Compound sustained-release tablet for treating diabetes and preparation method thereof

Abstract

The application discloses a dapagliflozin metformin sustained-release tablet, which comprises the following components: metformin hydrochloride, an isolation material, dapagliflozin propylene glycol monohydrate, a cosolvent, a lubricant, a diluent and a disintegrant. 90 The metformin hydrochloride is composed of three kinds of particles with different particle sizes, and the particle sizes D 90 of the three kinds of particles are 0.5-1.0 μm, 50-200 μm and 300-600 μm respectively. The weight composition ratio of the three kinds of particles is (0.5-1) : 1 : (0.5-1). The dapagliflozin metformin sustained-release tablet provided by the application has a longer action time, and can be uniformly and slowly released and chemically stable.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical materials technology, and in particular relates to a dapagliflozin metformin sustained-release tablet and its preparation method. Background Technology

[0002] Diabetes is a group of metabolic diseases characterized by hyperglycemia. Based on the pathogenesis, diabetes can be divided into type 1 diabetes, type 2 diabetes, gestational diabetes and special types of diabetes. Among them, type 2 diabetes is the most common type in clinical practice, accounting for more than 90% of the total diabetic population.

[0003] Dapagliflozin is a novel oral hypoglycemic agent, belonging to the sodium-glucose cotransporter 2 (SGLT2) inhibitor class. SGLT2 is expressed in the proximal renal tubules and is the main transporter responsible for the reabsorption of glucose filtered by the renal tubules. Dapagliflozin lowers blood glucose levels by inhibiting SGLT2 activity, thereby reducing the reabsorption of glucose by the kidneys and increasing urinary glucose excretion.

[0004] Metformin hydrochloride can improve insulin resistance, making cells more sensitive to insulin and thus enhancing the hypoglycemic effect of insulin. This mechanism of action helps promote the binding of insulin to target cells (such as muscle and fat), thereby promoting glucose uptake and utilization and lowering blood sugar levels.

[0005] Dapagliflozin metformin extended-release tablets are a combination drug primarily used to treat type 2 diabetes in adults, especially those whose type 2 diabetes cannot be well controlled by diet and exercise alone. It also helps improve symptomatic chronic heart failure and chronic kidney disease.

[0006] In existing technologies CN117695237A, CN113398097A, and CN106924208A, dapagliflozin-metformin extended-release tablets can achieve slow release over 10-12 hours. However, studies have shown that the dapagliflozin-metformin extended-release tablets prepared by these methods exhibit uneven release, sometimes releasing too much and sometimes too little within the shelf life. Providing a stable compound tablet with uniform slow release and a longer duration of action remains a problem to be solved in this field. Summary of the Invention

[0007] This application provides a dapagliflozin metformin extended-release tablet with uniform and slow release and a longer duration of action.

[0008] This application provides a dapagliflozin metformin sustained-release tablet, comprising: metformin hydrochloride, a separating material, dapagliflozin propylene glycol monohydrate, a solubilizer, a lubricant, a diluent, and a disintegrant. The metformin hydrochloride is composed of particles of various sizes, achieving continuous, uniform, stable, and sustained release.

[0009] Preferably, the metformin hydrochloride is composed of three different particle sizes, wherein the three particle sizes D 90 The corresponding sizes are 0.5–1.0 μm, 50–200 μm, and 300–600 μm, respectively.

[0010] Preferably, the weight composition ratio of the three particle sizes of metformin hydrochloride is (0.5-1):1:(0.5-1).

[0011] Preferably, the particle size D of the three types of metformin hydrochloride is... 90 The corresponding sizes are 0.8–1.0 μm, 50–100 μm, and 300–500 μm, respectively.

[0012] Preferably, the weight composition ratio of the three metformin hydrochloride compounds is (0.75-1):1:(0.75-1).

[0013] Preferably, the insulating material is one or more of polyvinylpyrrolidone K30, chitosan, gelatin, and polyvinyl alcohol.

[0014] Preferably, the weight ratio of the insulating material to metformin hydrochloride is 5-10:100.

