Pharmaceutical composition for reducing blood sugar and application thereof

Abstract

The invention discloses a pharmaceutical composition for reducing blood sugar and application thereof, and belongs to the technical field of preparation of drugs for reducing blood sugar. The pharmaceutical composition is prepared from the following components in parts by weight: 5 to 7 parts of empagliflozin, 30 to 40 parts of cortex cinnamomi extract, 500 to 700 parts of metformin, 60 to 80 parts of microcrystalline cellulose, 10 to 15 parts of polyvinylpolypyrrolidone, 100 to 120 parts of HPMC K100M, 50 to 60 parts of ethyl cellulose, 40 to 50 parts of Eudragit FS30D, 40 to 50 parts of soybean phospholipid and 10 to 20 parts of poloxamer 188. The composition is applied to preparation of sustained-release tablets for reducing blood sugar, and can reduce loss of islet cells and protect kidney functions and gastric mucosa.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of hypoglycemic drug preparation, and more particularly relates to a hypoglycemic drug composition and application thereof. BACKGROUND

[0002] Diabetic patients are in a high blood sugar state for a long time, which can lead to various complications such as diabetic nephropathy, retinopathy, neuropathy, cardiovascular disease, and seriously affect the quality of life and life span of patients. In the treatment process, existing hypoglycemic drugs often have many limitations. Some drugs have unsatisfactory hypoglycemic effect and are difficult to stably control blood glucose level for a long time; some drugs can lower blood glucose, but are insufficient in protecting islet cells and kidney function, and even can aggravate the damage of islet cells and the burden of kidney, and increase the risk of complications such as diabetic nephropathy. For example, some sulfonylurea drugs can cause further deterioration of islet cell function; some insulin sensitizers can have adverse effects on the kidney. Moreover, most drugs can cause blood glucose fluctuation, and further cause oxidative stress damage.

[0003] Moreover, in the drug release process, the drug release of immediate-release preparations (such as ordinary tablets and capsules) depends on simple disintegration and dissolution, and lacks precise sustained-release control mechanism. For example, metformin ordinary tablets disintegrate rapidly after entering the gastrointestinal tract, and the drug is released in a large amount in a short time, resulting in rapid increase of blood drug concentration (which can cause gastrointestinal irritation such as nausea and diarrhea); and the drug concentration rapidly decreases in the later stage of release, and effective therapeutic concentration cannot be maintained, the “peak-valley effect” is significant, and the stable release effect required by sustained release cannot be achieved. SUMMARY

[0004] The application provides a hypoglycemic drug composition and application thereof to solve the above problems.

[0005] To achieve the above purpose, the application adopts the following technical solutions. The application provides a hypoglycemic drug composition, which comprises the following components in parts by weight: empagliflozin 5-7 parts, cinnamon extract 30-40 parts, metformin 500-700 parts, microcrystalline cellulose 60-80 parts, crosslinked polyvinylpyrrolidone 10-15 parts, HPMC K100M 100-120 parts, ethyl cellulose 50-60 parts, Eudragit FS30D 40-50 parts, soybean phospholipid 40-50 parts, and poloxamer 188 10-20 parts.

[0006] Further, the pharmaceutical composition comprises the following components in the optimal weight parts: 6 parts of empagliflozin, 35 parts of cinnamon extract, 600 parts of metformin, 65 parts of microcrystalline cellulose, 10 parts of cross-linked povidone, 120 parts of HPMC K100M, 55 parts of ethyl cellulose, 45 parts of Eudragit FS30D, 45 parts of soybean phospholipid, and 18 parts of poloxamer 188.

[0007] Compared with the prior art, the empagliflozin and metformin are creatively added with the cinnamon extract, because the inventor accidentally finds that the addition of the cinnamon extract can reduce the side effects of the empagliflozin and metformin, reduce the bacterial flora disorder and osmotic diarrhea caused by the empagliflozin and metformin tablets. The invention proves that the cinnamon extract can significantly reduce the incidence of gastrointestinal reactions related to the empagliflozin and metformin tablets, and directly reduce the infection probability caused by the increase of urine sugar. Meanwhile, the inventor also finds that the addition of the cinnamon extract can reduce the accumulation of the metformin in the renal tubules, reduce the risk of lactic acidosis, and effectively protect the kidney function. Therefore, the empagliflozin, the cinnamon extract and the metformin are combined in the invention, which can effectively reduce blood sugar, protect the gastrointestinal tract, protect the pancreatic beta cells and the kidney function.

[0008] The second aspect of the invention provides an application of the pharmaceutical composition in the preparation of a blood sugar reducing sustained-release tablet.

[0009] Compared with the prior art, the above pharmaceutical composition is used in the preparation of the blood sugar reducing sustained-release tablet, which provides a theoretical basis for the research and development of the blood sugar reducing sustained-release tablet, and ensures the slow and phased release of the components.

[0010] The third aspect of the invention provides a preparation method of a blood sugar reducing sustained-release tablet, and the preparation process is as follows: Step one, each component is weighed according to the ratio of the pharmaceutical composition; Step two, the cinnamon extract, the soybean phospholipid and the poloxamer 188 are mixed, an ethanol-water mixed solvent is added, high-pressure homogenization, rotary evaporation and freeze-drying are performed, and a nanoparticle powder is obtained; Step three, the microcrystalline cellulose is granulated, the hydroxypropyl methyl cellulose aqueous solution of the nanoparticle powder is added, and coating treatment is performed to obtain a drug-loaded pellet core; then the cross-linked povidone and the lactose are dissolved in an ethanol solution, and the solution is uniformly sprayed on the surface of the drug-loaded pellet core to form a fast-release pellet core; Step four, the Eudragit FS30D and the triethyl citrate are dispersed in pure water to form a coating liquid, and the pellet core is coated to obtain an enteric-coated pellet; Step five, the metformin, the hydroxypropyl methyl cellulose and the ethyl cellulose are mixed and melted to form a matrix; then the melted sustained-release matrix is uniformly coated on the surface of the enteric-coated pellet to form a sustained-release enteric-coated pellet; Step six, mixing the sustained-release enteric micro-pellets with magnesium stearate, tabletting, coating, to obtain the blood sugar lowering sustained-release tablets.

