Tablet containing valsartan and SGLT-2 inhibitor and preparation method thereof

Abstract

The invention discloses a tablet containing valsartan and an SGLT-2 inhibitor and a preparation method of the tablet, and the tablet is prepared from the following components in parts by weight: 90-165 parts of valsartan, 7-24 parts of the SGLT-2 inhibitor, 115-1250 parts of microcrystalline cellulose and mannitol co-treatment substance, 1.5-5 parts of a lubricant and 11-20 parts of a disintegrating agent. According to the tablet containing the valsartan and the SGLT-2 inhibitor provided by the invention, the valsartan and the SGLT-2 inhibitor are prepared into the compound tablet, so that the medication frequency of a patient can be reduced, a treatment scheme is simplified, and the compliance of the patient can be improved, especially for elderly patients or groups with dysphagia.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical tablet preparation technology, specifically relating to a tablet containing valsartan and an SGLT-2 inhibitor and its preparation method. Background Technology

[0002] Chronic heart failure (CHF) is a common and fatal cardiovascular disease characterized by insufficient cardiac pumping capacity to meet the body's metabolic demands. According to the American Heart Association (AHA / ACC) guidelines (2021), the management of CHF includes pharmacological therapy, lifestyle interventions, and appropriate cardiac remodeling strategies. Angiotensin II receptor blockers (ARBs) and sodium-glucose cotransporter 2 inhibitors (SGLT-2 inhibitors) play crucial roles in the treatment of CHF.

[0003] Angiotensin II is one of the most important pressor factors in the human body, involved in regulating vasoconstriction, aldosterone secretion, and renal sodium reabsorption. By acting on angiotensin II receptors, especially the AT1 receptor, ARBs can effectively block the pathogenic effects of angiotensin II, thereby reducing vasoconstriction, alleviating cardiac workload, and improving hemodynamics. Valsartan, as an ARB, has been widely used to treat hypertension, heart failure, and chronic kidney disease. Clinical studies have shown that valsartan has a significant effect in reducing mortality and hospitalization rates in heart failure patients, especially when used in combination with other heart failure medications, such as SGLT-2 inhibitors, which can further improve patient clinical outcomes.

[0004] Although there are currently several combination therapy regimens based on valsartan and SGLT-2 inhibitors, most of these combinations still have issues with drug dosage, stability, and patient compliance. In particular, for heart failure patients, especially elderly patients, simplifying drug use, improving drug stability, and reducing side effects are key challenges in treatment. Summary of the Invention

[0005] To address the shortcomings of the existing technology, the present invention provides a tablet comprising valsartan and an SGLT-2 inhibitor and a method for preparing the same.

[0006] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0007] The present invention provides a tablet containing valsartan and an SGLT-2 inhibitor, which is used in the treatment of cardiovascular diseases. The tablet is composed of the following components in parts by weight: 90-165 parts of valsartan, 7-24 parts of SGLT-2 inhibitor, 115-1250 parts of microcrystalline cellulose mannitol co-processed product, 1.5-5 parts of lubricant, and 11-20 parts of disintegrant.

[0008] Optionally, the SGLT-2 inhibitor is dapagliflozin or empagliflozin.

[0009] Optionally, the disintegrant is one or more of croscarmellose sodium, croscarmellose, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose; the lubricant is one or more of magnesium stearate, talc and calcium stearate.

[0010] The present invention provides a method for preparing the above-mentioned tablet containing valsartan and SGLT-2 inhibitor, comprising:

[0011] The SGLT-2 inhibitor and colloidal silica were mixed at a weight ratio of 1:0.05 to 0.15 to obtain the first mixture;

[0012] The microcrystalline cellulose mannitol co-treated product and the first mixture were mixed at a weight ratio of 36-42:3-5 to dilute the first mixture and obtain the second mixture.

[0013] The second mixture, valsartan, and microcrystalline cellulose mannitol co-treated product were mixed at a weight ratio of 20–25:12–20:80–100 to obtain the third mixture;

[0014] A disintegrant, colloidal silica, and lubricant were added sequentially to the third mixture to obtain a fourth mixture.

[0015] The fourth mixture was compressed to obtain tablets containing valsartan and SGLT-2 inhibitors.

[0016] This invention provides another method for preparing the above-mentioned tablets containing valsartan and SGLT-2 inhibitors, comprising:

[0017] Valsartan in a molten state is loaded into the mesopores of macroporous silica to obtain valsartan-macroporous silica;

[0018] SGLT-2 inhibitor in a molten state is loaded into the mesopores of macroporous silica to obtain SGLT-2 inhibitor-macroporous silica;

[0019] The microcrystalline cellulose mannitol co-treated product and the SGLT-2 inhibitor-mesoporous silica were mixed at a weight ratio of 3 to 5:1 to dilute the SGLT-2 inhibitor-mesoporous silica, resulting in a fifth mixture.

[0020] The fifth mixture, valsartan-mesoporous silica and microcrystalline cellulose mannitol were mixed in a weight ratio of 10-13:18-20:1-3 to obtain the sixth mixture;

[0021] A disintegrant and a lubricant were added sequentially to the sixth mixture to obtain the seventh mixture.

[0022] The seventh mixture was compressed to obtain tablets containing valsartan and SGLT-2 inhibitors.

[0023] Optionally, valsartan in a molten state is loaded into the mesopores of macroporous silica to obtain valsartan-macroporous silica, comprising:

[0024] After valsartan is heated to a molten state, the molten valsartan is mixed with macroporous silica at a weight ratio of 1:0.8 to 1.2, so that the molten valsartan is loaded into the mesopores of the macroporous silica to obtain the first sample;

[0025] After the first sample cools to room temperature, it is ground and dispersed to obtain valsartan-mesoporous silica; and / or

[0026] SGLT-2 inhibitor in a molten state is loaded into the mesopores of macroporous silica to obtain SGLT-2 inhibitor-macroporous silica, comprising:

[0027] After heating the SGLT-2 inhibitor to a molten state, the molten SGLT-2 inhibitor is mixed with macroporous silica at a weight ratio of 1:1.2 to 3.5, so that the molten SGLT-2 inhibitor is loaded into the mesopores of macroporous silica to obtain a second sample.

[0028] After the second sample cooled to room temperature, it was ground and dispersed to obtain the SGLT-2 inhibitor-macroporous silica; and / or

[0029] The seventh mixture was compressed to obtain tablets containing valsartan and SGLT-2 inhibitors, including:

[0030] The seventh mixture was tableted using a compression pressure of 0.65 tons and a standard 10mm round punch to obtain tablets with a thickness of 3.2-3.5mm.

[0031] Optionally, it also includes determining the optimal parameters for the amount of lubricant, the amount of disintegrant, and the tableting pressure used during tableting. The determination of each optimal parameter includes:

[0032] The optimal parameters for the dosage of lubricant, disintegrant, and tableting pressure during tableting were determined using the star point design-response surface methodology. In the star point design-response surface methodology, the dissolution values ​​of valsartan, SGLT-2 inhibitors, and tablet hardness were used as effect variables.

[0033] Optionally, the optimal parameters for the dosage of lubricant, disintegrant, and tableting pressure during tableting are determined using the star-point design-response surface methodology, including:

[0034] The amount of lubricant, the amount of disintegrant, and the tableting pressure used during tableting are all factor levels of independent variables.

[0035] The codes corresponding to each factor level were assigned as -1, 0, and 1, respectively, and an experimental table was compiled based on the codes and level values ​​of each factor level.

[0036] Using the dissolution values ​​of valsartan, SGLT-2 inhibitors, and tablet hardness as effect variables, tablets were prepared according to the test table, and in vitro dissolution tests and hardness tests were conducted on the prepared tablets for valsartan and SGLT-2 inhibitors.

[0037] Based on the in vitro dissolution test results and hardness values ​​of the prepared tablets containing valsartan and SGLT-2 inhibitor, the optimal parameters for the amount of lubricant, the amount of disintegrant, and the tableting pressure used during tableting were determined.

[0038] Optionally, based on the in vitro dissolution test results and hardness values ​​of the prepared tablets containing valsartan and SGLT-2 inhibitor, the optimal parameters for the amount of lubricant, the amount of disintegrant, and the tableting pressure used during tableting are determined, including:

[0039] Based on the amount of lubricant, the amount of disintegrant, the tableting pressure used during tableting, and the in vitro dissolution test results and hardness values ​​of the prepared tablets for valsartan and SGLT-2 inhibitor, response curves corresponding to the in vitro dissolution of valsartan, the in vitro dissolution of SGLT-2 inhibitor, and hardness were plotted.

[0040] Based on the in vitro dissolution rates of valsartan, SGLT-2 inhibitors, and corresponding response curves for hardness, the optimal parameters for the amount of lubricant, disintegrant, and tableting pressure used during tableting were determined.

[0041] Optionally, based on the amount of lubricant, the amount of disintegrant, the compression pressure used during tableting, and the in vitro dissolution test results and hardness values ​​of the prepared tablets for valsartan and SGLT-2 inhibitor, response curves corresponding to the in vitro dissolution of valsartan, the in vitro dissolution of SGLT-2 inhibitor, and hardness are plotted, including:

[0042] Based on the amount of lubricant, the amount of disintegrant, the tableting pressure used during tableting, and the in vitro dissolution test results of valsartan in the prepared tablets, an in vitro dissolution fitting model for valsartan in tablets was constructed. The in vitro dissolution fitting model for valsartan in tablets was constructed using the following formula:

[0043] Y1=100.36986+0.158X1+0.344X2+1.852X3-0.0025X1X2+0.085X1X3+2.7975X2X3-2.72225X1 2 -0.722254X2 2 -0.812254X3 2

[0044] Where Y1 is the in vitro dissolution rate of valsartan in the tablet; X1 is the tableting pressure; X2 is the amount of lubricant; and X3 is the amount of disintegrant.

