A dapagliflozin metformin sustained-release tablet and its preparation method

Abstract

The present invention discloses a dapagliflozin metformin sustained-release tablet and a preparation method thereof. The sustained-release tablet comprises dapagliflozin, metformin or its hydrochloride, a crystal form stabilizer and a sustained-release material. The sustained-release tablet of the present invention can ensure the crystal form stability for at least 24 months. During the whole validity period, the crystal form of dapagliflozin is stable and the drug efficacy is consistent, ensuring the clinical medication effect. The sustained-release tablet of the present invention has a small dosage of the sustained-release material, a small tablet weight and a small tablet volume, and is more convenient for patients to take. The preparation process of the sustained-release tablet of the present invention is simplified, the production difficulty and cost are reduced, and the production efficiency is improved.

Description

Technical Field

[0001] The present invention relates to a dapagliflozin metformin sustained-release tablet, and also relates to a preparation method of the sustained-release tablet, belonging to the field of pharmaceutical preparations. Background Art

[0002] Diabetes is currently one of the most common endocrine and metabolic diseases, with genetic susceptibility and onset triggered by environmental factors. With the development of social economy, the change of people's lifestyle (such as increased energy intake and reduced exercise), and the aging of the population, the incidence of type II diabetes shows an increasing trend year by year globally, presenting an epidemic situation. Diabetes has now become the third non-communicable disease threatening people's health and life after cardiovascular diseases and tumors.

[0003] Currently, common drugs for treating type II diabetes include traditional drugs such as biguanides, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, etc., as well as new hypoglycemic drugs such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors and dipeptidyl peptidase-IV (DPP-IV) inhibitors.

[0004] The molecular formula of metformin hydrochloride is C4H 11 N5·HCl, and the molecular weight is 165.62. Metformin hydrochloride is a highly soluble and low-permeability drug of BCS class III, which mainly acts on extra-pancreatic tissues, inhibits intestinal glucose absorption, increases the utilization of glucose by peripheral tissues, and reduces hepatic glycogenolysis, thereby achieving the purpose of lowering blood sugar. Since metformin hydrochloride has an obvious hypoglycemic effect, does not cause hypoglycemia, and can significantly reduce postprandial hyperglycemia, it is suitable for type II diabetes patients and is a first-line drug for treating type II diabetes; at the same time, it can also improve insulin resistance, etc., so it is widely used clinically.

[0005] The molecular formula of dapagliflozin is C 21 H 25 ClO6·C3H8O2·H2O, and the molecular weight is 502.98. Dapagliflozin is a highly soluble and low-permeability drug of BCS class III and is an SGLT-2 inhibitor. By inhibiting SGLT-2, it reduces the reabsorption of filtered glucose, lowers the renal (glucose) threshold, and increases the excretion of glucose in urine.

[0006] Dapagliflozin and metformin are commonly used drugs for treating chronic diseases, and the two can produce a synergistic effect, so they often need to be used clinically in the form of a compound. However, there are the following problems when the two are made into a compound preparation: 1. The crystal form stability of dapagliflozin is poor, especially in the presence of metformin hydrochloride, and the stability is even worse, which is likely to cause loss of drug efficacy and affect the clinical medication effect; 2. The compressibility of metformin is poor, and the hardness of the tablet prepared is low, and it is easy to break during storage and transportation.

[0007] To solve the above problems, some solutions have been pointed out in the prior art, such as CN 102711739 B, CN116370430 A, CN 115414347 A, CN 113398097 A, WO 2017 / 114227 A1, CN 115804770 A, etc. In these prior arts, complex techniques such as pellet coating isolation and double-layer tableting are used to improve the crystal form stability of dapagliflozin. Although the crystal form transformation can be delayed to a certain extent, the techniques of pellet coating isolation and double-layer tableting are complex and cumbersome, with a long production cycle and high costs. By adding a sustained-release material, the drug is slowly released in the body. However, in order to meet the sustained-release requirements, the dosage of the sustained-release material is relatively large, and the volume of a single tablet is large when made into a tablet, making it difficult to swallow. In CN 115804770 A, aiming at the problems that metformin hydrochloride is a crystalline powder with poor compressibility and is prone to capping and unqualified friability during industrial production, by changing the addition method of the binder, the addition method of the filler, and controlling the ratio of co-grinding metformin hydrochloride with the lubricant or glidant, etc., the compressibility of the granules and the quality of the tablet surface properties of the tablet are improved. However, the control points of the preparation steps of this process are cumbersome, increasing the difficulty of quality assurance and monitoring in the industrial production of drugs. For example, the co-grinding process may cause inconsistent loss amounts of two substances with inconsistent adhesion characteristics in the crushing pretreatment process, thus affecting the feeding ratio and not being able to well meet the GMP requirements for drug production. Summary of the Invention

[0008] Aiming at the deficiencies of the above prior art, the present invention provides a dapagliflozin metformin sustained-release tablet, which contains a crystal form stabilizer and a sustained-release material at the same time. Through the combination of these two, the crystal form stability of dapagliflozin is improved, making the drug effect consistent throughout the shelf life of the sustained-release tablet, and the dosage of the sustained-release material is reduced. Under the condition of meeting the sustained-release requirements, the tablet weight and tablet volume are reduced, making it easier to take.