[0011] Compared with the prior art, in the preparation of the blood sugar lowering sustained-release tablets, the cinnamon extract is prepared into nanoparticles with the aid of soybean phospholipid and poloxamer 188, the nanostructure stability is maintained through high-pressure homogenization and freeze-drying processes, the solubility and dispersibility of the fat-soluble components can be significantly improved, the intestinal absorption is promoted, and the bioavailability is improved. The part of the drug can be rapidly released by the fast-release layer formed by the cross-linked povidone and lactose as high-efficiency disintegrants, the postprandial hyperglycemia is rapidly responded, and the rapid effect is achieved; metformin can be continuously and slowly released by the sustained-release layer formed by the melting coating of HPMC and EC as the sustained-release matrix, the stable blood drug concentration is maintained, the blood glucose fluctuation is avoided to be too large, and long-acting sugar control is achieved. The enteric layer formed by Eudragit FS30D (enteric coating material) and triethyl citrate (plasticizer) can make the micro-pellets not dissolved or slightly dissolved in the acidic gastric juice, and a large amount of drug can be released in the intestinal environment. The synergistic effect of the sustained-release matrix (HPMC, EC) and the enteric coating can significantly prolong the drug release time, reduce the frequency of daily drug taking, and improve the convenience and compliance of the patients in taking the drug.

[0012] The sustained-release tablet prepared by the above method has, from the inside to the outside, the effective component of cinnamon extract, metformin and empagliflozin. After the medicine enters the human body, the slow-release matrix layer starts to slowly release the medicine tablet into the stomach (acidic environment, pH 1-3). The outermost slow-release matrix layer (containing metformin, hydroxypropyl methylcellulose HPMC and ethyl cellulose EC) first contacts with the gastric juice. HPMC forms a gel barrier when it comes into contact with water, and ethyl cellulose serves as an insoluble skeleton. Together, they make metformin slowly release from the slow-release layer through the mechanism of "matrix erosion + drug diffusion", and start to play a long-acting hypoglycemic effect. This stage is the "slow-release start". At this time, the inner layer of enteric coating Eudragit FS30D does not dissolve in the acidic gastric juice, protecting the inner immediate-release pellet core and the drug-loaded pellet core from being destroyed by the gastric environment. After the tablet enters the intestine, the enteric coating material Eudragit FS30D dissolves under alkaline conditions, exposing the inner immediate-release pellet core. The cross-linked povidone (high-efficiency disintegrating agent) on the surface of the immediate-release pellet core rapidly absorbs water and swells, driving the lactose (promoting dissolution) to rapidly disintegrate, releasing the inner drug-loaded pellet core. The cinnamon extract nanoparticle powder in the drug-loaded pellet core is modified by soybean phospholipid and poloxamer 188, and then quickly disperses and dissolves in the intestinal fluid. The nanoparticles improve the solubility of the fat-soluble components, are quickly absorbed by the intestinal mucosa, achieve "rapid onset", and this stage is the "peak of rapid release". The slow-release matrix layer (HPMC + ethyl cellulose) started in the stomach continues to slowly erode and diffuse the drug through the gel barrier when it enters the intestine, continuously releases metformin, maintains a stable blood drug concentration, avoids blood glucose fluctuations, achieves "long-acting glycemic control", and this stage is the "sustained-release maintenance".

[0013] Further, in step two, the mixing is stirring at 50-55°C under water bath conditions until complete dissolution.

[0014] Further, the volume ratio of ethanol to water in the ethanol-water mixed solvent is 6-10:2-5.

[0015] Further, the high-pressure homogenization is a cycle treatment of 3-5 times under a pressure of 800-1000 bar, and the particle size is controlled to be 200±50 nm.

[0016] Further, the rotary evaporation is evaporation to remove ethanol under the conditions of 40-45°C and a vacuum of -0.08~-0.06 MPa, to obtain a concentrated solution.

[0017] Further, the freeze-drying is adding mannitol with a final mass fraction of 5% to the concentrated solution, pre-freezing for 2-3 h at -40~-50°C, and then freeze-drying under the conditions of -20~-30°C and a vacuum degree of 0.1-0.3 mbar for 40-50 h.

[0018] Further, in step three, the coating process is set to an inlet air temperature of 45-50℃, an atomization pressure of 1.0-1.2 bar, and a spraying rate of 5-8 mL / min, and a bottom-spray coating is performed until the weight gain is 30-40%.

[0019] Further, the mass fraction of the ethanol solution is 10-15%, and the mass ratio of the cross-linked povidone, lactose, and ethanol solution is 1g:2-3g:10ml.

[0020] Further, in step four, the coating process is set to an inlet air temperature of 38-42℃, a material temperature of 33-38℃, and a spraying rate of 3-4 g / min, and a bottom-spray coating is performed until the weight gain is 15-20%.

[0021] Further, in step five, the mixing and melting are set to 80-85℃ and 200-300 rpm.

[0022] Compared with the prior art, the above coating process and drying parameters can further improve the sustained-release effect of the sustained-release tablets. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of protection of the present application.

[0024] During the treatment process, existing hypoglycemic drugs often have many limitations. Some drugs have unsatisfactory hypoglycemic effect and are difficult to stably control blood glucose levels for a long time; some drugs can lower blood glucose, but are insufficient in protecting islet cells and kidney function, and may even aggravate the damage to islet cells and the burden on the kidneys, increasing the risk of complications such as diabetic nephropathy. For example, some sulfonylurea drugs may cause further deterioration of islet cell function; some insulin sensitizers may have adverse effects on the kidneys. Moreover, most drugs cause blood glucose fluctuations, which in turn causes oxidative stress damage.

[0025] Moreover, in the drug release process, the drug release of immediate-release preparations (such as ordinary tablets and capsules) depends on simple disintegration and dissolution, and lacks precise sustained-release control mechanisms. For example, metformin ordinary tablets disintegrate rapidly after entering the gastrointestinal tract, and the drug is released in large amounts in a short time, resulting in a rapid increase in blood drug concentration (which may cause gastrointestinal irritation, such as nausea and diarrhea); and the drug concentration rapidly decreases in the later stage of release, which cannot maintain an effective therapeutic concentration, and the “peak-valley effect” is significant, failing to achieve the stable release effect required for sustained release.

