Stable-dissolution dapagliflozin and metformin sustained release tablet and preparation method thereof

Abstract

The invention provides a dapagliflozin and metformin sustained-release tablet with stable dissolution and a preparation method of the dapagliflozin and metformin sustained-release tablet. Comprising the following steps: S1, respectively preparing metformin hydrochloride particles and dapagliflozin particles; s2, firstly tabletting and forming metformin hydrochloride particles, then adding dapagliflozin particles, and carrying out secondary tabletting, so as to obtain a dapagliflozin and metformin sustained-release tablet core; the mass ratio of the metformin hydrochloride particles to the dapagliflozin particles is (4-10): (0.1-1); and S3, coating the obtained tablet core with a coating solution to obtain the dapagliflozin and metformin sustained release tablet with stable dissolution. According to the dapagliflozin and metformin sustained release tablet, the RSD of the substance content of the metformin hydrochloride layer can reach 0.3%, the RSD of the substance content of the dapagliflozin layer can reach 0.1%, the sum of impurities of the metformin hydrochloride can not be detected, and the total impurity of the dapagliflozin can reach 0.06%. According to the invention, the process and the raw materials are optimally designed, so that the production link is simplified, and the problems of poor quality and the like caused by the distribution difference of the two effective components in the sustained release tablet are solved.

Description

Technical Field

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

[0002] Type 2 diabetes is a common chronic metabolic disease, characterized by insulin resistance and insufficient insulin secretion. This disease is usually closely related to obesity, poor eating habits, lack of exercise, genetic factors, etc. If type 2 diabetes is not effectively controlled, it may lead to serious complications, including cardiovascular diseases, renal failure, blindness, lower limb amputation, etc., posing a major threat to the life and health of patients.

[0003] There are a wide variety of existing drugs for the treatment of type 2 diabetes. The most common treatment methods include oral medications, insulin therapy, etc. Among oral medications, metformin and dapagliflozin are two commonly used drugs.

[0004] Metformin is a drug commonly used to treat type 2 diabetes. By reducing the production of glucose in the liver, increasing the uptake of glucose by peripheral tissues, and improving insulin resistance, it can effectively lower blood sugar levels. Metformin has good efficacy and safety, but common adverse reactions include gastrointestinal discomfort, such as nausea, vomiting, diarrhea, etc., especially in the initial stage of treatment. In order to reduce gastrointestinal adverse reactions, the sustained-release dosage form of metformin emerged. Its sustained-release characteristics help to reduce the peak concentration of the drug in the gastrointestinal tract, thus alleviating gastrointestinal discomfort.

[0005] Dapagliflozin is a selective SGLT2 inhibitor. By inhibiting the activity of sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubule of the kidney, it reduces the reabsorption of glucose in the kidney, promotes the excretion of glucose through urine, and thus achieves the effect of lowering blood sugar. In addition to controlling blood sugar, dapagliflozin also has a certain cardiovascular protection effect, which can reduce the risk of cardiovascular events. In addition, the renal protection effect of dapagliflozin has also received extensive attention, especially for diabetic patients with renal insufficiency, which has potential benefits.

[0006] In recent years, with the progress of diabetes treatment research, the development of compound drugs has become an important trend. Combining metformin and dapagliflozin can not only exert their respective pharmacological effects and synergistically control blood sugar levels, but also improve the treatment compliance of patients. Traditional metformin and dapagliflozin drugs usually need to be taken separately by patients in clinical applications, which not only increases the medication burden of patients, but also may affect the efficacy of the drugs and the compliance of patients. Therefore, developing a sustained-release tablet dosage form for the combination of the two to reduce the number of medication times of patients and improve the convenience of treatment has important clinical significance.

[0007] In the existing preparation process of dapagliflozin metformin sustained-release tablets, dry granulation is mostly used for dapagliflozin granules. The production cost is high and the process is complex through this kind of process, and the uniformity and dissolution of the product need to be improved.

[0008] In view of this, the present invention is specifically proposed. Summary of the Invention

[0009] The object of the present invention is to provide a preparation method of dapagliflozin metformin sustained-release tablets with stable dissolution. Aiming at the problems of complex preparation process and difficult to meet the requirements of product quality of the existing dapagliflozin metformin sustained-release tablets, through the optimized design of the process and raw materials, the present invention not only simplifies the production process, but also solves the problems such as large difference in tablet weight between dapagliflozin and metformin during the tabletting process, resulting in poor quality caused by the difference in the distribution of the two active ingredients in the sustained-release tablets.

[0010] To achieve the above object, the present invention provides a preparation method of dapagliflozin metformin sustained-release tablets with stable dissolution, including the following steps:

[0011] S1 Prepare metformin hydrochloride granules and dapagliflozin granules respectively;

[0012] S2 First, press the metformin hydrochloride granules into tablets, and then add the dapagliflozin granules for secondary tabletting to obtain the core of the dapagliflozin metformin sustained-release tablets; the mass ratio of the metformin hydrochloride granules to the dapagliflozin granules is (4 - 10):(0.1 - 1);

[0013] S3 Coat the obtained core with a coating solution to obtain the dapagliflozin metformin sustained-release tablets with stable dissolution;

[0014] In the prepared dapagliflozin metformin sustained-release tablets, the relative standard deviation of the metformin hydrochloride layer substance content can reach 0.3%, the relative standard deviation of the dapagliflozin layer substance content can reach 0.1%, and the total sum of metformin hydrochloride impurities can reach undetected, and the total impurities of dapagliflozin can reach 0.06%.