[0009] The specific technical solution of the present invention is as follows:

[0010] A dapagliflozin metformin sustained-release tablet, comprising a drug active ingredient, a crystal form stabilizer and a sustained-release material, wherein the drug active ingredient is dapagliflozin, metformin or its hydrochloride salt, and the crystal form stabilizer is at least one of sulfoaluminate, hydrotalcite and sucralfate.

[0011] Further, in the sustained-release tablet, the crystal form of dapagliflozin is its propylene glycol monohydrate crystal form.

[0012] Further, the particle size of the crystal form stabilizer is preferably controlled such that D90 is less than or equal to 30 um.

[0013] Further, the sustained-release material is at least one of hydroxypropyl methylcellulose, sodium carboxymethylcellulose, methylcellulose, carbomer, and sodium alginate, preferably a mixture of hydroxypropyl methylcellulose and carbomer, and the mass ratio of hydroxypropyl methylcellulose to carbomer is 1-9:1, such as 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1.

[0014] Preferably, the viscosity of hydroxypropyl methylcellulose is 50000-300000 cps, the viscosity of sodium carboxymethylcellulose is 1000-50000 cps, and the viscosity of methylcellulose is 1000-50000 cps.

[0015] Preferably, the carbomer can be at least one of carbomer 940, carbomer 980, carbomer 934, carbomer 934P, carbomer 941, carbomer 974P, etc.

[0016] Further, the crystal form stabilizer accounts for 5-15% of the total mass of the crystal form stabilizer and the sustained-release material, such as 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%.

[0017] Further, the total content of the crystal form stabilizer and the sustained-release material in the sustained-release tablet is 5-20 wt%, such as 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%.

[0018] Preferably, the crystal form stabilizer and the sustained-release material are first made into a complex, and then this complex is used to prepare the sustained-release tablet. Compounding the crystal form stabilizer and the sustained-release material in advance can make it easier to disperse and mix evenly during the preparation of the sustained-release tablet, making the performance of the sustained-release tablet more stable. In addition, making the complex in advance can also improve the compressibility and tableting speed of the sustained-release tablet, and tablets meeting the hardness requirements can be obtained at a lower tableting strength. The surface of the tableting finished product is beautiful and smooth, reducing energy consumption and improving efficiency.

[0019] Further, the complex of the crystal form stabilizer and the sustained-release material can be obtained by the following method a or method b:

[0020] Method a. The crystal form stabilizer is crushed to a particle size meeting the requirements, then mixed evenly with the sustained-release material and water to obtain a suspension, and the suspension is spray-dried to obtain the complex;

[0021] Method b. The crystal form stabilizer is crushed to a particle size meeting the requirements, then mixed with the sustained-release material and water to form a soft material, the soft material is melt-extruded to obtain an extrudate, and the extrudate is dried and crushed to obtain the complex.

[0022] Further, the crystal form stabilizer is pulverized to a particle size D90 of less than or equal to 30 microns, and preferably jet milling is used.

[0023] Further, in Method a, the following steps are specifically included: Dissolve the sustained-release material in water at 50-80 °C in an amount 0.5-10 times the mass of the sustained-release material, stir until dissolved and clarified, then add the pulverized crystal form stabilizer, stir and disperse to obtain a suspension, and connect the suspension to a spray dryer for spray drying to obtain a composite. Specific spray drying parameters can be: inlet air temperature 60-90 °C, such as 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C; inlet air flow rate 3-10 m³ / h, such as 3 m³ / h, 4 m³ / h, 5 m³ / h, 6 m³ / h, 7 m³ / h, 8 m³ / h, 9 m³ / h, 10 m³ / h; liquid inlet speed 10-50 HZ, such as 10 HZ, 20 HZ, 30 HZ, 40 HZ, 50 HZ; nozzle diameter 0.1-0.5 mm, such as 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm; liquid spraying pressure 0.1-1.0 MPa, such as 0.1 MPa, 0.2 MPa, 0.3 MPa, 0.4 MPa, 0.5 MPa, 0.6 MPa, 0.7 MPa, 0.8 MPa, 0.9 MPa, 1.0 MPa.

[0024] Further, in Method b, the following steps are specifically included: Mix the sustained-release material and the pulverized crystal form stabilizer evenly, add water to prepare a soft material with uniform dryness and wetness, add the soft material to a hot melt extruder for extrusion to obtain an extrudate, dry the extrudate using a fluidized bed, and then pulverize it using a hammer mill to obtain a composite.