[0026] To overcome the above-mentioned defects, in a first aspect, embodiments of the present application provide a hypoglycemic pharmaceutical composition, the pharmaceutical composition comprising the following components in parts by weight: empagliflozin 5-7 parts, cinnamon extract 30-40 parts, metformin 500-700 parts, microcrystalline cellulose 60-80 parts, cross-linked povidone 10-15 parts, HPMC K100M 100-120 parts, ethyl cellulose 50-60 parts, Eudragit FS30D 40-50 parts, soybean phospholipid 40-50 parts, and poloxamer 188 10-20 parts.

[0027] For example, a hypoglycemic pharmaceutical composition comprises: empagliflozin 6 parts, cinnamon extract 35 parts, metformin 600 parts, microcrystalline cellulose 65 parts, cross-linked povidone 10 parts, HPMC K100M 120 parts, ethyl cellulose 55 parts, Eudragit FS30D 45 parts, soybean phospholipid 45 parts, and poloxamer 188 18 parts.

[0028] For example, a hypoglycemic pharmaceutical composition comprises: empagliflozin 5 parts, cinnamon extract 30 parts, metformin 500 parts, microcrystalline cellulose 60 parts, cross-linked povidone 15 parts, HPMC K100M 100 parts, ethyl cellulose 50 parts, Eudragit FS30D 40 parts, soybean phospholipid 40 parts, and poloxamer 188 10 parts.

[0029] For example, a hypoglycemic pharmaceutical composition comprises: empagliflozin 7 parts, cinnamon extract 40 parts, metformin 700 parts, microcrystalline cellulose 80 parts, cross-linked povidone 12 parts, HPMC K100M 110 parts, ethyl cellulose 50 parts, Eudragit FS30D 50 parts, soybean phospholipid 50 parts, and poloxamer 188 20 parts.

[0030] When the above technical solution is used, the side effects of empagliflozin and metformin can be reduced, and the bacterial flora disorder and osmotic diarrhea caused by empagliflozin and metformin tablets can be reduced. The present application proves that the cinnamon extract can significantly reduce the incidence of gastrointestinal reactions related to empagliflozin and metformin tablets, and can directly reduce the probability of infection caused by increased urine sugar. At the same time, the inventors have found that the addition of the cinnamon extract can reduce the accumulation of metformin in the renal tubules, reduce the risk of lactic acidosis, and effectively protect the kidney function. Therefore, the combination of empagliflozin, cinnamon extract, and metformin in the present application can effectively lower blood sugar, protect the gastrointestinal tract, protect the pancreatic beta cells, and protect the kidney function.

[0031] In a second aspect, embodiments of the present application provide the use of the above-mentioned pharmaceutical composition in the preparation of a hypoglycemic sustained-release tablet.

[0032] When the technical scheme is adopted, the pharmaceutical composition is used in preparation of the hypoglycemic sustained-release tablet, which provides a theoretical basis for research and development of the hypoglycemic sustained-release tablet, and ensures slow and phased release of components.

[0033] In a third aspect, the embodiment of the present application provides a preparation method of the hypoglycemic sustained-release tablet, and the preparation process is as follows: Step one, each component is weighed according to the proportion of the pharmaceutical composition; Step two, the cinnamon extract, soybean phospholipid and poloxamer 188 are mixed, and then the ethanol-water mixed solvent is added, and high-pressure homogenization, rotary evaporation and freeze-drying are performed to obtain nanoparticle powder; Step three, the microcrystalline cellulose is granulated, and then the hydroxypropyl methyl cellulose aqueous solution of the nanoparticle powder is added, and coating treatment is performed to obtain a drug-loaded pellet core; then the cross-linked povidone and lactose are dissolved in an ethanol solution, and uniformly sprayed on the surface of the drug-loaded pellet core to form a fast-release pellet core; Step four, Eudragit FS30D and triethyl citrate are dispersed in pure water to form a coating liquid, and the pellet core is coated to obtain an enteric-coated pellet; Step five, metformin, hydroxypropyl methyl cellulose and ethyl cellulose are mixed and melted to form a matrix; then the melted sustained-release matrix is uniformly coated on the surface of the enteric-coated pellet to form a sustained-release enteric-coated pellet; Step six, the sustained-release enteric-coated pellet is mixed with magnesium stearate, and then tableting and coating are performed to obtain the hypoglycemic sustained-release tablet.

[0034] When the technical scheme is adopted, the prepared sustained-release tablets have the effective components of cinnamon extract, metformin and empagliflozin from inside to outside. After the medicine enters the human body, the slow-release matrix layer starts to slowly release the medicine tablets into the stomach (acidic environment, pH 1-3). The outermost slow-release matrix layer (containing metformin, hydroxypropyl methylcellulose HPMC and ethyl cellulose EC) first contacts with the gastric juice. HPMC forms a gel barrier when it contacts with water, and ethyl cellulose serves as an insoluble skeleton. The two together realize the slow release of metformin from the slow-release layer through the mechanism of “matrix erosion + drug diffusion”, and the long-acting hypoglycemic effect is started. This stage is the “slow-release start”. At this time, the inner enteric coating Eudragit FS30D does not dissolve in the acidic gastric juice, and protects the inner immediate-release pellet core and the drug-loaded pellet core from being damaged by the gastric environment. After the tablets enter the intestine, the enteric coating material Eudragit FS30D dissolves under alkaline conditions, exposing the inner immediate-release pellet core. The cross-linked povidone (high-efficiency disintegrating agent) on the surface of the immediate-release pellet core rapidly absorbs water and swells, driving the lactose (promoting dissolution) to rapidly disintegrate, and releasing the inner drug-loaded pellet core. The cinnamon extract nanoparticle powder in the drug-loaded pellet core is modified by soybean phospholipid and poloxamer 188, and then rapidly disperses and dissolves in the intestinal fluid. The nanoparticles improve the solubility of the fat-soluble components, are rapidly absorbed by the intestinal mucosa, realize “rapid onset”, and this stage is the “peak of rapid release”. The slow-release matrix layer (HPMC + ethyl cellulose) started in the stomach continues to slowly erode and diffuse the drug through the gel barrier after entering the intestine, continuously releases metformin, maintains a stable blood drug concentration, avoids blood glucose fluctuation, realizes “long-acting glycemic control”, and this stage is the “sustained-release maintenance”.

[0035] In some embodiments, in step two, the mixing is stirring at 50-55°C under water bath conditions until complete dissolution.

[0036] For example, the water bath temperature can be selected as 50°C, 52°C, 55°C or a range value composed of any point value, and is preferably 52-55°C.

