Empagliflozin and metformin compound sustained-release granule and preparation method thereof

Abstract

The invention discloses empagliflozin and metformin compound sustained-release granules and a preparation method thereof.The empagliflozin and metformin compound sustained-release granules comprise empagliflozin quick-release granules and metformin sustained-release coating granules, each metformin sustained-release coating granule comprises a core layer and a coating layer, the core layer is a mixture of metformin hydrochloride, an adhesive and sodium polystyrene sulfonate, and the coating layer is a mixture of metformin hydrochloride, an adhesive and sodium polystyrene sulfonate. The sodium polystyrenesulfonate accounts for 10%-30% of the total weight of the metformin sustained-release coated granules; the coating layer is a mixed material of polyvinyl acetate, triacetin and Tween 80, and the mass ratio of polyvinyl acetate to triacetin to Tween 80 is (75-85): (10-15): (5-10). Sodium polystyrenesulfonate and metformin hydrochloride are mixed and then coated with the coating layer, so that the bitter taste of metformin hydrochloride can be completely covered.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and specifically relates to empagliflozin metformin compound sustained-release granules and a preparation method thereof. Background Art

[0002] The statements herein merely provide background information related to the present invention and do not necessarily constitute prior art.

[0003] Empagliflozin metformin combination preparation is a hypoglycemic drug, and its marketed dosage form is tablets. Currently, there is no empagliflozin metformin sustained-release combination granules on the market.

[0004] The existing combination preparation of empagliflozin and metformin hydrochloride has a large size and bitter taste of metformin hydrochloride, which makes its tablets and / or capsules difficult to swallow and has poor compliance.

[0005] The existing production process of empagliflozin and metformin hydrochloride compound preparations is complicated, requiring tableting or filling into capsules, long equipment debugging time, and high production costs. In addition, batch-to-batch or intra-batch differences are prone to occur during tableting or capsule filling, resulting in poor reproducibility. Summary of the invention

[0006] In view of the deficiencies in the prior art, the object of the present invention is to provide an empagliflozin metformin compound sustained-release granules and a preparation method thereof.

[0007] In order to achieve the above object, the present invention is implemented through the following technical solutions:

[0008] In a first aspect, the present invention provides an empagliflozin metformin compound sustained-release granules, comprising empagliflozin immediate-release granules and metformin sustained-release coated granules, wherein:

[0009] The metformin sustained-release coated particles include a core layer and a coating layer, wherein the core layer is a mixture of metformin hydrochloride, a binder and a sustained-release material, and the sustained-release material accounts for 10%-30% of the total weight of the metformin sustained-release coated particles; the sustained-release material is sodium polystyrene sulfonate or calcium polystyrene sulfonate;

[0010] The coating layer is a mixed material of a coating material, a plasticizer and a solubilizer, and the mass ratio of the coating material, the plasticizer and the solubilizer is 75-85:10-15:5-10.

[0011] After sodium polystyrene sulfonate is mixed with metformin hydrochloride and then coated with a coating layer, the bitter taste of metformin hydrochloride can be completely covered up.

[0012] In some embodiments, the coating material is polyvinyl acetate, polyacrylic acid resin type E or polyvinyl alcohol, preferably polyvinyl acetate.

[0013] In some embodiments, the plasticizer is triacetin, polyethylene glycol, castor oil or triethyl citrate, preferably triacetin.

[0014] In some embodiments, the solubilizing agent is Tween 80 or sodium dodecyl sulfate, preferably Tween 80.

[0015] Polyvinyl acetate is a coating material with good film-forming properties; acetin is a plasticizer that can improve the fluidity of the coating solution and enhance the wear resistance and softness of the coating film; Tween 80 is a solubilizer that can increase the solubility of the coating material and shorten the dissolution time.

[0016] In some embodiments, the binder is hypromellose, sodium carboxymethylcellulose, povidone, or ethylcellulose.

[0017] Preferably, the binder is povidone and / or hypromellose.

[0018] The experiments showed that the addition of adhesives such as povidone and hydroxypropyl methylcellulose can synergistically control the sustained-release effect.

[0019] This product selected the oral compound preparation empagliflozin metformin sustained-release tablets as the reference preparation, and the original drug Synjardy XR, whose licensee is Boehringer Ingelheim Pharmaceuticals Inc, as the reference preparation. This product has the same release mechanism as the reference preparation: the empagliflozin component is immediate release, and the metformin hydrochloride component is sustained release. The release process of this product in vivo is evaluated by the similarity of the dissolution curve with the reference preparation.