[0045] The dosage of different lubricants, the dosage of disintegrants, and the tableting pressure used during tableting were input into the in vitro dissolution fitting model of valsartan to obtain the fitted in vitro dissolution of valsartan.

[0046] By using different amounts of lubricant, disintegrant, tableting pressure during tableting, and the fitted in vitro dissolution rate of valsartan, a response curve corresponding to the in vitro dissolution rate of valsartan was plotted.

[0047] Based on the amounts of lubricant and disintegrant, the tableting pressure used during tableting, and the in vitro dissolution test results of the SGLT-2 inhibitor in the prepared tablets, an in vitro dissolution fitting model for the SGLT-2 inhibitor in the tablets was constructed. The in vitro dissolution fitting model for the SGLT-2 inhibitor in the tablets was constructed using the following formula:

[0048] Y2=96.36+0.027X1-0.351X2+2.998X3+0.00375X1X2+0.34375X1X3+2.83625X2X3-0.778099X1 2 -2.6981X2 2 -0.803099X3 2

[0049] Where Y2 is the in vitro dissolution rate of the SGLT-2 inhibitor in the tablet; X1 is the tableting pressure; X2 is the amount of lubricant; and X3 is the amount of disintegrant.

[0050] Different amounts of lubricant, disintegrant, and tableting pressure during tableting were input into the in vitro dissolution fitting model of SGLT-2 inhibitor to obtain the fitted in vitro dissolution of SGLT-2 inhibitor.

[0051] By using different amounts of lubricant, disintegrant, tableting pressure during tableting, and the fitted in vitro dissolution rate of the SGLT-2 inhibitor, a response curve corresponding to the in vitro dissolution rate of the SGLT-2 inhibitor was plotted.

[0052] Based on the amounts of lubricant and disintegrant, the tableting pressure used during tableting, and the in vitro dissolution test results of the SGLT-2 inhibitor in the prepared tablets, a tablet hardness fitting model was constructed. The tablet hardness fitting model was constructed using the following formula:

[0053] Y3=95.08471+23.6X1+1.005X2-6.417X3

[0054] Where Y3 is the tablet hardness; X1 is the tableting pressure; X2 is the amount of lubricant used; and X3 is the amount of disintegrant used.

[0055] The amounts of different lubricants, disintegrants, and tableting pressures used during tableting are input into the hardness fitting model to obtain the fitted hardness.

[0056] By using different amounts of lubricant, disintegrant, tableting pressure during tableting, and fitted hardness, a response curve corresponding to hardness was plotted.

[0057] This invention provides a tablet containing valsartan and an SGLT-2 inhibitor, and a method for preparing the same. By formulating valsartan and an SGLT-2 inhibitor into a compound tablet, not only can the frequency of medication be reduced and treatment regimens simplified, but patient compliance can also be improved, especially for elderly patients or those with swallowing difficulties. The combined use of valsartan and the SGLT-2 inhibitor has a synergistic effect, which can improve the efficacy of heart failure treatment. Furthermore, this application optimizes the weight composition of valsartan, the SGLT-2 inhibitor, the lubricant, and the disintegrant to ensure that the final tablet containing valsartan and the SGLT-2 inhibitor has ideal in vitro dissolution rates for both valsartan and the SGLT-2 inhibitor, thereby demonstrating the potential for synergistic effects in the treatment of heart failure.

[0058] Other features and advantages of the invention will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the invention. The objects and other advantages of the invention may be realized and obtained by means of the structures particularly pointed out in the written description and the accompanying drawings.

[0059] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0060] Figure 1 Figure 1 shows the in vitro dissolution results of valsartan and dapagliflozin in valsartan-SGLT-2 inhibitor (dapagliflozin) tablets obtained according to the star-point design experiment. (Figure A shows the in vitro dissolution results of valsartan in valsartan-dapagliflozin tablets in the star-point design experiment group; Figure B shows the in vitro dissolution results of dapagliflozin in valsartan-dapagliflozin tablets in the star-point design experiment group).

[0061] Figure 2 The in vitro dissolution fitting model for valsartan is constructed using the data in Table 2. (Figures A, B, and C are three-dimensional effect surface plots of the influence of each factor on the dissolution of valsartan; Figures D, E, and F are two-dimensional contour plots of the influence of each factor on the dissolution of valsartan).

[0062] Figure 3 The in vitro dissolution fitting model for the SGLT-2 inhibitor (dapagliflozin) was constructed using the data in Table 2. (Figures A, B, and C are three-dimensional effect surface plots of the influence of various factors on the dissolution of dapagliflozin; Figures D, E, and F are two-dimensional contour plots of the influence of various factors on the dissolution of dapagliflozin).

[0063] Figure 4 A linear relationship diagram of the effect of valsartan-dapagliflozin tablets on hardness was constructed using the data in Table 2;

[0064] Figure 5 The response curves of valsartan in vitro dissolution were plotted by varying the amounts of lubricant, disintegrant, and compression pressure used during tableting.

[0065] Figure 6 This is a graph showing the in vitro dissolution curve of valsartan in the tablets containing valsartan-dapagliflozin in Example Group 1;

[0066] Figure 7 This is a graph showing the in vitro dissolution curve of dapagliflozin in the tablets containing valsartan-dapagliflozin in Example Group 1.

[0067] Figure 8This is a graph showing the in vitro dissolution curve of valsartan in the tablets containing valsartan-dapagliflozin in Example Group 2;

[0068] Figure 9 This is a graph showing the in vitro dissolution curve of dapagliflozin in the tablets containing valsartan-dapagliflozin in Example Group 2.

[0069] Figure 10 SEM of large-pore mesoporous silica used in this invention Figure 1 ;

[0070] Figure 11 SEM of large-pore mesoporous silica used in this invention Figure 2 ;

[0071] Figure 12 This is the nitrogen adsorption-desorption isotherm diagram of the macroporous silica used in this invention.

[0072] Figure 13 This is a pore size distribution diagram of the large mesoporous silica used in this invention;

[0073] Figure 14 DSC results for valsartan-mesoporous silica: ((a) valsartan active pharmaceutical ingredient, (b) mesoporous silica, (c) valsartan-mesoporous silica drug loading 1:1, (d) valsartan-mesoporous silica drug loading 1:2, (e) valsartan-mesoporous silica drug loading 1:3);

[0074] Figure 15 DSC results for dapagliflozin-mesoporous silica: ((a) dapagliflozin active pharmaceutical ingredient, (b) mesoporous silica, (c) dapagliflozin-mesoporous silica drug loading 1:1, (d) dapagliflozin-mesoporous silica drug loading 1:2, (e) dapagliflozin-mesoporous silica drug loading 1:3);

[0075] Figure 16 The in vitro dissolution curve of valsartan in the tablets containing valsartan and dapagliflozin prepared according to the present invention is shown in the figure.

[0076] Figure 17 The in vitro dissolution curve of dapagliflozin in the tablets containing valsartan and dapagliflozin prepared according to the present invention is shown. Detailed Implementation

[0077] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0078] The present invention provides a tablet containing valsartan and an SGLT-2 inhibitor, which is used in the treatment of cardiovascular diseases. The tablet is composed of the following components in parts by weight: 90-165 parts of valsartan, 7-24 parts of SGLT-2 inhibitor, 115-1250 parts of microcrystalline cellulose mannitol co-processed product, 1.5-5 parts of lubricant, and 11-20 parts of disintegrant.

[0079] Preferably, the tablets consist of the following components in parts by weight: 160 parts valsartan, 20 parts SGLT-2 inhibitor, 1168 parts microcrystalline cellulose mannitol co-processed product, 3 parts lubricant, and 12 parts disintegrant.

[0080] As another preferred embodiment, the tablets consist of the following components in parts by weight: 96 parts valsartan, 12 parts SGLT-2 inhibitor, 115 parts microcrystalline cellulose mannitol co-processed product, 3 parts lubricant, and 16 parts disintegrant.

[0081] To improve patient compliance and treatment efficacy, this study presents a combination tablet formulation of valsartan and an SGLT-2 inhibitor. This not only reduces the frequency of medication and simplifies treatment protocols but also improves patient compliance, particularly for elderly patients or those with swallowing difficulties. The combined use of valsartan and the SGLT-2 inhibitor exhibits a synergistic effect, enhancing the efficacy of heart failure treatment. Furthermore, this application optimizes the weight proportions of valsartan, the SGLT-2 inhibitor, the lubricant, and the disintegrant to ensure that the resulting tablet containing both valsartan and the SGLT-2 inhibitor exhibits ideal in vitro dissolution rates for both, thus demonstrating the potential for synergistic effects in heart failure treatment.

[0082] In some possible implementations, the SGLT-2 inhibitor is dapagliflozin or empagliflozin.

[0083] Dapagliflozin and empagliflozin, two SGLT-2 inhibitors, have significant benefits for patients with chronic heart failure, especially when used in combination with valsartan. Both dapagliflozin and empagliflozin can significantly reduce the incidence of cardiovascular events and improve the quality of life in patients with heart failure.

[0084] In some possible embodiments, the disintegrant is one or more of croscarmellose sodium, croscarmellose, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose; the lubricant is one or more of magnesium stearate, talc and calcium stearate.

[0085] The particle size of cross-linked sodium carboxymethyl cellulose is less than 60 mesh.

[0086] The present invention provides a method for preparing the above-mentioned tablet containing valsartan and SGLT-2 inhibitor, comprising the following steps:

[0087] S110. SGLT-2 inhibitor and colloidal silica are mixed at a weight ratio of 1:0.05 to 0.15 to obtain a first mixture.

