Pharmaceutical composition containing dapagliflozin and preparation method thereof

Abstract

The invention discloses a dapagliflozin-containing pharmaceutical composition. The dapagliflozin-containing pharmaceutical composition is prepared into tablets from the following components in parts by mass: 45-55 parts of dapagliflozin, 205-235 parts of a filler, 2-8 parts of a disintegrating agent and 3-6.5 parts of a lubricant, and coating the uncoated tablet with a coating agent to obtain the tablet. Wherein D90 of dapagliflozin is less than or equal to 20 microns; the filling agent is a combination of microcrystalline cellulose and lactose; and the lubricant is silicon dioxide and magnesium stearate. The pharmaceutical composition disclosed by the invention is rapid and complete in dissolution, stable in quality and high in bioavailability, and the content of related substances is controlled. The preparation method comprises the following steps: mixing with auxiliary materials for multiple times by adopting an equal-quantity gradually-increasing mixing method: firstly, mixing the active component with equal quantity of microcrystalline cellulose, and then mixing with lactose and silicon dioxide; adding the rest microcrystalline cellulose and disintegrating agent and mixing; and finally, magnesium stearate is added for total mixing, so that uniform mixing of the active components can be fully ensured, and the content uniformity of dapagliflozin is ensured.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and relates to a pharmaceutical composition containing dapagliflozin and a preparation method thereof, and specifically relates to a dapagliflozin tablet and a preparation method thereof. Background Art

[0002] Diabetes is a chronic disease characterized by hyperglycemia, caused by absolute or relative insulin deficiency and utilization disorders. 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. Some diabetic patients and families have a clustering phenomenon of the disease. In addition, the incidence and prevalence of diabetes are on the rise worldwide.

[0003] The symptoms of diabetes are mainly manifested as "three mores and one less", namely, drinking more, urinating more, eating more and losing weight. In addition, patients with a long course of the disease may develop chronic progressive lesions, functional impairment or even failure of tissues and organs such as the eyes, kidneys, nerves, heart, and blood vessels, and may also cause acute and severe metabolic disorders. Once you become a diabetic patient, you need to take medication for life. Diabetes not only affects the patient's quality of life, but may also shorten their lifespan.

[0004] Dapagliflozin (ForxigaTM), chemical name: (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)alkane-3,4,5-triol, is a new type of anti-diabetic drug jointly developed by Bristol-Myers Squibb and AstraZeneca. It was approved for marketing in Europe in November 2012 and is the first SGLT2 inhibitor approved for the treatment of type 2 diabetes. It can be used as an important choice in diabetes drug treatment and is suitable for adults with type 2 diabetes as an adjunct to diet and exercise to improve blood sugar control. It was approved for marketing in the United States in January 2014.

[0005] Dapagliflozin is a poorly soluble drug. Chinese patent application CN106606490A prepares it as a dispersion to solve the defect of low solubility. However, the dispersion process is complicated, and industrial production requires adding production lines for preparing the dispersion system, which is bound to increase production costs. At the same time, the more complicated process may lead to changes in the crystal form of the active ingredient and an increase in related substances.

[0006] Therefore, it is necessary to provide a method for preparing a pharmaceutical composition containing dapagliflozin with a simple preparation process, rapid and complete dissolution, stable quality and high bioavailability. Summary of the invention

[0007] The object of the present invention is to provide a pharmaceutical composition containing dapagliflozin which has a simple preparation process, rapid and complete dissolution, stable quality and high bioavailability.

[0008] The technical solution of the present invention is as follows:

[0009] A pharmaceutical composition containing dapagliflozin, wherein the pharmaceutical composition uses dapagliflozin as an active ingredient and is made into a plain tablet from the following components in parts by weight: 45-55 parts of dapagliflozin, 205-235 parts of a filler, 2-8 parts of a disintegrant, and 3-6.5 parts of a lubricant; and then the plain tablet is coated with a coating agent to obtain a tablet; wherein dapagliflozin D 90 ≤20μm; the filler is a combination of microcrystalline cellulose and lactose; the lubricant is silicon dioxide and magnesium stearate.