[0015] In a preferred embodiment, in step S1, the preparation of the dapagliflozin granules includes the following steps:

[0016] Mix anhydrous lactose, dapagliflozin, disintegrant and diluent for the first time until uniform. After sizing, add lubricant and mix for the second time until uniform to obtain.

[0017] In a preferred embodiment, in the step of preparing dapagliflozin granules, the mass ratio of dapagliflozin, anhydrous lactose, disintegrant, diluent and lubricant is (95 - 110):(500 - 515):(130 - 145):(1700 - 1710):(20 - 30); preferably, the mass ratio of dapagliflozin, anhydrous lactose, disintegrant, diluent and lubricant is (97 - 103):(506 - 512):(135 - 140):(1702 - 1706):(23 - 26), and more preferably, the mass ratio of dapagliflozin, anhydrous lactose, disintegrant, diluent and lubricant is 100:510:137:1705:25.

[0018] In a preferred embodiment, in the step of preparing dapagliflozin granules, the particle size of the anhydrous lactose is 80 - 120 mesh, and the particle size of the dapagliflozin is below 20 μm.

[0019] In a preferred embodiment, in the step of preparing dapagliflozin granules, the disintegrant includes at least one of corn starch, low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, colloidal silicon dioxide, microcrystalline cellulose or cross-linked carboxymethyl cellulose sodium.

[0020] In a preferred embodiment, in the step of preparing dapagliflozin granules, the diluent includes at least one of mannitol, corn starch, microcrystalline cellulose, lactose.

[0021] In a preferred embodiment, in the step of preparing dapagliflozin granules, the lubricant includes at least one of magnesium stearate, stearic acid or polyethylene glycol.

[0022] In a preferred embodiment, in step S1, the preparation of metformin hydrochloride granules includes the following steps:

[0023] (1) Metformin hydrochloride, binder and wetting agent are sequentially added into a high-shear wet granulator. After mixing evenly, wet screening is carried out, then it is placed in a fluidized bed for drying and then dry screening is carried out;

[0024] (2) After dry screening, a sustained-release agent, a disintegrant and a filler are added. After mixing evenly, a lubricant is added and mixed evenly again to obtain the product.

[0025] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, the mass ratio of metformin hydrochloride, binder, wetting agent, sustained-release agent, disintegrant, lubricant and filler is (9995 - 10007):(430 - 470):(1350 - 1470):(2845 - 2870):(130 - 150):(80 - 100):(0 - 400); preferably, the mass ratio of metformin hydrochloride, binder, wetting agent, sustained-release agent, disintegrant, lubricant and filler is (9998 - 10004):(440 - 460):(1380 - 1420):(2850 - 2865):(145 - 150):(87 - 95):(0 - 100); more preferably, the mass ratio of metformin hydrochloride, binder, wetting agent, sustained-release agent, disintegrant, lubricant and filler is 1000:45:140:286:15:9:0.

[0026] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (1), the particle size of the metformin hydrochloride is 90 - 200 μm.

[0027] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (1), the binder includes at least one of sodium carboxymethylcellulose, hydroxypropyl cellulose, methyl cellulose, and hypromellose.

[0028] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (1), the wetting agent includes at least one of purified water and ethanol.

[0029] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (1), after adding the metformin hydrochloride, the stirring conditions include: the stirring blade speed is 90 - 110 rpm, the cutter speed is 1000 - 1400 rpm, and the stirring time is 8 - 12 min; preferably, the stirring conditions include: the stirring blade speed is 100 rpm, the cutter speed is 1200 rpm, and the stirring time is 10 min.

[0030] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (1), after adding the binder, the stirring conditions include: the stirring blade speed is 100 - 140 rpm, the cutter speed is 1300 - 1700 rpm, and the stirring time is 3 - 7 min; preferably, the stirring conditions include: the stirring blade speed is 120 rpm, the cutter speed is 1500 rpm, and the stirring time is 5 min.

[0031] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (1), when the stirring blade speed is 90 - 110 rpm, the cutter speed is 1000 - 1400 rpm, and the atomization pressure of the wetting agent is 0.2 - 0.5 MPa, the wetting agent is added, and the addition time of the wetting agent does not exceed 3 min.

[0032] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (1), after adding the wetting agent, the stirring conditions include: stirring blade speed 90 - 110 rpm, cutter speed 1000 - 1400 rpm, stirring time 1 - 3 min; preferably, the stirring conditions include: stirring blade speed 100 rpm, cutter speed 1200 rpm, stirring time 2 min.

[0033] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (1), the screen specification for wet screening is 10 * 10 mm.

[0034] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (1), the fluidized bed drying conditions include: inlet air humidity 5.0 - 7.0 g / kg, fluidization air volume 800 - 1500 m 3 / h, loss on drying ≤ 3%.

[0035] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (1), the dry screening conditions include: using a 1.5 mm round hole V - shaped screen, and the speed of the dry screening machine is 500 - 600 rpm.

[0036] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (2), the sustained - release agent includes at least one of polyvinyl alcohol (PVA), hypromellose, liposome, microparticle, polyvinylpyrrolidone (PVP).

[0037] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (2), the disintegrant includes at least one of corn starch, low - substituted hydroxypropyl cellulose, crospovidone, colloidal silicon dioxide, sodium carboxymethyl starch, microcrystalline cellulose, or cross - linked carboxymethyl cellulose sodium.

[0038] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (2), the filler includes at least one of lactose and microcrystalline cellulose.

[0039] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (2), the lubricant includes at least one of magnesium stearate, stearic acid, or polyethylene glycol.