[0020] Further preferably, the binder accounts for 1%-5% of the mass of the metformin sustained-release coated particles.

[0021] In some embodiments, the mass of the coating layer accounts for 25%-50% of the mass of the metformin sustained-release coated particles.

[0022] In some embodiments, the weight of a single metformin extended-release coated particle is 1800-3000 mg.

[0023] In some embodiments, the empagliflozin immediate-release granules are composed of the following components, measured by mass: 2-8 parts of empagliflozin; 70-85 parts of diluent; 2-10 parts of binder; 0.01-1 parts of flavoring agent; 1-10 parts of suspending agent; 0.5-8 parts of lubricant; and 0.3-4 parts of deflocculant.

[0024] In some embodiments, the particle size of the empagliflozin immediate-release granules is such that the total mass of the granules that cannot pass through a 20-mesh sieve and the granules that can pass through a 150-mesh sieve shall not exceed 15%; the particle size of the metformin sustained-release coated granules is such that the total mass of the granules that cannot pass through a 20-mesh sieve and the granules that can pass through an 80-mesh sieve shall not exceed 10%.

[0025] The role of the diluent is to increase the volume of the main drug to increase the cohesion and fluidity of the prescription composition and release the drug smoothly.

[0026] The function of lubricant is to reduce the direct friction between particles and increase the fluidity of particles.

[0027] The empagliflozin immediate-release granules and metformin sustained-release coated granules prepared in the present invention have a small particle size and generally need to be taken with water. It has been found through preliminary experiments that the empagliflozin immediate-release granules and metformin sustained-release coated granules are easy to sink in water, and the empagliflozin immediate-release granules are easy to sink and aggregate and agglomerate, with poor fluidity and not easy to take. Therefore, two components, a suspending agent and a deflocculant, are added. The function of the suspending agent is to prevent the particles from sinking when the drug is taken, so that the drug has good fluidity, is easy to pour and take. The function of the deflocculant is to prevent the drug from agglomerating when taken, increase the dispersibility of the particles in water, and make it easy to take.

[0028] In some embodiments, the diluent is starch, dextrin, microcrystalline cellulose, dibasic calcium phosphate, or mannitol.

[0029] Preferably, the diluent is starch or microcrystalline cellulose.

[0030] In some embodiments, the binder is hypromellose, povidone, or starch slurry.

[0031] In some embodiments, the deflocculant is citric acid or D-malic acid.

[0032] In some embodiments, the flavoring agent is sucralose, sodium saccharin, or stevioside.

[0033] Preferably, the flavoring agent is sucralose.

[0034] In some embodiments, the suspending agent is sodium carboxymethylcellulose, microcrystalline cellulose-sodium carboxymethylcellulose, methylcellulose, tragacanth gum or sodium alginate.

[0035] In some embodiments, the lubricant is colloidal silicon dioxide.

[0036] Colloidal silica is prepared by vapor phase hydrolysis of chlorosilanes.

[0037] In some embodiments, the mass of a single empagliflozin immediate-release granule is 200-1000 mg.

[0038] In a second aspect, the present invention provides a method for preparing the empagliflozin metformin compound sustained-release granules, comprising the following steps:

[0039] The metformin hydrochloride, the binder and the sodium polystyrene sulfonate are uniformly mixed in proportion, and after granulation, the granules are coated with a mixed solution of polyvinyl acetate, triacetin and Tween 80 to obtain metformin sustained-release coated granules;

[0040] After empagliflozin, a deflocculant, a flavoring agent and a diluent are mixed in proportion, a binder is added and mixed to form granules, and then the granules are mixed with a suspending agent and a lubricant in proportion to obtain empagliflozin immediate-release granules;

[0041] Just pack the metformin sustained-release coated granules and empagliflozin immediate-release granules.

[0042] The beneficial effects achieved by one or more embodiments of the present invention are as follows:

[0043] Sodium polystyrene sulfonate and metformin hydrochloride are combined through chemical bonds to form a drug resin salt complex. After the complex reaches equilibrium in the high-electrolyte gastrointestinal environment in the body, it begins to release the drug, making the drug release smooth and avoiding sudden drug release.

[0044] The addition of binders such as povidone and hypromellose can synergistically control the sustained-release effect.

