Metformin hydrochloride sustained release tablet and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, relates to a metformin hydrochloride sustained-release tablet and a preparation method thereof, and aims to overcome the technical defects of insufficient release behavior regulation and control precision and poor stability of an existing metformin hydrochloride sustained-release preparation. The metformin hydrochloride sustained-release tablet disclosed by the invention takes metformin hydrochloride as an effective component, is matched with sustained-release materials including hydroxypropyl methyl cellulose, propylene carbonate, zein, a filling agent, an adhesive and a lubricating agent, and can be selectively matched with a gastric-soluble film coating material. According to the invention, the stable release of the medicine is realized, the initial burst release phenomenon is avoided, meanwhile, the stability of the preparation is remarkably improved, and the good slow release performance can still be maintained after long-term storage.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a metformin hydrochloride sustained-release tablet and a preparation method thereof. BACKGROUND

[0002] As a first-line drug for treating type 2 diabetes, metformin hydrochloride has a clear mechanism of action, mainly reduces blood glucose through the pathways of inhibiting the production and release of glucose in the liver, reducing the absorption of glucose in the intestinal tract, and improving the sensitivity of peripheral tissues to insulin, and does not cause weight gain. When used alone, the risk of hypoglycemia is extremely low, and it has been widely used in clinical practice. However, the ordinary dosage form of metformin hydrochloride has obvious limitations: the drug is rapidly absorbed in the gastrointestinal tract after oral administration, and has a short half-life. The conventional dosing regimen requires 3 times per day, and the compliance of patients is poor when long-term medication is used. At the same time, the blood drug concentration fluctuates greatly, and gastrointestinal adverse reactions such as nausea, vomiting and diarrhea are easily induced at the peak concentration, and the effective hypoglycemic concentration may not be maintained at the trough concentration, affecting the therapeutic effect.

[0003] To solve the above-mentioned defects of the ordinary dosage form, researchers have developed metformin hydrochloride sustained-release preparations, the core goal of which is to achieve slow release of the drug, prolong the action time, and stabilize the blood drug concentration. The currently disclosed metformin hydrochloride sustained-release preparations mainly include the following types: matrix type, membrane-controlled type, osmotic pump type, etc.

[0004] A metformin hydrochloride sustained-release tablet is disclosed in Chinese Patent Publication No. CN103816130A, which contains the following ingredients by weight: metformin hydrochloride 400-600 parts, sodium carboxymethyl cellulose 30-60 parts, hydroxypropyl methyl cellulose 200-250 parts, ethyl acrylate-methyl methacrylate copolymer aqueous dispersion 180-220 parts, and magnesium stearate 5-10 parts. Chinese Patent Publication No. CN112972411A discloses a metformin hydrochloride multi-unit sustained-release tablet composition, which contains a simple pill core, a coating layer and a filler. The simple pill core contains metformin hydrochloride, D-trehalose and hydroxypropyl cellulose. The coating layer contains D-trehalose, ethyl cellulose and magnesium stearate. The filler contains microcrystalline cellulose. Chinese Patent Publication No. CN113679686A discloses a metformin hydrochloride sustained-release tablet, which adopts a structure design of a core layer, an intermediate layer and an outer layer. When the sustained-release tablet is put into an aqueous medium, the aqueous medium slowly enters the intermediate layer, and the outer layer hinders the early release of the drug in the intermediate layer. The sodium chloride, tartaric acid and glyceryl behenate in the intermediate layer promote the transfer of the aqueous medium to the core layer. After the core layer contacts with the aqueous medium, it slowly swells to push the release of the drug, so that the intermediate layer is slowly released under the dual and bidirectional pressure of the core layer and the outer layer.

[0005] However, the existing metformin hydrochloride sustained-release preparations still have many technical problems: first, the release behavior regulation precision of some sustained-release preparations is insufficient, there is an initial "burst release" phenomenon, which leads to rapid increase of blood drug concentration and high incidence of gastrointestinal adverse reactions; or the release rate is too slow in the later stage, the blood drug concentration is lower than the therapeutic window, and the blood glucose cannot be effectively controlled. Second, the compatibility of some sustained-release materials is poor, and after long-term storage, problems such as aging of the skeleton structure and crystallization of the drug are prone to occur, which leads to attenuation of the sustained-release performance and poor product stability.

