018] The active ingredient is 6% to 8%, the sustained-release skeleton material is 20% to 45%, the pH regulator is 8% to 18%, the pore-forming agent is 30% to 55%, the adhesive is 5% to 15% and the lubricant is 0.5% to 2.5%.

[0019] In some embodiments, the present invention provides the following dapagliflozin sustained-release tablets, wherein the composition of the dapagliflozin sustained-release tablets is as follows by weight:

[0020] Dapagliflozin 10mg,

[0021] Glyceryl Behenate 50mg,

[0022]

[0023] On the other hand, the present invention also provides a method for preparing dapagliflozin sustained-release tablets, which specifically comprises the following steps:

[0024] (1) Premix the active ingredients and other pharmaceutical excipients except lubricants using a hopper mixer;

[0025] (2) using a twin-screw hot melt extruder to melt granulate at a granulation temperature of 70 ± 2 °C;

[0026] (3) granulating the granules prepared in step (2) using a wet granulator;

[0027] (4) Blending the granules obtained in step (3) with a lubricant to obtain a total mixed granule, and adding the total mixed granule to a high-speed tablet press to obtain dapagliflozin sustained-release tablets.

[0028] Compared with the prior art, the present invention has the following significant advantages:

[0029] 1. The present invention forms a stable release channel by combining the sustained-release skeleton material behenic acid glyceryl and the pH regulator in a specific ratio, which can achieve stable, uniform and slow release of the active ingredient and overcome the problem of dapagliflozin gelling when in contact with water.

[0030] 2. The present invention adopts a twin-screw melt granulation process, which is a one-step granulation process with a relatively simple procedure; and the twin-screw melt granulation process is easier to operate, stable and controllable, improves production efficiency, and reduces batch differences.

[0031] 3. The product of the present invention is taken once a day, which can not only improve the patient's compliance with treatment, but also avoid or reduce the phenomenon of large fluctuations in blood drug concentration, thereby reducing toxic side effects and greatly improving the safety and effectiveness of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The dissolution curve of dapagliflozin sustained-release tablets in pH 6.8 phosphate buffer (the dissolution curve of pH 6.8 phosphate buffer medium is as follows Figure 1 shown);

[0033] Figure 2 is the dissolution curve of dapagliflozin sustained-release tablets in pH 1.0 hydrochloride buffer (the dissolution curve of pH 1.0 hydrochloride buffer medium is as follows Figure 2 shown). DETAILED DESCRIPTION

[0034] In order to better understand the content of the present invention, the following is further described in conjunction with the examples, but the content of the present invention is not limited to these examples. All raw materials and reagents used in the experimental examples and preparation examples are commercially available unless otherwise specified.

[0035] The method for detecting the solubility of dapagliflozin in the solution in the test example is high performance liquid chromatography, and the specific detection conditions are as follows:

[0036] Instrument: High performance liquid chromatograph, Agilent 1260

[0037] Chromatographic column: SunFire C18 (4.6×150mm, 3.5μm)

[0038] Column temperature: 35°C

[0039] Detection wavelength: 220nm

[0040] Injection volume: 20 μl

[0041] Flow rate: 1.0ml / min

[0042] Mobile phase A: 20mmol / L potassium dihydrogen phosphate buffer (pH 3.0)

[0043] Mobile phase B: acetonitrile

[0044] Gradient elution program:

[0045]

[0046] Example 1 Preparation of Formulation 1

[0047]

[0048]

[0049] Dapagliflozin sustained-release tablets are prepared according to the formula in the above table. The preparation method is divided into the following steps:

[0050] (1) Premixing the API dapagliflozin with glyceryl behenate, mannitol, sodium carboxymethyl cellulose, and fumaric acid using a hopper mixer;

[0051] (2) Use a twin-screw hot melt extruder to granulate, with a granulation temperature of 70°C, a screw speed of 300 rpm, and a feed rate of 30 rpm;

[0052] (3) using a pelletizer to granulate the pellets prepared in step (2);

[0053] (4) granulating the granules obtained in step (3) using a wet granulator;

[0054] (5) blending the granules obtained in step (4) with magnesium stearate;

[0055] (6) The total mixed granules obtained in step (5) are added to a high-speed tablet press to prepare dapagliflozin sustained-release tablets, which are recorded as Preparation 1.