[0010] In a preferred embodiment, the plain tablet is made of the following components in parts by weight: 5-10 parts of dapagliflozin, 45-55 parts of lactose, 160-180 parts of microcrystalline cellulose, 2-8 parts of disintegrant, 2-5 parts of silicon dioxide, and 1-1.5 parts of magnesium stearate.

[0011] In a more preferred embodiment, the plain tablet is made of the following components in parts by weight: 10 parts of dapagliflozin, 50 parts of lactose, 170 parts of microcrystalline cellulose, 5 parts of disintegrant, 3 parts of silicon dioxide, and 1.25 parts of magnesium stearate.

[0012] In a preferred embodiment, the particle size range of dapagliflozin is: 10 0~5μm, D 50 5~10μm, D 90 10~20μm.

[0013] In a more preferred embodiment, the particle size range of dapagliflozin is: 10 0~3μm, D 50 5~8μm, D 90 It is 10 to 15 μm.

[0014] In a preferred embodiment, the plain tablets are prepared by first mixing dapagliflozin with an equal mass of microcrystalline cellulose, then mixing with lactose and silicon dioxide, then adding the remaining microcrystalline cellulose and disintegrant, and finally adding magnesium stearate to the mixture and tableting.

[0015] In a preferred embodiment, the disintegrant is cross-linked polyvinylpyrrolidone.

[0016] In a preferred embodiment, the lactose is anhydrous lactose.

[0017] In a preferred embodiment, the coating agent is a gastric soluble film coating premix.

[0018] In a preferred embodiment, the plain tablet is coated with a coating agent until the coating weight gain is 3% to 5%.

[0019] Another object of the present invention is to provide a method for preparing the pharmaceutical composition containing dapagliflozin, comprising the following steps:

[0020] Step (1), pretreatment: dapagliflozin is subjected to air flow grinding and sieving, and the filler, disintegrant, and lubricant are sifted separately;

[0021] Step (2), mixing: using an equal amount of progressive mixing method, dapagliflozin is mixed evenly with an equal amount of microcrystalline cellulose, then mixed evenly with lactose and silicon dioxide, then the remaining microcrystalline cellulose and disintegrant are added and mixed evenly, and finally magnesium stearate is added and mixed to obtain a mixed powder;

[0022] Step (3), tableting: adding the mixed powder obtained in step (2) into a tablet press to obtain a plain tablet;

[0023] Step (4), coating: a coating agent and purified water are prepared into a coating solution, and the plain tablets obtained in step (3) are coated to obtain dapagliflozin tablets.

[0024] In a preferred embodiment, in step (1), dapagliflozin is subjected to air flow pulverization using an air flow pulverizer, and the pressure of the air flow pulverization is 0.2 MPa to 0.5 MPa, preferably 0.3 MPa to 0.4 MPa.

[0025] In a preferred embodiment, in step (1), the filler, disintegrant and lubricant are sieved through a 60-mesh sieve respectively.

[0026] In a preferred embodiment, in step (3), a 9 mm round punch is used for tableting, the hardness of the plain tablet is 7-11 kg, and the tablet weight difference is ±5.0%.

[0027] In a preferred embodiment, in step (4), the concentration of the coating solution is 10% to 20%.

[0028] In a preferred embodiment, in step (4), the coating parameters are: inlet air temperature 45-50°C, tablet bed temperature 35-40°C, atomization pressure 0.1-0.15 MPa, and flattening pressure 0.1-0.12 MPa.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1. The present invention adopts air flow milling to control the particle size of dapagliflozin and optimizes the ratio between the components. The prepared pharmaceutical composition has rapid and complete dissolution, stable quality, high bioavailability, and controlled content of related substances.