[0040] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (2), after adding the sustained-release agent and disintegrant, the mixing conditions include: a mixing rotation speed of 5 - 9 rpm and a mixing time of 8 - 12 min; preferably, the mixing conditions include: a mixing rotation speed of 7 rpm and a mixing time of 10 min.

[0041] In a preferred embodiment, in the step of preparing metformin hydrochloride granules, in step (2), after adding the lubricant, the mixing conditions include: a mixing rotation speed of 5 - 9 rpm and a mixing time of 2 - 4 min; preferably, the mixing conditions include: a mixing rotation speed of 7 rpm and a mixing time of 3 min.

[0042] In a preferred embodiment, in step S2, the punching die selected for tableting is a 20.3 mm * 10.8 mm oval punch or a 19.8 mm * 10.1 mm capsule-shaped punch.

[0043] In a preferred embodiment, in step S2, the hardness of the tablet core after tableting the metformin hydrochloride granules is 1.0 - 5.0 kg; the hardness of the tablet core of the dapagliflozin metformin sustained-release tablet is 20.0 - 40.0 kg, the weight difference is ±5%, and the friability is not more than 0.8%.

[0044] In a preferred embodiment, in step S3, the mass ratio of the coating solution to the tablet core of the dapagliflozin metformin sustained-release tablet is (0.03 - 0.05):1, and the preparation method of the coating solution includes the following steps: slowly adding the coating premix into purified water under stirring, stirring evenly, and filtering through a 200-mesh wire sieve to obtain it, wherein the mass ratio of the purified water to the coating premix is 1:(0.1 - 0.2); preferably, the mass ratio of the purified water to the coating premix is 1:0.15; more preferably, the coating premix used in the present invention includes any one of 85F12372-CN, 85F93339-CN, and 85F94333-CN.

[0045] Another object of the present invention is to provide a dapagliflozin metformin sustained-release tablet with stable dissolution prepared by any one of the above methods. The dapagliflozin metformin sustained-release tablet provided by the present invention effectively solves many problems such as the complex preparation method of the dapagliflozin metformin sustained-release tablet, the low dissolution rate of the obtained product, and high related substances through precise dosage form design, dosage ratio, and process optimization.

[0046] The obtained high-quality dapagliflozin metformin sustained-release tablet can simultaneously slowly release dapagliflozin and metformin, maintain the stability of blood drug concentration, minimize adverse reactions to the greatest extent, and improve the therapeutic effect. In addition, the use of the sustained-release dosage form helps to extend the action time of the drug in the body, reduce the dosing frequency, and thus improve the compliance and quality of life of patients.

[0047] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0048] 1. In the present invention, through the optimized design of the process and raw materials, dapagliflozin granules and metformin granules with uniform particle size are obtained. In the subsequent tabletting process, after the metformin hydrochloride granules are first tabletted into shape, the dapagliflozin granules are directly added for secondary tabletting, which can solve the problems of large difference in tablet weight between the two substances and uneven distribution of the two active ingredients in the sustained-release tablets.

[0049] 2. In the present invention, metformin hydrochloride adopts the wet granulation process and the lubricant is added as an external auxiliary material finally, which effectively improves the product quality and reduces the relative standard deviation of the substance content. The dapagliflozin granules adopt the secondary direct mixing process, and the obtained granules can be directly tabletted with the metformin hydrochloride tablets, which not only reduces the process difficulty, but also effectively improves the product quality and process compliance.

[0050] 3. The dapagliflozin metformin sustained-release tablets prepared by the process of the present invention have high dissolution rate, excellent quality, reliable stability, and very small differences between batches. Moreover, the related substances of the dapagliflozin metformin sustained-release tablets are low, which not only indicates the high purity of the drug but also demonstrates excellent drug dissolution performance. Specific Embodiments

[0051] In order to enable those skilled in the art to better understand the present invention, the present invention will be further described in detail below in conjunction with specific embodiments. However, it should be understood that the protection scope of the present invention is not limited by the specific embodiments.

[0052] The embodiments of the present invention provide a method for preparing a dapagliflozin metformin sustained-release tablet with stable dissolution, which solves the problems of complex preparation method, low production efficiency, and poor product quality of the dapagliflozin metformin sustained-release tablet in the prior art.

[0053] The technical solution of the present application will be described in detail below through specific embodiments:

[0054] Unless otherwise specified, the technical means used in the present invention are conventional means well known to those skilled in the art. All kinds of raw materials, reagents, instruments, and equipment used in the present invention can be obtained through the market or can be prepared by existing methods. The reagents used in the present invention are of analytical purity unless otherwise specified. In the embodiments of the present invention, the particle size of the anhydrous lactose used is 80-120 mesh, the particle size of the dapagliflozin used is below 20 μm, and the coating premix is purchased from Shanghai Colorcon Coating Technology Co., Ltd., with the model number 85F93339-CN.

[0055] In the present invention, parts by weight may be weight units well known in the art such as μg, mg, g, kg, etc., or multiples thereof, such as 1 / 10, 1 / 100, 10 times, 100 times, etc.

[0056] Example 1

[0057] To prepare dapagliflozin metformin sustained-release tablets (specification: dapagliflozin 10 mg / metformin hydrochloride 1000 mg, hardness 20 kg - 30 kg), the following steps are included:

[0058] Prepare dapagliflozin granules: sequentially add 510 g of anhydrous lactose, 100 g of dapagliflozin, 95 g of crospovidone, 42 g of colloidal silicon dioxide, and 1705 g of microcrystalline cellulose into an automatic lifting hopper mixer, set the mixing speed at 8 rpm, and mix for 15 min. Use a granulating machine, install a 1.0 mm stainless steel sieve mesh, and granulate the above-mentioned mixed granules. Add the sieved material into the mixer, and add 25 g of magnesium stearate, set the mixing speed at 7 rpm, and mix for 5 min.