[0045] After sodium polystyrene sulfonate is combined with metformin hydrochloride, it is coated with powder, which can completely mask the bitter taste of metformin hydrochloride; at the same time, an appropriate amount of flavoring agent is added to the Engelijk granules, which tastes good and greatly improves patient compliance.

[0046] The preparation process is simplified: no tablet pressing or capsule filling is required, which greatly improves production efficiency.

[0047] The method of administration has been improved. It can be taken with warm water and is easier to swallow.

[0048] The production of different specifications only requires adjusting the weight during filling, which saves the adjustment of prescriptions and equipment between different specifications. The production process is simple and has good reproducibility, avoiding differences between batches and within batches. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0050] Figure 1 This is the dissolution curve of metformin hydrochloride in implementation case 1 (pH 6.8);

[0051] Figure 2 This is the dissolution curve of empagliflozin (pH 6.8) in implementation case 1;

[0052] Figure 3This is the dissolution curve of metformin hydrochloride (pH 6.8) in implementation case 2;

[0053] Figure 4 This is the dissolution curve of empagliflozin (pH 6.8) in implementation case 2;

[0054] Figure 5 This is the dissolution curve of metformin hydrochloride (pH 6.8) in implementation case 3;

[0055] Figure 6 Implementation case 3- dissolution curve of empagliflozin (pH 6.8). DETAILED DESCRIPTION

[0056] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0057] The present invention will be further described below in conjunction with the embodiments.

[0058] Example 1

[0059] Table 1

[0060]

[0061]

[0062] (II) Preparation process:

[0063] 1. Metformin sustained-release coated granules:

[0064] ① Premixing: Add metformin hydrochloride and sodium polystyrene sulfonate into a wet mixing granulator, with the stirring blade speed at 120 rpm and the cutting blade speed at 300 rpm, and mix for 5 minutes;

[0065] ② Granulation: Add purified water to povidone K25 to prepare a 15% povidone solution as a binder, add it into a wet granulation mixer to make soft material, the stirring paddle speed is 150rpm, the cutting knife speed is 1200rpm, the wetting agent addition rate is 70g / min, the atomization pressure is 0.04MPa, and after the addition of the binder, continue granulation for 3min, and pass the soft material through a 4*4mm square hole crushing and granulating machine for wet granulation;

[0066] ③ Drying: Fluidized bed air inlet temperature 55℃, air volume 65m 3 / h, add wet granules after preheating for 10 minutes, the material temperature does not exceed 45℃, and dry to moisture ≤3%.

[0067] ④ Granulation: Granulate through a 1.5mm round hole crushing and granulating machine to obtain metformin sustained-release granules

[0068] ⑤Prepare coating solution: dissolve the prescribed amount of polyvinyl acetate, triacetin and Tween 80 in an appropriate amount of purified water to prepare a solution with a coating powder solid content of 10%, and set aside.

[0069] ⑥Coating: Fluidized bed air inlet temperature 60℃, 1500m 3 / h, add metformin sustained-release granules after preheating for 10 minutes, when the material temperature reaches above 40°C, turn on the peristaltic pump and liquid adding spray gun, control the atomization pressure to 0.2MPa, the spray speed to 200g / min, and the material temperature to 45°C. After the spraying is completed, continue to dry to a moisture content of ≤4%. The dry granules are sieved through 18-mesh and 80-mesh sieves, and the granules with intermediate particle size are taken for later use.

[0070] ③ Add the sieved dry granules into a universal mixer, add microcrystalline cellulose 302, cross-linked polyvinylpyrrolidone, and magnesium stearate converted according to the weight of the dry granules, and mix for 10 minutes at a speed of 10 rpm on the main shaft and 10 rpm on the secondary shaft to obtain empagliflozin immediate-release coated mixed granules.

[0071] 2. Preparation of Empagliflozin Immediate-Release Granules:

[0072] ① Premixing: Add empagliflozin, citric acid, sucralose, povidone K25 and starch into a wet mixing granulator, with the stirring blade speed at 120 rpm and the cutting blade speed at 300 rpm, and mix for 15 min;

[0073] ② Granulation: Use purified water with a weight of 15% of the total weight of the premixed material as a wetting agent, add it into the wet granulation mixer to make soft material, the stirring paddle speed is 150rpm, the cutting knife speed is 1200rpm, the wetting agent addition rate is 60g / min, the atomization pressure is 0.04MPa, and continue granulation for 3min after the wetting agent is added. Pass the soft material through a 4*4mm square hole crushing and granulating machine for wet granulation;

[0074] ③ Drying: Fluidized bed air inlet temperature 50℃, air volume 60m 3 / h, add wet granules after preheating for 10 minutes, the material temperature does not exceed 40℃, and dry to moisture ≤4%.