[0037] In some embodiments, the volume ratio of ethanol to water in the ethanol-water mixed solvent is 6-10:2-5.

[0038] For example, the volume ratio of ethanol to water can be specifically selected as 6:2, 10:5, 7:3 or a range value composed of any point value, and is preferably 7-10:3-5.

[0039] In some embodiments, the high-pressure homogenization is cyclic treatment for 3-5 times under a pressure of 800-1000 bar, and the particle size is controlled to be 200±50 nm.

[0040] For example, the pressure during homogenization can be selected as 800 bar, 900 bar, 1000 bar, or a range of values with any point value, preferably 900-1000 bar.

[0041] For example, the number of cycles can be selected as 3, 4, 5.

[0042] For example, the particle size can be selected as 150 nm, 200 nm, 250 nm, or a range of values with any point value, preferably 150-200 nm.

[0043] In some embodiments, the rotary evaporation is performed at 40-45℃, -0.08~-0.06 MPa vacuum to remove ethanol and obtain a concentrated solution.

[0044] For example, the temperature during rotary evaporation can be selected as 40℃, 42℃, 45℃, or a range of values with any point value, preferably 42-45℃.

[0045] For example, the vacuum pressure can be selected as -0.08 MPa, -0.07 MPa, -0.06 MPa, or a range of values with any point value, preferably -0.08 MPa~-0.07 MPa.

[0046] In some embodiments, the freeze-drying is performed by adding mannitol with a final mass fraction of 5% to the concentrated solution, pre-freezing at -40~-50℃ for 2~3h, and then freeze-drying at -20~-30℃, 0.1~0.3mbar for 40~50h.

[0047] For example, the pre-freezing conditions can be selected as -40℃ for 3h, -50℃ for 2h, -45℃ for 2.5h.

[0048] For example, the freeze-drying conditions can be selected as -20℃, 0.3mbar for 50h, -30℃, 0.1mbar for 40h, or -25℃, 0.2mbar for 45h.

[0049] In step three, during the coating process, the inlet air temperature is set to 45-50℃, the atomization pressure is set to 1.0-1.2 bar, the liquid spray rate is set to 5-8 mL / min, and bottom spray coating is performed to increase the weight by 30-40%.

[0050] For example, the inlet air temperature can be selected as 45℃, 48℃, 50℃, or a range of values with any point value, preferably 48-50℃.

[0051] For example, the atomization pressure can be selected as 1.0 bar, 1.1 bar, 1.2 bar or any point value consisting of a range value, preferably 1.1-1.2 bar.

[0052] For example, the liquid spraying rate can be selected as 5 mL / min, 7 mL / min, 8 mL / min or any point value consisting of a range value, preferably 7-8 mL / min.

[0053] In some embodiments, the mass fraction of the ethanol solution is 10-15%, and the mass ratio of the cross-linked povidone, lactose and ethanol solution is 1g:2-3g:10ml.

[0054] For example, the mass fraction of the ethanol solution can be selected as 10%, 12%, 15% or any point value consisting of a range value, preferably 10-12%.

[0055] For example, the mass ratio of the cross-linked povidone, lactose and ethanol solution is 1g:2g:10ml, and the mass ratio of the cross-linked povidone, lactose and ethanol solution is 1g:3g:10ml, and the mass ratio of the cross-linked povidone, lactose and ethanol solution is 1g:2.5g:10ml.

[0056] In some embodiments, in step four, during the coating process, the inlet air temperature is set to 38-42℃, the material temperature is set to 33-38℃, the liquid spraying rate is set to 3-4 g / min, and the bottom spraying coating is performed to increase the weight by 15-20%.

[0057] For example, the inlet air temperature can be selected as 38℃, 42℃, 40℃ or any point value consisting of a range value, preferably 40-42℃.

[0058] For example, the material temperature can be selected as 38℃, 33℃, 35℃ or any point value consisting of a range value, preferably 35-38℃.

[0059] For example, the liquid spraying rate can be selected as 3 g / min, 4 g / min, 3.5 g / min.

[0060] In some embodiments, in step five, the mixing and melting is set to 80-85℃ and 200-300 rpm.

[0061] For example, the temperature during melting can be selected as 80℃, 82℃, 85℃ or any point value consisting of a range value, preferably 80-82℃.

[0062] For example, the stirring speed can be selected as 200 rpm, 260 rpm, 300 rpm or any point value consisting of a range value, preferably 260-300 rpm.

[0063] By adopting the technical scheme, the sustained-release effect of the sustained-release tablet can be further improved.

[0064] In order to better illustrate the technical scheme of the present application, the following examples are provided, and it should be understood that, unless otherwise specified, the raw materials described in the examples of the present application are all commercially available raw materials.

[0065] Example 1 A hypoglycemic pharmaceutical composition comprises empagliflozin 6 parts, cinnamon extract 35 parts, metformin 600 parts, microcrystalline cellulose 65 parts, cross-linked povidone 10 parts, HPMC K100M 120 parts, ethyl cellulose 55 parts, Eudragit FS30D 45 parts, soybean phospholipid 45 parts, and poloxamer 188 18 parts.

[0066] The process for preparing the hypoglycemic sustained-release tablet from the above pharmaceutical composition is as follows: The cinnamon extract, soybean phospholipid, and poloxamer 188 are stirred to complete dissolution under the condition of a 50℃ water bath, an ethanol-water mixed solvent with a volume ratio of ethanol to water of 6:2 is added, and the particle size is controlled to 150nm by circulating treatment 3 times under a pressure of 800bar, and then the ethanol is removed by evaporation under the condition of 40℃ and a vacuum of -0.08 MPa to obtain a concentrated solution; 5% mannitol by mass fraction is added to the concentrated solution, pre-frozen for 2h at -40℃, and then freeze-dried at -20℃ under a vacuum degree of 0.1mbar for 50h to obtain a nanoparticle powder; Step three, the microcrystalline cellulose is granulated, 5% hydroxypropyl methyl cellulose aqueous solution (mass-volume ratio of nanoparticle powder to hydroxypropyl methyl cellulose aqueous solution is 1mg:20ml) in which the nanoparticle powder is dissolved is added, the inlet temperature is 45℃, the atomization pressure is 1.0-bar, and the liquid spraying rate is 5mL / min, bottom spray coating is performed to an increase of 30%, and a drug-loaded pellet core is obtained; then cross-linked povidone and lactose are dissolved in an ethanol solution with a mass fraction of 10%, and uniformly sprayed on the surface of the drug-loaded pellet core to form a fast-release pellet core; the mass ratio of cross-linked povidone, lactose, and ethanol solution is 1g:2g:10ml; Step four, Eudragit FS30D and triethyl citrate are dispersed in pure water to form a coating liquid, and the pellet core is coated, the inlet temperature is set to 38℃, the material temperature is set to 33℃, the liquid spraying rate is set to 3g / min, and bottom spray coating is performed to an increase of 15% to obtain an enteric-coated pellet; wherein the mass-volume ratio of Eudragit FS30D to pure water is 1mg:30ml.