[0088] Here, the weight ratio between the SGLT-2 inhibitor and colloidal silica can be one of 1:0.05, 1:0.08, 1:0.1, 1:0.12, or 1:0.15, with 1:0.1 being the preferred weight ratio.

[0089] In the process of mixing SGLT-2 inhibitor and colloidal silica at a weight ratio of 1:0.05 to 0.15 to obtain the first mixture, the SGLT-2 inhibitor and colloidal silica at a weight ratio of 1:0.05 to 0.15 can be weighed and added to a mixer. After mixing for 3 minutes to obtain a homogeneous mixture, the mixture is depolymerized through an 80-mesh sieve (180 μm) to obtain the first mixture. The first mixture is then sealed and stored in the dark.

[0090] S120. The microcrystalline cellulose mannitol co-treated product and the first mixture are mixed at a weight ratio of 36-42:3-5 to dilute the first mixture and obtain the second mixture.

[0091] Here, the dilution treatment of the first mixture using the microcrystalline cellulose mannitol co-treatment product may include the following steps:

[0092] S121. Weigh the first mixture and microcrystalline cellulose mannitol in a weight ratio of 3-5:3-5, and put them into a mixer and mix at 15 rpm for 10 min.

[0093] S122. Weigh the mixture from step S121 and microcrystalline cellulose mannitol in a weight ratio of 6-10:26-36, and put them into a mixer and mix at 15 rpm for 15 minutes to obtain a second mixture.

[0094] Preferably, the weight ratio of the first mixture and microcrystalline cellulose mannitol in step S121 is 1:1; the weight ratio of the mixture and microcrystalline cellulose mannitol in step S122 is 1:4.

[0095] S130. The second mixture, valsartan and microcrystalline cellulose mannitol co-treated product are mixed at a weight ratio of 20-25:12-20:80-100 to obtain the third mixture.

[0096] Here, before mixing, valsartan is sieved through a 100-mesh sieve (150μm). If the humidity of valsartan is >50%RH, it is dried at 40°C for 2 hours under nitrogen protection.

[0097] Preferably, the weight ratio of the second mixture, valsartan, and microcrystalline cellulose mannitol co-treated product is 22:16:97.

[0098] S140. Add disintegrant, colloidal silica and lubricant to the third mixture in sequence to obtain the fourth mixture.

[0099] Here, the preferred weight ratio between the third mixture, the disintegrant, the colloidal silica, and the lubricant is 1350:12:4:3.

[0100] In this step, after adding the disintegrant to the third mixture and mixing for 10 minutes, colloidal silica is added and mixed for 5 minutes. Then, the lubricant is added and mixed for 5 minutes to obtain the fourth mixture.

[0101] S150. The fourth mixture is compressed to obtain tablets containing valsartan and SGLT-2 inhibitors.

[0102] When compressing the fourth mixture into tablets, the compression pressure can be selected as 0.65 tons; the punch can be a 10mm standard round punch, controlling the tablet thickness to 3.2-3.5mm. The compression environment can be selected as: temperature 25±2℃, RH≤35%.

[0103] Since most existing compound tablets use wet granulation, this can cause stability issues for certain drugs, particularly valsartan. Specifically, valsartan may degrade during wet granulation, affecting its efficacy and stability. Therefore, this application employs a direct powder compression process to prepare tablets containing valsartan and an SGLT-2 inhibitor, which not only simplifies the preparation process but also increases the stability of the formulation.

[0104] Another method for preparing the above-mentioned tablet containing valsartan and SGLT-2 inhibitor provided by the present invention includes:

[0105] S210. Valsartan in a molten state is loaded into the mesopores of macroporous silica to obtain valsartan-macroporous silica.

[0106] Prior to step S210, the macroporous silica was further treated. The treatment process included: adding macroporous silica, 25 mL of deionized water, and 68.03 mg of triethanolamine to a 250 mL Erlenmeyer flask; ultrasonicating (40 kHz, 300 W) to obtain a uniform dispersion; then placing the flask in a constant-temperature magnetic stirrer (80 ± 2 °C) for 30 minutes of pre-activation; followed by the stepwise addition of hexadecyltrimethylammonium bromide (380.06 mg) and sodium salicylate (168.04 mg), maintaining a stirring rate of 500 rpm for 60 minutes. Then, 4.00 mL of tetraethyl orthosilicate was slowly added dropwise, and the system continued to react for 2 hours. After the reaction system cooled naturally to 25°C, solid-liquid separation was performed using a high-speed centrifuge (10,000 rpm, 15 min). After washing three times with an ethanol-water (V / V = 3:1) mixed solution, the precursor was placed in a muffle furnace for gradient calcination (heating at 10°C / min to 550°C, held at that temperature for 6 h), ultimately obtaining a large-pore mesoporous silica material with a radial channel structure. Figure 10 As shown, the mesoporous silica nanoparticles obtained after the above treatment have a uniform spherical structure, are monodisperse, and have a particle size of approximately 280 nm. Figure 11 As shown, the nanoparticles of macroporous silica have a uniform monodisperse spherical structure with radial channels that are narrow inside and wide outside. Their large pore size is beneficial for the melt loading of drugs.

[0107] Furthermore, the specific surface area of ​​the macroporous silica nanoparticles, calculated using the Brunauer-Emmett-Teller (BET) single-point method, is 624.1835 m². 2 / g, total pore volume is 3.5742cm³ 3 / g, the pore size of the support calculated using the Barrett-Joyner-Halenda (BJH) desorption curve is 26.4852 nm. According to the regulations of the International Union of Pure and Applied Chemistry (IUPAC), Figure 12 The nitrogen adsorption / desorption isotherm curves are typical type III isotherms, proving that the nanoparticles of macroporous silica have relatively large pore sizes. Figure 13 The pore size distribution results also show that the pore size distribution of the mesoporous silica nanoparticles is concentrated in the range of 15-50 nm.

[0108] S220. Load the molten SGLT-2 inhibitor into the mesopores of macroporous silica to obtain SGLT-2 inhibitor-macroporous silica.

[0109] S230. The microcrystalline cellulose mannitol co-treated product and SGLT-2 inhibitor-mesoporous silica are mixed at a weight ratio of 3 to 5:1 to dilute the SGLT-2 inhibitor-mesoporous silica and obtain the fifth mixture.

[0110] Here, the dilution treatment of the SGLT-2 inhibitor-macroporous silica with microcrystalline cellulose mannitol co-treatment product may include the following steps:

[0111] S231. Weigh SGLT-2 inhibitor-mesoporous silica and microcrystalline cellulose mannitol in a weight ratio of 3-5:3-5, and put them into a mixer and mix at 15 rpm for 10 min.

[0112] S232. Weigh the mixture from step S121 and microcrystalline cellulose mannitol in a weight ratio of 6-10:9-15, and put them into a mixer and mix at 15 rpm for 15 minutes to obtain the fifth mixture.

[0113] Preferably, the weight ratio of SGLT-2 inhibitor-mesoporous silica and microcrystalline cellulose mannitol in step S121 is 1:1; the weight ratio of the mixture in step S231 and microcrystalline cellulose mannitol in step S232 is 1:1.5.

[0114] S240. Mix the fifth mixture, valsartan-mesoporous silica and microcrystalline cellulose mannitol in a weight ratio of 10-13:18-20:1-3 to obtain the sixth mixture;

[0115] Preferably, the weight ratio of the fifth mixture, valsartan-mesoporous silica, and microcrystalline cellulose mannitol co-treated product is 60:96:11.

[0116] S250. Add the disintegrant and lubricant to the sixth mixture in sequence to obtain the seventh mixture.

[0117] Here, the preferred weight ratio between the sixth mixture, the disintegrant, the colloidal silica, and the lubricant is 1670:90:14.

[0118] In this step, after adding the disintegrant to the sixth mixture and mixing for 10 minutes, the lubricant is added and mixed for 5 minutes to obtain the seventh mixture.

[0119] S260. The seventh mixture is compressed to obtain tablets containing valsartan and SGLT-2 inhibitors.

[0120] When compressing the seventh mixture into tablets, the compression pressure can be selected as 0.65 tons; the punch can be a 10mm standard round punch, controlling the tablet thickness to 3.2-3.5mm. The compression environment can be selected as: temperature 25±2℃, RH≤35%.

[0121] In this embodiment, since the active pharmaceutical ingredients in the tablets containing valsartan and SGLT-2 inhibitors are both poorly water-soluble, the drugs were nano-sized. Although solvent evaporation is a high-efficiency and low-cost drug loading method, it suffers from solvent residue. Therefore, this application uses a melt loading method to separately load valsartan and SGLT-2 inhibitors onto large-pore silica, avoiding the introduction of other organic reagents. Furthermore, since melt loading cannot effectively penetrate the pores of small-pore carriers, this application constructs a large-pore silica carrier for efficient drug loading. Simultaneously, this application uses a direct powder compression method for tablet preparation, simplifying the formulation process and facilitating subsequent industrial production.

[0122] In some possible embodiments, loading molten valsartan into the mesopores of macroporous silica to obtain valsartan-macroporous silica may include the following steps:

[0123] (1) After heating valsartan to a molten state, the molten valsartan is mixed with macroporous silica at a weight ratio of 1:0.8 to 1.2, so that the molten valsartan is loaded into the mesopores of macroporous silica to obtain the first sample;

[0124] (2) After the first sample is cooled to room temperature, the first sample is ground and dispersed to obtain valsartan-mesoporous silica.

[0125] Here, valsartan has a melting point of 102°C, so by heating valsartan to 102°C, valsartan in a molten state can be obtained.