[0075] ④ Granulation: Granulate through a 1.0mm round hole crusher.

[0076] ⑤ Total mixing: Add the whole granules into a universal mixer, add the prescribed amount of microcrystalline cellulose-sodium carboxymethyl cellulose and colloidal silicon dioxide, set the main shaft to 10 rpm and the secondary shaft to 10 rpm, mix for 10 minutes, and obtain empagliflozin immediate-release granules.

[0077] 3. Packaging

[0078] A dual-channel granule filling and sealing machine was used to adjust the weight of metformin coated granules and empagliflozin immediate-release granules respectively before filling and sealing.

[0079] In each package, the mass of metformin coated granules: group 1 is 1.95g, group 2 is 2.36g, group 3 is 2.8g, group 4 is 2.54g, and group 5 is 2.48g; the mass of Engelijk immediate-release granules: group 1 is 0.9g, group 2 is 0.9g, group 3 is 0.95g, group 4 is 1g, and group 5 is 1.05g.

[0080] The dissolution curve of the prepared metformin sustained-release coated granules is as follows: Figure 1 As shown, the reference preparation is Synjardy XR, the license holder is Boehringer Ingelheim Pharmaceuticals Inc., the manufacturer is Boehringer Ingelheim Pharma GmbH & Co. KG, and the auxiliary materials of the reference preparation include: tablet core: polyoxyethylene, hydroxypropyl methylcellulose, magnesium stearate; film coating and ink: hydroxypropyl methylcellulose, titanium dioxide, polydextrose, polyethylene glycol, talcum powder, carnauba wax, purified water, iron oxide, propylene glycol, isopropyl alcohol, FD&C blue #2, iron oxide yellow (only 25mg / 1000mg specification), batch number 3200323. It can be seen that the dissolution curve of metformin hydrochloride in the metformin sustained-release coated granules prepared in Example 1 is highly consistent with the dissolution curve of the reference preparation, and has a good sustained-release performance.

[0081] The dissolution curve of empagliflozin in the prepared empagliflozin immediate-release granules is as follows: Figure 2 As shown, the dissolution curve of the preparation is highly consistent with that of the reference preparation.

[0082] Taste test of compound granules: take one pack of medicine prepared from group 1, group 2, group 3, group 4 and group 5 respectively, add about 100 ml of warm water respectively and stir evenly, randomly select 20 people (with normal taste and able to distinguish taste normally) to test the taste, start timing after the medicine liquid enters the mouth, stay for 30 seconds before spitting it out, and record the bitterness level.

[0083] Bitterness evaluation level: 1. No bitterness, 2. Almost no bitterness, 3. Slightly bitter, 4. Moderately bitter, 5. Strongly bitter. The test results of Group 1, Group 2, Group 3, Group 4 and Group 5 are shown in Table 2-1, Table 2-2, Table 2-3, Table 2-4 and Table 2-5, respectively.

[0084] Table 2-1

[0085] serial number 1 2 3 4 5 6 7 8 9 10 Bitterness level Level 1 Level 1 Level 2 Level 1 Level 1 Level 1 Level 1 Level 2 Level 1 Level 1 serial number 11 12 13 14 15 16 17 18 19 20 Bitterness level Level 1 Level 1 Level 1 Level 1 Level 1 Level 1 Level 1 Level 1 Level 1 Level 1

[0086] Table 2-2

[0087] serial number 1 2 3 4 5 6 7 8 9 10 Bitterness level Level 1 Level 1 Level 1 Level 1 Level 2 Level 1 Level 1 Level 1 Level 1 Level 1 serial number 11 12 13 14 15 16 17 18 19 20 Bitterness level Level 1 Level 1 Level 1 Level 1 Level 2 Level 1 Level 1 Level 2 Level 1 Level 1

[0088] Table 2-3

[0089] serial number 1 2 3 4 5 6 7 8 9 10 Bitterness level Level 1 Level 1 Level 1 Level 1 Level 1 Level 2 Level 1 Level 1 Level 1 Level 1 serial number 11 12 13 14 15 16 17 18 19 20 Bitterness level Level 1 Level 1 Level 1 Level 1 Level 2 Level 1 Level 1 Level 1 Level 1 Level 1