[0015] Preferably, the weight ratio of the insulating material to metformin hydrochloride is 8-10:100.

[0016] This application also provides a method for preparing dapagliflozin metformin extended-release tablets, comprising the following steps:

[0017] (1) Dissolve the prescribed amount of metformin hydrochloride of different particle sizes and the isolation material in water or organic solvent in sequence to prepare a solution for later use;

[0018] (2) The solution described in (1) is spray-dried using a spray dryer and cooled to room temperature to obtain metformin hydrochloride granules;

[0019] 3) Mix metformin hydrochloride granules, dapagliflozin propylene glycol monohydrate, solubilizer, diluent, disintegrant, pulverize, and finally mix with lubricant to form granules;

[0020] 4) Granulation and tableting.

[0021] Beneficial effects:

[0022] Through extensive experimentation, the inventors discovered that metformin hydrochloride particles of different sizes exhibit varying degrees of ease of release. Smaller particles have a larger contact area, resulting in faster release, while larger particles have a smaller contact area, leading to slower release. Optimal weight ratios of different particle sizes effectively achieve a uniform and slow release of metformin hydrochloride over a specific time. Furthermore, to enhance the stability of dapagliflozin-metformin extended-release tablets, an insulating layer was added to the metformin diacid. This insulating layer not only improves the stability of the tablets but also prolongs the release time of the active ingredient, further extending the therapeutic effect. Attached Figure Description

[0023] Figure 1 This is an in vitro release curve of metformin hydrochloride in 0.1M hydrochloric acid solution of the dapagliflozin metformin sustained-release tablets prepared in Examples 1-4.

[0024] Figure 2 Example 1: In vitro release curves of metformin hydrochloride in 0.1M hydrochloric acid solution of dapagliflozin metformin extended-release tablets prepared in Comparative Examples 1-6.

[0025] Figure 3 In vitro release curves of metformin hydrochloride in 0.1M hydrochloric acid solution in dapagliflozin metformin sustained-release tablets prepared in Examples 1, 5-7.

[0026] Figure 4 Example 1: In vitro release curves of metformin hydrochloride in 0.1M hydrochloric acid solution of dapagliflozin metformin extended-release tablets prepared in Comparative Examples 7-10.

[0027] Figure 5 In vitro release curves of metformin hydrochloride in 0.1M hydrochloric acid solution in dapagliflozin metformin sustained-release tablets prepared in Examples 1, 8-10.

[0028] Figure 6 In vitro release curves of metformin hydrochloride in 0.1M hydrochloric acid solution in the dapagliflozin metformin sustained-release tablets prepared in Examples 1 and 11-12.

[0029] Figure 7 Example 1: In vitro release curves of metformin hydrochloride in 0.1M hydrochloric acid solution of dapagliflozin metformin extended-release tablets prepared in Comparative Examples 11-12. Detailed Implementation

[0030] The technical solutions in the embodiments of this application are clearly described below. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0031] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those illustrated or described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0032] This application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

[0033] This application provides a dapagliflozin metformin sustained-release tablet, comprising: metformin hydrochloride, a separating material, dapagliflozin propylene glycol monohydrate, a solubilizer, a lubricant, a diluent, and a disintegrant. The metformin hydrochloride is composed of particles of various sizes, achieving continuous, uniform, stable, and sustained release.

[0034] The insulating material is one or more of polyvinylpyrrolidone K30, chitosan, gelatin, and polyvinyl alcohol.

[0035] The cosolvent may be one or more of polyethylene glycol 3350, propylene glycol, and polysorbate 80; the lubricant may be magnesium stearate, sodium stearate fumarate, or talc; the diluent may be anhydrous lactose, microcrystalline cellulose, starch, or mannitol; and the disintegrant may be low-substituted hydroxypropyl cellulose, pregelatinized starch, or croscarmellose sodium, but is not limited to these.