[0031] 2. The present invention adopts a mixed direct compression process, which will not cause the active ingredient to change its crystal form and does not need to be exposed to a high temperature and high humidity environment, thereby solving the stability problem of the preparation process; and the intermediate (i.e., the mixed powder obtained in step (2)) has good compressibility, the drug composition disintegrates quickly, and the dissolution rate of the active ingredient can be increased. The results of long-term stability studies show that the quality of the finished preparation is stable and reliable.

[0032] 3. Since the active ingredient accounts for a small proportion in the pharmaceutical composition of the present invention, the conventional mixing method may result in uneven mixing; the present invention adopts an equal-incremental mixing method to mix with the excipients multiple times: first, the active ingredient is mixed with an equal amount of microcrystalline cellulose, and then mixed with lactose and silicon dioxide; the remaining microcrystalline cellulose and the disintegrant cross-linked polyvinylpyrrolidone are added and mixed; finally, magnesium stearate is added and mixed; the mixing method in the present invention can fully ensure that the active ingredient is mixed evenly, and ensure the uniformity of the content of dapagliflozin. DETAILED DESCRIPTION

[0033] The pharmaceutical composition containing dapagliflozin of the present invention is further described by the following examples, but these examples do not constitute any limitation to the present invention.

[0034] Example 1

[0035] 1. Preprocessing

[0036] The raw material dapagliflozin was crushed and sieved by a jet mill (crushing pressure of 0.3MPa to 0.4MPa) to obtain a particle size of dapagliflozin: D 10 =1.17μm, D 50 =7.36μm, D 90 =14.22μm; Excipients: microcrystalline cellulose, anhydrous lactose, silicon dioxide, cross-linked polyvinylpyrrolidone, magnesium stearate are sieved through 60 mesh sieves respectively and set aside.

[0037] 2. Mix

[0038] 2.1 In a mixing hopper, mix 10 g of dapagliflozin and 10 g of microcrystalline cellulose evenly according to 1000 dosage units, add 50 g of lactose and 3 g of silicon dioxide and mix evenly, add the remaining 160 g of microcrystalline cellulose and 5 g of cross-linked polyvinylpyrrolidone and mix evenly, then add 1.25 g of magnesium stearate and mix evenly to obtain a mixed powder (i.e., an intermediate).

[0039] 3. Tablet pressing

[0040] The tablet weight is determined according to the intermediate test results, the mixed powder is added to the tablet press, and a round 9mm punch is used for tableting. The hardness of the plain tablet is 7-11kg; the tablet weight difference is ±5.0%.

[0041] 4. Coating

[0042] 4.1 Prepare a coating solution with a concentration of 18% by mixing the gastric soluble film coating premix (manufacturer: Shanghai Colorcon Coating Technology Co., Ltd., model: 85F92582-CN, the same below) and purified water.

[0043] 4.2 Use a laboratory high-efficiency coating machine to coat the plain tablets with the coating liquid. The coating parameters are: inlet air temperature 45-50°C, tablet bed temperature 35-40°C, atomization pressure 0.1-0.15MPa, flattening pressure 0.1-0.12MPa, and coating weight gain 4%.

[0044] Example 2

[0045] 1. Preprocessing

[0046] The raw material dapagliflozin was crushed and sieved by a jet mill (crushing pressure of 0.3MPa to 0.4MPa) to obtain a particle size of dapagliflozin: D 10 =1.50μm, D 50 =6.28μm, D 90 =13.49μm; Excipients: microcrystalline cellulose, anhydrous lactose, cross-linked polyvinylpyrrolidone, and magnesium stearate are sieved through 60 mesh sieves respectively for later use.

[0047] 2. Mix

[0048] 2.1 In a mixing hopper, mix 10 g of dapagliflozin and 10 g of microcrystalline cellulose evenly according to 1000 dosage units, add 50 g of lactose and 3 g of silicon dioxide and mix evenly, add the remaining 160 g of microcrystalline cellulose and 5 g of cross-linked polyvinylpyrrolidone and mix evenly, then add 1.25 g of magnesium stearate and mix evenly to obtain an intermediate.

