Dapagliflozin and metformin sustained release tablet and preparation method thereof

Abstract

The invention discloses a dapagliflozin and metformin sustained release tablet and a preparation method thereof. The dapagliflozin sustained-release tablet is prepared from the following raw materials in percentage by mass: 1.5 to 5.0 percent of dapagliflozin, 70.0 to 80.0 percent of metformin hydrochloride, 20 to 70 percent of filling agent, 3 to 8 percent of disintegrating agent, 2.0 to 10.0 percent of sustained-release material, 0.5 to 5.0 percent of adhesive solution, 20.0 to 30.0 percent of wetting agent, 0.5 to 2 percent of lubricating agent and 0.2 to 1.5 percent of flow aid. By adopting a wet granulation process, the dissolution rate of dapagliflozin and the release rate of metformin hydrochloride in the dapagliflozin and metformin hydrochloride sustained-release tablet can be increased, the content uniformity is good, the release is complete, and the stability and effectiveness of the product and the use safety of a patient are greatly improved.

Description

Technical Field

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

[0002] Dapagliflozin metformin sustained-release tablets are a combination of dapagliflozin (a sodium-glucose cotransporter 2 (SGLT2) inhibitor) and metformin, and can be used as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes. Dapagliflozin is applicable to adults with type 2 diabetes to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes and diagnosed cardiovascular disease or multiple cardiovascular risk factors.

[0003] Sodium-glucose cotransporter 2 (SGLT2) is expressed in the proximal renal tubules and is the main transporter responsible for the reabsorption of filtered glucose in the renal tubules. Dapagliflozin is an SGLT2 inhibitor that reduces the reabsorption of filtered glucose by inhibiting SGLT2, lowers the renal threshold of glucose, and thus increases urinary glucose excretion. Dapagliflozin can also reduce sodium reabsorption and increase the delivery of sodium to the distal tubules. Metformin hydrochloride can improve glucose tolerance in patients with type 2 diabetes, lower fasting blood glucose and postprandial blood glucose. It can inhibit gluconeogenesis of liver glycogen, reduce intestinal absorption of glucose, and improve the sensitivity of peripheral tissues to insulin by increasing the uptake and utilization of glucose by peripheral tissues. Although the treatment with metformin hydrochloride can reduce fasting insulin levels and the insulin response throughout the day, insulin secretion generally does not change. Summary of the Invention

[0004] The present invention provides a safe and effective dapagliflozin metformin sustained-release tablet and a preparation method thereof.

[0005] The raw material mass percentage composition of the described dapagliflozin metformin sustained-release tablets is as follows: dapagliflozin 1.5% - 5.0%, metformin hydrochloride 70.0% - 80.0%, filler 20% - 70%, disintegrant 3% - 8%, sustained-release and controlled-release material 2.0% - 10.0%, binder solution 0.5% - 5.0%, wetting agent 20.0 - 30.0%, lubricant 0.5% - 2%, glidant 0.2% - 1.5%.

[0006] The filler is selected from one or more of microcrystalline cellulose, lactose, and mannitol; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, crospovidone, and sodium carboxymethylcellulose; the sustained-release and controlled-release material is one or more of hydroxypropyl methylcellulose and methylcellulose; the binder is selected from one or more of sodium carboxymethylcellulose and povidone, and the solvent of the binder solution is an ethanol aqueous solution; the wetting agent is purified water; the lubricant is one or more of magnesium stearate and sodium stearyl fumarate; the glidant is colloidal silica.

[0007] The preparation method of the dapagliflozin metformin sustained-release tablets: (1) Add dapagliflozin, filler, and disintegrant into a wet granulation pot and mix evenly; (2) Add the binder solution to the wet granulation pot for granulation; (3) After granulation, dry and size the granules, and add glidant and lubricant; (4) Add metformin hydrochloride, binder, and sustained-release and controlled-release material into a wet granulation pot and mix evenly; (5) Add the wetting agent to the wet granulation pot for granulation; (6) After granulation, dry and size the granules, add glidant and lubricant, then press the metformin hydrochloride layer first, and then co-press with the dapagliflozin layer granules, and finally coat.