[0036] Preferably, the metformin hydrochloride is composed of three different particle sizes, wherein the three particle sizes D 90 The particle sizes are 0.5–1.0 μm, 50–200 μm, and 300–600 μm, respectively. The three particle sizes D... 90It can be 0.5μm, 50μm, 300μm; 0.5μm, 75μm, 300μm; 0.5μm, 100μm, 300μm; 0.5μm, 125μm, 300μm; 0.5μm, 150μm, 300μm; 0.5μm, 175μm, 300μm; 0.5μm, 200μm, 30 0μm;0.75μm、50μm、300μm;0.75μm、75μm、300μm;0.75μm、100μm、300μm;0.75μm、125μm、300μm;0.75μm、150μm、300μm;0.75μm、175μm、300μm;0.75μm、 200μm, 300μm;0.8μm, 50μm, 300μm;0.8μm, 75μm, 300μm;0.8μm, 100μm, 300μm;0.8μm, 125μm, 300μm;0.8μm, 150μm, 300μm;0.8μm, 175μm, 300μm;0.8μm ,200μm,300μm;1.0μm,50μm,300μm;1.0μm,75μm,300μm;1.0μm,100μm,300μm;1.0μm,125μm,300μm;1.0μm,150μm,300μm;1.0μm,175μm,300μm;1.0μm ,200μm,300μm;0.5μm,50μm,350μm;0.5μm,75μm,350μm;0.5μm,100μm,350μm;0.5μm,125μm,350μm;0.5μm,150μm,350μm;0.5μm,175μm,350μm;0.5μm m、200μm、350μm;0.5μm、50μm、400μm;0.5μm、75μm、400μm;0.5μm、100μm、4 00μm;0.5μm、125μm、400μm;0.5μm、150μm、400μm;0.5μm、175μm、400μm;0.5 μm、200μm、400μm;0.5μm、50μm、500μm;0.5μm、75μm、500μm;0.5μm、100μm、 500μm;0.5μm、125μm、500μm;0.5μm、150μm、500μm;0.5μm、175μm、500μm;0. 5μm, 200μm, 500μm;0.5μm, 50μm, 450μm;0.5μm, 75μm, 450μm;0.5μm, 100μm, 450μm;0.5μm, 125μm, 450μm;0.5μm, 150μm, 450μm;0.5μm, 175μm, 450μm;0.5μm, 200μm, 450μm; 0.5μm, 50μm, 550μm; 0.5μm, 75μm, 550μm; 0.5μm, 100μm, 550μm ;0.5μm, 125μm, 550μm; 0.5μm, 150μm, 550μm; 0.5μm, 175μm, 550μm; 0.5μm, 200μm, 5 50μm; 0.5μm, 50μm, 600μm; 0.5μm, 75μm, 600μm; 0.5μm, 100μm, 600μm; 0.5μm, 125μm, 600μm; 0.5μm, 150μm, 600μm; 0.5μm, 175μm, 600μm; 0.5μm, 200μm, 600μm; but not limited to these.

[0037] Preferably, the weight composition ratio of the three types of metformin hydrochloride with different particle sizes is (0.5-1):1:(0.5-1), and the weight composition ratio of the three types of metformin hydrochloride is 0.5:1:0.5, 0.75:1:0.5, 1:1:0.5, 0.75:1:0.75, 0.75:1:1, 1:1:1, but is not limited to these.

[0038] Preferably, the weight ratio of the insulating material to metformin hydrochloride is 5 to 10:100, and the weight ratio of the insulating material to metformin hydrochloride is 5:100, 7.5:100, 8:100, 8.5:100, 9:100, or 10:100, but is not limited to these.

[0039] This application also provides a method for preparing dapagliflozin metformin extended-release tablets, comprising the following steps:

[0040] (1) Dissolve the prescribed amount of metformin hydrochloride of different particle sizes and the isolation material in water or organic solvent in sequence to prepare a solution for later use;

[0041] (2) The solution described in (1) is spray-dried using a spray dryer and cooled to room temperature to obtain metformin hydrochloride granules;

[0042] 3) Mix metformin hydrochloride granules, dapagliflozin propylene glycol monohydrate, solubilizer, diluent, disintegrant, pulverize, and finally mix with lubricant to form granules;

[0043] 4) Granulation and tableting.