[0067] Step five, the metformin, hydroxypropyl methyl cellulose and ethyl cellulose are put into a double screw hot melt extruder, mixed and melted at 80 °C and 200 rpm to form a matrix; the enteric coated pellets are put into a centrifugal granulator, and the melted sustained release matrix is uniformly coated on the surface of the pellets, immediately pass in 4 °C cold air to solidify for 10 min to form a sustained release layer with a thickness of 150 μm, and obtain sustained release enteric coated pellets; Step six, the enteric coated sustained release pellets are put into a V-type mixer with 0.5% magnesium stearate (w / w) at a rotation speed of 20 rpm for 10 min, and a rotary tablet press is used to press the tablet cores with a 10 mm circular punch under a pressure of 8 kN to control the hardness in the range of 8-10 kp, and the tablet cores are put into a coating pan to spray 3% Opadry® II (85F series) water dispersion. The inlet air temperature is set to 50 °C, the tablet bed temperature is set to 38 °C, the spraying rate is set to 15 g / min, and the coating is performed until the weight gain is 3%.

[0068] Example 2 A hypoglycemic pharmaceutical composition includes empagliflozin 5 parts, cinnamon extract 30 parts, metformin 500 parts, microcrystalline cellulose 60 parts, cross-linked povidone 15 parts, HPMC K100M 100 parts, ethyl cellulose 50 parts, Eudragit FS30D 40 parts, soybean phospholipid 40 parts, and poloxamer 188 10 parts.

[0069] The process of preparing the hypoglycemic sustained release tablets from the above pharmaceutical composition is as follows: The cinnamon extract, soybean phospholipid and poloxamer 188 are stirred to complete dissolution under the condition of 55 °C water bath, and then an ethanol-water mixed solvent with a volume ratio of ethanol to water of 10:5 is added, and the particle size is controlled to 250 nm after 5 times of circulation treatment under a pressure of 1000 bar. Then, the ethanol is evaporated under the condition of 45 °C and -0.06 MPa vacuum to obtain a concentrated solution. Then, 5% mannitol by mass fraction is added to the concentrated solution, pre-frozen for 3 h at -50 °C, and then freeze-dried for 50 h under the condition of -30 °C and 0.3 mbar vacuum to obtain a nanoparticle powder; Step three, the microcrystalline cellulose is granulated, and a 5% hydroxypropyl methyl cellulose aqueous solution in which the nanoparticle powder is dissolved (the mass-volume ratio of the nanoparticle powder to the hydroxypropyl methyl cellulose aqueous solution is 1 mg:20 ml) is added, the inlet air temperature is 50 °C, the atomization pressure is 1.2 bar, and the liquid spraying rate is 8 mL / min, and the bottom spraying coating is performed until the weight gain is 40% to obtain a drug-loaded pellet core. Then, the cross-linked povidone and lactose are dissolved in an ethanol solution with a mass fraction of 15%, and uniformly sprayed on the surface of the drug-loaded pellet core to form a immediate release pellet core; the mass ratio of the cross-linked povidone, lactose and ethanol solution is 1 g:3 g:10 ml; Step four, disperse Eudragit FS30D and triethyl citrate in pure water to form a coating liquid, and coat the pellet core, set the inlet air temperature to 42°C, the material temperature to 38°C, the liquid spray rate to 4 g / min, and perform bottom spray coating to a weight gain of 20% to obtain enteric-coated pellets; wherein the mass-volume ratio of Eudragit FS30D to pure water is 1 mg:30 ml.

[0070] Step five, put metformin, hydroxypropyl methylcellulose, and ethyl cellulose into a double-screw hot melt extruder, mix and melt at 85°C and 300 rpm to form a matrix; put the enteric-coated pellets into a centrifugal granulator, uniformly coat the molten sustained-release matrix on the surface of the pellets, immediately pass in 4°C cold air to solidify for 10 min to form a sustained-release layer with a thickness of 170 μm, and obtain sustained-release enteric-coated pellets; Step six, put the enteric-coated sustained-release pellets and 0.5% magnesium stearate (w / w) into a V-type mixer, mix at a speed of 20 rpm for 10 min, use a rotary tablet press, use a 10 mm circular punch, press the tablet core under a pressure of 10 kN to form a tablet core with a weight of 1000 mg, control the hardness in the range of 8-10 kp, put the tablet core into a coating pan, and spray 3% Opadry® II (85F series) water dispersion. Set the inlet air temperature to 50°C, the tablet bed temperature to 38°C, and the spray rate to 15 g / min, and coat to a weight gain of 3%.

[0071] Example 3 A hypoglycemic pharmaceutical composition, the pharmaceutical composition comprising the following components by weight: empagliflozin 7 parts, cinnamon extract 40 parts, metformin 700 parts, microcrystalline cellulose 80 parts, cross-linked povidone 12 parts, HPMC K100M 110 parts, ethyl cellulose 50 parts, Eudragit FS30D 50 parts, soybean phospholipid 50 parts, and poloxamer 188 20 parts.