[0025] Further, the hot melt extruder is a twin-screw type, the extrusion head is an inverted fish scale-shaped mesh, the extrusion temperature is 60-90 °C, such as 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C; the extrusion speed is 10-30 HZ, such as 10 HZ, 20 HZ, 30 HZ; the aperture of the mesh of the extrusion head is 0.6-2 mm, such as 0.6 mm, 1 mm, 1.5 mm, 2 mm.

[0026] Further, the feeding speed of the hammer mill is 10-30 HZ, such as 10 HZ, 20 HZ, 30 HZ; the pulverizing rotation speed is 3000-20000 rpm, such as 3000 rpm, 5000 rpm, 8000 rpm, 10000 rpm, 15000 rpm, 20000 rpm; the aperture of the mesh is 0.2-0.6 mm, such as 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm.

[0027] Furthermore, metformin hydrochloride is also known as metformin. The content of metformin or its hydrochloride in the sustained-release tablet is 50-90 wt%, such as 50%, 60%, 70%, 80%, 90%. The content of dapagliflozin in the sustained-release tablet is 0.5-5 wt%, such as 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%.

[0028] Furthermore, the sustained-release tablet may further contain at least one of a filler, a disintegrant, a lubricant, and a coating agent.

[0029] Furthermore, the filler may be a filler disclosed in the pharmaceutical field, such as one or more of corn starch, microcrystalline cellulose, lactose, mannitol, dextrin, sucrose powder, etc. The content of the filler in the sustained-release tablet may be 0-50 wt%, such as 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%.

[0030] Furthermore, the disintegrant may be a disintegrant disclosed in the pharmaceutical field, such as one or more of sodium carboxymethyl starch, croscarmellose sodium, calcium carboxymethyl cellulose, crospovidone, etc. The content of the disintegrant in the sustained-release tablet may be 0.1-5 wt%, such as 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%.

[0031] Furthermore, the lubricant may be a lubricant disclosed in the pharmaceutical field, such as one or more of magnesium stearate, talc powder, stearic acid, etc. The content of the lubricant in the sustained-release tablet may be 0.1-1 wt%, such as 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%.

[0032] Furthermore, the coating agent may be a coating agent disclosed in the pharmaceutical field, such as Opadry, Colorcon, Eudragit, etc. The content of the coating agent in the sustained-release tablet may be 0-3 wt%, such as 0%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%.

[0033] Furthermore, in a specific embodiment of the present invention, a specific formulation of the sustained-release tablet is disclosed, and the weight percentage content of each component is as follows:

[0034] Metformin or its hydrochloride 50%-90%;

[0035] Dapagliflozin 0.5% - 5%;

[0036] Crystal form stabilizer 0.5% - 2.5%;

[0037] Sustained - release material 3% - 16%;

[0038] Filler 0 - 50%;

[0039] Disintegrant 0.1% - 5%;

[0040] Lubricant 0.1% - 1%.

[0041] The present invention also provides a preparation method of a dapagliflozin metformin sustained - release tablet, and the method comprises the following steps:

[0042] A. Crush the crystal form stabilizer to a particle size meeting the requirements, then mix it evenly with the sustained - release material and water to obtain a suspension or soft material. Spray - dry the suspension or hot - melt extrude and then dry and crush the soft material to obtain a composite of the crystal form stabilizer and the sustained - release material;

[0043] B. Granulate the drug active ingredient and the composite of the crystal form stabilizer and the sustained - release material by wet granulation. Dry and screen the obtained wet granules to obtain dry granules. Mix the dry granules with the filler, disintegrant, and lubricant, and compress the obtained mixture to obtain tablets;

[0044] Or, granulate the drug active ingredient, the composite of the crystal form stabilizer and the sustained - release material, the filler, and the disintegrant by wet granulation. Dry and screen the obtained wet granules to obtain dry granules. Mix the dry granules with the lubricant, and compress the obtained mixture to obtain tablets;

[0045] C. After obtaining the tablets, preferably, the obtained tablets can be further coated to obtain coated tablets.

[0046] The present invention has the following beneficial effects:

[0047] 1. The present invention adds a crystal form stabilizer to the sustained - release tablet to improve the stability of the crystal form of dapagliflozin propylene glycol monohydrate, solves the problems of crystal form transformation and poor crystal form stability in the presence of dapagliflozin and metformin hydrochloride, and extends the product shelf life. Through experimental verification, the sustained - release tablet can ensure the crystal form stability for at least 24 months. The crystal form of dapagliflozin is stable and the drug efficacy is consistent throughout the shelf life, ensuring the clinical medication effect.

[0048] 2. The present invention uses the crystal form stabilizer in combination with the sustained - release material, reduces the dosage of the sustained - release material, can achieve the expected sustained - release effect under the condition of a lower dosage of the sustained - release material, reduces the tablet weight and tablet volume, and is more convenient for patients to take.