[0049] 3. Tablet pressing

[0050] The tablet weight is determined according to the intermediate test results, the mixed powder is added to the tablet press, and a round 9mm punch is used for tableting. The hardness of the plain tablet is 7-11kg; the tablet weight difference is ±5.0%.

[0051] 4. Coating

[0052] 4.1 Prepare a coating solution with a concentration of 18% by mixing the gastric soluble film coating premix with purified water.

[0053] 4.2 Use a laboratory high-efficiency coating machine to coat the plain tablets with the coating liquid. The coating parameters are: inlet air temperature 45-50°C, tablet bed temperature 35-40°C, atomization pressure 0.1-0.15MPa, flattening pressure 0.1-0.12MPa, and coating weight gain 4%.

[0054] Example 3

[0055] 1. Preprocessing

[0056] The raw material dapagliflozin was crushed and sieved by a jet mill (crushing pressure of 0.3MPa to 0.4MPa) to obtain a particle size of dapagliflozin: D 10 =1.02μm, D 50 =7.19μm, D 90 =13.11 μm; Excipients: microcrystalline cellulose, anhydrous lactose, cross-linked polyvinylpyrrolidone, and magnesium stearate are sieved through 60 mesh sieves respectively for later use.

[0057] 2. Mix

[0058] 2.1 In a mixing hopper, mix 10 g of dapagliflozin and 10 g of microcrystalline cellulose evenly according to 1000 dosage units, add 50 g of lactose and 3 g of silicon dioxide and mix evenly, add the remaining 160 g of microcrystalline cellulose and 5 g of cross-linked polyvinylpyrrolidone and mix evenly, then add 1.25 g of magnesium stearate and mix evenly to obtain an intermediate.

[0059] 3. Tablet pressing

[0060] The tablet weight is determined according to the intermediate test results, the mixed powder is added to the tablet press, and a round 9mm punch is used for tableting. The hardness of the plain tablet is 7-11kg; the tablet weight difference is ±5.0%.

[0061] 4. Coating

[0062] 4.1 Prepare a coating solution with a concentration of 18% by mixing the gastric soluble film coating premix with purified water.

[0063] 4.2 Use a laboratory high-efficiency coating machine to coat the plain tablets with the coating liquid. The coating parameters are: inlet air temperature 45-50°C, tablet bed temperature 35-40°C, atomization pressure 0.1-0.15MPa, flattening pressure 0.1-0.12MPa, and coating weight gain 4%.

[0064] Comparative Example 1

[0065] 1. Preprocessing

[0066] The raw material dapagliflozin was crushed and sieved by a jet mill (crushing pressure of 0.3MPa to 0.4MPa) to obtain a particle size of dapagliflozin: D 10 =6.18μm, D 50=16.45μm, D 90 =27.11 μm; Excipients: microcrystalline cellulose, anhydrous lactose, cross-linked polyvinylpyrrolidone, and magnesium stearate are sieved through 60 mesh sieves respectively for later use.

[0067] 2. Mix

[0068] 2.1 In a mixing hopper, mix 10 g of dapagliflozin and 10 g of microcrystalline cellulose evenly according to 1000 dosage units, add 50 g of lactose and 3 g of silicon dioxide and mix evenly, add the remaining 160 g of microcrystalline cellulose and 5 g of cross-linked polyvinylpyrrolidone and mix evenly, then add 1.25 g of magnesium stearate and mix evenly to obtain an intermediate.

[0069] 3. Tablet pressing

[0070] The tablet weight is determined according to the intermediate test results, the mixed powder is added to the tablet press, and a round 9mm punch is used for tableting. The hardness of the plain tablet is 7-11kg; the tablet weight difference is ±5.0%.