[0059] Prepare metformin hydrochloride granules: Use a dust-free grinder for metformin hydrochloride, and install a 100-mesh sieve to crush metformin hydrochloride. Add 10000 g of metformin hydrochloride into a wet granulating machine, set the stirring paddle speed at 100 revolutions per minute, the cutter speed at 1200 revolutions per minute, and mix for 10 min. After the chopping is completed, add 450 g of sodium carboxymethylcellulose, set the stirring paddle speed at 120 revolutions per minute, the cutter speed at 1500 revolutions per minute, and mix for 5 minutes. Weigh 1400 g of purified water as a wetting agent, set the stirring paddle speed at 100 revolutions per minute, the cutter speed at 1200 revolutions per minute, the atomization pressure of the wetting agent at 0.2 - 0.5 MPa in the wet granulating machine, add the wetting agent, and the addition time of the wetting agent does not exceed 3 min. After the wetting agent is added, keep the stirring paddle speed at 100 revolutions per minute and the cutter speed at 1200 revolutions per minute, and continue granulating for 2 minutes. Use a 10*10 mm sieve mesh to wet-granulate the soft material. Pump the granulated wet particles into a fluidized bed, set the inlet air humidity at 7.0 g / kg, the fluidization air volume at 800 - 1500 m 3 / h, dry the wet particles, and require the loss on drying ≤ 3%. Install a 1.5 mm round hole V-shaped sieve mesh in the granulating machine, set the dry granulating machine speed at 500 revolutions per minute, and dry-granulate the dried particles. Add the dry-granulated particles into the mixer and add 2860 g of hypromellose and 150 g of colloidal silicon dioxide, set the speed at 7 rpm, and perform the first-step mixing for 10 min. After the first-step mixing is completed, add 90 g of magnesium stearate, set the speed at 7 rpm, and mix for 3 min.

[0060] Preparation of dapagliflozin metformin sustained-release tablets: Compress the two kinds of granules prepared above. First, compress metformin. The required tablet core hardness is 1.0 kg - 5.0 kg. After the metformin granules are compressed into shape, add dapagliflozin granules for secondary compression to obtain the dapagliflozin metformin sustained-release tablet core, with the hardness requirement of 20 kg - 40 kg. Coat the coating solution and the dapagliflozin metformin sustained-release tablet core at a mass ratio of 0.04:1 to obtain the dapagliflozin metformin sustained-release tablets.

[0061] Example 2

[0062] Preparation of dapagliflozin metformin sustained-release tablets (specification: dapagliflozin 10 mg / metformin hydrochloride 1000 mg, hardness 30 kg - 40 kg) includes the following steps:

[0063] Preparation of dapagliflozin granules: Sequentially add 510 g of anhydrous lactose, 100 g of dapagliflozin, 90 g of crospovidone, 47 g of colloidal silicon dioxide, and 1705 g of microcrystalline cellulose into an automatic lifting hopper mixer. Set the mixing speed at 8 rpm and mix for 15 min. Use a granulating machine and install a 1.0 mm stainless steel sieve mesh to granulate the mixed granules above. Add the sieved material into the mixer, and add 25 g of magnesium stearate. Set the mixing speed at 7 rpm and mix for 5 min.

[0064] Preparation of metformin hydrochloride granules: Use a dust-free crusher for metformin hydrochloride and install a 100-mesh sieve to crush metformin hydrochloride. Add 10000 g of metformin hydrochloride into a wet granulator. Set the stirring paddle speed at 100 revolutions per minute and the cutter speed at 1200 revolutions per minute, and mix for 10 min. After chopping is completed, add 450 g of sodium carboxymethylcellulose. Set the stirring paddle speed at 120 revolutions per minute and the cutter speed at 1500 revolutions per minute, and mix for 5 minutes. Weigh 1400 g of purified water as a wetting agent. Set the stirring paddle speed at 100 revolutions per minute and the cutter speed at 1200 revolutions per minute in the wet granulator. The atomization pressure of the wetting agent is 0.2 - 0.5 MPa. Add the wetting agent, and the addition time of the wetting agent does not exceed 3 min. After the wetting agent is added, keep the stirring paddle speed at 100 revolutions per minute and the cutter speed at 1200 revolutions per minute, and continue granulating for 2 minutes. Wet-granulate the soft material using a 10*10 mm sieve mesh. Pump the granulated wet granules into a fluidized bed, set the inlet air humidity at 6.0 g / kg, and the fluidization air volume at 800 - 1500 m 3 / h, dry the wet granules, and require the loss on drying to be ≤ 3%. Install a 1.5-mm round-hole V-shaped sieve mesh on the granulator, set the speed of the dry granulator at 500 revolutions per minute, and perform dry granulation on the dried granules. Add the dry granulated granules to the mixer, add 2,860 g of hypromellose and 150 g of colloidal silicon dioxide, set the rotation speed at 7 rpm, and perform the first mixing for 10 min. After the first mixing is completed, add 90 g of magnesium stearate, set the rotation speed at 7 rpm, and mix for 3 min.