[0006] Based on the above technical deficiencies of the prior art, it is of important clinical value and market significance to develop a metformin hydrochloride sustained-release tablet with stable release behavior and high stability, which can improve patient medication compliance and enhance therapeutic effect, and has become a technical problem to be solved in the field. SUMMARY

[0007] The present application aims to overcome the technical defects of the existing metformin hydrochloride sustained-release preparations, such as insufficient release behavior regulation precision and poor stability, and provides a metformin hydrochloride sustained-release tablet with stable release and excellent stability, as well as a preparation method thereof, to ensure sustained and effective hypoglycemic effect and improve patient medication compliance.

[0008] Specifically, the technical solutions of the present application are as follows: Formulation of metformin hydrochloride sustained-release tablet The metformin hydrochloride sustained-release tablet comprises the following components by weight: Active ingredient: metformin hydrochloride 500 parts; sustained-release material: 45-90 parts, specifically hydroxypropyl methylcellulose 30-60 parts, propylene carbonate 10-20 parts, and corn protein 5-10 parts; filler: 40-100 parts, selected from at least one of microcrystalline cellulose, lactose, calcium hydrogen phosphate, mannitol, starch, and dextrin; binding agent: 4-8 parts, selected from at least one of sodium carboxymethyl cellulose, gelatin, and povidone K30; lubricant: 0.5-2 parts, selected from at least one of magnesium stearate, microcrystalline silica, and sodium stearyl fumarate; optional component: film coating material 8-12 parts, which is a gastric soluble film coating premix.

[0009] Preparation method of metformin hydrochloride sustained-release tablet (1) Pretreatment of raw materials: grind, sieve and dry metformin hydrochloride; prepare a 5-12% (w / v) solution of the binding agent with purified water, and let it stand for defoaming; sieve the filler. (2) Preparation of sustained-release matrix: the hydroxypropyl methyl cellulose is treated by low-temperature plasma with a vacuum degree of 0.05 MPa, a power of 80 W, a time of 60 s, and argon and oxygen (4:1); the propylene carbonate and the corn protein are sheared and dispersed at 45 DEG C and 1500 r / min for 30 min to form a dispersion liquid; the treated hydroxypropyl methyl cellulose is stirred with purified water to form a suspension, and the temperature is raised to 50 DEG C; the dispersion liquid is added dropwise at a rate of 5 mL / min, and stirring is carried out for 1 h; then, pre-freezing is carried out at -40 DEG C for 2 h, and vacuum sublimation drying is carried out for 12 h; and the sustained-release matrix is obtained by crushing and sieving.

[0010] (3) Wet mixing and granulation: the metformin hydrochloride, the sustained-release matrix, and the filler are dry-mixed, and then the binder is sprayed to granulate.

[0011] (4) Fluidized bed drying: the inlet air temperature is controlled at 45 DEG C, the outlet air temperature is controlled at 30 DEG C or less, the air speed is controlled at 1.2-1.5 m / s, and drying is carried out until the moisture content is 1.0%-1.5%.

[0012] (5) Granulation and total mixing: after granulation through a 16-mesh sieve, the lubricant is added and uniformly mixed.

[0013] (6) Tablet compression: the sustained-release tablets with a hardness of 4-6 kgf and a friability of 0.5% or less are obtained by compression.

[0014] Compared with the prior art, the technical effect of the present application is that: (1) The metformin hydrochloride sustained-release tablets have stable release behavior: through the synergistic effect of hydroxypropyl methyl cellulose, propylene carbonate, and corn protein and the specific treatment process, the initial burst release of the metformin hydrochloride sustained-release tablets is avoided, the 0.5 h cumulative release degree is only 14.7%-16.3%, and the 24 h cumulative release degree is 98.2%-99.1%.

[0015] (2) The metformin hydrochloride sustained-release tablets have excellent stability: after 6 months of accelerated testing (40 DEG C, RH 75%), the similarity factor (f2) of the release curve of the metformin hydrochloride sustained-release tablets of the present application and the initial sample is 88.0-91.5, which is much higher than the standard value (f2≥50). DETAILED DESCRIPTION

[0016] In order to make the purpose, technical scheme of the present application clearer, the present application is further explained below in combination with examples, but the protection scope of the present application is not limited to these examples, and the examples are only used to explain the present application. Those skilled in the art should understand that any change or equivalent replacement without departing from the concept of the present application is included in the protection scope of the present application.