[0126] The molten valsartan and macroporous silica are preferably in a weight ratio of 1:1.

[0127] Furthermore, the seventh mixture is subjected to tableting to obtain tablets containing valsartan and SGLT-2 inhibitors, including: tableting the seventh mixture by a compression pressure of 0.65 ton and a 10 mm standard round punch to obtain tablets with a thickness of 3.2 to 3.5 mm.

[0128] In some possible embodiments, loading the molten SGLT-2 inhibitor into the mesopores of macroporous silica to obtain SGLT-2 inhibitor-macroporous silica may include the following steps:

[0129] (1) After heating the SGLT-2 inhibitor to a molten state, the molten SGLT-2 inhibitor is mixed with macroporous silica at a weight ratio of 1:1.2 to 3.5, so that the molten SGLT-2 inhibitor is loaded into the mesopores of macroporous silica to obtain the second sample;

[0130] (2) After the second sample is cooled to room temperature, the second sample is ground and dispersed to obtain SGLT-2 inhibitor-mesoporous silica.

[0131] When dapagliflozin is selected as the SGLT-2 inhibitor, since its melting point is 55-58°C, it can be obtained in a molten state by heating it to 55-58°C. The preferred weight ratio of molten dapagliflozin to macroporous silica is 1:2.

[0132] When empagliflozin is selected as the SGLT-2 inhibitor, since its melting point is 150°C, it can be obtained in a molten state by heating it to 150°C. The preferred weight ratio of the molten empagliflozin to macroporous silica is 1:3.

[0133] like Figure 14 As shown, valsartan exhibits a distinct endothermic crystallization peak near 102℃, indicating that the active pharmaceutical ingredient exists in a crystalline state. Based on the drug loading of three different formulations, doses equivalent to 1.6 mg of valsartan were weighed and subjected to DSC experiments. The results showed that no endothermic peaks were observed in the 1:1, 1:2, and 1:3 formulations. This indicates that loading valsartan into the channels of large-porous silica via a melt-loading method, even with a drug-to-carrier mass ratio increased to 1:1, does not lead to valsartan crystallization. This provides a possibility for reducing the use of nanomaterials and lowering formulation costs in subsequent clinical translations. Furthermore, reducing the amount of nanoparticles can significantly reduce the overall tablet weight. Figure 15 The DSC results for dapagliflozin also yielded similar results, demonstrating the great potential of macroporous silica nanoparticles for drug loading.

[0134] Furthermore, this application prepared valsartan nanoformulations with valsartan and mesoporous silica at mass ratios of 1:1, 1:2, and 1:3, and dapagliflozin nanoformulations with mass ratios of dapagliflozin and mesoporous silica at 1:1, 1:2, and 1:3. This not only reduced the crystallinity of valsartan and dapagliflozin and increased the dispersion of the active pharmaceutical ingredients (APIs), but also improved the flowability of the APIs, effectively simplifying the formulation process of direct powder compression tableting. Valsartan-dapagliflozin tablets were prepared according to the optimal formulation and process conditions. The in vitro dissolution test results of the formulations are as follows. Figure 16 , 17As shown, both valsartan and empagliflozin exhibited good dissolution behavior, with the cumulative dissolution rate of valsartan and empagliflozin in different strengths reaching over 85% within 30 minutes.

[0135] In some possible embodiments, the method further includes determining the optimal parameters for the amount of lubricant, the amount of disintegrant, and the tableting pressure used when tableting the fourth mixture. The determination of each parameter may include: using a star-point design-response surface methodology to determine the optimal parameters for the amount of lubricant, the amount of disintegrant, and the tableting pressure used when tableting; wherein, in the star-point design-response surface methodology, the dissolution value of valsartan, the dissolution value of the SGLT-2 inhibitor, and the tablet hardness are used as effect variables.

[0136] The parameter corresponding to the amount of lubricant can be understood as the ratio of the amount of lubricant to the sum of the amounts of valsartan, SGLT-2 inhibitor, lubricant and disintegrant. The parameter corresponding to the amount of SGLT-2 inhibitor can be understood as the ratio of the amount of SGLT-2 inhibitor to the sum of the amounts of valsartan, SGLT-2 inhibitor, lubricant and disintegrant.

[0137] Since the three factors of tableting pressure, lubricant dosage, and disintegrant dosage have a significant impact on the overall score of the prepared tablets containing valsartan and SGLT-2 inhibitors, the overall score here refers to the score made based on the 30-minute in vitro dissolution (including the dissolution value of valsartan and the dissolution value of SGLT-2 inhibitor), the tablet hardness, and whether tablet cracking and fragmentation occur. Therefore, using the compression pressure (A), lubricant dosage (B), and disintegrant dosage (C) as independent variables, and the dissolution values ​​of valsartan, SGLT-2 inhibitor, and tablet hardness as effect variables, the optimal parameters for the lubricant dosage, disintegrant dosage, and compression pressure during tableting can be determined using a star-point design-response surface methodology. This allows tablets prepared using the determined optimal parameters to possess ideal in vitro dissolution (including the dissolution values ​​of valsartan and SGLT-2 inhibitor) and tablet hardness, providing a reliable, scientific, and effective preparation method for tablets containing valsartan and SGLT-2 inhibitor.

[0138] In some possible embodiments, the optimal parameters for the amount of lubricant, the amount of disintegrant, and the tableting pressure used during tableting are determined using the star-point design-response surface methodology, including the following steps:

[0139] S310. The amount of lubricant, the amount of disintegrant, and the tableting pressure used during tableting are all factor levels as independent variables.

[0140] S320. Determine the codes corresponding to each factor level as -1, 0, and 1 respectively, and compile the experimental table according to the codes and level values ​​of each factor level.

[0141] For example, with tableting pressure (A) of 0.5 ton, 0.6 ton and 0.7 ton, lubricant dosage of 0.4%, 0.7% and 1.0%, and disintegrant dosage of 2%, 3.5% and 5%, the test table is shown in Table 1.

[0142] Table 1. Experimental Tables Corresponding Factor Level Values ​​for Star-shaped Design-Response Surface Experiments

[0143]

[0144] S330. Using the dissolution values ​​of valsartan, SGLT-2 inhibitors, and tablet hardness as effect variables, tablets were prepared according to the test table, and in vitro dissolution tests and hardness tests were conducted on the prepared tablets for valsartan and SGLT-2 inhibitors.

[0145] Here, a three-factor, three-level (see Table 1) star point design-response surface methodology was used to design a total of 15 experiments (see Table 2). Y1: 30-minute dissolution value of valsartan; Y2: 30-minute dissolution value of SGLT-2 inhibitor (dapagliflozin); Y3: tablet hardness were used as effect variables to optimize the formulation of tablets containing valsartan and SGLT-2 inhibitor.

[0146] Following the example in step S320, by selecting the component composition of the tablet by weight as 80 parts valsartan, 10 parts SGLT-2 inhibitor, 142 parts microcrystalline cellulose mannitol co-processed product, and various corresponding parameters for lubricant, disintegrant and tableting pressure in Table 1, tablets containing valsartan and SGLT-2 inhibitor were prepared, and the test results shown in Table 2 were obtained.

[0147] Table 2 Results of the Star Point Design Experiment

[0148] Test No. <![CDATA[A(X1)]]> <![CDATA[B(X2)]]> <![CDATA[C(X3)]]> Y1 Y2 Y3 1 -1 -1 -1 96.02 92.18 74.24 2 +1 -1 -1 96.51 91.45 129.18 3 -1 +1 -1 91.21 86.2 80.69 4 +1 +1 -1 90.94 85.26 129.61 5 -1 -1 +1 94.94 92.6 66.96 6 +1 -1 +1 95.02 93.02 102.01 7 -1 +1 +1 100.57 97.74 67.67 8 +1 +1 +1 101.39 98.4 111.93 9 -1 0 0 98.57 95.03 64.76 10 +1 0 0 99.03 95.89 117.59 11 0 -1 0 99.89 94.47 95.51 12 0 +1 0 101.71 92.61 88.05 13 0 0 -1 100.07 93.78 104.82 14 0 0 +1 101.35 97.09 105.8 15 0 0 0 98.46 96.29 92.54

[0149] Furthermore, experiments were conducted according to the aforementioned star-shaped design, and the in vitro dissolution test results for valsartan and dapagliflozin in the valsartan-SGLT-2 inhibitor (dapagliflozin) tablets are as follows: Figure 1 As shown.

[0150] S340. Based on the in vitro dissolution test results of the prepared tablets for valsartan and SGLT-2 inhibitor, as well as the hardness value, determine the optimal parameters for the amount of lubricant, the amount of disintegrant, and the tableting pressure used during tableting.

[0151] Since the star point design-response surface methodology can describe the relationship between variables (the amount of lubricant, the amount of disintegrant, and the tableting pressure used in the tableting process) and response effects (the in vitro dissolution test results of the prepared tablets for valsartan and SGLT-2 inhibitors, and the hardness value), the optimal process conditions can be obtained based on the described relationship, that is, the optimal parameters corresponding to the amount of lubricant, the amount of disintegrant, and the tableting pressure used in the tableting process.

[0152] In some possible embodiments, based on the in vitro dissolution test results of the prepared tablets for valsartan and SGLT-2 inhibitor, and the hardness value, the optimal parameters for the amount of lubricant, the amount of disintegrant, and the tableting pressure used during tableting are determined, which may include the following steps:

[0153] S410. Based on the amount of lubricant, the amount of disintegrant, the tableting pressure used during tableting, and the in vitro dissolution test results and hardness values ​​of the prepared tablets for valsartan and SGLT-2 inhibitor, plot the response curves corresponding to the in vitro dissolution of valsartan, the in vitro dissolution of SGLT-2 inhibitor, and hardness, respectively.