[0008] When granulating, the dosage of purified water accounts for 20%-25% of the dry mixed materials, and the dosage of the binder solution accounts for 40% - 55% of the dry mixed materials.

[0009] The granulation time is 0.5 min - 3 min.

[0010] The LOD of the granules after granulation and drying is ≤ 3.0%.

[0011] The main pressure for pressing the metformin hydrochloride layer is 0.1 - 3.0 KN, and the main pressure for co-pressing is 15 - 55 KN.

[0012] The weight gain after coating is 2.0% - 6.5%.

[0013] The particle size d90 of the dapagliflozin metformin raw material is < 60 μm.

[0014] The present invention adopts a wet granulation process. Dapagliflozin and metformin hydrochloride are both BCS class III drugs, belonging to highly soluble and low-permeability drugs. Through the method of the present invention, the dissolution rate of dapagliflozin and the release rate of metformin hydrochloride in the dapagliflozin metformin sustained-release tablets can be improved, the content uniformity is good, the release is complete, and the stability, effectiveness, and patient use safety of the product are greatly improved. Specific embodiments

[0015] The following examples are helpful for understanding the present invention, but the protection scope of the present invention is not limited thereto.

[0016] Example 1:

[0017] The preparation method is as follows: Add dapagliflozin, lactose, microcrystalline cellulose, and crospovidone to a wet granulation pot and mix for 10 min. Add povidone to the prepared ethanol aqueous solution as a binder solution. Add the binder solution to the wet granulation pot and granulate for 2 min. After granulation, the wet granules are sized and then dried in a fluidized bed until the LOD < 3.0%. The dried granules are mixed with colloidal silicon dioxide for 8 min and magnesium stearate for 5 min.

[0018] Add metformin hydrochloride tablets, sodium carboxymethylcellulose, and hypromellose to a wet granulation pot and mix evenly. Add purified water to the wet granulation pot and granulate for 1 min. After granulation, the wet granules are sized and then dried in a fluidized bed until the LOD < 3.0%.

[0019] The dried granules are mixed with colloidal silicon dioxide for 10 min and magnesium stearate for 5 min, and then co - compressed with the dapagliflozin granules. The main pressure of the metformin hydrochloride layer is 0.4 KN, and the main pressure of co - compression is 30 KN.

[0020] The plain tablets after compression are coated with Opadry, the tablet bed temperature is controlled at 35°C - 45°C, and the coating weight gain is 2% - 6.0%.

[0021] Example 2:

[0022] The preparation method is as follows: Add dapagliflozin, lactose, microcrystalline cellulose, and crospovidone to a wet granulation pot and mix for 10 min. Add povidone to the prepared ethanol aqueous solution as a binder solution. Add the binder solution to the wet granulation pot and granulate for 2 min. After granulation, the wet granules are sized and then dried in a fluidized bed until the LOD < 3.0%. The dried granules are mixed with colloidal silicon dioxide for 10 min and magnesium stearate for 5 min.

[0023] Add metformin hydrochloride tablets, sodium carboxymethylcellulose, and hypromellose to a wet granulation pot and mix evenly. Add purified water to the wet granulation pot and granulate for 1 min. After granulation, the wet granules are sized and then dried in a fluidized bed until the LOD < 3.0%.

[0024] The dried granules are mixed with colloidal silicon dioxide for 10 min and sodium stearyl fumarate for 5 min, and then co - compressed with the dapagliflozin layer granules. The main pressure of the metformin hydrochloride layer is 0.4 KN, and the main pressure of co - compression is 30 KN.