[0056] Example 2 Preparation of Formulation 2

[0057]

[0058] Dapagliflozin sustained-release tablets are prepared according to the formula in the above table. The preparation method is divided into the following steps:

[0059] (1) Premixing the API dapagliflozin with glyceryl behenate, sorbitol, povidone, and fumaric acid using a hopper mixer;

[0060] (2) Use a twin-screw hot melt extruder to granulate, with a granulation temperature of 70°C, a screw speed of 300 rpm, and a feed rate of 30 rpm;

[0061] (3) using a pelletizer to granulate the pellets prepared in step (2);

[0062] (4) granulating the granules obtained in step (3) using a wet granulator;

[0063] (5) blending the granules obtained in step (4) with sodium stearyl fumarate;

[0064] (6) The total mixed granules obtained in step (5) are added to a high-speed tablet press to prepare dapagliflozin sustained-release tablets, which are recorded as Preparation 2.

[0065] Example 3 Preparation of Formulation 3

[0066]

[0067] Dapagliflozin sustained-release tablets are prepared according to the formula in the above table. The preparation method is divided into the following steps:

[0068] (1) Premixing the API dapagliflozin with glyceryl behenate, sucrose, hydroxypropyl cellulose, and fumaric acid using a hopper mixer;

[0069] (2) Use a twin-screw hot melt extruder to granulate, with a granulation temperature of 70°C, a screw speed of 300 rpm, and a feed rate of 30 rpm;

[0070] (3) using a pelletizer to granulate the pellets prepared in step (2);

[0071] (4) granulating the granules obtained in step (3) using a wet granulator;

[0072] (5) blending the granules obtained in step (4) with magnesium stearate;

[0073] (6) The total mixed granules obtained in step (5) are added to a high-speed tablet press to prepare dapagliflozin sustained-release tablets, which are recorded as Preparation 3.

[0074] Example 4 Preparation of Formulation 4

[0075]

[0076] Dapagliflozin sustained-release tablets are prepared according to the formula in the above table. The preparation method is divided into the following steps:

[0077] (1) Premixing the API dapagliflozin with glyceryl behenate, mannitol, sodium carboxymethyl cellulose, and fumaric acid using a hopper mixer;

[0078] (2) Use a twin-screw hot melt extruder to granulate, with a granulation temperature of 70°C, a screw speed of 300 rpm, and a feed rate of 30 rpm;

[0079] (3) using a pelletizer to granulate the pellets prepared in step (2);

[0080] (4) granulating the granules obtained in step (3) using a wet granulator;

[0081] (5) blending the granules obtained in step (4) with magnesium stearate;

[0082] (6) The total mixed granules obtained in step (5) are added to a high-speed tablet press to prepare dapagliflozin sustained-release tablets, which are recorded as Preparation 4.

[0083] Example 5 Preparation of Formulation 5

[0084]

[0085]

[0086] Dapagliflozin sustained-release tablets are prepared according to the formula in the above table. The preparation method is divided into the following steps:

[0087] (1) Premixing the API dapagliflozin with glyceryl behenate, mannitol, sodium carboxymethyl cellulose, and fumaric acid using a hopper mixer;

[0088] (2) Use a twin-screw hot melt extruder to granulate, with a granulation temperature of 70°C, a screw speed of 300 rpm, and a feed rate of 30 rpm;

[0089] (3) using a pelletizer to granulate the pellets prepared in step (2);

[0090] (4) granulating the granules obtained in step (3) using a wet granulator;

[0091] (5) blending the granules obtained in step (4) with magnesium stearate;

[0092] (6) The total mixed granules obtained in step (5) are added to a high-speed tablet press to prepare dapagliflozin sustained-release tablets, which are recorded as Preparation 5.