[0154] S420. Based on the in vitro dissolution rates of valsartan, SGLT-2 inhibitors, and corresponding response curves for hardness, the optimal parameters for the amount of lubricant, disintegrant, and tableting pressure used during tableting are determined.

[0155] In this embodiment, after determining that the range of independent variables such as tableting pressure (X1, ton), lubricant dosage (X2, %), and disintegrant dosage (X3, %) are key factors affecting the dissolution of valsartan, dissolution of GLT-2 inhibitor, and tablet hardness of valsartan-SGLT-2 inhibitor, response surface methodology was used to design data using DesignExpert 13.0.5.0 software (Stat Ease Inc., MN, USA) and surface response curves were plotted. This allowed for the prediction of the optimal parameters corresponding to the dosage of lubricant, the dosage of disintegrant, and the tableting pressure used during tableting.

[0156] Optionally, based on the amount of lubricant, the amount of disintegrant, the tableting pressure used during tableting, and the in vitro dissolution test results and hardness values ​​of the prepared tablets for valsartan and SGLT-2 inhibitor, response curves corresponding to the in vitro dissolution of valsartan, the in vitro dissolution of SGLT-2 inhibitor, and hardness can be plotted, which may include the following steps:

[0157] S510. Based on the amount of lubricant, the amount of disintegrant, the tableting pressure used during tableting, and the in vitro dissolution test results of valsartan in the prepared tablets, construct an in vitro dissolution fitting model for valsartan in the tablets; wherein, the in vitro dissolution fitting model for valsartan in the tablets is constructed using the following formula:

[0158] Y1=100.36986+0.158X1+0.344X2+1.852X3-0.0025X1X2+0.085X1X3+2.7975X2X3-2.72225X1 2 -0.722254X2 2 -0.812254X3 2

[0159] Where Y1 is the in vitro dissolution rate of valsartan in the tablet; X1 is the tableting pressure; X2 is the amount of lubricant; and X3 is the amount of disintegrant.

[0160] Using the data in Table 2 of step 330 as an example, an in vitro dissolution fitting model for valsartan in tablets was constructed using the above formula, resulting in the following... Figure 2 The in vitro dissolution fitting model for valsartan is shown.

[0161] from Figure 2 It can be seen that the factor affecting valsartan dissolution is the quadratic term of the tableting pressure (X1). 2 The amounts of lubricant (crosslinked carboxymethyl cellulose sodium) (X3), disintegrant (magnesium stearate), and the interaction term (X2X3) between the amounts of crosslinked carboxymethyl cellulose sodium (X4) and X5 are considered. Among these, the interaction term (X2X3) between the amounts of magnesium stearate and crosslinked carboxymethyl cellulose sodium (X4) has the greatest impact on the in vitro dissolution of valsartan, which can also be inferred from the 3D model diagram. Figure 2 When the amount of magnesium stearate remained constant, increasing the amount of croscarmellose sodium resulted in a decrease in the in vitro dissolution rate of valsartan; similarly, increasing the amount of magnesium stearate also decreased the in vitro dissolution rate of valsartan. However, when both the amount of magnesium stearate and the amount of croscarmellose sodium were increased simultaneously, the in vitro dissolution rate of valsartan significantly increased.

[0162] S520. Input the amounts of different lubricants, disintegrants, and tableting pressures used during tableting into the in vitro dissolution fitting model of valsartan to obtain the fitted in vitro dissolution of valsartan.

[0163] Here, the amounts of different lubricants, disintegrants, and tableting pressures used during tableting can be randomly determined parameters. By inputting the amounts of different lubricants, disintegrants, and tableting pressures used during tableting into the in vitro dissolution fitting model of valsartan, the different in vitro dissolution rates of valsartan fitted by the in vitro dissolution fitting model can be obtained, thereby expanding the amount of data required in step S530 when plotting the response curve corresponding to the in vitro dissolution rate of valsartan.

[0164] S530. Using different amounts of lubricant, disintegrant, tableting pressure during tableting, and the fitted in vitro dissolution rate of valsartan, a response curve corresponding to the in vitro dissolution rate of valsartan is plotted.

[0165] S540. Based on the amount of lubricant, the amount of disintegrant, the tableting pressure used during tableting, and the in vitro dissolution test results of the SGLT-2 inhibitor in the prepared tablets, an in vitro dissolution fitting model for the SGLT-2 inhibitor in the tablets is constructed; wherein, the in vitro dissolution fitting model for the SGLT-2 inhibitor in the tablets is constructed using the following formula:

[0166] Y2=96.36+0.027X1-0.351X2+2.998X3+0.00375X1X2+0.34375X1X3+2.83625X2X3-0.778099X1 2 -2.6981X2 2 -0.803099X3 2

[0167] Where Y2 is the in vitro dissolution rate of the SGLT-2 inhibitor in the tablet; X1 is the tableting pressure; X2 is the amount of lubricant; and X3 is the amount of disintegrant.

[0168] Using the data in Table 2 of step 330 as an example, an in vitro dissolution fitting model for the SGLT-2 inhibitor (dapagliflozin) in tablets was constructed using the above formula, resulting in the following... Figure 3 The in vitro dissolution fitting model for dapagliflozin is shown.

[0169] from Figure 3 It can be seen that the factors affecting the in vitro dissolution rate of dapagliflozin are the amount of lubricant (cross-linked carboxymethyl cellulose sodium) (X3) and the quadratic term of the amount of disintegrant (magnesium stearate) (X2).2 The interaction term (X2X3) between the amounts of magnesium stearate and croscarmellose sodium was observed. Among these, the interaction term (X2X3) had the greatest impact on the dissolution of dapagliflozin. This can be inferred from the 3D model diagram. Figure 3 It can be seen that the amount of croscarmellose sodium is directly proportional to the in vitro dissolution rate of dapagliflozin. The tableting pressure and the amount of magnesium stearate both have a nonlinear effect on the in vitro dissolution behavior of dapagliflozin. Both have an optimal range, and deviating from this range will lead to a decrease in the dissolution rate.

[0170] S550. Input the amounts of different lubricants, disintegrants, and tableting pressures used during tableting into the in vitro dissolution fitting model of the SGLT-2 inhibitor to obtain the fitted in vitro dissolution of the SGLT-2 inhibitor.

[0171] Here, the amounts of different lubricants, disintegrants, and tableting pressures used during tableting can be randomly determined parameters. By inputting the amounts of different lubricants, disintegrants, and tableting pressures used during tableting into the in vitro dissolution fitting model of the SGLT-2 inhibitor, the in vitro dissolution rates of different SGLT-2 inhibitors fitted by the in vitro dissolution fitting model can be obtained, thereby expanding the amount of data required in step S560 when plotting the response curve corresponding to the in vitro dissolution rate of the SGLT-2 inhibitor.

[0172] S560. Using different amounts of lubricant, disintegrant, tableting pressure during tableting, and the fitted in vitro dissolution rate of the SGLT-2 inhibitor, a response curve corresponding to the in vitro dissolution rate of the SGLT-2 inhibitor is plotted.

[0173] S570. Based on the amount of lubricant, the amount of disintegrant, the tableting pressure used during tableting, and the in vitro dissolution test results of the SGLT-2 inhibitor in the prepared tablets, a tablet hardness fitting model is constructed; wherein, the tablet hardness fitting model is constructed using the following formula:

[0174] Y3=95.08471+23.6X1+1.005X2-6.417X3

[0175] Where Y3 is the tablet hardness; X1 is the tableting pressure; X2 is the amount of lubricant used; and X3 is the amount of disintegrant used.

[0176] Taking the data in Table 2 of step 330 as an example, the hardness fitting model for the tablet is constructed using the above formula, resulting in the following: Figure 4The in vitro dissolution fitting model for dapagliflozin is shown.

[0177] from Figure 4 As can be seen from the above formulas, the main factor affecting tablet hardness is compression pressure; increasing compression pressure significantly increases tablet hardness. The amount of lubricant (cross-linked carboxymethyl cellulose sodium) is inversely proportional to tablet hardness. The amount of disintegrant (magnesium stearate) has no effect on tablet hardness.

[0178] S580. Input the amounts of different lubricants, disintegrants, and tableting pressures used during tableting into the hardness fitting model to obtain the fitted hardness.

[0179] Here, the amounts of different lubricants, disintegrants, and tableting pressures used during tableting can be randomly determined parameters. By inputting the amounts of different lubricants, disintegrants, and tableting pressures used during tableting into the hardness fitting model, different hardnesses fitted by the hardness fitting model can be obtained, thereby expanding the amount of data required in step S590 to plot the response curve corresponding to the hardness.

[0180] S590. Using different amounts of lubricant, disintegrant, tableting pressure during tableting, and fitted hardness, a response curve corresponding to the hardness is plotted.

[0181] Figure 5 To illustrate the response curves for valsartan's in vitro dissolution rate, SGLT-2 inhibitors' in vitro dissolution rate, and hardness under 17 different dosages of lubricant, disintegrant, and compression pressure during tableting, this study plotted response curves for each of the following: Figure 5 As shown in the graph, the target value for the in vitro dissolution rate (30 min) of valsartan is maximized (bottom left graph); the target value for the in vitro dissolution rate (30 min) of dapagliflozin is maximized (second row of graphs); and the target value for tablet hardness is 100 N. Based on the above dependent variable targets, the parameters corresponding to the amount of lubricant, the amount of disintegrant, and the tableting pressure used during tableting are optimized as a whole to obtain the optimal formulation: the coding value for tableting pressure is 0.46; the coding value for the amount of lubricant is 0.46; and the coding value for the amount of disintegrant is 1.00. Converting the coded values ​​to the actual values, the optimal parameters are: tableting pressure of 0.65 ton, lubricant amount of 0.84%, and disintegrant amount of 5.0%.