[0044] The dapagliflozin metformin sustained-release tablets prepared by this invention have a longer duration of action, release slowly and evenly, and have stable chemical properties.

[0045] The following examples illustrate the proportions further.

[0046] Example 1

[0047] The prescription quantities are shown in Table 1:

[0048] Table 1. Prescription composition and dosage for Example 1

[0049]

[0050]

[0051] Preparation process:

[0052] (1) Dissolve the prescribed amounts of metformin hydrochloride and povidone K30 and K25 of three particle sizes in water to prepare an aqueous solution for later use.

[0053] (2) The above aqueous solution was spray dried using a spray dryer. The atomizer frequency was set to 480±10Hz, the inlet air temperature to 200℃, the peristaltic pump speed to 20~25rpm, and the outlet air temperature was controlled at 100~120℃. After spray drying, the material was discharged and cooled to room temperature to obtain metformin hydrochloride granules.

[0054] 3) Mix metformin hydrochloride granules, dapagliflozin propylene glycol monohydrate, polyethylene glycol 3350, anhydrous lactose, and low-substituted hydroxypropyl cellulose in a laboratory hopper mixer for 10 minutes at 8 rpm; after mixing, pass the mixture through a 1.0 mm pulverizer and finally place the sieved mixture and sodium stearate in a mixer and mix for 10 minutes.

[0055] 4) Granulation and tableting.

[0056] Examples 2-4

[0057] The only difference between Examples 2-4 and Example 1 is the particle size of the three types of metformin hydrochloride particles. In Example 2, the particle size D of the three types of metformin hydrochloride particles is different. 90 The particle sizes were 0.6 μm, 50 μm, and 600 μm, respectively; in Example 3, the particle sizes D of the three metformin hydrochloride products were... 90 The particle sizes D of the three metformin hydrochloride samples were 1.0 μm, 100 μm, and 300 μm, respectively; in Example 4, the particle sizes D of the three metformin hydrochloride samples were... 90 The thicknesses were 0.8 μm, 200 μm, and 500 μm, respectively. Other formulation components, dosages, and preparation processes were consistent with those in Example 1.

[0058] Examples 5-7

[0059] The only difference between Examples 5-7 and Example 1 is the weight ratio of the three metformin hydrochloride compounds. In Example 5, the weight ratio of the three metformin hydrochloride compounds is 0.5:1:0.75; in Example 6, the weight ratio is 1:1:0.5; and in Example 7, the weight ratio is 1:1:1. All other formulations, dosages, and preparation processes are the same as in Example 1.

[0060] Examples 8-10

[0061] The only difference between Examples 8-10 and Example 1 is the type of separating material used to encapsulate metformin hydrochloride. In Example 8, the separating material was chitosan; in Example 9, it was gelatin; and in Example 10, it was polyvinyl alcohol. All other formulations, dosages, and preparation processes remained the same as in Example 1.

[0062] Examples 11-12

[0063] The only difference between Examples 11 and 12 and Example 1 is the amount of povidone K30, the insulating material surrounding metformin hydrochloride, used. In Example 11, the amount of povidone K30 is 5% of the weight of metformin hydrochloride, i.e., 50 mg / tablet; in Example 12, the amount of povidone K30 is 10% of the weight of metformin hydrochloride, i.e., 100 mg / tablet. All other formulations, dosages, and preparation processes are the same as in Example 1.