[0049] 3. The preparation method of the present invention is simple. In the presence of a crystal form stabilizer and a sustained-release material, dapagliflozin and metformin or its hydrochloride can be mixed and granulated together, without complex operations such as pellet coating isolation and double-layer tableting, which simplifies the preparation process, reduces the production difficulty and cost, and improves the production efficiency.

[0050] 4. The present invention preferably pre-forms a complex of a crystal form stabilizer and a sustained-release material, and then mixes it with other components, which can improve the compressibility of the sample, obtain tablets with higher hardness at lower pressures, reduce the die wear during the production process, increase the tableting speed, reduce the energy consumption of tableting, and significantly save energy and increase efficiency.

[0051] 5. The crystal form stabilizer of the present invention selects inorganic salts with relatively large hardness and brittleness such as calcium sulfoaluminate, hydrotalcite, and sucralfate. First forming a complex of the crystal form stabilizer and a sustained-release material with relatively high toughness can eliminate the batch-to-batch differences caused by different sources and preparation processes of the sustained-release material. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 It is the XRD pattern of the sample of Example 1 at 0 month.

[0053] Figure 2 It is the XRD pattern of the sample of Example 1 at 24 months.

[0054] Figure 3 It is the XRD pattern of the sample of Comparative Example 2 at 0 month.

[0055] Figure 4 It is the XRD pattern of the sample of Comparative Example 2 at 24 months.

[0056] Figure 5 It is the picture of the sample of Example 1 with in vitro release for 10 hours.

[0057] Figure 6 It is the picture of the sample of Comparative Example 1 with in vitro release for 10 hours.

[0058] Figure 7 It is the picture of the sample of Comparative Example 2 with in vitro release for 10 hours. DETAILED DESCRIPTION OF THE INVENTION

[0059] The following gives an illustration of the exemplary embodiments of the present invention, including various details of the embodiments of the present invention to facilitate understanding, which should be considered merely exemplary. Therefore, those of ordinary skill in the art should recognize that various changes and modifications can be made to the embodiments described herein without departing from the scope and spirit of the present invention. Similarly, for clarity and conciseness, the description below omits the description of well-known functions, operations, and structures.

[0060] Unless otherwise defined, the technical and scientific terms used in this specification have the same meanings as those commonly understood by those skilled in the art. Although methods and materials similar or equivalent to those described herein can be used in experiments or practical applications, the materials and methods are described below. In case of conflict, the present specification, including the definitions therein, shall prevail.

[0061] Example 1

[0062] A dapagliflozin metformin sustained-release tablet has the following formulation as described in the table below:

[0063]

[0064] The preparation method of the sustained-release tablet is as follows:

[0065] 1. Prepare the complex of the crystal stabilizer and the sustained-release material:

[0066] 1.1. Micronize calcium sulfoaluminate using an air jet mill to obtain calcium sulfoaluminate powder, and measure the particle size of the powder by dry laser. The test results show that D50 is 5 μm and D90 is 13 μm.

[0067] 1.2. Mix hydroxypropyl methylcellulose (viscosity 100,000 cps) and carbomer (934P) with an equal mass multiple of purified water, then heat to 70 °C, stir until the solution is clear, and then slowly add the calcium sulfoaluminate powder obtained in 1.1, stir and disperse evenly to obtain a suspension.

[0068] 1.3. Connect the suspension in 1.2 to a spray dryer and perform spray drying using the parameters of an inlet air temperature of 80 °C, an inlet air flow rate of 5 m³ / h, a liquid inlet speed of 25 HZ, a nozzle diameter of 0.2 mm, and a liquid spraying pressure of 0.6 MPa to obtain the complex of the crystal stabilizer and the sustained-release material.

[0069] 2. Granulation

[0070] 2.1. Add metformin hydrochloride, dapagliflozin, and the complex of the crystal stabilizer and the sustained-release material prepared in step 1 to a high-efficiency wet granulator, first dry mix at a stirring speed of 300 rpm for 5 min. After the dry mixing is completed, add 15 wt% of purified water to the dry-mixed material in 2 - 5 min, and wet mix at 1500 rpm for 3 min to prepare a soft material.

[0071] 2.2. Granulate the soft material using a rapid granulator equipped with a 4*4 square screen and a square knife to obtain wet granules. Transfer the wet granules to a fluidized bed for drying. The inlet air temperature of the drying bed is 70 °C, and the inlet air volume is 10 m³ / h. Stop heating when the moisture content of the granules is lower than 5%. Screen the dry granules using a rapid granulator equipped with a 2.0 mm round screen and a round knife to obtain dry granules.

[0072] 2.3. Put the whole dry granules, microcrystalline cellulose, sodium carboxymethyl starch and magnesium stearate into the material tank of the hopper mixer in proportion and mix them at a speed of 15HZ for 30 minutes to obtain the intermediate product of tablets.