[0182] Here, the optimal parameters for the finally determined amount of lubricant, disintegrant, and tableting pressure used during tableting are further verified. The verification examples are as follows:

[0183] Example 1

[0184] A method for preparing the above-mentioned tablet containing valsartan and SGLT-2 inhibitor includes the following steps:

[0185] (1) Dapagliflozin was selected as the SGLT-2 inhibitor. 5g of dapagliflozin and 1g of colloidal silica were mixed to obtain 6g of the first mixture.

[0186] (2) Mix 56g of microcrystalline cellulose mannitol co-treated product and 6g of the first mixture to dilute the first mixture and obtain 62g of the second mixture;

[0187] (3) Mix 62g of the second mixture, 80g of valsartan and 86.875g of microcrystalline cellulose mannitol co-treated product to obtain 228.875g of the third mixture;

[0188] (4) Add 12.525g CCNa, 2g colloidal silica and 2.1042g magnesium stearate to 228.875g of the third mixture in sequence to obtain the fourth mixture;

[0189] (5) The fourth mixture was tableted at a temperature of 25±2℃ and RH≤35% using a standard round punch with a tableting pressure of 0.65ton and a punch of 10mm to obtain 1000 tablets containing valsartan and SGLT-2 inhibitor with a thickness of 3.2-3.5mm.

[0190] Example 2

[0191] A method for preparing the above-mentioned tablet containing valsartan and SGLT-2 inhibitor includes the following steps:

[0192] (1) Dapagliflozin was selected as the SGLT-2 inhibitor. 10g of dapagliflozin and 1g of colloidal silica were mixed to obtain 11g of the first mixture.

[0193] (2) Mix 99g of microcrystalline cellulose mannitol co-treated product and 11g of the first mixture to dilute the first mixture and obtain 110g of the second mixture;

[0194] (3) Mix 110g of the second mixture, 80g of valsartan and 43.8708g of microcrystalline cellulose mannitol co-treated product to obtain 233.8708g of the third mixture;

[0195] (4) Add 12.525g CCNa, 2g colloidal silica and 2.1042g magnesium stearate to 233.8708g of the third mixture in sequence to obtain the fourth mixture;

[0196] (5) The fourth mixture was tableted at a temperature of 25±2℃ and RH≤35% using a standard round punch with a tableting pressure of 0.65ton and a punch of 10mm to obtain 1000 tablets containing valsartan and SGLT-2 inhibitor with a thickness of 3.2-3.5mm.

[0197] Example 3

[0198] A method for preparing the above-mentioned tablet containing valsartan and SGLT-2 inhibitor includes the following steps:

[0199] (1) Dapagliflozin was selected as the SGLT-2 inhibitor. 5g of dapagliflozin and 1.95g of colloidal silica were mixed to obtain 6.95g of the first mixture.

[0200] (2) Mix 62.55g of microcrystalline cellulose mannitol co-treated product and 6.95g of the first mixture to dilute the first mixture and obtain 69.5g of the second mixture;

[0201] (3) Mix 69.5g of the second mixture, 160g of valsartan and 91.187g of microcrystalline cellulose mannitol co-treated product to obtain 320.687g of the third mixture;

[0202] (4) Add 15g CCNa, 3.9g colloidal silica and 2.52g magnesium stearate to 320.687g of the third mixture in sequence to obtain the fourth mixture;

[0203] (5) The fourth mixture was tableted at a temperature of 25±2℃ and RH≤35% using a standard round punch with a tableting pressure of 0.65ton and a punch of 10mm to obtain 1000 tablets containing valsartan and SGLT-2 inhibitor with a thickness of 3.2-3.5mm.

[0204] Example 4

[0205] A method for preparing the above-mentioned tablet containing valsartan and SGLT-2 inhibitor includes the following steps:

[0206] (1) Dapagliflozin was selected as the SGLT-2 inhibitor. 10g of dapagliflozin and 1.95g of colloidal silica were mixed to obtain 11.95g of the first mixture.

[0207] (2) Mix 67.55g of microcrystalline cellulose mannitol co-treated product and 11.95g of the first mixture to dilute the first mixture and obtain 79.5g of the second mixture;

[0208] (3) Mix 79.5g of the second mixture, 160g of valsartan and 39.1g of microcrystalline cellulose mannitol co-treated product to obtain 280.687g of the third mixture;

[0209] (4) Add 15g CCNa, 3.9g colloidal silica and 2.52g magnesium stearate to 280.687g of the third mixture in sequence to obtain the fourth mixture;

[0210] (5) The fourth mixture was tableted at a temperature of 25±2℃ and RH≤35% using a standard round punch with a tableting pressure of 0.65ton and a punch of 10mm to obtain 1000 tablets containing valsartan and SGLT-2 inhibitor with a thickness of 3.2-3.5mm.

[0211] The in vitro dissolution rates of valsartan and dapagliflozin corresponding to the tablets prepared in Examples 1 to 4 were tested, and the test results are as follows: Figure 6 and 7 As shown.

[0212] After investigation Figure 6 and Figure 7 Analysis revealed that valsartan and dapagliflozin in each tablet exhibited good dissolution behavior, meaning that the cumulative in vitro dissolution rate of valsartan and dapagliflozin in each formulation reached over 90% within 30 minutes.

[0213] Example 5

[0214] A method for preparing the above-mentioned tablet containing valsartan and SGLT-2 inhibitor includes the following steps:

[0215] (1) Empagliflozin was selected as the SGLT-2 inhibitor. 10g of empagliflozin and 1g of colloidal silica were mixed to obtain 11g of the first mixture.

[0216] (2) Mix 99g of microcrystalline cellulose mannitol co-treated product and 11g of the first mixture to dilute the first mixture and obtain 110g of the second mixture;

[0217] (3) Mix 110g of the second mixture, 80g of valsartan and 53.875g of microcrystalline cellulose mannitol co-treated product to obtain 234.875g of the third mixture;

[0218] (4) Add 12.525g CCNa, 2g colloidal silica and 2.1g magnesium stearate to 234.875g of the third mixture in sequence to obtain the fourth mixture;

[0219] (5) The fourth mixture was tableted at a temperature of 25±2℃ and RH≤35% using a standard round punch with a tableting pressure of 0.65ton and a punch of 10mm to obtain 1000 tablets containing valsartan and SGLT-2 inhibitor with a thickness of 3.2-3.5mm.

[0220] Example 6

[0221] A method for preparing the above-mentioned tablet containing valsartan and SGLT-2 inhibitor includes the following steps:

[0222] (1) Empagliflozin was selected as the SGLT-2 inhibitor. 25g of empagliflozin and 1g of colloidal silica were mixed to obtain 26g of the first mixture.

[0223] (2) Mix 67.55g of microcrystalline cellulose mannitol co-treated product and 26g of the first mixture to dilute the first mixture and obtain 93.55g of the second mixture;

[0224] (3) Mix 93.55g of the second mixture, 80g of valsartan and 60.325g of microcrystalline cellulose mannitol co-treated product to obtain 233.875g of the third mixture;

[0225] (4) Add 12.525g CCNa, 2g colloidal silica and 2.1g magnesium stearate to 233.875g of the third mixture in sequence to obtain the fourth mixture;

[0226] (5) The fourth mixture was tableted at a temperature of 25±2℃ and RH≤35% using a standard round punch with a tableting pressure of 0.65ton and a punch of 10mm to obtain 1000 tablets containing valsartan and SGLT-2 inhibitor with a thickness of 3.2-3.5mm.

[0227] Example 7

[0228] A method for preparing the above-mentioned tablet containing valsartan and SGLT-2 inhibitor includes the following steps:

[0229] (1) Empagliflozin was selected as the SGLT-2 inhibitor. 10g of empagliflozin and 1.95g of colloidal silica were mixed to obtain 11.95g of the first mixture.

[0230] (2) Mix 107.55g of microcrystalline cellulose mannitol co-treated product and 11.95g of the first mixture to dilute the first mixture and obtain 119.5g of the second mixture;

[0231] (3) Mix 119.5g of the second mixture, 160g of valsartan and 46.187g of microcrystalline cellulose mannitol co-treated product to obtain 325.687g of the third mixture;

[0232] (4) Add 17.5g CCNa, 3.9g colloidal silica and 2.933g magnesium stearate to 325.687g of the third mixture in sequence to obtain the fourth mixture;

[0233] (5) The fourth mixture was tableted at a temperature of 25±2℃ and RH≤35% using a standard round punch with a tableting pressure of 0.65ton and a punch of 10mm to obtain 1000 tablets containing valsartan and SGLT-2 inhibitor with a thickness of 3.2-3.5mm.

[0234] Example 8

[0235] A method for preparing the above-mentioned tablet containing valsartan and SGLT-2 inhibitor includes the following steps:

[0236] (1) Empagliflozin was selected as the SGLT-2 inhibitor. 25g of empagliflozin and 1.95g of colloidal silica were mixed to obtain 26g of the first mixture.

[0237] (2) Mix 107.55g of microcrystalline cellulose mannitol co-treated product and 26g of the first mixture to dilute the first mixture and obtain 133.26g of the second mixture;

[0238] (3) Mix 133.26g of the second mixture, 160g of valsartan and 31.187g of microcrystalline cellulose mannitol co-treated product to obtain 324.447g of the third mixture;

[0239] (4) Add 17.5g CCNa, 3.9g colloidal silica and 2.933g magnesium stearate to 324.447g of the third mixture in sequence to obtain the fourth mixture;

[0240] (5) The fourth mixture was tableted at a temperature of 25±2℃ and RH≤35% using a standard round punch with a tableting pressure of 0.65ton and a punch of 10mm to obtain 1000 tablets containing valsartan and SGLT-2 inhibitor with a thickness of 3.2-3.5mm.