[0071] 4. Coating

[0072] 4.1 Prepare a coating solution with a concentration of 18% by mixing the gastric soluble film coating premix with purified water.

[0073] 4.2 Use a laboratory high-efficiency coating machine to coat the plain tablets with the coating liquid. The coating parameters are: inlet air temperature 45-50°C, tablet bed temperature 35-40°C, atomization pressure 0.1-0.15MPa, flattening pressure 0.1-0.12MPa, and coating weight gain 4%.

[0074] Comparative Example 2

[0075] 1. Preprocessing

[0076] The raw material dapagliflozin was crushed and sieved by a jet mill (crushing pressure of 0.3MPa to 0.4MPa) to obtain a particle size of dapagliflozin: D 10 =1.53μm, D 50 =8.76μm, D 90 =14.02μm; Excipients: microcrystalline cellulose, anhydrous lactose, cross-linked polyvinylpyrrolidone, and magnesium stearate are sieved through 60 mesh sieves respectively for later use.

[0077] 2. Mix

[0078] 2.1 In a mixing hopper, mix 10g of dapagliflozin with 170g of microcrystalline cellulose, 50g of lactose, 3g of silicon dioxide and 5g of cross-linked polyvinylpyrrolidone according to 1000 dosage units, and then add 1.25g of magnesium stearate and mix well.

[0079] 3. Tablet pressing

[0080] The tablet weight is determined according to the intermediate test results, the mixed powder is added to the tablet press, and a round 9mm punch is used for tableting. The hardness of the plain tablet is 7-11kg; the tablet weight difference is ±5.0%.

[0081] 4. Coating

[0082] 4.1 Prepare a coating solution with a concentration of 18% by mixing the gastric soluble film coating premix with purified water.

[0083] 4.2 Use a laboratory high-efficiency coating machine to coat the plain tablets with the coating liquid. The coating parameters are: inlet air temperature 45-50°C, tablet bed temperature 35-40°C, atomization pressure 0.1-0.15MPa, flattening pressure 0.1-0.12MPa, and coating weight gain 4%.

[0084] Experimental Results

[0085] 1. Comparative study on the dissolution curves of dapagliflozin tablets prepared in Example 1 to Example 3 and Comparative Example 1 in in vitro dissolution media

[0086] Reference preparation: Dapagliflozin tablets (Andatang).

[0087] Detection method: pH 4.5 acetate buffer was used as the dissolution medium, the volume was 900 mL, the rotation speed was 50 revolutions per minute, and the operation was carried out according to the law. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 minutes respectively. The dissolution curve results are shown in Table 1.

[0088] Table 1. Summary of dissolution results

[0089]

[0090] 2. Mixing uniformity test of Example 1 and Comparative Example 2

[0091] Mixing uniformity detection method: Referring to the "Technical Guidance for the Study of Mixing Uniformity and Central Control Dosage Unit Uniformity of Chemical Oral Solid Preparations", samples were taken at 11 points in the mixing hopper to measure the content and calculate the RSD. The mixing uniformity results of Example 1 and Comparative Example 2 are shown in Table 2.

[0092] Table 2. Summary of mixing uniformity results

[0093]

[0094] 3. Example 1 Stability Study Long-term Experiment

[0095] Table 3. Summary of long-term stability results

[0096]

[0097]

[0098] Note: Impurity A: Impurity B: Impurity C:

[0099] It can be seen from the dissolution curve data and stability test results that the filler, disintegrant, lubricant and their dosage and addition method of the present invention are the best choice, the particle size control of the raw materials is within the best control range, and the quality of the prepared pharmaceutical composition is uniform and stable, which can meet the quality requirements.

[0100] It can be seen from the investigation results of mixing uniformity that it is necessary for the present invention to adopt an equal amount incremental mixing method, and only by adopting an equal amount incremental method can the intermediate mixing uniformity meet the requirements.