[0073] 3. Press tablets using a shallow concave punch with a diameter of φ8.5mm according to a tablet weight of 600mg per tablet. The tableting pressure is 5 - 15KN, the tableting speed is 50KT / h, and the hardness of the obtained tablets is 17 - 18kg.

[0074] Example 2

[0075] Prepare dapagliflozin metformin sustained-release tablets by referring to the method of Example 1, except that: its formula is as described in the following table:

[0076]

[0077] Example 3

[0078] Prepare dapagliflozin metformin sustained-release tablets by referring to the method of Example 1, except that: its formula is as described in the following table:

[0079]

[0080] Example 4

[0081] Prepare dapagliflozin metformin sustained-release tablets by referring to the method and formula of Example 1, except that: replace calcium sulfoaluminate with an equal amount of hydrotalcite, and replace the sustained-release material with an equal amount of carbomer (974P).

[0082] Example 5

[0083] Prepare dapagliflozin metformin sustained-release tablets by referring to the method and formula of Example 1, except that: replace calcium sulfoaluminate with an equal amount of sucralfate, and replace the sustained-release material with an equal amount of sodium alginate (ultra-high viscosity type II).

[0084] Example 6

[0085] Prepare dapagliflozin metformin sustained-release tablets by referring to the method of Example 1, except that: the total content of the crystal form stabilizer and the sustained-release material in the sustained-release tablets is 5wt%, and the formula is as follows:

[0086]

[0087] Example 7

[0088] Prepare dapagliflozin metformin sustained-release tablets by referring to the method of Example 1, except that: the total content of the crystal form stabilizer and the sustained-release material in the sustained-release tablets is 15.5wt%, and the formula is as follows:

[0089]

[0090] Example 8

[0091] Prepare the dapagliflozin metformin sustained-release tablets according to the formulation of Example 1, except that: the crystal form stabilizer and the sustained-release material are not made into a compound, and the method is as follows:

[0092] 1. Micronize calcium sulfoaluminate using a jet mill to obtain calcium sulfoaluminate powder. Measure the particle size of the powder by dry laser, and it shows that its D50 is 5μm and D90 is 13μm.

[0093] 2. Granulation

[0094] 2.1. Add metformin hydrochloride, dapagliflozin, crystal form stabilizer and sustained-release material to a high-efficiency wet granulator in sequence. First, dry mix at a stirring speed of 300 rpm for 5 min. After the dry mixing is completed, add 15 wt% of purified water of the dry-mixed material within 2 - 5 min, and wet mix at 1500 rpm for 3 min to prepare soft materials.

[0095] 2.2. Granulate the soft materials using a rapid granulator equipped with a 4*4 square screen and a square knife to obtain wet granules. Transfer the wet granules to a fluidized bed for drying. The inlet air temperature of the drying bed is 70°C, and the inlet air volume is 10 m³ / h. Stop heating when the moisture content of the granules is lower than 5%. Granulate the dry granules using a rapid granulator equipped with a 2.0 mm round screen and a round knife to obtain dry granules.

[0096] 2.3. Put the granulated dry granules, microcrystalline cellulose, sodium carboxymethyl starch and magnesium stearate into the material tank of a hopper-type mixer in proportion, and mix at a speed of 15 HZ for 30 min to obtain the intermediate product of tablets.

[0097] 4. Press tablets using a shallow concave punch with a circular φ8.5 mm according to the tablet weight of 600 mg per tablet. The tableting pressure is 20 - 30 KN, the tableting speed is 35 - 45 KT / h, and the hardness of the obtained tablets is 15 - 17 kg.

[0098] Example 9

[0099] Refer to the formulation and method of Example 1 to prepare the dapagliflozin metformin sustained-release tablets, except that: omit step 1.1, and do not micronize calcium sulfoaluminate using a jet mill.

[0100] Example 10

[0101] Refer to the method of Example 1 to prepare the dapagliflozin metformin sustained-release tablets, except that: its formulation is as described in the following table:

[0102]

[0103] Comparative Example 1

[0104] A dapagliflozin metformin sustained-release tablet, the formula of which is as described in the following table:

[0105]

[0106] The preparation method of the sustained-release tablet is as follows:

[0107] 1. Granulation

[0108] 1.1. Add metformin hydrochloride, dapagliflozin, and hypromellose (viscosity 100,000 cps) to a high-efficiency wet granulator in sequence. First, dry mix at a stirring speed of 300 rpm for 5 min. After the dry mixing is completed, add 15 wt% of purified water of the dry-mixed material within 2 - 5 min, and wet mix at 1500 rpm for 3 min to prepare a soft material.

