Dapagliflozin tablet and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a dapagliflozin tablet and a preparation method thereof. The dapagliflozin tablet comprises the following raw materials in parts by mass: 1-5 parts of dapagliflozin, 50-80 parts of a filler, 5-15 parts of a disintegrating agent, 1-5 parts of an adhesive, 0.5-3 parts of a stabilizer and 0.5-2 parts of a lubricant, according to the dapagliflozin tablet and the preparation method thereof, raw materials and the preparation method are improved, the in-vitro dissolution of the prepared dapagliflozin tablet can be consistent with that of an original drug, the dissolution uniformity is superior to that of the original drug, related substances of the preparation are not remarkably increased, the stability is good, the preparation process is simple, and the preparation method is suitable for industrial production. The method is suitable for large-scale low-cost production and application.

Description

Technical Field

[0001] This application relates to the technical field of pharmaceutical preparations, and in particular to a dapagliflozin tablet and a method for preparing the same. Background Technology

[0002] Dapagliflozin is an SGLT2 inhibitor used to treat type 2 diabetes, heart failure, and other diseases. Its chemical name is (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, and its chemical structure is as follows:

[0003] Dapagliflozin contains multiple hydroxyl groups, which are prone to degradation under humid and hot conditions, generating degradation impurities such as dehydration products and oxidation products. This leads to decreased formulation stability, affects efficacy, and may increase safety risks. Existing dapagliflozin tablets, such as the original drug, mostly use conventional excipients, such as microcrystalline cellulose as a filler without specific stabilizers. After accelerated storage at 40°C / 75%RH for 6 months, the content of related substances may exceed 0.5%, which does not meet pharmacopoeia limits, and stability still needs improvement.

[0004] In addition, dapagliflozin has low solubility, with a solubility of about 1.0 mg / mL in water. Conventional tablets may have poor dissolution, which affects bioavailability.

[0005] Therefore, there is an urgent need to develop a dapagliflozin tablet with high stability and good dissolution. Summary of the Invention

[0006] To address the shortcomings of existing dapagliflozin tablets, such as poor stability, excessive levels of related substances, and uneven dissolution, this application provides a dapagliflozin tablet and its preparation method. The prepared dapagliflozin tablet can significantly improve the stability of dapagliflozin, reduce the formation of related substances during storage, and improve the drug's dissolution.

[0007] This application discloses a dapagliflozin tablet and its preparation method, which has similar in vitro dissolution characteristics to the original formulation, and better homogeneity than the original formulation. The related substances in the formulation do not increase significantly, and the stability is good. Moreover, the preparation process is simple and suitable for large-scale low-cost production applications.

[0008] In a first aspect, this application provides a dapagliflozin tablet, which adopts the following technical solution: A dapagliflozin tablet comprising the following raw materials in parts by weight: Dapagliflozin 1-5 servings; 50-80 parts of filler; 5-15 parts disintegrant; 1-5 parts adhesive; Stabilizer 0.5-3 parts; 0.5-2 parts of lubricant. Preferably, the filler includes mannitol and microcrystalline cellulose.

[0009] Preferably, the mass ratio of mannitol to microcrystalline cellulose is (1-3):1.

[0010] By adopting the above technical solution, the added mannitol can improve the dissolution performance of tablets, and the added microcrystalline cellulose can enhance the tablet formability. The two work together to balance dissolution and formability.

[0011] Preferably, the disintegrant comprises crospovidone.

[0012] By adopting the above technical solution, the added cross-linked polyvinylpyrrolidone has strong disintegration ability and is insoluble in water, which can effectively disperse the active pharmaceutical ingredient and avoid agglomeration.

[0013] Preferably, the adhesive comprises hydroxypropyl methylcellulose.

[0014] By adopting the above technical solution, hydroxypropyl methylcellulose is used as a binder in this application. It has moderate viscosity, can form a stable particulate structure, and does not affect the dissolution of the active pharmaceutical ingredient. Preferably, the stabilizer includes disodium hydrogen phosphate and vitamin E.

[0015] Preferably, the mass ratio of disodium hydrogen phosphate to vitamin E is (2-4):1.