[0072] The process of preparing a hypoglycemic sustained-release tablet from the above pharmaceutical composition is as follows: Stir the cinnamon extract, soybean phospholipid, and poloxamer 188 under the condition of a 52°C water bath until completely dissolved, add an ethanol-water mixed solvent with a volume ratio of ethanol to water of 7:3, and cycle under a pressure of 800-1000 bar for 4 times to control the particle size to 200 nm. Then, evaporate the ethanol under the condition of 42°C and -0.07 MPa vacuum to obtain a concentrated solution. Add mannitol with a final mass fraction of 5% to the concentrated solution, pre-freeze at -45°C for 2.5 h, and then freeze-dry at -25°C under a vacuum degree of 0.2 mbar for 45 h to obtain nanoparticle powder. Step three, the microcrystalline cellulose is granulated, and a 5% (mass fraction) hydroxypropyl methyl cellulose aqueous solution in which the nanoparticle powder is dissolved is added (the mass-volume ratio of the nanoparticle powder to the hydroxypropyl methyl cellulose aqueous solution is 1 mg:20 ml), the inlet air temperature is 48°C, the atomization pressure is 1.1 bar, the liquid spraying rate is 7 mL / min, bottom spraying coating is performed until the weight gain is 35%, and a drug-loaded pellet core is obtained; then cross-linked povidone and lactose are dissolved in a 12% (mass fraction) ethanol solution, and the drug-loaded pellet core is uniformly sprayed on the surface to form a rapid-release pellet core; the mass ratio of the cross-linked povidone, lactose, and the ethanol solution is 1 g:2.5 g:10 ml; Step four, Eudragit FS30D and triethyl citrate are dispersed in pure water to form a coating liquid, and the pellet core is coated, the inlet air temperature is set to 40°C, the material temperature is 35°C, the liquid spraying rate is 3.5 g / min, and bottom spraying coating is performed until the weight gain is 16%, and an enteric-coated pellet is obtained; wherein the mass-volume ratio of Eudragit FS30D to pure water is 1 mg:30 ml.

[0073] Step five, metformin, hydroxypropyl methyl cellulose, and ethyl cellulose are put into a double-screw hot melt extruder, mixed and melted at 83°C and 260 rpm to form a matrix; the enteric-coated pellet is put into a centrifugal granulator, and the molten sustained-release matrix is uniformly coated on the surface of the pellet, and immediately cooled for 10 min by blowing 4°C cold air to form a sustained-release layer with a thickness of 130 μm, and a sustained-release enteric-coated pellet is obtained; Step six, the enteric-sustained-release pellet and 0.5% magnesium stearate (w / w) are put into a V-type mixer and mixed at a speed of 20 rpm for 10 min, a rotary tablet press is used, a 10 mm circular punch is used, and the tablet core is pressed under a pressure of 9 kN to form a tablet core with a weight of 1000 mg, the hardness is controlled in the range of 8-10 kp, the tablet core is put into a coating pan, and 3% Opadry® II (85F series) water dispersion is sprayed. The inlet air temperature is set to 50°C, the tablet bed temperature is 38°C, the spraying rate is 15 g / min, and the coating is performed until the weight gain is 3%.

[0074] Comparative Example 1 For example, compared with Example 1, the difference lies in that the cinnamon extract is removed, and the cinnamon extract is replaced with an equal amount of empagliflozin and metformin, the weight fraction of empagliflozin is increased to 21 parts, and the weight of metformin is increased to 620 parts, and the rest of the components and the preparation process remain unchanged.

[0075] Comparative Example 2 For example, compared with Example 1, the difference lies in that the empagliflozin is removed, and the empagliflozin is replaced with an equal amount of cinnamon extract and metformin, the weight fraction of the cinnamon extract is increased to 38 parts, and the weight of metformin is increased to 603 parts, and the rest of the components and the preparation process remain unchanged.

[0076] Comparative Example 3 Example 1 as an example, compared with Example 1, the difference is that metformin is removed, and the metformin is replaced with an equal amount of cinnamon extract and empagliflozin, the weight of the cinnamon extract is increased to 335 parts, and the weight of the empagliflozin is increased to 306 parts, and the rest of the components and the preparation process remain unchanged.

[0077] Comparative Example 4 Example 1 as an example, compared with Example 1, the difference is that the preparation process is changed: Preparation of excipients: the empagliflozin raw material is crushed and sieved to 80 mesh using a crusher, and the metformin is sieved to 40 mesh, respectively; Premixing: the metformin hydrochloride, empagliflozin, microcrystalline cellulose HPMC K100M, ethyl cellulose, Eudragit FS30D, soybean phospholipid, and poloxamer 188 are placed in a column hopper mixer and mixed at a speed of 8 r / min for 10 min to obtain the raw material; Fluidized bed granulation: Preparation of granulation liquid: copolymerone is dissolved in purified water to obtain a copolymerone solution with a concentration of 21.2% (w / w), and then the raw material is slowly added and uniformly dispersed by stirring to obtain a drug-containing granulation liquid, which is placed in a fluidized bed. The inlet air temperature is set to 70-80°C, and the frequency of the air blower is set to 20Hz. When the material temperature rises above 45°C, granulation is started, and the tablets are pressed using a rotary tablet press, with the pressure controlled at 3.0KN-6.0KN; Coating: a coating liquid with a solid content of 13% (w / w) is prepared, and the coating weight gain is controlled at 2.0%-5.0%.

[0078] Performance test I. Evaluation of sustained-release (in vitro dissolution test) Experimental process Instruments and reagents: intelligent dissolution instrument (model RCZ-8A), high performance liquid chromatograph (model Agilent 1260); 0.1 mol / L hydrochloric acid (simulated gastric juice), pH 6.8 phosphate buffer (simulated intestinal juice); empagliflozin reference substance (purity 99.2%), metformin reference substance (purity 99.0%), and cinnamaldehyde reference substance (purity 98.5%).

[0079] Sample treatment: 6 tablets of each of the preparations of Examples 1-3 and Comparative Examples 1-4 were placed in a dissolution cup, the paddle method was used, the rotation speed was 50 rpm, and the temperature was 37.0±0.5°C. The first 2 h used 0.1 mol / L hydrochloric acid 900 mL, and after 2 h, the pH 6.8 phosphate buffer 900 mL was replaced.

[0080] Sampling and detection: 5 mL was sampled at 0.5, 1, 2, 4, 6, 8, 12, 24 h, and an equal amount of medium was added at the same time. After filtration through a 0.45 μm filter membrane, the concentrations of empagliflozin, metformin and cinnamaldehyde were determined by high performance liquid chromatography, and the cumulative release rate was calculated.