[0064] Comparative Examples 1-6

[0065] The only difference between Comparative Examples 1-6 and Example 1 is that the particle sizes of the three metformin hydrochloride formulations are different. In Comparative Example 1, the particle size D of the three metformin hydrochloride formulations is different. 90 The particle sizes were 0.3 μm, 150 μm, and 400 μm, respectively; in Comparative Example 2, the particle sizes D of the three metformin hydrochloride products were... 90 The particle sizes were 1.5 μm, 150 μm, and 400 μm, respectively; in Comparative Example 3, the particle sizes D of the three metformin hydrochloride products were... 90 The particle sizes were 0.8 μm, 10 μm, and 400 μm, respectively; in Comparative Example 4, the particle sizes D of the three metformin hydrochloride products were... 90 The particle sizes were 0.8 μm, 300 μm, and 400 μm, respectively; in Comparative Example 5, the particle sizes D of the three metformin hydrochloride products were... 90 The particle sizes were 0.8 μm, 150 μm, and 200 μm, respectively; in Comparative Example 6, the particle sizes D of the three metformin hydrochloride products were... 90The micrometers were 0.8 μm, 150 μm, and 700 μm, respectively. Other formulation components, dosages, and preparation processes were consistent with those in Example 1.

[0066] Comparative Examples 7-10

[0067] The only difference between Comparative Examples 1-6 and Example 1 is the weight ratio of the three metformin hydrochloride compounds. In Comparative Example 7, the weight ratio of the three metformin hydrochloride compounds is 0.25:1:0.75; in Comparative Example 8, the weight ratio is 1.25:1:0.75; in Comparative Example 9, the weight ratio is 0.75:1:1.25; and in Comparative Example 10, the weight ratio is 0.75:1:0.25. All other formulations, dosages, and preparation processes are the same as in Example 1.

[0068] Comparative Examples 11-12

[0069] The only difference between Comparative Examples 11 and 12 and Example 1 is the amount of povidone K30, the insulating material surrounding metformin hydrochloride, used. In Comparative Example 11, the amount of povidone K30 was 3% of the weight of metformin hydrochloride, i.e., 30 mg / tablet; in Example 12, the amount of povidone K30 was 12% of the weight of metformin hydrochloride, i.e., 120 mg / tablet. All other formulations, dosages, and preparation processes were the same as in Example 1.

[0070] The experimental variable settings in each embodiment and comparative example are shown in Table 2.

[0071] Table 2. Experimental variable settings in each embodiment and comparative example.

[0072]

[0073]

[0074]

[0075] The stability of the dapagliflozin metformin extended-release tablets prepared in Examples 1-12 and Comparative Examples 1-12 was evaluated:

[0076] The dapagliflozin-metformin extended-release tablets prepared in Examples 1-12 and Comparative Examples 1-12 were placed at 60℃, 25℃, 92.5%RH, and 4500lx±500lx for 0 days, 10 days, and 30 days, respectively. The contents of dapagliflozin and metformin-related substances in each tablet were detected, and the results are shown in Table 3.

[0077] Table 3. Stability data of dapagliflozin-metformin extended-release tablets prepared in Examples 1-12 and Comparative Examples 1-12.

[0078]

[0079]

[0080]

[0081]

[0082]

[0083] Observing Table 3, the following conclusions can be drawn:

[0084] Comparing the dapagliflozin-metformin extended-release tablets prepared in Examples 1-7 and Comparative Examples 1-10, after being placed under high temperature, high humidity, and light conditions for 10 days and 30 days respectively, the changes in related substances of dapagliflozin and metformin in Examples 1-7 were relatively small, while the changes in related substances of dapagliflozin and metformin in Comparative Examples 1-10 were larger, but still within the standard limits, with no significant difference. Therefore, it can be seen that the particle size of metformin hydrochloride and the weight ratio of different particle sizes have little effect on the stability of dapagliflozin-metformin extended-release tablets.

[0085] Comparing Examples 11-12 with Comparative Examples 11-12, it can be seen that after being placed under high temperature, high humidity, and light conditions for 10 days and 30 days respectively, the changes in related substances of dapagliflozin and metformin in Examples 11-12 and Comparative Example 12 were relatively small, while the changes in related substances of dapagliflozin and metformin in Comparative Example 11 were relatively large, and both exceeded the standard limits at 30 days. Therefore, it can be seen that the amount of the isolation layer material outside metformin hydrochloride has an impact on the stability of dapagliflozin-metformin sustained-release tablets. A small amount of isolation layer material will lead to instability of the prepared dapagliflozin-metformin sustained-release tablets.