[0090] Table 2-4

[0091] serial number 1 2 3 4 5 6 7 8 9 10 Bitterness level Level 1 Level 1 Level 2 Level 1 Level 1 Level 1 Level 1 Level 2 Level 1 Level 1 serial number 11 12 13 14 15 16 17 18 19 20 Bitterness level Level 1 Level 1 Level 1 Level 2 Level 1 Level 1 Level 1 Level 1 Level 1 Level 1

[0092] Table 2-5

[0093] serial number 1 2 3 4 5 6 7 8 9 10 Bitterness level Level 1 Level 1 Level 2 Level 1 Level 1 Level 1 Level 1 Level 1 Level 1 Level 1 serial number 11 12 13 14 15 16 17 18 19 20 Bitterness level Level 1 Level 1 Level 2 Level 1 Level 1 Level 1 Level 2 Level 1 Level 1 Level 1

[0094] The above data show that the compound granules prepared according to Example 1 have good taste masking effect.

[0095] Example 2

[0096] Table 3

[0097]

[0098] (II) Preparation process:

[0099] 1. Metformin sustained-release coated granules:

[0100] ① Premixing: Add metformin hydrochloride, sodium polystyrene sulfonate and hypromellose into a wet mixing granulator, with the stirring blade rotating at 120 rpm and the cutting blade rotating at 300 rpm, and mix for 10 min;

[0101] ② Granulation: Use purified water with a weight of 15% of the total weight of the premixed materials as a wetting agent to prepare the soft material in a wet granulation mixer, with a stirring blade speed of 150rpm, a cutting blade speed of 1200rpm, a wetting agent addition rate of 60g / min, and an atomization pressure of 0.04MPa. After the wetting agent is added, continue granulation for 3min, and pass the soft material through a 4*4mm square hole crushing and granulating machine for wet granulation;

[0102] ③ Drying: Fluidized bed air inlet temperature 55℃, air volume 65m 3 / h, add wet granules after preheating for 10 minutes, the material temperature does not exceed 45℃, and dry to moisture ≤3%.

[0103] ④ Granulation: Granulate through a 1.5mm round hole crushing and granulating machine to obtain metformin sustained-release granules

[0104] ⑤Prepare coating solution: dissolve the prescribed amount of polyvinyl acetate, triacetin and Tween 80 in an appropriate amount of purified water to prepare a solution with a coating powder solid content of 10%, and set aside.

[0105] ⑥Coating: Fluidized bed air inlet temperature 60℃, 1500m 3 / h, add metformin sustained-release granules after preheating for 10 minutes, when the material temperature reaches above 40°C, turn on the peristaltic pump and liquid adding spray gun, control the atomization pressure to 0.3MPa, the spray speed to 200g / min, and the material temperature to 45°C. After the spraying is completed, continue to dry to a moisture content of ≤4%. The dry granules are sieved through 18-mesh and 80-mesh sieves, and the granules with intermediate particle size are taken for later use.

[0106] ③ Add the sieved dry granules into a universal mixer, add microcrystalline cellulose 302, cross-linked polyvinylpyrrolidone, and magnesium stearate converted according to the weight of the dry granules, and mix for 10 minutes at a speed of 10 rpm on the main shaft and 10 rpm on the secondary shaft to obtain empagliflozin immediate-release coated mixed granules.

[0107] 2. Preparation of Empagliflozin Immediate-Release Granules:

[0108] ① Premixing: Add empagliflozin, citric acid, sucralose and microcrystalline cellulose into a wet mixing granulator, with the stirring blade speed at 120 rpm and the cutting blade speed at 300 rpm, and mix for 15 min;

[0109] ② Granulation: Prepare starch slurry with 10% solid content by slurry slurry, add it into wet granulation mixer to make soft material, stir the paddle speed at 150rpm, cutter speed at 1200rpm, wetting agent adding speed at 60g / min, atomization pressure at 0.04MPa, continue granulation for 3min after wetting agent is added, and pass the soft material through 4*4mm square hole crushing and granulating machine for wet granulation;

[0110] ③ Drying: Fluidized bed air inlet temperature 50℃, air volume 60m 3 / h, add wet granules after preheating for 10 minutes, the material temperature does not exceed 40℃, and dry to moisture ≤4%.