[0065] Prepare dapagliflozin metformin sustained-release tablets: Press the two kinds of granules prepared above into tablets. First, press metformin, and the hardness of the tablet core is required to be 1.0 kg - 5.0 kg. After the metformin granules are pressed into shape, add the dapagliflozin granules for secondary pressing to obtain the dapagliflozin metformin sustained-release tablet core, and the hardness is required to be 20 kg - 40 kg. Coat the coating solution and the dapagliflozin metformin sustained-release tablet core at a mass ratio of 0.04:1 to obtain the dapagliflozin metformin sustained-release tablets.

[0066] Example 3

[0067] Prepare dapagliflozin metformin sustained-release tablets (specification: dapagliflozin 10 mg / metformin hydrochloride 1000 mg, hardness 20 kg - 30 kg), including the following steps:

[0068] Prepare dapagliflozin granules: Add 510 g of anhydrous lactose, 100 g of dapagliflozin, 90 g of crospovidone, 47 g of colloidal silicon dioxide, and 1,705 g of microcrystalline cellulose to an automatic lifting hopper mixer in sequence. Set the mixing rotation speed at 8 rpm and mix for 15 min. Use a granulator and install a 1.0-mm stainless steel sieve mesh to granulate the granules after mixing above. Add the sieved material to the mixer, add 25 g of magnesium stearate, set the mixing rotation speed at 7 rpm, and mix for 5 min.

[0069] Preparation of metformin hydrochloride granules: Metformin hydrochloride is pulverized using a dust-free pulverizer, and a 100-mesh sieve is installed to pulverize metformin hydrochloride. 10000 g of metformin hydrochloride is added into a wet granulator, the stirring paddle speed is set at 100 revolutions per minute, the cutter speed is set at 1200 revolutions per minute, and the mixture is stirred for 10 min. After the chopping is completed, 450 g of sodium carboxymethylcellulose is added, the stirring paddle speed is set at 120 revolutions per minute, the cutter speed is set at 1500 revolutions per minute, and the mixture is stirred for 5 minutes. 1400 g of purified water is weighed as a wetting agent. The wet granulator is set with a stirring paddle speed of 100 revolutions per minute, a cutter speed of 1200 revolutions per minute, and a wetting agent atomization pressure of 0.2 - 0.5 MPa. The wetting agent is added, and the addition time of the wetting agent does not exceed 3 min. After the addition of the wetting agent is completed, the stirring paddle speed is maintained at 100 revolutions per minute and the cutter speed is maintained at 1200 revolutions per minute, and granulation is continued for 2 minutes. The soft material is wet-screened using a 10*10 mm sieve. The wet granules after screening are pumped into a fluidized bed, the inlet air humidity is set at 7.0 g / kg, and the fluidization air volume is 800 - 1500 m 3 / h, and the wet granules are dried, with the requirement that the loss on drying ≤ 3%. A 1.5 mm round-hole V-shaped sieve is installed in the granulator, the speed of the dry granulator is set at 500 revolutions per minute, and the dried granules are dry-screened. The dry-screened granules are added to a mixer, and 2860 g of hypromellose, 90 g of colloidal silicon dioxide, and 60 g of microcrystalline cellulose are added. The rotation speed is set at 7 rpm for the first-step mixing, and the mixing time is 10 min. After the first-step mixing is completed, 90 g of magnesium stearate is added, the rotation speed is set at 7 rpm, and the mixing time is 3 min.

[0070] Preparation of dapagliflozin metformin sustained-release tablets: The two kinds of granules prepared above are compressed into tablets. First, metformin is compressed. The hardness of the tablet core is required to be 1.0 kg - 5.0 kg. After the metformin granules are compressed into shape, dapagliflozin granules are added for secondary compression to obtain the dapagliflozin metformin sustained-release tablet core, with the hardness requirement of 20 kg - 40 kg. The coating solution and the dapagliflozin metformin sustained-release tablet core are coated at a mass ratio of 0.04:1, and the dapagliflozin metformin sustained-release tablets are obtained.

[0071] Example 4

[0072] Preparation of dapagliflozin metformin sustained-release tablets (specification: dapagliflozin 10 mg / metformin hydrochloride 1000 mg, hardness 20 kg - 40 kg) includes the following steps:

[0073] Preparation of dapagliflozin granules: 510 g of anhydrous lactose, 100 g of dapagliflozin, 95 g of crospovidone, 42 g of colloidal silicon dioxide, and 1705 g of microcrystalline cellulose were sequentially added to an automatic lifting hopper mixer, and the mixing speed was set at 8 rpm for 15 min. Use a granulator, install a 1.0 mm stainless steel sieve mesh, and granulate the mixed granules above. Add the sieved material into the mixer, and add 25 g of magnesium stearate. Set the mixing speed at 7 rpm and mix for 5 min.

[0074] Preparation of metformin hydrochloride granules: Metformin hydrochloride was pulverized using a dust-free pulverizer, and a 100-mesh sieve was installed to pulverize metformin hydrochloride. 10000 g of metformin hydrochloride was added to a wet granulator, the stirring paddle speed was set at 100 revolutions per minute, the cutter speed was set at 1200 revolutions per minute, and mixed for 10 min. After chopping, 450 g of sodium carboxymethylcellulose was added, the stirring paddle speed was set at 120 revolutions per minute, the cutter speed was set at 1500 revolutions per minute, and mixed for 5 minutes. Weigh 1400 g of purified water as a wetting agent. The wet granulator was set with a stirring paddle speed of 100 revolutions per minute, a cutter speed of 1200 revolutions per minute, and a wetting agent atomization pressure of 0.2 - 0.5 MPa. Add the wetting agent, and the addition time of the wetting agent does not exceed 3 min. After the addition of the wetting agent, keep the stirring paddle speed at 100 revolutions per minute and the cutter speed at 1200 revolutions per minute, and continue granulating for 2 minutes. The soft material was wet-granulated using a 10*10 mm sieve mesh. The wet granules after granulation were pumped into a fluidized bed, the inlet air humidity was set at 7.0 g / kg, and the fluidization air volume was 800 - 1500 m 3 / h, and the wet granules were dried, with the requirement of drying loss ≤ 3%. Install a 1.5 mm round hole V-shaped sieve mesh in the granulator, set the dry granulator speed at 500 revolutions per minute, and dry-granulate the dried granules. Add the dry-granulated granules into the mixer, and add 2860 g of hypromellose, 150 g of colloidal silicon dioxide, and 10 g of microcrystalline cellulose. Set the speed at 7 rpm for the first-step mixing for 10 min. After the first-step mixing, add 90 g of magnesium stearate, set the speed at 7 rpm, and mix for 3 min.