Claims

1. A pharmaceutical composition containing dapagliflozin, characterized in that: The pharmaceutical composition uses dapagliflozin as an active ingredient, and is prepared into a plain tablet from the following components by mass: 45-55 parts of dapagliflozin, 205-235 parts of a filler, 2-8 parts of a disintegrant, and 3-6.5 parts of a lubricant; and then the plain tablet is coated with a coating agent to obtain a tablet; wherein, dapagliflozin D 90 ≤20μm; the filler is a combination of microcrystalline cellulose and lactose; the lubricant is silicon dioxide and magnesium stearate.

2. The pharmaceutical composition containing dapagliflozin according to claim 1, characterized in that: The plain tablet is made of the following components in parts by weight: 5 to 10 parts of dapagliflozin, 45 to 55 parts of lactose, 160 to 180 parts of microcrystalline cellulose, 2 to 8 parts of disintegrant, 2 to 5 parts of silicon dioxide, and 1 to 1.5 parts of magnesium stearate.

3. The pharmaceutical composition containing dapagliflozin according to claim 2, characterized in that: The plain tablet is made of the following components in parts by weight: 10 parts of dapagliflozin, 50 parts of lactose, 170 parts of microcrystalline cellulose, 5 parts of disintegrant, 3 parts of silicon dioxide, and 1.25 parts of magnesium stearate.

4. The pharmaceutical composition containing dapagliflozin according to claim 1, characterized in that: The particle size range of dapagliflozin is: D 10 0~5μm, D 50 5~10μm, D 90 10 to 20 μm; preferably, the particle size range of dapagliflozin is: D 10 0~3μm, D 50 5~8μm, D 90 It is 10 to 15 μm.

5. The pharmaceutical composition containing dapagliflozin according to any one of claims 1 to 3, characterized in that: The plain tablets are prepared by first mixing dapagliflozin with an equal mass of microcrystalline cellulose, then mixing with lactose and silicon dioxide, then adding the remaining microcrystalline cellulose and disintegrant, and finally adding magnesium stearate to the mixture and tableting.

6. The pharmaceutical composition containing dapagliflozin according to any one of claims 1 to 3, characterized in that: The disintegrant is cross-linked polyvinylpyrrolidone; and the coating agent is a gastric soluble film coating premix.

7. The pharmaceutical composition containing dapagliflozin according to any one of claims 1 to 3, characterized in that: The plain tablets are coated with a coating agent until the coating weight gain is 3% to 5%.

8. A method for preparing the pharmaceutical composition containing dapagliflozin according to claim 1, characterized in that: The following steps are involved: Step (1), pretreatment: dapagliflozin is subjected to air flow grinding and sieving, and the filler, disintegrant, and lubricant are sieving respectively; Step (2), mixing: using an equal amount of progressive mixing method, dapagliflozin is mixed evenly with an equal amount of microcrystalline cellulose, then mixed evenly with lactose and silicon dioxide, then the remaining microcrystalline cellulose and disintegrant are added and mixed evenly, and finally magnesium stearate is added and mixed to obtain a mixed powder; Step (3), tableting: adding the mixed powder obtained in step (2) into a tablet press to obtain a plain tablet; Step (4), coating: a coating agent and purified water are prepared into a coating solution, and the plain tablets obtained in step (3) are coated to obtain dapagliflozin tablets.

9. The method for preparing the pharmaceutical composition containing dapagliflozin according to claim 8, characterized in that: In step (1), dapagliflozin is subjected to air flow pulverization using an air flow mill, and the pressure of the air flow pulverization is 0.2MPa-0.5MPa, preferably 0.3MPa-0.4MPa; the filler, disintegrant, and lubricant are respectively sieved through a 60-mesh sieve; in step (3), a 9mm round punch is used for tableting, the hardness of the plain tablet is 7-11kg, and the tablet weight difference is: ±5.0%.

10. The method for preparing the pharmaceutical composition containing dapagliflozin according to claim 8, characterized in that: In step (4), the concentration of the coating solution is 10% to 20%.

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