[0093] Example 6 Preparation of Formulation 6

[0094]

[0095] Dapagliflozin sustained-release tablets are prepared according to the formula in the above table. The preparation method is divided into the following steps:

[0096] (1) Premixing the API dapagliflozin with glyceryl behenate, mannitol, povidone, and fumaric acid using a hopper mixer;

[0097] (2) Use a twin-screw hot melt extruder to granulate, with a granulation temperature of 70°C, a screw speed of 300 rpm, and a feed rate of 30 rpm;

[0098] (3) using a pelletizer to granulate the pellets prepared in step (2);

[0099] (4) granulating the granules obtained in step (3) using a wet granulator;

[0100] (5) blending the granules obtained in step (4) with magnesium stearate;

[0101] (6) The total mixed granules obtained in step (5) are added to a high-speed tablet press to prepare dapagliflozin sustained-release tablets, which are recorded as Preparation 6.

[0102] Example 7 Preparation of Formulation 7

[0103]

[0104] Dapagliflozin sustained-release tablets are prepared according to the formula in the above table. The preparation method is divided into the following steps:

[0105] (1) Premixing the API dapagliflozin with glyceryl behenate, mannitol, povidone, and fumaric acid using a hopper mixer;

[0106] (2) Use a twin-screw hot melt extruder to granulate, with a granulation temperature of 70°C, a screw speed of 300 rpm, and a feed rate of 30 rpm;

[0107] (3) using a pelletizer to granulate the pellets prepared in step (2);

[0108] (4) granulating the granules obtained in step (3) using a wet granulator;

[0109] (5) blending the granules obtained in step (4) with magnesium stearate;

[0110] (6) The total mixed granules obtained in step (5) are added to a high-speed tablet press to prepare dapagliflozin sustained-release tablets, which are recorded as Preparation 7.

[0111] Comparative Example 1 Preparation of Formulation 8

[0112]

[0113] Dapagliflozin sustained-release tablets are prepared according to the formula in the above table. The preparation method is divided into the following steps:

[0114] (1) Premixing the API dapagliflozin with carnauba wax, mannitol, sodium carboxymethyl cellulose, and fumaric acid using a hopper mixer;

[0115] (2) Use a twin-screw hot melt extruder to granulate, with a granulation temperature of 78°C, a screw speed of 300 rpm, and a feed rate of 30 rpm;

[0116] (3) using a pelletizer to granulate the pellets prepared in step (2);

[0117] (4) granulating the granules obtained in step (3) using a wet granulator;

[0118] (5) blending the granules obtained in step (4) with magnesium stearate;

[0119] (6) The total mixed granules obtained in step (5) are added to a high-speed tablet press to prepare dapagliflozin sustained-release tablets, which are recorded as Preparation 8.

[0120] Comparative Example 2 Preparation of Formulation 9

[0121]

[0122]

[0123] Dapagliflozin sustained-release tablets are prepared according to the formula in the above table. The preparation method is divided into the following steps:

[0124] (1) Mixing the API dapagliflozin with hypromellose, mannitol, sodium carboxymethyl cellulose, fumaric acid, and magnesium stearate using a hopper mixer;

[0125] (2) The total mixed granules obtained in step (1) are added to a high-speed tablet press to prepare dapagliflozin sustained-release tablets, which are recorded as Preparation 9.

[0126] Comparative Example 3 Preparation of Formulation 10

[0127]

[0128] Dapagliflozin sustained-release tablets are prepared according to the formula in the above table. The preparation method is divided into the following steps:

[0129] (1) Premixing the API dapagliflozin with glyceryl behenate, mannitol, sodium carboxymethyl cellulose, and fumaric acid using a hopper mixer;

[0130] (2) Use a twin-screw hot melt extruder to granulate, with a granulation temperature of 70°C, a screw speed of 300 rpm, and a feed rate of 30 rpm;

[0131] (3) using a pelletizer to granulate the pellets prepared in step (2);

[0132] (4) granulating the granules obtained in step (3) using a wet granulator;

[0133] (5) blending the granules obtained in step (4) with magnesium stearate;

[0134] (6) The total mixed granules obtained in step (5) are added to a high-speed tablet press to prepare dapagliflozin sustained-release tablets, which are recorded as Preparation 10.