[0016] By adopting the above technical solution, the added disodium hydrogen phosphate can adjust the ionic strength of the formulation, shield the surface charge of molecules, reduce aggregation and maintain crystal stability; in addition, it can chelate metal ions introduced by raw materials or production equipment, eliminate metal catalysis, and effectively reduce the growth of related substances; the added vitamin E can resist oxidation and prevent the oxidative degradation of the raw drug, and the two work together to improve stability. Preferably, the lubricant comprises magnesium stearate.

[0017] By adopting the above technical solution, adding lubricant can reduce the friction between particles and equipment, improve the uniformity of tablet hardness, and avoid excessive addition affecting dissolution.

[0018] Secondly, this application provides a method for preparing dapagliflozin tablets, using the following technical solution: A method for preparing dapagliflozin tablets includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone, disodium hydrogen phosphate and vitamin E through an 80-mesh sieve for later use; (2) Dapagliflozin was mixed with 1 / 2 of mannitol and disodium hydrogen phosphate and then air-jet pulverized to obtain mixture I; (3) Mix mixture I with 1 / 3 of the amount of cross-linked polyvinylpyrrolidone and vitamin E to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, 1 / 2 of the amount of mannitol and microcrystalline cellulose to obtain mixture III; (5) Mix hydroxypropyl methylcellulose and water to obtain a mixed solution with a mass concentration of 5%-8%. Add mixture III to the mixed solution for mixing, granulation, drying, and sieving. (6) The sieved particles are mixed with magnesium stearate to obtain total mixed particles; (7) Compress the total granules into tablets to obtain dapagliflozin tablets.

[0019] Preferably, in step (2), the D of mixture I 90 It is 55-75μm.

[0020] Preferably, in step (2), during the airflow pulverization process, the pulverization pressure is 0.6-0.8MPa, the airflow velocity is 180-230m / s, the feeding rate is 5-10kg / h, and the pulverization chamber temperature is ≤40℃.

[0021] Preferably, the mixing time in step (3) is 10-15 minutes.

[0022] Preferably, the mixing time in step (4) is 20-25 minutes.

[0023] Preferably, the drying step in step (5) is as follows: the particles are dried at 45-55°C until the moisture content is 2.0-3.0%.

[0024] Preferably, the mixing time in step (6) is 5-8 minutes.

[0025] In one specific implementation, a method for preparing dapagliflozin tablets includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone, disodium hydrogen phosphate and vitamin E through an 80-mesh sieve for later use; (2) After mixing dapagliflozin raw material with 1 / 2 of mannitol and disodium hydrogen phosphate, the mixture is subjected to air jet milling to control the particle size D. 90 The thickness is 55-75 μm, resulting in mixture I; During the airflow milling process, the milling pressure is 0.6-0.8MPa, the airflow velocity is 180-230m / s, the feed rate is 5-10kg / h, and the milling chamber temperature is ≤40℃.

[0026] (3) Mix mixture I with 1 / 3 of the amount of cross-linked polyvinylpyrrolidone and vitamin E for 10-15 minutes to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, 1 / 2 of the amount of mannitol and microcrystalline cellulose for 20-25 minutes to obtain mixture III; (5) Granulation: Hydroxypropyl methylcellulose is prepared into a mixed solution with purified water at a mass concentration of 5%-8%. The mixed solution is added to mixture III for mixing and granulation to obtain soft material. The soft material is granulated through a 20-mesh sieve, and the granules are dried at 45-55℃ until the moisture content is 2.0%-3.0%. (6) Granulation and mixing: After drying, the granules are sized by passing them through an 18-mesh sieve, and magnesium stearate is added and mixed for 5-8 minutes to obtain the mixed granules; (7) Tableting: Compress the total mixed granules into tablets, controlling the tablet hardness to be 4-6 kgf and the tablet weight difference to be within ±5%.

[0027] By adopting the above technical solution, this application improves the preparation method by premixing dapagliflozin with the filler mannitol and the stabilizer disodium hydrogen phosphate, and then using an air jet milling process to refine the mixture and control the particle size D. 90 With a particle size of 55-75μm, the premixing step can ensure controllable particle size and prevent dapagliflozin from undergoing crystal transformation during the pulverization process, which would affect in vitro dissolution and the growth of related substances.

[0028] In this application, dapagliflozin is first mixed with mannitol and disodium hydrogen phosphate to ensure the stability of the raw materials during air jet milling. The added mannitol acts as a filler and protectant, while the disodium hydrogen phosphate can adjust the ionic strength to prevent the pulverized raw materials from re-aggregating and maintain crystal stability.