[0086] Observing Examples 1, 8-10, it can be seen that the dapagliflozin metformin sustained-release tablets prepared in Examples 1, 8-10 showed little change in related substances after being placed under high temperature, high humidity, and light conditions for 10 days and 30 days, respectively. Therefore, it can be seen that when the isolation layer material outside metformin hydrochloride is povidone K30, chitosan, gelatin, or polyvinyl alcohol, the stability of the prepared dapagliflozin metformin sustained-release tablets is good.

[0087] The in vitro release properties of the dapagliflozin metformin extended-release tablets prepared in Examples 1-12 and Comparative Examples 1-12 were evaluated:

[0088] The dissolution curves of dapagliflozin-metformin extended-release tablets prepared in Examples 1-12 and Comparative Examples 1-12 were tested. The dissolution medium was 0.1M hydrochloric acid solution (simulating the pH environment of gastric juice). The dissolution conditions were as follows: 1000mL of dissolution medium, 12 tablets of the test sample were placed in a sedimentation basket, the rotation speed was 75rpm, and the procedure was followed. Samples were taken at 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, and 20h to test the metformin hydrochloride. Samples were taken at 5min, 10min, 15min, 20min, 30min, and 45min to test the dapagliflozin. The test results are shown in Tables 4-5.

[0089] Table 4. Cumulative dissolution rate of metformin hydrochloride in 0.1M hydrochloric acid solution of dapagliflozin metformin extended-release tablets prepared in Examples 1-12 and Comparative Examples 1-12 (I)

[0090]

[0091]

[0092] Table 4. Cumulative dissolution rate of metformin hydrochloride in 0.1M hydrochloric acid solution of dapagliflozin metformin extended-release tablets prepared in Examples 1-12 and Comparative Examples 1-12 (II)

[0093]

[0094]

[0095] Table 4. Cumulative dissolution rate of metformin hydrochloride in 0.1M hydrochloric acid solution of dapagliflozin metformin extended-release tablets prepared in Examples 1-12 and Comparative Examples 1-12 (III)

[0096]

[0097] Table 5. Cumulative dissolution of dapagliflozin in 0.1M hydrochloric acid solution in dapagliflozin-metformin extended-release tablets prepared in Examples 1-12 and Comparative Examples 1-12.

[0098]

[0099]

[0100] Table 4 shows the cumulative dissolution rate of metformin hydrochloride in 0.1M hydrochloric acid solution. Figures 1-7 .

[0101] observe Figure 1 and Figure 2As can be seen, in Examples 1-4, metformin hydrochloride was uniformly and stably released within 20 hours in 0.1M hydrochloric acid solution. However, in Comparative Examples 1-6, the release of metformin hydrochloride within 20 hours was uneven; some samples released too quickly initially and too slowly later, while others released slowly initially and too quickly later, and some were not completely released within 20 hours. Therefore, under the same conditions, the particle size D of metformin hydrochloride... 90 When the distribution is at 0.5–1.0 μm, 50–200 μm, and 300–600 μm, respectively, the metformin hydrochloride in the prepared dapagliflozin metformin can be stably and uniformly released within 20 hours, with stable efficacy and high bioavailability.

[0102] observe Figure 3 and Figure 4 As can be seen, in Examples 1 and 5-7, metformin hydrochloride was released uniformly and stably within 20 hours in 0.1M hydrochloric acid solution. However, in Comparative Examples 7-10, the release of metformin hydrochloride in 0.1M hydrochloric acid solution was uneven within 20 hours; some samples released too quickly in the early stages and too slowly in the later stages, while others released slowly in the early stages and too quickly in the later stages, and some were not completely released within 20 hours. Therefore, when other conditions are the same, and the weight composition ratio of metformin hydrochloride with different particle sizes is 0.5-1:1:0.5-1, the metformin hydrochloride in the prepared dapagliflozin metformin can be released stably and uniformly within 20 hours, with stable efficacy and high bioavailability.