[0075] Preparation of dapagliflozin metformin sustained-release tablets: The two kinds of granules prepared above were compressed into tablets. First, metformin was compressed. The hardness requirement of the tablet core was 1.0 kg - 5.0 kg. After the metformin granules were compressed into shape, dapagliflozin granules were added for secondary compression to obtain the dapagliflozin metformin sustained-release tablet core, with a hardness requirement of 20 kg - 40 kg. Coating was carried out on the coating solution and the dapagliflozin metformin sustained-release tablet core according to a mass ratio of 0.04:1, and the dapagliflozin metformin sustained-release tablets were obtained.

[0076] Effect example

[0077] The dapagliflozin metformin sustained-release tablets prepared in Examples 1-4 of the present invention were subjected to in vitro dissolution tests and related substance tests, and the results are as follows:

[0078] I. Powder properties of metformin hydrochloride granules

[0079] 1. Test method: The sample quantity was 10 g, the frequency was 100 times / min, and the number of oscillations was 500 times.

[0080] 2. The test results are shown in Table 1.

[0081] Table 1

[0082]

[0083] II. Results of mixing uniformity of dapagliflozin granules

[0084] 1. Test method:

[0085] Test solution: Take this product (transfer the whole amount), weigh accurately, place it in a 100-ml volumetric flask, add an appropriate amount of 50% acetonitrile water, ultrasonicate in a 40°C water bath for about 60 min, cool to room temperature, dilute to the mark with 50% acetonitrile water, shake well, and filter through a 0.45-μm PVDF membrane; accurately measure an appropriate amount of the continued filtrate, and quantitatively dilute it with 50% acetonitrile water to prepare a solution containing about 10 μg of dapagliflozin per 1 ml.

[0086] Reference solution: Take an appropriate amount of dapagliflozin reference substance, dissolve it with 50% acetonitrile water and quantitatively dilute it to a solution containing about 10 μg of dapagliflozin per 1 ml.

[0087] Chromatographic conditions: Use octadecylsilane-bonded silica gel as the filler (YMC-Pack Pro C18, 150 mm x 4.6 mm, 3 μm, a chromatographic column with equivalent efficiency), and use a trapping column; use water: triacetic acid (1500:1) as mobile phase A; use acetonitrile: triacetic acid (1500:1) as mobile phase B, the detection wavelength is 254 nm, the column temperature is 30°C; the flow rate is 1.0 ml per minute; the injection volume is 10 μl.

[0088] 2. The test results are shown in Table 2.

[0089] Table 2

[0090]

[0091] III. In-process control metering of tablet core

[0092] 1. Test method: Refer to the content inspection method of the imported registration standard to detect the substance content of the dapagliflozin layer and the metformin hydrochloride layer respectively.

[0093] 2. The test results are shown in Table 3 and Table 4.

[0094] Table 3 Detection Results of Dapagliflozin Layer

[0095]

[0096] Table 4 Detection Results of Metformin Hydrochloride Layer

[0097]

[0098] IV. Dissolution

[0099] 1. Test method:

[0100] Dissolution conditions: Using 1000 ml of pH 6.8 phosphate buffer solution as the dissolution medium, the rotation speed is 100 revolutions per minute. Operate according to the law, and sample at 30 minutes, 1 hour, 3 hours, and 10 hours.

[0101] Test solution: Appropriately take the dissolution solutions at 30 minutes, 1 hour, 3 hours, and 10 hours, filter, and take the subsequent filtrate. For the reference solution, appropriately take the reference substances of dapagliflozin and metformin hydrochloride, dissolve them in the medium and quantitatively dilute to a mixed solution containing about 10 μg of dapagliflozin and 1 mg of metformin hydrochloride per 1 ml.

[0102] Chromatographic conditions: Using octadecylsilane-bonded silica gel as the filler (YMC-Pack Pro C18, 150 mm x 4.6 mm, 3 μm, a chromatographic column with equivalent efficiency), and using a trapping column; using water: triacetic acid (1500:1) as mobile phase A; using acetonitrile: triacetic acid (1500:1) as mobile phase B, the detection wavelength is 254 nm, the column temperature is 30 °C; the flow rate is 1.0 ml per minute; the injection volume is 10 μl.

[0103] Determination method: Precisely measure the reference solution and the test solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate according to the external standard method with the peak area.

[0104] Limit: The dissolution amount of dapagliflozin should not be less than 80% of the labeled amount at 30 min, and the dissolution amount of metformin hydrochloride should be 20%-40% of the labeled amount at 1 hour, 45%-65% of the labeled amount at 3 hours, and not less than 85% after 10 hours.

[0105] 2. The test results are shown in Table 5.