[0029] In summary, this application includes at least one of the following beneficial technical effects: 1. This application discloses a dapagliflozin tablet and its preparation method. In this application, by improving the raw materials, disodium hydrogen phosphate and vitamin E are used as stabilizers. By adding a combination of disodium hydrogen phosphate and vitamin E as stabilizers, the growth of impurities can be effectively controlled and the drug stability can be greatly improved. 2. This application improves the preparation method by using a premixing step, in which dapagliflozin is first mixed with the filler mannitol and the stabilizer disodium hydrogen phosphate and then air-jet pulverized to control the particle size to 55-75μm, and then mixed with other excipients. This enables the in vitro dissolution to be consistent with the original drug, and the dissolution uniformity is better than that of the original drug, which is conducive to achieving bioequivalence between generic drugs and original drugs. 3. This application discloses a dapagliflozin tablet and its preparation method, which is scientific, simple, reliable in quality, and easy to mass-produce industrially. Detailed Implementation

[0030] The technical solutions of this application are further illustrated by specific embodiments below. These specific embodiments do not represent a limitation on the scope of protection of this application. Any non-essential modifications and adjustments made by others based on the concept of this application still fall within the scope of protection of this application.

[0031] All raw materials involved in this application are commercially available products, among which, Dapagliflozin raw material, Zhejiang Huahai Pharmaceutical Co., Ltd.; Microcrystalline cellulose, CAS number 9004-34-6; Cross-linked polyvinylpyrrolidone, CAS number 9003-39-8; Hydroxypropyl methylcellulose, CAS No. 9004-65-3; The present application will be further described in detail below with reference to embodiments and comparative examples.

[0032] Example 1:

[0033] Dapagliflozin tablets, the prescription composition is shown in Table 1: Table 1 Prescription Composition

[0034] The preparation method of dapagliflozin tablets includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone, disodium hydrogen phosphate and vitamin E through an 80-mesh sieve for later use; (2) After mixing dapagliflozin raw material with 1 / 2 of mannitol and disodium hydrogen phosphate, the mixture is subjected to air jet milling to control the particle size D. 90 The thickness is 60-65 μm, resulting in mixture I; During the airflow pulverization process, the pulverization pressure is 0.7 MPa, the airflow velocity is 200 m / s, the feed rate is 8 kg / h, and the pulverization chamber temperature is ≤40℃.

[0035] (3) Mix mixture I with 1 / 3 of the amount of crospovidone and vitamin E for 12 minutes to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, 1 / 2 of the amount of mannitol and microcrystalline cellulose for 22 minutes to obtain mixture III; (5) Prepare a 6% (w / w) mixed solution of hydroxypropyl methylcellulose with purified water, add the mixed solution to mixture III and mix and granulate to obtain soft material; granulate the soft material through a 20-mesh sieve, and dry the granules at 50°C to a moisture content of 2.5%; (6) The dried granules were sieved through an 18-mesh sieve, and magnesium stearate was added and mixed for 6 minutes to obtain the total mixed granules; (7) Compress the total mixture of granules into tablets and control the tablet hardness to 5 kgf.

[0036] Example 2:

[0037] Dapagliflozin tablets, the prescription composition is shown in Table 2: Table 2 Prescription Composition

[0038] The preparation method of dapagliflozin tablets includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone, disodium hydrogen phosphate and vitamin E through an 80-mesh sieve for later use; (2) After mixing dapagliflozin raw material with 1 / 2 of mannitol and disodium hydrogen phosphate, the mixture is subjected to air jet milling to control the particle size D. 90 The thickness is 60-65 μm, resulting in mixture I; During the airflow pulverization process, the pulverization pressure is 0.7 MPa, the airflow velocity is 200 m / s, the feed rate is 8 kg / h, and the pulverization chamber temperature is ≤40℃.

[0039] (3) Mix mixture I with 1 / 3 of the amount of crospovidone and vitamin E for 12 minutes to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, 1 / 2 of the amount of mannitol and microcrystalline cellulose for 22 minutes to obtain mixture III; (5) Prepare a 6% (w / w) mixed solution of hydroxypropyl methylcellulose with purified water, add the mixed solution to mixture III and mix and granulate to obtain soft material; granulate the soft material through a 20-mesh sieve, and dry the granules at 50°C to a moisture content of 2.5%; (6) The dried granules were sieved through an 18-mesh sieve, and magnesium stearate was added and mixed for 8 minutes to obtain the total mixed granules; (7) Tableting: Compress the total mixed granules into tablets and control the tablet hardness to 6 kgf.