[0103] observe Figure 5 As can be seen from Examples 1, 8-10, metformin hydrochloride can be uniformly and stably released within 20 hours in a 0.1M hydrochloric acid solution. Therefore, when other conditions are the same, and the isolation layer material of metformin hydrochloride is selected from povidone K30, chitosan, gelatin, or polyvinyl alcohol, the metformin hydrochloride in the prepared dapagliflozin metformin can be stably and uniformly released within 20 hours, with stable efficacy and high bioavailability.

[0104] observe Figure 6 and Figure 7 As can be seen, in Examples 1 and 11-12, metformin hydrochloride was released uniformly and stably within 20 hours in 0.1M hydrochloric acid solution. However, in Comparative Examples 11-12, the release of metformin hydrochloride in 0.1M hydrochloric acid solution was uneven within 20 hours; some samples released too quickly in the early stages and too slowly in the later stages, while others released slowly in the early stages and too quickly in the later stages, and some were not completely released within 20 hours. Therefore, when other conditions are the same, and the weight ratio of the isolation layer material to metformin hydrochloride is 5-10:100, the metformin hydrochloride in the prepared dapagliflozin metformin can be released stably and uniformly within 20 hours, with stable efficacy and high bioavailability.

[0105] It is understood that the above embodiments are merely exemplary implementations used to illustrate the principles of this application, and this application is not limited thereto. For those skilled in the art, various modifications and improvements can be made without departing from the spirit and substance of this application, and these modifications and improvements are also considered to be within the scope of protection of this invention.

Claims

1. A compound sustained-release tablet for treating diabetes, characterized in that, include: The product contains metformin hydrochloride, a separating material, dapagliflozin propylene glycol monohydrate, a cosolvent, a lubricant, a diluent, and a disintegrant. The metformin hydrochloride is composed of particles of various sizes to achieve continuous, uniform, stable, and sustained release.

2. The compound sustained-release tablet for treating diabetes according to claim 1, characterized in that, The metformin hydrochloride is composed of three different particle sizes, namely D. 90 The corresponding sizes are 0.5–1.0 μm, 50–200 μm, and 300–600 μm, respectively.

3. The compound sustained-release tablet for treating diabetes according to claim 2, characterized in that, The weight composition ratio of the three particle sizes of metformin hydrochloride is (0.5-1):1:(0.5-1).

4. The compound sustained-release tablet for treating diabetes according to claim 2, characterized in that, The three types of metformin hydrochloride have particle sizes D 90 The corresponding sizes are 0.8–1.0 μm, 50–100 μm, and 300–500 μm, respectively.

5. The compound sustained-release tablet for treating diabetes according to claim 2, characterized in that, The weight composition ratio of the three metformin hydrochloride compounds is (0.75-1):1:(0.75-1).

6. The compound sustained-release tablet for treating diabetes according to claim 1, characterized in that, The insulating material is one or more of polyvinylpyrrolidone K30, chitosan, gelatin, and polyvinyl alcohol.

7. The compound sustained-release tablet for treating diabetes according to claim 1, characterized in that, The weight ratio of the insulating material to metformin hydrochloride is 5-10:

100.

8. The compound sustained-release tablet for treating diabetes according to claim 1, characterized in that, The weight ratio of the insulating material to metformin hydrochloride is 8-10:

100.

9. The method for preparing the compound sustained-release tablets for treating diabetes according to any one of claims 1 to 8, characterized in that, Includes the following steps: (1) Dissolve the prescribed amount of metformin hydrochloride of different particle sizes and the isolation material in water or organic solvent in sequence to prepare a solution for later use; (2) The solution described in (1) is spray-dried using a spray dryer and cooled to room temperature to obtain metformin hydrochloride granules; 3) Mix metformin hydrochloride granules, dapagliflozin propylene glycol monohydrate, solubilizer, diluent, disintegrant, pulverize, and finally mix with lubricant to form granules; 4) Granulation and tableting.

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