[0106] Table 5

[0107]

[0108] V. Related substances

[0109] 1. Test method:

[0110] (1) Dapagliflozin

[0111] Solvent: Phosphate buffer solution with pH 11.0 (0.05 mol / L potassium dihydrogen phosphate solution, adjusted to pH 11.0 with 45% potassium hydroxide solution): Acetonitrile (50:50).

[0112] Test solution: Take this product and place it in a 200 ml volumetric flask. Accurately measure 100 ml of the solvent and add it to the volumetric flask. Ultrasonically oscillate for about 60 minutes (ensure that the tablets do not stick to the bottom or wall of the volumetric flask). Take an appropriate amount of the solution, filter it with a glass syringe (equipped with a 0.45 mm PVDF filter membrane), and take the subsequent filtrate as the test solution.

[0113] System suitability solution: Take appropriate amounts of dapagliflozin and impurity C reference substances, dissolve them with the solvent and quantitatively dilute to prepare a mixed solution containing about 0.1 mg of dapagliflozin and 0.2 μg of impurity C per 1 ml.

[0114] Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (YMC-Pack Pro C18, 4.6 mm x 150 mm, 3 μm or a chromatographic column with equivalent efficiency), and use a trapping column; use water: trifluoroacetic acid (2000:1) as mobile phase A; use acetonitrile: triacetic acid (2000:1) as mobile phase B; the column temperature is 35 °C; the flow rate is 1.0 ml per minute; the detection wavelength is 220 nm; the injection volume is 15 μl.

[0115] In the chromatogram of the system suitability solution, the elution order of each component is dapagliflozin and impurity C in turn. The resolution between the main peak and its adjacent chromatographic peaks should not be less than 2.0; the tailing factor of the dapagliflozin peak should be between 0.8 and 1.5.

[0116] Limit: In the chromatogram of the test solution, if impurity peaks appear, calculate by the area normalization method with correction factors (see the following table). Impurity B shall not exceed 0.4%, impurities E, D, and C shall not exceed 0.2% each, other unknown impurities shall not exceed 0.2%, and the total impurities shall not exceed 0.9%. A known impurity peak of metformin solution can be observed at a relative retention time of about 0.20, so only impurity peaks with a relative retention time greater than 0.2 are calculated. For the 5 mg / 500 mg specification of dapagliflozin metformin sustained-release tablets, a chromatographic peak related to the coating material may be observed at a relative retention time of about 0.5 (relative to the main peak of dapagliflozin), and this peak should not be counted as a chromatographic peak related to dapagliflozin.

[0117] (2) Metformin hydrochloride

[0118] Test solution: Weigh accurately an appropriate amount of the finely ground powder of this product (equivalent to about 100 mg of metformin hydrochloride), place it in a dry 100-ml volumetric flask, add an appropriate amount of the mobile phase, sonicate in a water bath at 40 °C for about 30 min (ensure complete dispersion of the finely ground powder), cool to room temperature, dilute to the mark with the mobile phase, shake well, filter, and take the subsequent filtrate as the test solution.

[0119] Reference solution: Take an appropriate amount of the test solution and quantitatively dilute it with the mobile phase to prepare a solution containing 5 μg per 1 ml.

[0120] Reference standard solution: Take an appropriate amount of the dicyandiamide reference standard, dissolve it in the mobile phase and quantitatively dilute it to prepare a solution containing 0.2 μg per 1 ml.

[0121] System suitability solution: Take appropriate amounts of metformin hydrochloride and melamine reference standards, dissolve them in water and dilute to prepare a solution containing 0.25 mg of metformin hydrochloride and 0.1 mg of melamine per 1 ml. Accurately measure 1 ml, place it in a 50-ml volumetric flask, dilute to the mark with the mobile phase, and shake well.

[0122] Chromatographic conditions: Use sulfonic acid group cation exchange bonded silica gel as the filler (Phenomenex Luna SCX column, 4.6 mm × 250 mm, 5 μm or a chromatographic column of equivalent efficiency); use 17 g / L ammonium dihydrogen phosphate solution (adjust the pH value to 3.0 with phosphoric acid) as the mobile phase; the column temperature is 30 °C; the flow rate is 1.0 ml per minute; the detection wavelength is 218 nm; the injection volume is 20 μl. In the chromatogram of the system suitability solution, the resolution between the metformin peak and the melamine peak should be greater than 10.0. Assay method: Accurately measure the system suitability solution, reference standard solution, reference solution and test solution, inject them into the liquid chromatograph respectively, and record the chromatogram until twice the retention time of the main peak.

[0123] Limit: If there is a peak in the chromatogram of the test solution with the same retention time as dicyandiamide, calculate by the external standard method with the peak area, and it shall not exceed 0.02% of the labeled amount of metformin hydrochloride. The area of any other single impurity peak shall not be greater than 0.2 times (0.1%) of the main peak area of the reference solution. The sum of the areas of other impurity peaks shall not be greater than 1 times (0.5%) of the main peak area of the reference solution. The dapagliflozin peak with a relative retention time of about 0.3 shall not be integrated.

[0124] 2. The test results are shown in Table 6.

[0125] Table 6

[0126]

[0127] Six. Conclusion

[0128] As can be seen from Table 1-6, the prepared dapagliflozin metformin sustained-release tablets in Examples 1-3 showed good dissolution, good content uniformity of dapagliflozin granules, good particle size distribution of metformin granules, and low relative standard deviations of the respective active ingredients, indicating excellent product quality, reliable stability, very small differences among batches, low related content, and high dissolution. Thus, the dapagliflozin metformin sustained-release tablets prepared by the method of the present invention have excellent drug dissolution performance and stable quality, and the process is simple and the cost is low, especially suitable for large-scale industrial production.