[0040] Example 3:

[0041] Dapagliflozin tablets, the prescription composition is shown in Table 3: Table 3 Prescription Composition

[0042] The preparation method of dapagliflozin tablets includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone, disodium hydrogen phosphate and vitamin E through an 80-mesh sieve for later use; (2) After mixing dapagliflozin raw material with 1 / 2 of mannitol and disodium hydrogen phosphate, the mixture is subjected to air jet milling to control the particle size D. 90 The thickness is 55-60 μm, resulting in mixture I; During the airflow milling process, the milling pressure is 0.75 MPa, the airflow velocity is 210 m / s, the feed rate is 8 kg / h, and the milling chamber temperature is ≤40℃.

[0043] (3) Mix mixture I with 1 / 3 of the amount of crospovidone and vitamin E for 12 minutes to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, 1 / 2 of the amount of mannitol and microcrystalline cellulose for 22 minutes to obtain mixture III; (5) Prepare a 6% (w / w) mixed solution of hydroxypropyl methylcellulose with purified water, add the mixed solution to mixture III and mix and granulate to obtain soft material; granulate the soft material through a 20-mesh sieve, and dry the granules at 50°C to a moisture content of 2.5%; (6) The dried granules were sieved through an 18-mesh sieve, and magnesium stearate was added and mixed for 6 minutes to obtain the total mixed granules; (7) Compress the total mixture of granules into tablets and control the tablet hardness to 5 kgf.

[0044] Example 4:

[0045] Dapagliflozin tablets, the prescription composition is shown in Table 4: Table 4 Prescription Composition

[0046] The preparation method of dapagliflozin tablets includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone, disodium hydrogen phosphate and vitamin E through an 80-mesh sieve for later use; (2) After mixing dapagliflozin raw material with 1 / 2 of mannitol and disodium hydrogen phosphate, the mixture is subjected to air jet milling to control the particle size D. 90 The thickness is 65-75 μm, resulting in mixture I; During the airflow milling process, the milling pressure is 0.65 MPa, the airflow velocity is 190 m / s, the feed rate is 8 kg / h, and the milling chamber temperature is ≤40℃.

[0047] (3) Mix mixture I with 1 / 3 of the amount of crospovidone and vitamin E for 12 minutes to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, 1 / 2 of the amount of mannitol and microcrystalline cellulose for 22 minutes to obtain mixture III; (5) Prepare a 6% (w / w) mixed solution of hydroxypropyl methylcellulose with purified water, add the mixed solution to mixture III and mix and granulate to obtain soft material; granulate the soft material through a 20-mesh sieve, and dry the granules at 50°C to a moisture content of 2.5%; (6) The dried granules were sieved through an 18-mesh sieve, and magnesium stearate was added and mixed for 6 minutes to obtain the total mixed granules; (7) Compress the total mixture of granules into tablets and control the tablet hardness to 5 kgf.

[0048] Example 5:

[0049] Dapagliflozin tablets, the prescription composition is shown in Table 5: Table 5 Prescription Composition

[0050] The preparation method of dapagliflozin tablets includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone, disodium hydrogen phosphate and vitamin E through an 80-mesh sieve for later use; (2) After mixing dapagliflozin raw material with 1 / 2 of mannitol and disodium hydrogen phosphate, the mixture is subjected to air jet milling to control the particle size D. 90 The thickness is 60-65 μm, resulting in mixture I; During the airflow pulverization process, the pulverization pressure is 0.7 MPa, the airflow velocity is 200 m / s, the feed rate is 8 kg / h, and the pulverization chamber temperature is ≤40℃.

[0051] (3) Mix mixture I with 1 / 3 of the amount of cross-linked polyvinylpyrrolidone and vitamin E for 10 minutes to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, 1 / 2 of the amount of mannitol and microcrystalline cellulose for 20 minutes to obtain mixture III; (5) Prepare a 5% (w / w) mixed solution of hydroxypropyl methylcellulose with purified water, add the mixed solution to mixture III and mix and granulate to obtain a soft material; granulate the soft material through a 20-mesh sieve, and dry the granules at 50°C to a moisture content of 2.5%; (6) The dried granules are sieved through an 18-mesh sieve, and magnesium stearate is added and mixed for 5 minutes to obtain the total mixed granules; (7) Compress the total mixture of granules into tablets and control the tablet hardness to 5 kgf.