[0111] ④ Granulation: Granulate through a 1.0mm round hole crusher.

[0112] ⑤ Total mixing: Add the whole granules into a universal mixer, add the prescribed amount of microcrystalline cellulose-sodium carboxymethyl cellulose and colloidal silicon dioxide, set the main shaft to 10 rpm and the secondary shaft to 10 rpm, mix for 10 minutes, and obtain empagliflozin immediate-release granules.

[0113] 3. Packaging

[0114] A dual-channel granule filling and sealing machine was used to adjust the weight of metformin coated granules and Engelijk immediate-release granules respectively before filling and sealing.

[0115] In each package, the mass of metformin coated granules is: 2.6g for group 1, 2.6g for group 2, and 2.25g for group 3; the mass of Engelijk immediate-release granules is: 0.45g for group 1, 0.5g for group 2, and 0.5g for group 3.

[0116] The dissolution curve of the prepared metformin sustained-release coated granules is as follows: Figure 3 As shown, the reference preparation is Synjardy XR, the licensee is Boehringer Ingelheim Pharmaceuticals Inc, the manufacturer is Boehringer Ingelheim Pharma GmbH & Co. KG, and the auxiliary materials of the reference preparation include: tablet core: polyoxyethylene, hydroxypropyl methylcellulose, magnesium stearate; film coating and ink: hydroxypropyl methylcellulose, titanium dioxide, polydextrose, polyethylene glycol, talc, carnauba wax, purified water, iron oxide, propylene glycol, isopropyl alcohol, FD&C blue #2, iron oxide yellow (only 25mg / 1000mg specification), batch number 3200323. It can be seen that the dissolution curve of metformin hydrochloride in the metformin sustained-release coated granules prepared in Example 2 is highly consistent with the dissolution curve of the reference preparation, and has good sustained-release performance.

[0117] The dissolution curve of empagliflozin in the prepared empagliflozin immediate-release granules is as follows: Figure 4 As shown, the dissolution curve of the preparation is highly consistent with that of the reference preparation.

[0118] Taste test of compound granules: Take 1 pack of the medicine prepared in Group 1, Group 2 and Group 3 respectively, add about 100 ml of warm water and stir to mix, randomly select 20 people (with normal taste and able to distinguish taste normally) to test the taste, start timing after the medicine liquid enters the mouth, stay for 30 seconds before spitting it out, and record the bitterness level.

[0119] Bitterness evaluation level: 1. No bitterness, 2. Almost no bitterness, 3. Slightly bitter, 4. Moderately bitter, 5. Strongly bitter. The specific results are shown in Tables 4-1, 4-2 and 4-3.

[0120] Table 4-1

[0121] serial number 1 2 3 4 5 6 7 8 9 10 Bitterness level Level 1 Level 1 Level 1 Level 1 Level 1 Level 1 Level 1 Level 1 Level 2 Level 1 serial number 11 12 13 14 15 16 17 18 19 20 Bitterness level Level 1 Level 1 Level 1 Level 1 Level 1 Level 2 Level 1 Level 1 Level 1 Level 1

[0122] Table 4-2

[0123] serial number 1 2 3 4 5 6 7 8 9 10 Bitterness level Level 1 Level 1 Level 1 Level 2 Level 1 Level 1 Level 1 Level 1 Level 1 Level 1 serial number 11 12 13 14 15 16 17 18 19 20 Bitterness level Level 1 Level 1 Level 1 Level 2 Level 1 Level 2 Level 1 Level 1 Level 1 Level 1

[0124] Table 4-3

[0125] serial number 1 2 3 4 5 6 7 8 9 10 Bitterness level Level 1 Level 1 Level 1 Level 1 Level 1 Level 2 Level 1 Level 1 Level 2 Level 1 serial number 11 12 13 14 15 16 17 18 19 20 Bitterness level Level 1 Level 1 Level 1 Level 2 Level 1 Level 1 Level 1 Level 1 Level 1 Level 1

[0126] The above data show that the compound granules prepared according to Example 2 have good taste masking effect.