[0081] The data results (cumulative release rate, %, n=6) are shown in Table 1. Table 1 Time (h) Environment Index Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 0.5 Gastric acid (pH 1.2) Metformin 18.5±1.2 19.2±1.3 17.8±1.1 20.1±1.4 21.3±1.5 - 35.6±2.3 0.5 Gastric acid (pH 1.2) Empagliflozin 5.2±0.4 5.5±0.5 5.0±0.3 8.6±0.7 - 42.3±2.1 28.5±1.8 0.5 Gastric acid (pH 1.2) Cinnamaldehyde 1.2±0.2 1.3±0.2 1.1±0.1 - 1.5±0.2 1.8±0.2 12.3±1.0 2 Gastric acid (pH 1.2) Metformin 32.6±1.5 33.8±1.7 31.9±1.4 35.2±1.8 36.5±1.9 - 68.5±3.2 2 Gastric acid (pH 1.2) Empagliflozin 12.5±0.8 13.2±0.9 12.1±0.7 20.3±1.2 - 65.8±2.5 45.6±2.1 2 Gastric acid (pH 1.2) Cinnamaldehyde 1.8±0.3 1.9±0.3 1.7±0.2 - 2.1±0.3 2.3±0.3 25.6±1.5 4 Intestine (pH 6.8) Metformin 45.2±2.0 46.5±2.1 44.8±1.9 48.3±2.3 49.6±2.4 - 78.2±3.5 4 Intestine (pH 6.8) Empagliflozin 25.3±1.3 26.1±1.4 24.9±1.2 35.6±1.8 - 78.5±2.8 62.3±2.5 4 Intestine (pH 6.8) Cinnamaldehyde 30.5±1.5 31.2±1.6 29.8±1.4 - 33.6±1.7 35.2±1.8 68.5±2.7 8 Intestine (pH 6.8) Metformin 62.3±2.2 63.5±2.3 61.7±2.1 65.8±2.5 67.2±2.6 - 88.6±3.2 8 Intestine (pH 6.8) Empagliflozin 48.6±2.0 49.8±2.1 47.9±1.9 58.5±2.3 - 89.2±3.0 75.8±2.8 8 Intestine (pH 6.8) Cinnamaldehyde 55.2±2.1 56.3±2.2 54.8±2.0 - 58.6±2.3 60.3±2.4 82.4±3.0 12 Intestine (pH 6.8) Metformin 78.5±2.5 79.6±2.6 77.8±2.4 82.3±2.7 83.5±2.8 - 93.2±3.5 12 Intestine (pH 6.8) Empagliflozin 68.2±2.3 69.3±2.4 67.5±2.2 75.6±2.6 - 95.8±3.2 85.6±3.0 12 Intestine (pH 6.8) Cinnamaldehyde 76.3±2.4 77.5±2.5 75.8±2.3 - 79.2±2.6 81.5±2.7 90.3±3.2 24 Intestine (pH 6.8) Metformin 90.2±2.8 91.3±2.9 89.5±2.7 93.6±3.0 94.8±3.1 - 98.5±3.6 24 Intestine (pH 6.8) Empagliflozin 85.3±2.6 86.5±2.7 84.6±2.5 90.2±2.9 - 98.6±3.3 93.5±3.2 24 Intestine (pH 6.8) Cinnamaldehyde 88.6±2.7 89.8±2.8 87.9±2.6 - 92.3±2.9 94.5±3.0 96.8±3.4 II. Evaluation of kidney protection (diabetic rat model) Experimental process Animal model: SPF level SD male rats weighing 200±20 g were selected and randomly divided into a normal group, a model group, Example 1-3 groups and Comparative Example 1-4 groups, 10 rats in each group. The model group and each drug group were intraperitoneally injected with 60 mg / kg of STZ (dissolved in 0.1 mol / L citric acid buffer), and 72 h later, tail blood glucose≥11.1 mmol / L was considered as successful modeling.

[0082] Dosing: The normal group and the model group were given physiological saline by gavage, and each drug group was given the clinical equivalent dose of 6.3 times the adult dose by gavage once a day for 6 consecutive weeks.

[0083] Detection index: At the end of 6 weeks, serum was collected, and creatinine (Scr) was measured by a creatinine detection kit, and urea nitrogen (BUN) was measured by a urea nitrogen detection kit; 24-hour urine was collected, and urinary microalbumin (mAlb) was measured by a urinary microalbumin detection kit; kidney tissue was taken for HE staining, and pathological scoring was performed according to 0-4 points (0 points for normal and 4 points for severe injury).

[0084] The data results (x±s, n=10) are shown in Table 2. Table 2 Index Normal group Model group Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Scr (μmol / L) 58.2±4.1 135.6±8.2 72.5±5.3 75.1±5.6 71.8±5.2 98.3±6.7 102.5±7.1 120.3±8.5 95.6±6.5 BUN (mmol / L) 6.3±0.5 21.5±1.8 8.9±0.7 9.2±0.8 8.7±0.6 14.2±1.2 15.1±1.3 19.8±1.6 13.8±1.1 mAlb (mg / 24h) 12.5±1.3 85.6±6.2 25.3±2.1 26.8±2.3 24.9±2.0 52.6±3.8 55.2±4.1 78.5±5.6 49.8±3.6 Kidney pathological score 0.2±0.1 3.5±0.3 1.1±0.2 1.2±0.2 1.0±0.1 2.3±0.3 2.5±0.3 3.2±0.2 2.2±0.2 III. Evaluation of islet cell protection (diabetic rat model) Experimental process Animals and models: The same grouping, modeling and dosing period as in the kidney protection experiment.

[0085] Detection index: At the end of 6 weeks, serum was collected, and insulin level was measured by an insulin ELISA kit; pancreatic tissue was taken to make paraffin sections, and immunohistochemical staining (using insulin antibody) was performed, and the relative area of islet beta cells (insulin positive area / total islet area) was calculated by Image-Pro Plus software; the apoptosis rate of islet cells was detected by TUNEL method.

[0086] The data results (x±s, n=10) are shown in Table 3.

[0087] Table 3 Index Normal group Model group Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Serum insulin (mU / L) 25.6±2.1 8.2±0.7 18.5±1.5 17.9±1.4 19.2±1.6 12.3±1.1 11.8±1.0 9.5±0.8 11.5±1.0 Islet β cell relative area (%) 85.3±4.2 32.6±3.1 68.5±3.5 66.2±3.3 70.1±3.6 45.2±3.0 43.8±2.9 35.6±2.8 42.5±2.7 Islet cell apoptosis rate (%) 2.1±0.3 35.8±2.6 12.5±1.2 13.2±1.3 11.9±1.1 22.6±1.8 24.1±1.9 32.5±2.3 21.8±1.7 IV. Evaluation of gastrointestinal irritation (normal rat model) Experimental procedure Animals: SPF grade SD male rats weighing 200 ± 20 g were selected and randomly divided into normal group, Example 1-3 groups, Comparative Example 1-4 groups, 8 rats in each group, fasting for 12 h (not water restriction).