[0129] The foregoing description of specific exemplary embodiments of the invention has been presented for purposes of illustration and example. These descriptions are not intended to limit the invention to the precise forms disclosed, and obviously, many modifications and variations are possible in light of the above teaching. The purpose of selecting and describing exemplary embodiments is to explain the specific principles of the invention and its practical application so that those skilled in the art can implement and utilize the various different exemplary embodiments of the invention as well as various different selections and modifications. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A method for preparing a dapagliflozin metformin sustained-release tablet with stable dissolution, characterized in that: The following steps are involved: S1 prepares metformin hydrochloride granules and dapagliflozin granules respectively; S2: firstly compressing the metformin hydrochloride granules into tablets, and then adding the dapagliflozin granules for secondary tableting to obtain dapagliflozin metformin sustained-release tablet cores; the mass ratio of the metformin hydrochloride granules to the dapagliflozin granules is (4-10): (0.1-1); S3 coating the obtained tablet core with a coating liquid to obtain dapagliflozin metformin sustained-release tablets with stable dissolution; In the prepared dapagliflozin metformin sustained-release tablets, the content of metformin hydrochloride layer substances can reach a relative standard deviation of 0.3%, the content of dapagliflozin layer substances can reach a relative standard deviation of 0.1%, the total impurities of metformin hydrochloride can reach undetectable, and the total impurities of dapagliflozin can reach 0.06%.

2. The method for preparing the dapagliflozin metformin sustained-release tablets with stable dissolution as claimed in claim 1, characterized in that: In step S1, the preparation of dapagliflozin granules comprises the following steps: Anhydrous lactose, dapagliflozin, disintegrant and diluent are mixed for the first time until uniform, and after granulation, lubricant is added and mixed for the second time until uniform to obtain the product.

3. The method for preparing the dapagliflozin metformin sustained-release tablets with stable dissolution as claimed in claim 2, characterized in that: In the step of preparing dapagliflozin granules, the mass ratio of dapagliflozin, anhydrous lactose, disintegrant, diluent and lubricant is (95-110): (500-515): (130-145): (1700-1710): (20-30).

4. The method for preparing the dapagliflozin metformin sustained-release tablets with stable dissolution as claimed in claim 2, characterized in that: In the step of preparing dapagliflozin particles, the particle size of the anhydrous lactose is 80-120 mesh, and the particle size of the dapagliflozin is less than 20 μm; The disintegrant comprises at least one of corn starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, colloidal silicon dioxide, microcrystalline cellulose or cross-linked sodium carboxymethyl cellulose; The diluent includes at least one of mannitol, corn starch, microcrystalline cellulose, and lactose; The lubricant includes at least one of magnesium stearate, stearic acid or polyethylene glycol.

5. The method for preparing the dapagliflozin metformin sustained-release tablets with stable dissolution as claimed in claim 1, characterized in that: In step S1, the preparation of metformin hydrochloride granules comprises the following steps: (1) adding metformin hydrochloride, a binder and a wetting agent into a wet granulator in sequence, mixing them evenly, and then performing wet granulation, and then drying them in a fluidized bed, and then performing dry granulation; (2) After the dry granules are granulated, a sustained-release agent, a disintegrant and a filler are added, and after mixing evenly, a lubricant is added, and the mixture is mixed evenly again to obtain the product.

6. The method for preparing the dapagliflozin metformin sustained-release tablets with stable dissolution as claimed in claim 5, characterized in that: In the step of preparing metformin hydrochloride granules, the mass ratio of metformin hydrochloride, binder, wetting agent, sustained-release agent, disintegrant, lubricant and filler is (9995-10007): (430-470): (1350-1470): (2845-2870): (130-150): (80-100): (0-400).

7. The method for preparing the dapagliflozin metformin sustained-release tablets with stable dissolution as claimed in claim 5, characterized in that: In the step of preparing metformin hydrochloride particles, in step (1), the particle size of the metformin hydrochloride is 90-200 μm; The binder comprises at least one of sodium carboxymethylcellulose, hydroxypropyl cellulose, methyl cellulose and hypromellose; The wetting agent includes at least one of purified water and ethanol.

8. The method for preparing the dapagliflozin metformin sustained-release tablets with stable dissolution as claimed in claim 5, characterized in that: In the step of preparing metformin hydrochloride particles, in step (2), the sustained-release agent includes at least one of polyvinyl alcohol (PVA), hydroxypropyl methylcellulose, liposomes, microparticles, and polyvinyl pyrrolidone (PVP); The disintegrant comprises at least one of corn starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, colloidal silicon dioxide, sodium carboxymethyl starch, microcrystalline cellulose or cross-linked sodium carboxymethyl cellulose; The filler includes at least one of lactose and microcrystalline cellulose; The lubricant includes at least one of magnesium stearate, stearic acid or polyethylene glycol.

9. The method for preparing the dapagliflozin metformin sustained-release tablets with stable dissolution as claimed in claim 1, characterized in that: In step S2, the tablet core hardness of the metformin hydrochloride granules after tableting is 1.0-5.0 kg; the tablet core hardness of the dapagliflozin metformin sustained-release tablets is 20.0-40.0 kg, the weight difference is ±5%, and the brittleness is no more than 0.8%.

10. Dapagliflozin metformin sustained-release tablets with stable dissolution prepared by the method according to any one of claims 1 to 9.

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