[0052] Example 6:

[0053] Dapagliflozin tablets, the prescription composition is shown in Table 6: Table 6 Prescription Composition

[0054] The preparation method of dapagliflozin tablets includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone, disodium hydrogen phosphate and vitamin E through an 80-mesh sieve for later use; (2) After mixing dapagliflozin raw material with 1 / 2 of mannitol and disodium hydrogen phosphate, the mixture is subjected to air jet milling to control the particle size D. 90 The thickness is 60-65 μm, resulting in mixture I; During the airflow pulverization process, the pulverization pressure is 0.7 MPa, the airflow velocity is 200 m / s, the feed rate is 8 kg / h, and the pulverization chamber temperature is ≤40℃.

[0055] (3) Mix mixture I with 1 / 3 of the amount of cross-linked polyvinylpyrrolidone and vitamin E for 15 minutes to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, 1 / 2 of the amount of mannitol and microcrystalline cellulose for 25 minutes to obtain mixture III; (5) Prepare a mixed solution of hydroxypropyl methylcellulose with purified water with a mass concentration of 8%, add the mixed solution to mixture III for mixing and granulation to obtain soft material; granulate the soft material through a 20-mesh sieve, and dry the granules at 50°C to a moisture content of 2.5%; (6) The dried granules were sieved through an 18-mesh sieve, and magnesium stearate was added and mixed for 8 minutes to obtain the total mixed granules; (7) Compress the total mixture of granules into tablets and control the tablet hardness to 5 kgf.

[0056] Comparative Example 1:

[0057] Dapagliflozin tablets, the prescription composition is shown in Table 7: Table 7 Prescription Composition

[0058] The preparation method of dapagliflozin tablets includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone, disodium hydrogen phosphate and vitamin E through an 80-mesh sieve for later use; (2) After mixing dapagliflozin raw material with 1 / 2 of mannitol and disodium hydrogen phosphate, the mixture is subjected to air jet milling to control the particle size D. 90 The thickness is 40-55 μm, resulting in mixture I; During the airflow milling process, the milling pressure is 0.8 MPa, the airflow velocity is 220 m / s, the feed rate is 9 kg / h, and the milling chamber temperature is ≤40℃.

[0059] (3) Mix mixture I with 1 / 3 of the amount of crospovidone and vitamin E for 12 minutes to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, 1 / 2 of the amount of mannitol and microcrystalline cellulose for 22 minutes to obtain mixture III; (5) Prepare a 6% (w / w) mixed solution of hydroxypropyl methylcellulose with purified water, add the mixed solution to mixture III and mix and granulate to obtain soft material; granulate the soft material through a 20-mesh sieve, and dry the granules at 50°C to a moisture content of 2.5%; (6) The dried granules were sieved through an 18-mesh sieve, and magnesium stearate was added and mixed for 6 minutes to obtain the total mixed granules; (7) Compress the total mixture of granules into tablets and control the tablet hardness to 5 kgf.

[0060] Comparative Example 2:

[0061] Dapagliflozin tablets, the prescription composition is shown in Table 8: Table 8 Prescription Composition

[0062] The preparation method of dapagliflozin tablets includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone, disodium hydrogen phosphate and vitamin E through an 80-mesh sieve for later use; (2) After mixing dapagliflozin raw material with 1 / 2 of mannitol and disodium hydrogen phosphate, the mixture is subjected to air jet milling to control the particle size D. 90 The thickness is 75-80 μm, resulting in mixture I; During the airflow milling process, the milling pressure is 0.6 MPa, the airflow velocity is 190 m / s, the feed rate is 9 kg / h, and the milling chamber temperature is ≤40℃.

[0063] (3) Mix mixture I with 1 / 3 of the amount of crospovidone and vitamin E for 12 minutes to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, 1 / 2 of the amount of mannitol and microcrystalline cellulose for 22 minutes to obtain mixture III; (5) Prepare a 6% (w / w) mixed solution of hydroxypropyl methylcellulose with purified water, add the mixed solution to mixture III and mix and granulate to obtain soft material; granulate the soft material through a 20-mesh sieve, and dry the granules at 50°C to a moisture content of 2.5%; (6) The dried granules were sieved through an 18-mesh sieve, and magnesium stearate was added and mixed for 6 minutes to obtain the total mixed granules; (7) Compress the total mixture of granules into tablets and control the tablet hardness to 5 kgf.