[0088] Dosing: The normal group was given physiological saline by gavage, and each drug group was given 2 times of the clinical equivalent dose by gavage, once a day, for 7 consecutive days.

[0089] Detection index: After the animals were sacrificed, the stomach, duodenum and jejunum were taken to observe the mucosal injury and score according to 0-4 (0 normal, 1 mild congestion, 2 congestion + erosion, 3 multiple erosion, 4 ulcer); the IL-1β level of gastric mucosa was measured by IL-1β ELISA kit.

[0090] Data results (x ± s, n = 8) are shown in Table 4.

[0091] Table 4 Index Normal group Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Gastric mucosa injury score 0.1±0.1 0.3±0.1 0.4±0.1 0.3±0.1 1.2±0.2 1.1±0.2 1.3±0.2 1.5±0.3 Duodenum injury score 0.2±0.1 0.4±0.1 0.5±0.1 0.4±0.1 1.5±0.3 1.4±0.2 1.6±0.3 1.8±0.3 Jejunum injury score 0.1±0.1 0.3±0.1 0.3±0.1 0.2±0.1 1.0±0.2 0.9±0.2 1.1±0.2 1.3±0.2 Gastric mucosa IL-1β (pg / mL) 35.2±3.1 42.5±3.5 43.8±3.7 41.9±3.4 78.6±5.2 75.3±4.9 82.5±5.6 85.2±5.8 The various embodiments in the specification are described in a progressive manner, and each embodiment focuses on the difference from other embodiments. The same or similar parts between the various embodiments can be referred to each other. The above description of the disclosed embodiments enables a person skilled in the art to implement or use the present application. Various modifications to the embodiments will be apparent to those skilled in the art, and the general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present application. Therefore, the present application will not be limited to these embodiments shown herein, but will conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A hypoglycemic pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the following components in parts by weight: 5-7 parts empagliflozin, 30-40 parts cinnamon extract, 500-700 parts metformin, 60-80 parts microcrystalline cellulose, 10-15 parts crospovidone, 100-120 parts HPMC K100M, 50-60 parts ethyl cellulose, 40-50 parts Eudragit FS30D, 40-50 parts soybean lecithin, and 10-20 parts poloxamer 188.

2. The hypoglycemic pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition comprises the following components in the following optimal weight parts: 6 parts empagliflozin, 35 parts cinnamon extract, 600 parts metformin, 65 parts microcrystalline cellulose, 10 parts crospovidone, 120 parts HPMC K100M, 55 parts ethyl cellulose, 45 parts Eudragit FS30D, 45 parts soybean lecithin, and 18 parts poloxamer 188.

3. The use of the pharmaceutical composition according to any one of claims 1 to 2 in the preparation of hypoglycemic sustained-release tablets.

4. A method for preparing a hypoglycemic sustained-release tablet, characterized in that, The preparation process is as follows: Step 1: Weigh each component according to the proportions of the pharmaceutical composition according to any one of claims 1 to 2; Step 2: Mix cinnamon extract, soybean lecithin and poloxamer 188, add ethanol-water mixed solvent, homogenize under high pressure, rotary evaporate and freeze dry to obtain nanoparticle powder. Step 3: Granulate microcrystalline cellulose, add an aqueous solution of hydroxypropyl methylcellulose nanoparticle powder, and coat the granules to obtain drug-loaded pellet cores; then dissolve cross-linked polyvinylpyrrolidone and lactose in an ethanol solution and spray them evenly onto the surface of the drug-loaded pellet cores to form immediate-release pellet cores. Step 4: Disperse Eudragit FS30D and triethyl citrate in pure water to form a coating solution, and then coat the pellet core to obtain enteric-coated microspheres. Step 5: Metformin, hydroxypropyl methylcellulose and ethylcellulose are mixed and melted to form a matrix; then the molten sustained-release matrix is ​​uniformly coated on the surface of the enteric-coated microspheres to form sustained-release enteric-coated microspheres; Step 6: Mix the sustained-release enteric-coated microcapsules with magnesium stearate, compress them into tablets, and coat them to obtain the hypoglycemic sustained-release tablets.

5. The method for preparing a hypoglycemic sustained-release tablet according to claim 4, characterized in that, In step two, the mixing is performed by stirring in a water bath at 50-55°C until completely dissolved; and / or, In an ethanol-water mixed solvent, the volume ratio of ethanol to water is 6-10:2-5; and / or, The high-pressure homogenization involves cyclic treatment at 800-1000 bar pressure for 3-5 cycles, controlling the particle size to 200±50 nm; and / or, The rotary evaporation is performed by removing ethanol at 40-45°C and a vacuum of -0.08 to -0.06 MPa to obtain a concentrated solution; and / or, The freeze-drying process involves adding 5% mannitol to the concentrate, pre-freezing at -40 to -50°C for 2 to 3 hours, and then freeze-drying at -20 to -30°C and a vacuum of 0.1 to 0.3 mbar for 40 to 50 hours.

6. The method for preparing a hypoglycemic sustained-release tablet according to claim 5, characterized in that, In step three, during the coating process, the inlet air temperature is set to 45-50℃, the atomization pressure to 1.0-1.2 bar, and the spray rate to 5-8 mL / min, and bottom spray coating is performed until the weight gain is 30-40%; and / or, The ethanol solution has a mass fraction of 10-15%, and the mass ratio of crospovidone, lactose and ethanol solution is 1g:2-3g:10ml.

7. The method for preparing a hypoglycemic sustained-release tablet according to claim 5, characterized in that, In step four, during the coating process, the inlet air temperature is set to 38-42℃, the material temperature to 33-38℃, and the spraying rate to 3-4 g / min, and bottom spray coating is performed to achieve a weight gain of 15-20%.

8. The method for preparing a hypoglycemic sustained-release tablet according to claim 5, characterized in that, In step five, the mixing and melting process is set to 80-85℃ and 200-300 rpm.