[0109] 1.2. Granulate the soft material using a rapid granulator equipped with a 4*4 square screen and a square knife to obtain wet granules. Transfer the wet granules to a fluidized bed for drying. The inlet air temperature of the drying bed is 70 °C, and the inlet air volume is 10 m³ / h. Stop heating when the moisture content of the granules is lower than 5%. Granulate the dry granules using a rapid granulator equipped with a 2.0 mm round screen and a round knife to obtain dry granules.

[0110] 1.3. Put the granulated dry granules, microcrystalline cellulose, sodium carboxymethyl starch, and magnesium stearate into the material tank of a hopper mixer in proportion, and mix at a speed of 15 HZ for 30 min to obtain an intermediate tablet product.

[0111] 2. Press tablets using a shallow concave punch with a circular φ8.5 mm according to a tablet weight of 600 mg per tablet. The tableting pressure is 45 - 55 KN, the tableting speed is 15 KT / h, and the hardness of the obtained tablets is 17 - 18 kg.

[0112] Comparative Example 2

[0113] A dapagliflozin metformin sustained-release tablet, the difference is that: the formula is as described in the following table:

[0114]

[0115] The preparation method of the sustained-release tablet is as follows:

[0116] 1. Granulation

[0117] 1.1. Add metformin hydrochloride, dapagliflozin, and hypromellose (viscosity 100,000 cps) to a high - efficiency wet granulator in sequence. First, dry - mix at a stirring speed of 300 rpm for 5 min. After the dry - mixing is completed, add purified water accounting for 15% of the dry - mixed material within 2 - 5 min, and wet - mix at 1500 rpm for 3 min to prepare the soft material.

[0118] 1.2. Granulate the soft material using a rapid granulator equipped with a 4*4 square screen and a square knife to obtain wet granules. Transfer the wet granules to a fluidized bed for drying. The inlet air temperature of the drying bed is 70°C, and the air intake is 10 m³ / h. Stop heating when the moisture content of the granules is lower than 5%. Screen the dry granules using a rapid granulator equipped with a 2.0 mm round screen and a round knife to obtain dry granules.

[0119] 1.3. Put the screened dry granules, microcrystalline cellulose, sodium carboxymethyl starch, and magnesium stearate into the material tank of a hopper - type mixer in proportion and mix at a speed of 15 HZ for 30 min to obtain the intermediate product of tablets.

[0120] 2. Press tablets using a shallow - concave punch with an orbit of 12*8.5 mm according to a tablet weight of 600 mg per tablet. The pressing pressure is 50 - 65 KN, the pressing speed is 10 KT / h, and the hardness of the obtained tablets is 13 - 15 kg.

[0121] Comparative Example 3

[0122] Prepare dapagliflozin metformin sustained - release tablets with reference to the method of Example 3, except that: its formula is as described in the following table:

[0123]

[0124] Performance verification

[0125] 1. Dapagliflozin stability test

[0126] 1.1 Store the sustained - release tablet samples prepared in each example and comparative example at 25°C ± 2°C and relative humidity 60% ± 10% for 24 months, and test the content of dapagliflozin and the crystal form of dapagliflozin in each sustained - release tablet at the 0th month, 12th month, and 24th month.

[0127] 1.2 The content of dapagliflozin is determined with reference to the high - performance liquid chromatography method (General Principles 0512, Volume IV, Chinese Pharmacopoeia 2020 Edition) as follows:

[0128] Weigh the sustained-release tablet samples of each example and comparative example according to the amount of 100 mg of dapagliflozin, place them in a 1000 ml volumetric flask, add about 80 ml of 75 wt% acetonitrile aqueous solution, place it in a water bath at about 55 °C and ultrasonicate for 20 minutes to dissolve it. Then cool it to room temperature, dilute it to the mark with 75 wt% acetonitrile aqueous solution, shake well to obtain the test solution.

[0129] Weigh an appropriate amount of dapagliflozin reference standard accurately, dissolve it in 75 wt% acetonitrile aqueous solution and quantitatively dilute it to prepare a solution containing 0.1 mg per 1 ml to obtain the reference solution.

[0130] Chromatographic conditions: Use octadecylsilane-bonded silica gel as the filler (Thermo Betasil C8 250 mm × 4.6 mm); use 10 mmol / L potassium dihydrogen phosphate buffer solution (adjust the pH value to 3.0 ± 0.05 with phosphoric acid)-methanol-acetonitrile (volume ratio 55:6:39) as the mobile phase; the flow rate is 1.2 ml per minute; the column temperature is 35 °C; the detection wavelength is 290 nm; the injection volume is 10 μl.

[0131] Precisely take the test solution and the reference solution, inject them into the liquid chromatograph respectively, and calculate the content of dapagliflozin by the external standard method based on the peak area.

[0132] 1.3 The crystal form of dapagliflozin was determined by X-ray diffraction method (XRD) as follows:

[0133] Grind the sustained-release tablet samples of each example and comparative example into fine powder that meets the requirements of the pharmacopoeia as the test sample.