[0127] Comparative Example 1

[0128] Table 5

[0129]

[0130]

[0131] (II) Preparation process:

[0132] 1. Metformin sustained-release coated granules:

[0133] ① Premixing: Add metformin hydrochloride and sodium polystyrene sulfonate into a wet mixing granulator, with the stirring blade speed at 120 rpm and the cutting blade speed at 300 rpm, and mix for 10 minutes;

[0134] ② Granulation: Use purified water with a weight of 15% of the total weight of the premixed materials as a wetting agent to prepare the soft material in a wet granulation mixer, with a stirring blade speed of 150rpm, a cutting blade speed of 1200rpm, a wetting agent addition rate of 60g / min, and an atomization pressure of 0.04MPa. After the wetting agent is added, continue granulation for 3min, and pass the soft material through a 4*4mm square hole crushing and granulating machine for wet granulation;

[0135] ③ Drying: Fluidized bed air inlet temperature 55℃, air volume 65m 3 / h, add wet granules after preheating for 10 minutes, the material temperature does not exceed 45℃, and dry to moisture ≤3%;

[0136] ④ Granulation: Granulate through a 1.5 mm round hole crushing and granulation machine to obtain metformin sustained-release granules;

[0137] ⑤Prepare coating solution: dissolve the prescribed amount of polyvinyl acetate, triacetin and Tween 80 in an appropriate amount of purified water to prepare a solution with a coating powder solid content of 10%, and set aside;

[0138] ⑥Coating: Fluidized bed air inlet temperature 60℃, 1500m 3 / h, add metformin sustained-release granules after preheating for 10 minutes, when the material temperature reaches above 40°C, turn on the peristaltic pump and liquid adding spray gun, control the atomization pressure to 0.2MPa, the spray speed to 200g / min, and the material temperature to 45°C. After the spraying is completed, continue to dry to a moisture content of ≤4%. The dry granules are sieved through 18-mesh and 80-mesh sieves, and the granules with intermediate particle size are taken for later use.

[0139] ③ Add the sieved dry granules into a universal mixer, add microcrystalline cellulose 302, cross-linked polyvinylpyrrolidone, and magnesium stearate converted according to the weight of the dry granules, and mix for 10 minutes at a speed of 10 rpm on the main shaft and 10 rpm on the secondary shaft to obtain empagliflozin immediate-release coated mixed granules.

[0140] 2. Preparation of Empagliflozin Immediate-Release Granules:

[0141] ① Premixing: Add empagliflozin, citric acid, sucralose and microcrystalline cellulose into a wet mixing granulator, with the stirring blade speed at 120 rpm and the cutting blade speed at 300 rpm, and mix for 15 min;

[0142] ② Granulation: Prepare starch slurry with 10% solid content by slurry slurry, add it into wet granulation mixer to make soft material, stir the paddle speed at 150rpm, cutter speed at 1200rpm, wetting agent adding speed at 60g / min, atomization pressure at 0.04MPa, continue granulation for 3min after wetting agent is added, and pass the soft material through 4*4mm square hole crushing and granulating machine for wet granulation;

[0143] ③ Drying: Fluidized bed air inlet temperature 50℃, air volume 60m 3 / h, add wet granules after preheating for 10 minutes, the material temperature does not exceed 40℃, and dry to moisture ≤4%.

[0144] ④ Granulation: Granulate through a 1.0mm round hole crusher.

[0145] ⑤ Total mixing: Add the whole granules into a universal mixer, add the prescribed amount of microcrystalline cellulose-sodium carboxymethyl cellulose and colloidal silicon dioxide, set the main shaft to 10 rpm and the secondary shaft to 10 rpm, mix for 10 minutes, and obtain empagliflozin immediate-release granules.

[0146] 3. Packaging

[0147] A dual-channel granule filling and sealing machine was used to adjust the weight of metformin coated granules and Engelijk immediate-release granules respectively before filling and sealing;

[0148] In each package, the mass of metformin coated granules is 2.6g, and the mass of Engelijk immediate-release granules is 0.45g in Group 1 and 0.5g in Group 2.

[0149] The dissolution curve of the prepared metformin sustained-release coated granules is as follows: Figure 5 As shown, the reference preparation is Synjardy XR, the licensee is Boehringer Ingelheim Pharmaceuticals Inc, the manufacturer is Boehringer Ingelheim Pharma GmbH & Co. KG, and the auxiliary materials of the reference preparation include: tablet core: polyoxyethylene, hydroxypropyl methylcellulose, magnesium stearate; film coating and ink: hydroxypropyl methylcellulose, titanium dioxide, polydextrose, polyethylene glycol, talc, carnauba wax, purified water, iron oxide, propylene glycol, isopropyl alcohol, FD&C blue #2, iron oxide yellow (only 25mg / 1000mg specification), batch number 3200323. It can be seen that the dissolution curve of metformin hydrochloride in the metformin sustained-release coated granules prepared in Comparative Example 1 deviates far from the dissolution curve of the reference preparation, and the sustained-release effect is far inferior to that of the reference preparation.