[0064] Comparative Example 3:

[0065] Dapagliflozin tablets, the prescription composition is shown in Table 9: Table 9 Prescription Composition

[0066] The preparation method of dapagliflozin tablets includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone, disodium hydrogen phosphate and vitamin E through an 80-mesh sieve for later use; (2) After mixing dapagliflozin raw material with 1 / 2 of mannitol, the mixture is subjected to air jet milling to control the particle size D. 90 The thickness is 60-65 μm, resulting in mixture I; During the airflow pulverization process, the pulverization pressure is 0.7 MPa, the airflow velocity is 200 m / s, the feed rate is 8 kg / h, and the pulverization chamber temperature is ≤40℃.

[0067] (3) Mix mixture I with 1 / 3 of the amount of crospovidone and vitamin E for 12 minutes to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, 1 / 2 of the amount of mannitol, disodium hydrogen phosphate and microcrystalline cellulose for 22 minutes to obtain mixture III; (5) Prepare a 6% (w / w) mixed solution of hydroxypropyl methylcellulose with purified water, add the mixed solution to mixture III and mix and granulate to obtain soft material; granulate the soft material through a 20-mesh sieve, and dry the granules at 50°C to a moisture content of 2.5%; (6) The dried granules were sieved through an 18-mesh sieve, and magnesium stearate was added and mixed for 6 minutes to obtain the total mixed granules; (7) Compress the total mixture of granules into tablets and control the tablet hardness to 5 kgf.

[0068] Comparative Example 4:

[0069] Dapagliflozin tablets, the prescription composition is shown in Table 10: Table 10 Prescription Composition

[0070] The preparation method of dapagliflozin tablets includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone, disodium hydrogen phosphate and vitamin E through an 80-mesh sieve for later use; (2) After mixing dapagliflozin raw material with disodium hydrogen phosphate, the mixture is subjected to air jet milling to control the particle size D. 90 The thickness is 60-65 μm, resulting in mixture I; During the airflow pulverization process, the pulverization pressure is 0.7 MPa, the airflow velocity is 200 m / s, the feed rate is 8 kg / h, and the pulverization chamber temperature is ≤40℃.

[0071] (3) Mix mixture I with 1 / 3 of the amount of crospovidone and vitamin E for 12 minutes to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, mannitol and microcrystalline cellulose for 22 minutes to obtain mixture III; (5) Prepare a 6% (w / w) mixed solution of hydroxypropyl methylcellulose with purified water, add the mixed solution to mixture III and mix and granulate to obtain soft material; granulate the soft material through a 20-mesh sieve, and dry the granules at 50°C to a moisture content of 2.5%; (6) The dried granules were sieved through an 18-mesh sieve, and magnesium stearate was added and mixed for 6 minutes to obtain the total mixed granules; (7) Compress the total mixture of granules into tablets and control the tablet hardness to 5 kgf.

[0072] Comparative Example 5:

[0073] Dapagliflozin tablets, the prescription composition is shown in Table 11: Table 11 Prescription Composition

[0074] The preparation method of dapagliflozin tablets includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone, disodium hydrogen phosphate and vitamin E through an 80-mesh sieve for later use; (2) The dapagliflozin raw material is air-jet pulverized to control the particle size D. 90 The thickness is 60-65 μm, resulting in mixture I; During the airflow pulverization process, the pulverization pressure is 0.7 MPa, the airflow velocity is 200 m / s, the feed rate is 8 kg / h, and the pulverization chamber temperature is ≤40℃.

[0075] (3) Mix mixture I with 1 / 3 of the amount of crospovidone and vitamin E for 12 minutes to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, mannitol, disodium hydrogen phosphate and microcrystalline cellulose for 22 minutes to obtain mixture III; (5) Prepare a 6% (w / w) mixed solution of hydroxypropyl methylcellulose with purified water. Add mixture III to the mixed solution and mix. Then, granulate by wet granulation to form a soft mass. Granulate the soft mass through a 20-mesh sieve and dry it at 50°C to a moisture content of 2.5%. (6) The dried granules were sieved through an 18-mesh sieve, and magnesium stearate was added and mixed for 6 minutes to obtain the total mixed granules; (7) Compress the total mixture of granules into tablets and control the tablet hardness to 5 kgf.