[0134] Perform XRD detection on the test sample with an X-ray diffractometer, use Cu target Kα ray as the radiation source, the working voltage is 40 kV, and the working current is 50 mA; the scanning speed is 5° per minute, and the scanning range is 5° - 50°; the step size is 0.02°, and the counting time is 10 seconds per step. By comparing the diffraction peak positions, intensities and shapes of the test samples placed at different times, judge the crystal form change. If the diffraction peak positions of the test samples placed for 12 months and 24 months are the same as those of the test sample placed for 0 months, and the relative intensity error is within ±5%, it is determined that the crystal form is qualified, otherwise it is unqualified.

[0135] 1.4 Experimental results

[0136] The changes in the content of dapagliflozin and crystal form of the products prepared in each example and comparative example at different time periods are shown in Table 1 below. The XRD patterns of the samples of Example 1 and Comparative Example 2 at 0 month and 24 months are as Figures 1 - 4 shown.

[0137] Table 1

[0138]

[0139] From Figure 1 and Figure 2 It can be seen that the XRD pattern results of the sample of Example 1 at 0 month and 24 months are consistent, and the crystal form has good stability. From Figure 3 and Figure 4 it can be seen that for the sample of Comparative Example 2, after being placed for 24 months, the peak at about 5.4° of the 2θ angle disappears, the peaks at about 44.8°, 48.9°, and 53.6° increase, and the peak intensities at about 17.7° and 22.4° decrease, and the change amplitude of these peaks exceeds 5%, indicating a large change in the crystal form, which affects the drug efficacy.

[0140] Combined with Table 1 and Figures 1 - 4 it can be seen that the crystal forms of the samples prepared in each example of the present invention meet the requirements within 24 months. Although the content of dapagliflozin shows a downward trend, it is still > 95% at the end of 24 months, which can meet the clinical drug efficacy, and the sample of Example 1 has the best performance. However, the samples of each comparative example show unstable crystal forms within 24 months, which affects the drug efficacy.

[0141] 2. Compare the tabletting and in vitro release of Example 1, Comparative Example 1, and Comparative Example 2, and the results are shown in Table 2 below and Figures 5 - 7 as follows.

[0142] Refer to the dissolution and release determination method (General Chapter 0931, Method 1, Volume IV of Chinese Pharmacopoeia 2020 Edition) to determine the in vitro release of dapagliflozin. The method is as follows:

[0143] Use phosphate buffer solution (pH 6.8 ± 0.05) filtered through a 0.45 μm filter membrane as the dissolution medium. Take 1 sustained-release tablet sample of each example and comparative example, add it to 900 ml of the dissolution medium, rotate at 100 revolutions per minute, and use a 20-mesh rotating basket, and operate according to the law. Take 10 ml of the dissolution solution at 2 h, 5 h, and 10 h respectively, and replenish the same volume of the dissolution medium in time.

[0144] Filter the dissolution solutions at 2 h and 5 h as the test solutions at 2 h and 5 h; filter the dissolution solution at 10 h and dilute it with an equal volume of the dissolution medium as the test solution at 10 h.

[0145] Take 17 mg of dapagliflozin reference standard, weigh it accurately, place it in a 100 ml volumetric flask, dissolve it with 5 ml of acetonitrile, and then dilute it to the scale with the dissolution medium, shake well, and use it as the reference solution.

[0146] Using the dissolution medium as the blank control, take each test sample solution and the reference solution, and according to the ultraviolet-visible spectrophotometry (General Principles 0401, Volume IV of Chinese Pharmacopoeia 2020 Edition), measure the absorbance of each solution at a wavelength of 242 nm, and then calculate the release rate of dapagliflozin in each tablet sample at different times respectively. Release rate = mass of dapagliflozin in the dissolution solution at different time points / mass of dapagliflozin in the sustained-release tablet * 100%.

[0147] Table 2

[0148]

[0149] It can be clearly seen from the experimental results in Table 2 above that the tableting of Example 1 is faster and more energy-saving. During the tableting process, the main pressure of Example 1 is only one-fifth of that of Comparative Example 2, and the obtained sample hardness value is higher. According to the experience in the die and mold machinery industry, it can be known that using the solution of Example 1 can at least extend the die and mold life by more than 3 times and improve the production speed.

[0150] Figures 5 - 7 Shows the release of the samples of Example 1 and Comparative Examples 1-2 in vitro for 10 h. Combining the figure and the release rate data, it can be seen that the release rate data of the sample of Example 1 meet the requirements, and the sample at the release end presents as a complete gel-like tablet. The release rate of the sample of Comparative Example 1 does not meet the requirements, especially there is a burst release phenomenon at 5 hours, and the release end presents as scattered gel-like, unable to form a continuous phase. The release rate of the sample of Comparative Example 2 meets the requirements, but the end point value is low (this is a common situation for ordinary gel matrix tablets), and the release end presents as a complete gel-like tablet, but the volume is large.