[0150] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. An empagliflozin metformin compound sustained-release granules, characterized in that: It includes empagliflozin immediate-release granules and metformin sustained-release coated granules, among which, The metformin sustained-release coated particles include a core layer and a coating layer, wherein the core layer is a mixture of metformin hydrochloride, a binder and a sustained-release material, and the sustained-release material accounts for 10%-30% of the total weight of the metformin sustained-release coated particles; the sustained-release material is sodium polystyrene sulfonate or calcium polystyrene sulfonate; The coating layer is a mixed material of a coating material, a plasticizer and a solubilizer, and the mass ratio of the coating material, the plasticizer and the solubilizer is 75-85:10-15:5-10.

2. The empagliflozin metformin compound sustained-release granules according to claim 1, characterized in that: The coating material is polyvinyl acetate, polyacrylic acid resin type E or polyvinyl alcohol, preferably polyvinyl acetate; Or, the plasticizer is triacetin, polyethylene glycol, castor oil or triethyl citrate, preferably triacetin; Or, the solubilizing agent is Tween 80 or sodium dodecyl sulfate, preferably Tween 80; Preferably, the binder is hypromellose, sodium carboxymethylcellulose, povidone or ethyl cellulose; Preferably, the binder is povidone and / or hypromellose; Preferably, the binder accounts for 1%-5% of the mass of the metformin sustained-release coated particles.

3. The empagliflozin metformin compound sustained-release granules according to claim 1, characterized in that: The mass of the coating layer accounts for 25%-50% of the mass of the metformin sustained-release coated particles.

4. The empagliflozin metformin compound sustained-release granules according to claim 1, characterized in that: The empagliflozin immediate-release granules are composed of the following components, measured by mass: 2-8 parts of empagliflozin; 70-85 parts of diluent; 2-10 parts of binder; 0.01-1 parts of flavoring agent; 1-10 parts of suspending agent; 0.5-8 parts of lubricant; and 0.3-4 parts of deflocculant.

5. The empagliflozin metformin compound sustained-release granules according to claim 4, characterized in that: The particle size of empagliflozin immediate-release granules is such that the sum of the mass that cannot pass through a 20-mesh sieve and the mass that can pass through a 150-mesh sieve shall not exceed 15%; The particle size of the metformin sustained-release coated granules is such that the total mass of the particles that cannot pass through a 20-mesh sieve and can pass through an 80-mesh sieve shall not exceed 10%.

6. The empagliflozin metformin compound sustained-release granules according to claim 4, characterized in that: The diluent is starch, dextrin, microcrystalline cellulose, calcium hydrogen phosphate or mannitol; Preferably, the diluent is starch or microcrystalline cellulose; The binder is hydroxypropyl methylcellulose, povidone or starch slurry.

7. The empagliflozin metformin compound sustained-release granules according to claim 4, characterized in that: The deflocculating agent is citric acid or D-malic acid.

8. The empagliflozin metformin compound sustained-release granules according to claim 4, characterized in that: The flavoring agent is sucralose, sodium saccharin or stevioside; Preferably, the flavoring agent is sucralose.

9. The empagliflozin metformin compound sustained-release granules according to claim 4, characterized in that: The suspending agent is sodium carboxymethylcellulose, microcrystalline cellulose-sodium carboxymethylcellulose, methylcellulose, tragacanth gum or sodium alginate; Preferably, the lubricant is colloidal silicon dioxide.

10. The method for preparing the empagliflozin metformin compound sustained-release granules according to any one of claims 1 to 9, characterized in that: The steps include: The metformin hydrochloride, the binder and the sodium polystyrene sulfonate are uniformly mixed in proportion, and after granulation, the granules are coated with a mixed solution of polyvinyl acetate, triacetin and Tween 80 to obtain metformin sustained-release coated granules; After empagliflozin, a deflocculant, a flavoring agent and a diluent are mixed in proportion, a binder is added and mixed to form granules, and then the granules are mixed with a suspending agent and a lubricant in proportion to obtain empagliflozin immediate-release granules; Just pack the metformin sustained-release coated granules and empagliflozin immediate-release granules.

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