[0135] Comparative Example 4 Preparation of Formulation 11

[0136]

[0137] Dapagliflozin sustained-release tablets are prepared according to the formula in the above table. The preparation method is divided into the following steps:

[0138] (1) Premixing the API dapagliflozin with glyceryl behenate, mannitol, sodium carboxymethyl cellulose, and fumaric acid using a hopper mixer;

[0139] (2) Use a twin-screw hot melt extruder to granulate, with a granulation temperature of 70°C, a screw speed of 300 rpm, and a feed rate of 30 rpm;

[0140] (3) using a pelletizer to granulate the pellets prepared in step (2);

[0141] (4) granulating the granules obtained in step (3) using a wet granulator;

[0142] (5) blending the granules obtained in step (4) with magnesium stearate;

[0143] (6) The total mixed granules obtained in step (5) are added to a high-speed tablet press to prepare dapagliflozin sustained-release tablets, which are recorded as Preparation 11.

[0144] Test Example 1 Dissolution Study

[0145] According to the first method of dissolution and release determination method 0931 of the fourth part of the Chinese Pharmacopoeia 2020 edition, preparations 1 to 11 were placed in a dissolution cup, and 1000 ml of degassed pH 6.8 phosphate buffer and pH 1.0 hydrochloride buffer were used as release media, respectively. The rotation speed was 100 rpm and the temperature was (37±0.5)°C. 10 ml of release medium was taken at 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 h, respectively. Each time the release medium was taken out, an equal amount of fresh medium at the same temperature was supplemented. The medium was filtered through a 0.45 μm microporous filter membrane, and the filtrate was diluted and detected by UV-visible spectrophotometer.

[0146] Take about 25 mg of dapagliflozin reference substance, weigh it accurately, put it in a 25 ml volumetric flask, add solvent to dissolve and dilute to scale, shake well. Accurately measure 5 ml of the above solution, put it in a 50 ml volumetric flask, dilute to scale with solvent, shake well, and obtain a reference substance solution with a concentration of 10 μg / ml. Determine in the same way and calculate the cumulative release percentage of dapagliflozin by external standard method.

[0147] Dissolution phenomenon of preparation 1-preparation 11: At the beginning, the tablets rotated at the bottom of the dissolution basket. After 6 hours, they gradually floated up along the wall of the basket and floated on the top of the dissolution basket at the end of dissolution. The appearance of the tablets remained intact without obvious defects, and the dissolution solution was relatively clear.

[0148] Table 1 Dissolution comparison of dapagliflozin sustained-release tablets (pH 6.8 phosphate buffer)

[0149]

[0150] Table 2 Comparison of dissolution of dapagliflozin sustained-release tablets (pH 1.0 hydrochloride buffer)

[0151]

[0152] Preparation 1, Preparation 2 and Preparation 3 have different prescription compositions. Under the same production process, Preparations 1 to 3 show good sustained-release effects in pH 6.8 phosphate buffer and pH 1.0 hydrochloride buffer media, and the batch-to-batch differences are small.

[0153] Preparation 4 and Preparation 5 have different dosages of behenic acid glyceryl ester. The more the dosage of behenic acid glyceryl ester is, the slower the dissolution trend is in the pH 6.8 phosphate buffer and pH 1.0 hydrochloride buffer media.

[0154] Preparation 6 and Preparation 7 have different fumaric acid dosages. The less fumaric acid is used, the slower the dissolution trend is in the pH 6.8 phosphate medium.

[0155] Table 3 Dissolution comparison of dapagliflozin sustained-release tablets (pH 6.8 phosphate buffer)

[0156]

[0157] Table 4 Dissolution comparison of dapagliflozin sustained-release tablets (pH 1.0 hydrochloride buffer)

[0158]

[0159] Preparation 8 and Preparation 9 have different sustained-release skeleton materials. Carnauba wax is used as the skeleton material. The dissolution in pH 6.8 phosphate buffer and pH 1.0 hydrochloride buffer medium shows a burst release phenomenon. Hydroxypropyl methylcellulose is used as the skeleton material. The API further forms a gel with the skeleton material, resulting in incomplete dissolution at the endpoint.