[0025] The plain tablets after tabletting are coated with Opadry, the tablet bed temperature is controlled at 35°C - 45°C, and the coating weight gain is 2% - 6.5%: Example 3:

[0026] The preparation method is as follows: Dapagliflozin, microcrystalline cellulose, mannitol, and crospovidone are added to a wet granulation pot and mixed for 10 min. Polyvinylpyrrolidone is added to the prepared ethanol aqueous solution as a binder solution. The binder solution is added to the wet granulation pot and granulated for 1.5 min. The wet granules after granulation are sized and then dried in a fluidized bed until the LOD < 3.0%. The dried granules are mixed with colloidal silicon dioxide for 8 min and magnesium stearate for 5 min.

[0027] Metformin hydrochloride, sodium carboxymethylcellulose, and hypromellose are added to a wet granulation pot and mixed evenly. Purified water is added to the wet granulation pot and granulated for 2 min. The wet granules after granulation are sized and then dried in a fluidized bed until the LOD < 3.0%.

[0028] The dried granules are mixed with colloidal silicon dioxide for 10 min and magnesium stearate for 5 min, and then tableted together with the dapagliflozin layer granules. The main pressure of the metformin hydrochloride layer is 0.4 KN, and the main pressure of the co - tabletting is 30 KN.

[0029] The plain tablets after tabletting are coated with Opadry, the tablet bed temperature is controlled at 35°C - 45°C, and the coating weight gain is 2% - 6.0%.

Claims

1. A dapagliflozin metformin sustained-release tablet, characterized in that: The raw materials of the sustained-release tablet are composed of 1.5%-5.0% dapagliflozin, 70.0%-80.0% metformin hydrochloride, 20%-70% filler, 3%-8% disintegrant, 2.0%-10.0% sustained-release material, 0.5%-5.0% adhesive solution, 20.0%-30.0% wetting agent, 0.5%-2% lubricant, and 0.2%-1.5% glidant.

2. The dapagliflozin metformin sustained-release tablet according to claim 1, characterized in that: The filler is selected from one or more of microcrystalline cellulose, lactose, and mannitol; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and sodium carboxymethyl cellulose; the sustained-release material is one or more of hydroxypropyl methylcellulose and methyl cellulose; the binder is selected from one or more of sodium carboxymethyl cellulose and polyvinylpyrrolidone, and the solvent of the binder solution is ethanol aqueous solution; the wetting agent is purified water; the lubricant is one or more of magnesium stearate and sodium stearyl fumarate; and the glidant is colloidal silicon dioxide.

3. The method for preparing the dapagliflozin metformin sustained-release tablets according to claim 1 or 2, characterized in that: The following steps are involved: (1) Add dapagliflozin, filler, and disintegrant into a wet granulation pot and mix evenly; (2) Adding the binder solution into the wet granulation pot for granulation; (3) After granulation, the granules are dried and granulated, and a flow aid and a lubricant are added; (4) Add metformin hydrochloride, binder, and sustained-release material into a wet granulation pot and mix evenly; (5) Adding a wetting agent to the wet granulation pot for granulation; (6) After granulation, the granules are dried and granulated, and after adding a glidant and a lubricant, the metformin hydrochloride layer is first compressed, and then the dapagliflozin layer granules are compressed together and finally coated.

4. The preparation method according to claim 3, characterized in that: During granulation, the amount of purified water used accounts for 20%-25% of the dry mixed materials, and the amount of binder solution used accounts for 40%~55% of the dry mixed materials.

5. The preparation method according to claim 3, characterized in that: Granulation time 0.5min-3min.

6. The preparation method according to claim 3, characterized in that: After granulation and drying, the LOD of the granules is ≤3.0%.

7. The preparation method according to claim 3, characterized in that: The main pressure of the metformin hydrochloride tableting layer is 0.1~3.0KN, and the main pressure of the joint tableting is 15~55KN.

8. The preparation method according to claim 3, characterized in that: The coating weight gain after coating is 2.0%-6.5%.

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