Claims

1. A dapagliflozin metformin sustained-release tablet, characterized in that: It contains a drug active ingredient, a crystal form stabilizer and a sustained-release material. The drug active ingredient is dapagliflozin, metformin or its hydrochloride salt. The content of metformin or its hydrochloride salt is 50 - 90 wt%, and the content of dapagliflozin is 0.5 - 5 wt%. The crystal form stabilizer is at least one of sulfoaluminate, hydrotalcite, sucralfate. The sustained-release material is at least one of hydroxypropyl methylcellulose, sodium carboxymethylcellulose, methylcellulose, carbomer, sodium alginate. The crystal form of dapagliflozin is propylene glycol monohydrate crystal form. The crystal form stabilizer accounts for 5 - 15% of the total mass of the crystal form stabilizer and the sustained-release material, and the total content of the crystal form stabilizer and the sustained-release material in the sustained-release tablet is 5 - 20 wt%.

2. The dapagliflozin metformin sustained-release tablets according to claim 1, characterized in that: The particle size control D90 of the crystal form stabilizer is less than or equal to 30 um.

3. The dapagliflozin metformin sustained-release tablets according to claim 1, characterized in that: The sustained-release material is a mixture of hydroxypropyl methylcellulose and carbomer.

4. The dapagliflozin metformin sustained-release tablets according to claim 3, wherein: The mass ratio of hydroxypropyl methylcellulose to carbomer is 1 - 9:

1.

5. The dapagliflozin metformin sustained-release tablets according to any one of claims 1-4, characterized in that: The crystal form stabilizer and the sustained-release material are added to the sustained-release tablet in the form of a complex. The complex of the crystal form stabilizer and the sustained-release material is obtained by the following method a or method b: a. The crystal form stabilizer is crushed to meet the particle size requirements, then mixed evenly with the sustained-release material and water, and the obtained suspension is spray-dried to obtain the complex. b. The crystal form stabilizer is crushed to meet the particle size requirements, then mixed with the sustained-release material and water to form a soft material. The soft material is melt-extruded to obtain an extrudate, and the extrudate is dried and crushed to obtain the complex.

6. The dapagliflozin metformin sustained-release tablets according to any one of claims 1-4, characterized in that: It also contains at least one of a filler, a disintegrant, a lubricant, and a coating agent.

7. The dapagliflozin metformin sustained-release tablets according to any one of claims 1-4, characterized in that: It also contains a filler, a disintegrant and a lubricant.

8. The dapagliflozin metformin sustained release tablets according to claim 6, characterized in that: The filler is one or more of corn starch, microcrystalline cellulose, lactose, mannitol, dextrin, sucrose powder.

9. The dapagliflozin metformin sustained-release tablets according to claim 6, characterized in that: The content of the filler in the sustained-release tablet is 0 - 50 wt%.

10. The dapagliflozin metformin sustained release tablets according to claim 6, characterized in that: The disintegrant is one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked povidone.

11. The dapagliflozin metformin sustained-release tablets according to claim 6, characterized in that: The content of the disintegrant in the sustained-release tablet is 0.1 - 5 wt%.

12. The dapagliflozin metformin sustained-release tablets according to claim 6, wherein: The lubricant is one or more of magnesium stearate, talc powder, stearic acid.

13. The dapagliflozin metformin sustained-release tablets according to claim 6, characterized in that: The content of the lubricant in the sustained-release tablet is 0.1 - 1 wt%.

14. The dapagliflozin metformin sustained release tablets according to claim 6, characterized in that: The content of the coating agent in the sustained-release tablet is 0 - 3 wt%.

15. A preparation method of the dapagliflozin metformin sustained-release tablets according to claim 7, characterized in that It includes the following steps: A. The crystal form stabilizer is crushed to meet the particle size requirements, then mixed evenly with the sustained-release material and water to obtain a suspension or a soft material. The suspension is spray-dried or the soft material is melt-extruded and then dried and crushed to obtain the complex of the crystal form stabilizer and the sustained-release material. B. The drug active ingredient, the complex of the crystal form stabilizer and the sustained-release material are wet granulated. The obtained wet granules are dried and sized to obtain dry granules. The dry granules are mixed with the filler, the disintegrant, and the lubricant, and the obtained mixture is compressed into tablets. Or, the drug active ingredient, the complex of the crystal form stabilizer and the sustained-release material, the filler, and the disintegrant are wet granulated. The obtained wet granules are dried and sized to obtain dry granules. The dry granules are mixed with the lubricant, and the obtained mixture is compressed into tablets.

16. The preparation method according to claim 15, characterized in that: It also includes the step of coating the obtained tablets to obtain coated tablets.

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