[0241] The in vitro dissolution rates of valsartan and empagliflozin corresponding to the tablets prepared in Examples 4 to 8 were tested, and the test results are as follows: Figure 8 and 9 As shown.

[0242] After investigation Figure 8 and Figure 9 Analysis revealed that valsartan and empagliflozin in each tablet exhibited good dissolution behavior, meaning that the cumulative in vitro dissolution rate of valsartan and empagliflozin in each formulation reached over 90% within 30 minutes.

[0243] Example 9

[0244] A method for preparing the above-mentioned tablet containing valsartan and SGLT-2 inhibitor includes the following steps:

[0245] (1) After heating valsartan to a molten state, the molten valsartan is mixed with macroporous silica at a weight ratio of 1:0.8, so that the molten valsartan is loaded into the mesopores of macroporous silica to obtain the first sample;

[0246] (2) After the first sample is cooled to room temperature, the first sample is ground and dispersed to obtain valsartan-mesoporous silica;

[0247] (3) After heating the SGLT-2 inhibitor to a molten state, the molten SGLT-2 inhibitor is mixed with macroporous silica at a weight ratio of 1:1.2, so that the molten SGLT-2 inhibitor is loaded into the mesopores of macroporous silica to obtain the second sample; wherein, the SGLT-2 inhibitor is selected as dapagliflozin.

[0248] (4) After the second sample is cooled to room temperature, the second sample is ground and dispersed to obtain dapagliflozin-mesoporous silica.

[0249] (5) Mix 0.48g of microcrystalline cellulose mannitol co-treated product and 0.12g of dapagliflozin-mesoporous silica to dilute the dapagliflozin-mesoporous silica and obtain the fifth mixture;

[0250] In this step, 0.12g of dapagliflozin-mesoporous silica and 0.12g of microcrystalline cellulose mannitol co-treatment were mixed in a three-dimensional mixer at 15 rpm for 10 min, and then the above mixture and 0.36g of microcrystalline cellulose mannitol co-treatment were mixed in a three-dimensional mixer at 15 rpm for 15 min to obtain the fifth mixture.

[0251] (6) Mix 0.6g of the fifth mixture, 0.96g of valsartan-mesoporous silica and 0.1111g of microcrystalline cellulose mannitol to obtain the sixth mixture;

[0252] (7) Add 0.09g of disintegrant (CCNa), 0.0144g of lubricant (magnesium stearate) and 0.0245g of microcrystalline cellulose mannitol to the sixth mixture in step (6) to obtain the seventh mixture;

[0253] (8) The seventh mixture is tableted by a compression pressure of 0.65 ton and a standard round punch of 10 mm to obtain tablets with a thickness of 3.2-3.5 mm.

[0254] Example 10

[0255] A method for preparing the above-mentioned tablet containing valsartan and SGLT-2 inhibitor includes the following steps:

[0256] (1) After heating valsartan to a molten state, the molten valsartan is mixed with macroporous silica at a weight ratio of 1:1, so that the molten valsartan is loaded into the mesopores of macroporous silica to obtain the first sample;

[0257] (2) After the first sample is cooled to room temperature, the first sample is ground and dispersed to obtain valsartan-mesoporous silica;

[0258] (3) After heating the SGLT-2 inhibitor to a molten state, the molten SGLT-2 inhibitor is mixed with macroporous silica at a weight ratio of 1:2.5, so that the molten SGLT-2 inhibitor is loaded into the mesopores of macroporous silica to obtain the second sample; wherein, the SGLT-2 inhibitor is selected as dapagliflozin.

[0259] (4) After the second sample is cooled to room temperature, the second sample is ground and dispersed to obtain dapagliflozin-mesoporous silica.

[0260] (5) Mix 0.72g of microcrystalline cellulose mannitol co-treated product and 0.18g of dapagliflozin-mesoporous silica to dilute the dapagliflozin-mesoporous silica and obtain the fifth mixture.

[0261] In this step, 0.18g of dapagliflozin-mesoporous silica and 0.18g of microcrystalline cellulose mannitol co-treatment were mixed in a three-dimensional mixer at 15 rpm for 10 min, and then the above mixture and 0.54g of microcrystalline cellulose mannitol co-treatment were mixed in a three-dimensional mixer at 15 rpm for 15 min to obtain the fifth mixture.

[0262] (6) Mix 0.9g of the fifth mixture, 1.44g of valsartan-mesoporous silica and 0.5311g of microcrystalline cellulose mannitol to obtain the sixth mixture;

[0263] (7) Add 0.09g of disintegrant (CCNa), 0.0144g of lubricant (magnesium stearate) and 0.0245g of microcrystalline cellulose mannitol to the sixth mixture in step (6) to obtain the seventh mixture;

[0264] (8) The seventh mixture is tableted by a compression pressure of 0.65 ton and a standard round punch of 10 mm to obtain tablets with a thickness of 3.2-3.5 mm.

[0265] Example 11

[0266] A method for preparing the above-mentioned tablet containing valsartan and SGLT-2 inhibitor includes the following steps:

[0267] (1) After heating valsartan to a molten state, the molten valsartan is mixed with macroporous silica at a weight ratio of 1:1.2, so that the molten valsartan is loaded into the mesopores of macroporous silica to obtain the first sample;

[0268] (2) After the first sample is cooled to room temperature, the first sample is ground and dispersed to obtain valsartan-mesoporous silica;

[0269] (3) After heating the SGLT-2 inhibitor to a molten state, the molten SGLT-2 inhibitor is mixed with macroporous silica at a weight ratio of 1:3.5, so that the molten SGLT-2 inhibitor is loaded into the mesopores of macroporous silica to obtain the second sample; wherein, the SGLT-2 inhibitor is selected as dapagliflozin.

[0270] (4) After the second sample is cooled to room temperature, the second sample is ground and dispersed to obtain dapagliflozin-mesoporous silica.

[0271] (5) Mix 0.48g of microcrystalline cellulose mannitol co-treated product and 0.24g of dapagliflozin-mesoporous silica to dilute the dapagliflozin-mesoporous silica and obtain the fifth mixture;

[0272] In this step, 0.24g of dapagliflozin-mesoporous silica and 0.12g of microcrystalline cellulose mannitol co-treatment were mixed in a three-dimensional mixer at 15 rpm for 10 min, and then the above mixture and 0.36g of microcrystalline cellulose mannitol co-treatment were mixed in a three-dimensional mixer at 15 rpm for 15 min to obtain the fifth mixture.

[0273] (6) Mix 0.72g of the fifth mixture, 1.92g of valsartan-mesoporous silica and 0.2311g of microcrystalline cellulose mannitol to obtain the sixth mixture;

[0274] (7) Add 0.09g of disintegrant (CCNa), 0.0144g of lubricant (magnesium stearate) and 0.0245g of microcrystalline cellulose mannitol to the sixth mixture in step (6) to obtain the seventh mixture;

[0275] (8) The seventh mixture is tableted by a compression pressure of 0.65 ton and a standard round punch of 10 mm to obtain tablets with a thickness of 3.2-3.5 mm.

[0276] The in vitro dissolution rates of valsartan and dapagliflozin corresponding to the tablets prepared in Examples 9 to 11 were tested, and the test results are as follows: Figure 16 and 17 As shown.

[0277] After investigation Figure 16 and Figure 17 Analysis revealed that valsartan and dapagliflozin in each tablet exhibited good dissolution behavior, meaning that the cumulative in vitro dissolution rate of valsartan and dapagliflozin in each formulation reached over 90% within 30 minutes.

[0278] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A tablet comprising valsartan and an SGLT-2 inhibitor for use in a medicament for the treatment of a cardiovascular disease, characterized in that, The tablet is composed of the following ingredients by weight: valsartan 90-165 parts, SGLT-2 inhibitor 7-24 parts, microcrystalline cellulose mannitol co-processing product 115-1250 parts, lubricant 1.5-5 parts, disintegrant 11-20 parts.

2. The tablet comprising valsartan and SGLT-2 inhibitor according to claim 1, characterized in that, The SGLT-2 inhibitor is dapagliflozin or empagliflozin.

3. The tablet comprising valsartan and SGLT-2 inhibitor according to claim 1, characterized in that, The disintegrant is one or several of crosslinked sodium carboxymethyl cellulose, crosslinked povidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose; the lubricant is one or several of magnesium stearate, talc and calcium stearate.

4. A process for the preparation of a tablet comprising valsartan and an SGLT-2 inhibitor according to any one of claims 1 to 3, characterized in that, The method comprises the following steps: The SGLT-2 inhibitor and colloidal silicon dioxide are mixed in a weight ratio of 1:0.05-0.15 to obtain a first mixture; The microcrystalline cellulose mannitol co-processing product and the first mixture are mixed in a weight ratio of 36-42:3-5 to dilute the first mixture and obtain a second mixture; The second mixture, valsartan and the microcrystalline cellulose mannitol co-processing product are mixed in a weight ratio of 20-25:12-20:80-100 to obtain a third mixture; The disintegrant, colloidal silicon dioxide and lubricant are sequentially added to the third mixture to obtain a fourth mixture; The fourth mixture is tableted to obtain a tablet containing valsartan and SGLT-2 inhibitor.