[0076] Comparative Example 6:

[0077] Dapagliflozin tablets, the prescription composition is shown in Table 12: Table 12 Prescription Composition

[0078] The preparation method of dapagliflozin tablets includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone and disodium hydrogen phosphate through an 80-mesh sieve for later use; (2) After mixing dapagliflozin raw material with 1 / 2 of mannitol and disodium hydrogen phosphate, the mixture is subjected to air jet milling to control the particle size D. 90 The thickness is 60-65 μm, resulting in mixture I; During the airflow pulverization process, the pulverization pressure is 0.7 MPa, the airflow velocity is 200 m / s, the feed rate is 8 kg / h, and the pulverization chamber temperature is ≤40℃.

[0079] (3) Mix mixture I with 1 / 3 of the cross-linked polyvinylpyrrolidone for 12 minutes to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, 1 / 2 of the amount of mannitol and microcrystalline cellulose for 22 minutes to obtain mixture III; (5) Prepare a 6% (w / w) mixed solution of hydroxypropyl methylcellulose with purified water, add the mixed solution to mixture III and mix and granulate to obtain soft material; granulate the soft material through a 20-mesh sieve, and dry the granules at 50°C to a moisture content of 2.5%; (6) The dried granules were sieved through an 18-mesh sieve, and magnesium stearate was added and mixed for 6 minutes to obtain the total mixed granules; (7) Compress the total mixture of granules into tablets and control the tablet hardness to 5 kgf.

[0080] Performance testing:

[0081] 1. Dissolution curve detection The drug dissolution in phosphate medium at pH 6.8 was tested according to Method 2 (paddle method) of General Chapter 0931, Part IV, 2025 edition of the Chinese Pharmacopoeia. The dissolution method was the paddle method, with a medium volume of 900 ml, a water bath temperature of 37 ± 0.5 °C, and a paddle speed of 50 r / min. The dissolution curves of the original drug FORXIGA® and the examples and comparative examples were determined according to the procedure. The results are shown in Table 13. Table 13 Dissolution curves for different formulations

[0082] The results showed that the dissolution curves of Examples 1, 2, 3, 4, 5, and 6 in this application in pH 6.8 phosphate buffer medium were similar to those of the control example - FORXIGA® original drug. They all showed rapid dissolution, and the final dissolution rate was higher than that of the original drug. The relative average deviation was better than that of the original drug, and the dissolution was more uniform.

[0083] Comparative Example 1: Dapagliflozin particle size tablet sample (i.e., D of Mixture I) 90 (40-55 μm), dapagliflozin tablet sample of Comparative Example 2 (i.e., D of Mixture I). 90 The particle size of the first mixture (75-80 μm) did not reach 85% or higher within 15 minutes, which is not similar to the original FORXIGA® control. The dissolution results of Examples 1-4 showed that the dissolution rate was greater than 85% within 15 minutes, similar to the original FORXIGA® control, and with better dissolution uniformity. Based on the dissolution results, when preparing dapagliflozin tablets, mixture I can be selected with a particle size range of 55-75 µm. Preferably, the Dg of mixture I is... 90 With a size of 60-65 μm, it exhibits excellent in vitro dissolution properties, ensuring bioequivalence in vivo.

[0084] Based on the dissolution results of Examples 1 and 2 and Comparative Examples 3, 4, and 5, Comparative Examples 4 and 5, which did not have mannitol added during the pretreatment stage, did not achieve a dissolution rate of 85% within 15 minutes, which is dissimilar to the control example - FORXIGA® original drug. The other examples were similar. Therefore, mannitol can improve dissolution performance; thus, it is preferable to add a certain amount of mannitol during the pretreatment stage.