[0160] Preparations 10 and 11 have different fumaric acid contents. The sustained-release tablets of Preparation 10 without fumaric acid obviously have incomplete dissolution. Although the release effect of Preparation 11 is not much different from that of Preparation 11, the acidity of the preparation is too strong, which may have a greater impact on gastrointestinal side effects.

[0161] Test Example 2 Stability Study

[0162] Preparation 1, Preparation 2, Preparation 3 and the commercially available preparation of dapagliflozin immediate-release tablets (Andatang) were subjected to stability studies, and the changes of related substances were observed under high temperature (60°C) and high humidity (RH75%) conditions for 30 days to investigate the stability of the tablets. The specific experimental results are shown in the following table:

[0163] Table 5 Stability study of dapagliflozin sustained-release tablets

[0164]

[0165] The impurity growth of the commercially available preparations was faster after being placed under high temperature (60°C) and high humidity (RH75%) conditions for 30 days. The impurity growth trend of the preparations obtained by the method of the present invention under high temperature and high humidity conditions after being placed for 30 days was consistent with that of the commercially available immediate-release preparations (Andatang). The impurity growth trend under high temperature conditions was better than that of the commercially available immediate-release preparations (Andatang).

Claims

1. A dapagliflozin sustained-release tablet, characterized in that: Including active ingredients and pharmaceutical excipients; The active ingredient is dapagliflozin or a pharmaceutically acceptable salt thereof; The pharmaceutical excipients include a sustained-release skeleton material and a pH regulator; the mass ratio of the sustained-release skeleton material to the pH regulator is 4:1-2:1; the pH regulator accounts for 8% to 18% of the mass of the sustained-release tablet; The sustained-release matrix material is glyceryl behenate, and the pH regulator is one or more of fumaric acid, tartaric acid, maleic acid, and citric acid.

2. The dapagliflozin sustained-release tablet according to claim 1, characterized in that: The pH adjuster is fumaric acid.

3. The dapagliflozin sustained-release tablet according to claim 1 or 2, characterized in that: The pharmaceutical excipients also include pore-forming agents, adhesives, and lubricants.

4. The dapagliflozin sustained-release tablet according to claim 3, characterized in that: The pore-forming agent is one or a combination of sucrose, D-mannitol, sorbitol and xylitol.

5. The dapagliflozin sustained-release tablet according to claim 3, characterized in that: The binder is selected from one or more of hydroxypropyl cellulose, povidone, hypromellose, and sodium carboxymethyl cellulose.

6. The dapagliflozin sustained-release tablet according to claim 3, characterized in that: The lubricant is selected from one or more combinations of magnesium stearate, talc, sodium stearyl fumarate, and micro-powder silica gel.

7. The dapagliflozin sustained-release tablet according to claim 3, characterized in that: The contents of the components of the dapagliflozin sustained-release tablets are as follows by weight percentage: The active ingredient is 6% to 8%, the sustained-release skeleton material is 20% to 45%, the pH regulator is 8% to 18%, the pore-forming agent is 30% to 55%, the adhesive is 5% to 15% and the lubricant is 0.5% to 2.5%.

8. The dapagliflozin sustained-release tablet according to claim 7, characterized in that: The composition of the dapagliflozin sustained-release tablets is as follows by weight:

9. The method for preparing the dapagliflozin sustained-release tablets according to any one of claims 1 to 8, characterized in that: The specific steps include: (1) Premix the active ingredients and other pharmaceutical excipients except lubricants using a hopper mixer; (2) using a twin-screw hot melt extruder to melt granulate at a granulation temperature of 70 ± 2 °C; (3) granulating the granules prepared in step (2) using a wet granulator; (4) Blending the granules obtained in step (3) with a lubricant to obtain a total mixed granule, and adding the total mixed granule to a high-speed tablet press to obtain dapagliflozin sustained-release tablets.

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