5. A process for the preparation of a tablet comprising valsartan and an SGLT-2 inhibitor according to any one of claims 1 to 3, characterized in that, The method comprises the following steps: The valsartan in a molten state is loaded into the mesopores of the large mesoporous silica to obtain valsartan-large mesoporous silica; The SGLT-2 inhibitor in a molten state is loaded into the mesopores of the large mesoporous silica to obtain SGLT-2 inhibitor-large mesoporous silica; The microcrystalline cellulose mannitol co-processing product and the SGLT-2 inhibitor-large mesoporous silica are mixed in a weight ratio of 3-5:1 to dilute the SGLT-2 inhibitor-large mesoporous silica and obtain a fifth mixture; The fifth mixture, the valsartan-large mesoporous silica and the microcrystalline cellulose mannitol are mixed in a weight ratio of 10-13:18-20:1-3 to obtain a sixth mixture; The disintegrant and lubricant are sequentially added to the sixth mixture to obtain a seventh mixture; The seventh mixture is tableted to obtain a tablet containing valsartan and SGLT-2 inhibitor.

6. The process of preparing a tablet comprising valsartan and an SGLT-2 inhibitor according to claim 5, characterized in that, The method of loading the valsartan in a molten state into the mesopores of the large mesoporous silica to obtain valsartan-large mesoporous silica comprises the following steps: After the valsartan is heated to a molten state, the valsartan in a molten state and the large mesoporous silica are mixed in a weight ratio of 1:0.8-1.2 to load the valsartan in a molten state into the mesopores of the large mesoporous silica to obtain a first sample; After the first sample is cooled to room temperature, the first sample is ground and dispersed to obtain valsartan-large mesoporous silica; and / or The method of loading the SGLT-2 inhibitor in a molten state into the mesopores of the large mesoporous silica to obtain SGLT-2 inhibitor-large mesoporous silica comprises the following steps: After the SGLT-2 inhibitor is heated to a molten state, the SGLT-2 inhibitor in the molten state is mixed with the large mesoporous silica at a weight ratio of 1:1.2-3.5, so that the SGLT-2 inhibitor in the molten state is loaded in the mesopores of the large mesoporous silica, to obtain a second sample; After the second sample is cooled to room temperature, the second sample is ground and dispersed to obtain a SGLT-2 inhibitor-large mesoporous silica; and / or The seventh mixture is subjected to tabletting processing to obtain a tablet containing valsartan and a SGLT-2 inhibitor, including: The seventh mixture is subjected to tabletting processing by a tabletting pressure of 0.65 tons and a standard round punch of 10 mm, to obtain a tablet with a tablet thickness of 3.2-3.5 mm.

7. Process for the preparation of a tablet comprising valsartan and an SGLT-2 inhibitor according to any one of claims 4 to 5, characterized in that, Also included is the determination of optimal parameters corresponding to the amount of lubricant, the amount of disintegrant, and the tabletting pressure used when the fourth mixture is subjected to tabletting processing, respectively, and each of the determination of the optimal parameters includes: The optimal parameters corresponding to the amount of lubricant, the amount of disintegrant, and the tabletting pressure used when the fourth mixture is subjected to tabletting processing are determined by a central composite design-response surface method, wherein the dissolution values of valsartan, the dissolution values of the SGLT-2 inhibitor, and the hardness of the tablet are used as effect variables.

8. The process for the preparation of a tablet comprising valsartan and an SGLT-2 inhibitor according to claim 7, characterized in that, The determination of the optimal parameters corresponding to the amount of lubricant, the amount of disintegrant, and the tabletting pressure used when the fourth mixture is subjected to tabletting processing by the central composite design-response surface method includes: The amount of lubricant, the amount of disintegrant, and the tabletting pressure used when the fourth mixture is subjected to tabletting processing are all used as factor levels of independent variables; The codes corresponding to each of the factor levels are determined as -1, 0, and 1, respectively, and a test table is compiled according to the codes corresponding to each of the factor levels and the level values corresponding to each of the factor levels; The dissolution values of valsartan, the dissolution values of the SGLT-2 inhibitor, and the hardness of the tablet are used as effect variables, and tablets are prepared according to the test table, and in vitro dissolution tests of valsartan and the SGLT-2 inhibitor and hardness tests of the prepared tablets are carried out; Based on the in vitro dissolution test results of valsartan and the SGLT-2 inhibitor and the hardness values of the prepared tablets, the optimal parameters corresponding to the amount of lubricant, the amount of disintegrant, and the tabletting pressure used when the fourth mixture is subjected to tabletting processing are determined.

9. The process for the preparation of a tablet comprising valsartan and an SGLT-2 inhibitor according to claim 8, characterized in that, The determination of the optimal parameters corresponding to the amount of lubricant, the amount of disintegrant, and the tabletting pressure used when the fourth mixture is subjected to tabletting processing based on the in vitro dissolution test results of valsartan and the SGLT-2 inhibitor and the hardness values of the prepared tablets includes: drawing a response curve corresponding to the in-vitro dissolution of the valsartan, the in-vitro dissolution of the SGLT-2 inhibitor, and the hardness, respectively, according to the amount of the lubricant, the amount of the disintegrant, the tabletting pressure used in the tabletting process of the fourth mixture, and the in-vitro dissolution test results and the hardness values of the valsartan and the SGLT-2 inhibitor in the prepared tablets; determining the optimal parameters of the amount of the lubricant, the amount of the disintegrant, and the tabletting pressure used in the tabletting process of the fourth mixture, respectively, based on the response curves corresponding to the in-vitro dissolution of the valsartan, the in-vitro dissolution of the SGLT-2 inhibitor, and the hardness, respectively.

10. The process for the preparation of a tablet comprising valsartan and an SGLT-2 inhibitor according to claim 9, characterized in that, The drawing of the response curve corresponding to the in-vitro dissolution of the valsartan, the in-vitro dissolution of the SGLT-2 inhibitor, and the hardness, respectively, according to the amount of the lubricant, the amount of the disintegrant, the tabletting pressure used in the tabletting process of the fourth mixture, and the in-vitro dissolution test results and the hardness values of the valsartan and the SGLT-2 inhibitor in the prepared tablets, comprises: constructing an in-vitro dissolution fitting model of the valsartan in the tablet according to the amount of the lubricant, the amount of the disintegrant, the tabletting pressure used in the tabletting process of the fourth mixture, and the in-vitro dissolution test results of the valsartan in the prepared tablet; wherein the in-vitro dissolution fitting model of the valsartan in the tablet is constructed by using the following formula: Y1 = 100.36986 + 0.158X1 + 0.344X2 + 1.852X3 - 0.0025X1X2 + 0.085X1X3 + 2.7975X2X3 - 2.72225X1 2 -0.722254X2 2 -0.812254X3 2 wherein Y1 is the in-vitro dissolution of the valsartan in the tablet; X1 is the tabletting pressure; X2 is the amount of the lubricant; X3 is the amount of the disintegrant; inputting the amount of the lubricant, the amount of the disintegrant, and the tabletting pressure used in the tabletting process of the fourth mixture into the in-vitro dissolution fitting model of the valsartan, respectively, to obtain the fitted in-vitro dissolution of the valsartan; drawing a response curve corresponding to the in-vitro dissolution of the valsartan according to the amount of the lubricant, the amount of the disintegrant, the tabletting pressure used in the tabletting process of the fourth mixture, and the fitted in-vitro dissolution of the valsartan; constructing an in-vitro dissolution fitting model of the SGLT-2 inhibitor in the tablet according to the amount of the lubricant, the amount of the disintegrant, the tabletting pressure used in the tabletting process of the fourth mixture, and the in-vitro dissolution test results of the SGLT-2 inhibitor in the prepared tablet; wherein the in-vitro dissolution fitting model of the SGLT-2 inhibitor in the tablet is constructed by using the following formula: Y2 = 96.36 + 0.027X1 - 0.351X2 + 2.998X3 + 0.00375X1X2 + 0.34375X1X3 + 2.83625X2X3 - 0.778099X1 2 -2.6981X2 2 -0.803099X3 2 wherein Y2 is the in-vitro dissolution of the SGLT-2 inhibitor in the tablet; X1 is the tabletting pressure; X2 is the amount of the lubricant; X3 is the amount of the disintegrant; inputting the amount of the lubricant, the amount of the disintegrant, and the tabletting pressure used in the tabletting process of the fourth mixture into the in-vitro dissolution fitting model of the SGLT-2 inhibitor, respectively, to obtain the fitted in-vitro dissolution of the SGLT-2 inhibitor; A response curve corresponding to the in-vitro dissolution of the SGLT-2 inhibitor is drawn by using the amount of the lubricant, the amount of the disintegrant, the tabletting pressure used in the tabletting process of the fourth mixture, and the in-vitro dissolution of the SGLT-2 inhibitor fitted out; A hardness fitting model of the tablet is constructed according to the amount of the lubricant, the amount of the disintegrant, the tabletting pressure used in the tabletting process of the fourth mixture, and the in-vitro dissolution test result of the SGLT-2 inhibitor in the prepared tablet; wherein the hardness fitting model of the tablet is constructed by using the following formula: Y3 = 95.08471 + 23.6X1 + 1.005X2 - 6.417X3 wherein Y3 is the hardness of the tablet; X1 is the tabletting pressure; X2 is the amount of the lubricant; and X3 is the amount of the disintegrant; The amount of the lubricant, the amount of the disintegrant, and the tabletting pressure used in the tabletting process of the fourth mixture are respectively input into the hardness fitting model to obtain the fitted hardness; A response curve corresponding to the hardness is drawn by using the amount of the lubricant, the amount of the disintegrant, the tabletting pressure used in the tabletting process of the fourth mixture, and the fitted hardness.

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