[0085] 2. Stability Comparison Test Referring to the Guidelines for Stability Testing of Raw Materials and Preparations in General Chapter 9001 of the 2025 Edition of the Chinese Pharmacopoeia, the original drug FORXIGA® (from the examples, comparative examples, and control examples) were continuously placed for 30 days under accelerated testing conditions (temperature 40℃±2℃, relative humidity 75%±5%) to examine the changes in related substances of each sample. The results are shown in Table 14. Table 14 Stability Results

[0086] The results showed that, under accelerated testing conditions, the increase in related substances in Examples 1-6 of this application (with disodium hydrogen phosphate added in the pretreatment stage and vitamin E added in the mixing stage) was less than 0.5% after 30 days, while the increases in related substances in Comparative Example 3 (without disodium hydrogen phosphate), Comparative Example 5 (without mannitol or disodium hydrogen phosphate), and Control Example - the original drug FORXIGA were significantly lower. ® The increase in related substances was above 0.5% in all cases. Comparative Example 4, which added the stabilizer disodium hydrogen phosphate during the pretreatment stage, showed a 0.26% increase in related substances after 30 days in the accelerated testing. Comparative Example 6, without the addition of vitamin E, showed a 0.76% increase in related substances. Although the increase in related substances in Comparative Example 6 was controlled, it still exceeded 0.5% after 30 days. Therefore, this application demonstrates that the use of a combination of disodium hydrogen phosphate and vitamin E stabilizers effectively controls impurity growth and ensures that the formulation meets quality requirements.

[0087] The dapagliflozin tablets prepared in this application showed similar dissolution curves to the original drug in a phosphate medium at pH 6.8, with better dissolution uniformity. Furthermore, after being continuously stored for 30 days under accelerated testing conditions (i.e., temperature 40℃±2℃, relative humidity 75%±5%), the related substances remained stable (total impurity increase was less than 0.5%).

Claims

1. A dapagliflozin tablet, characterized in that: The raw materials include the following parts by weight: Dapagliflozin 1-5 servings; 50-80 parts of filler; 5-15 parts disintegrant; 1-5 parts adhesive; Stabilizer 0.5-3 parts; 0.5-2 parts of lubricant.

2. The dapagliflozin tablet according to claim 1, characterized in that: The filler includes mannitol and microcrystalline cellulose.

3. A dapagliflozin tablet according to claim 2, characterized in that: The mass ratio of mannitol to microcrystalline cellulose is (1-3):

1.

4. A dapagliflozin tablet according to claim 1, characterized in that: The disintegrant includes crospovidone; the binder includes hydroxypropyl methylcellulose; and the lubricant includes magnesium stearate.

5. A dapagliflozin tablet according to claim 1, characterized in that: The stabilizer includes disodium hydrogen phosphate and vitamin E.

6. A dapagliflozin tablet according to claim 5, characterized in that: The mass ratio of disodium hydrogen phosphate to vitamin E is (2-4):

1.

7. A method for preparing dapagliflozin tablets according to any one of claims 1-6, characterized in that, Includes the following steps: (1) Pass mannitol, microcrystalline cellulose, crospovidone, disodium hydrogen phosphate and vitamin E through an 80-mesh sieve for later use; (2) Dapagliflozin was mixed with 1 / 2 of mannitol and disodium hydrogen phosphate and then air-jet pulverized to obtain mixture I; (3) Mix mixture I with 1 / 3 of the amount of cross-linked polyvinylpyrrolidone and vitamin E to obtain mixture II; (4) Mix mixture II with 2 / 3 of the amount of cross-linked polyvinylpyrrolidone, 1 / 2 of the amount of mannitol and microcrystalline cellulose to obtain mixture III; (5) Mix hydroxypropyl methylcellulose and water to obtain a mixed solution with a mass concentration of 5%-8%. Add mixture III to the mixed solution for mixing, granulation, drying, and sieving. (6) The sieved particles are mixed with magnesium stearate to obtain total mixed particles; (7) Compress the total granules into tablets to obtain dapagliflozin tablets.

8. The method for preparing dapagliflozin tablets according to claim 7, characterized in that: In step (2), the D of mixture I 90 It is 55-75μm.

9. The method for preparing dapagliflozin tablets according to claim 7, characterized in that: In step (2), during the airflow pulverization process, the pulverization pressure is 0.6-0.8MPa, the airflow velocity is 180-230m / s, the feeding rate is 5-10kg / h, and the pulverization chamber temperature is ≤40℃.

10. The method for preparing dapagliflozin tablets according to claim 7, characterized in that: The mixing time in step (3) is 10-15 minutes; The mixing time in step (4) is 20-25 minutes; The mixing time in step (6) is 5-8 minutes; The drying step in step (5) is as follows: the particles are dried at 45-55℃ until the moisture content is 2.0-3.0%.

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