[0017] Example 1: Metformin hydrochloride sustained-release tablets Formula: Preparation method: (1) The raw materials were pretreated: metformin hydrochloride was micronized through a 120-mesh sieve, vacuum dried at 60°C for 2 h (moisture ≤0.5%), and cooled for standby. The filler was passed through a 100-mesh sieve; the binder was prepared into a 10% (w / v) solution with purified water, stirred and dissolved, and then left to stand for 30 min to remove bubbles for standby.

[0018] (2) The sustained-release material was treated: hydroxypropyl methyl cellulose was laid on a low-temperature plasma treatment instrument, and the parameters were as follows: vacuum degree 0.05 MPa, power 80 W, time 60 s, and gas argon and oxygen (4:1). After treatment, it was sealed and stored; carbonic acid propyl ester was added to a high-speed shearing dispersion machine, and corn protein was added under stirring at 1500 r / min. The mixture was sheared and dispersed at 45°C for 30 min to form a dispersion liquid; the treated hydroxypropyl methyl cellulose was added to purified water, and a suspension was formed by stirring at 800 r / min. The temperature was raised to 50°C, and the dispersion liquid was added dropwise at a rate of 5 mL / min. The stirring was continued for 1 h, and then freeze-drying (pre-freezing at -40°C for 2 h, vacuum sublimation drying for 12 h) was performed. The product was passed through a 100-mesh sieve to obtain the sustained-release matrix, which was stored for standby.

[0019] (3) Wet mixing and granulation: metformin hydrochloride, sustained-release matrix, and filler were put into a wet mixing and granulating machine, and dry mixing was performed at 300 r / min for 10 min. The binder was sprayed under stirring at 600 r / min and shearing at 1500 r / min, and granulation was performed for 8-10 min.

[0020] (4) Fluidized bed drying: the inlet air temperature was 45°C, the outlet air temperature was ≤30°C, the air speed was 1.2-1.5 m / s, and the drying was performed until the moisture content was 1.0%-1.5%. The temperature was cooled to room temperature.

[0021] (5) Granulation and total mixing: 16-mesh sieve granulation, and 25 r / min mixing in a three-dimensional mixer for 15 min.

[0022] (6) Tabletting: hardness (4-6 kgf), and friability (≤0.5%).

[0023] Example 2: Metformin hydrochloride sustained-release tablets Formulation: Preparation method: (1) The raw materials were pretreated: metformin hydrochloride was micronized through a 120-mesh sieve, vacuum dried at 60°C for 2 h (moisture ≤0.5%), and cooled for standby. The filler was passed through a 100-mesh sieve; the binder was prepared into a 10% (w / v) solution with purified water, stirred and dissolved, and then left to stand for 30 min to remove bubbles for standby.

[0024] (2) Sustained-release material processing: Hydroxypropyl methylcellulose is laid on a low-temperature plasma treatment instrument, parameters: vacuum degree 0.05 MPa, power 80 W, time 60 s, gas argon and oxygen (4:1), after treatment, seal preservation; add propylene carbonate in a high-speed shearing disperser, add corn protein under 1500 r / min stirring, shear and disperse at 45°C for 30 min to form a dispersion liquid; add treated hydroxypropyl methylcellulose and purified water to form a suspension under 800 r / min stirring, heat to 50°C, add the dispersion liquid at 5 mL / min, continue to stir for 1 h, freeze-drying (pre-freezing at -40°C for 2 h, vacuum sublimation drying for 12 h), crush through a 100 mesh sieve, to obtain a sustained-release matrix, ready for use.

[0025] (3) Wet mixing granulation: Metformin hydrochloride, sustained-release matrix, and filler are put into a wet mixing granulator, dry mix at 300 r / min for 10 min; spray the binder under 600 r / min stirring and 1500 r / min cutter speed, granulate for 8-10 min.

[0026] (4) Fluidized bed drying: inlet air temperature 45°C, outlet air temperature ≤30°C, air speed 1.2-1.5 m / s, dry to moisture 1.0%-1.5%, cool to room temperature.

[0027] (5) Granulation and total mixing: 16 mesh sieve granulation, add lubricant in a three-dimensional mixer, mix at 25 r / min for 15 min.

[0028] (6) Tabletting: hardness (4-6 kgf), friability (≤0.5%).

[0029] Example 3 Metformin hydrochloride sustained-release tablets Formula: Preparation method: (1) Raw material pretreatment: Metformin hydrochloride is micronized through a 120 mesh sieve, vacuum dried at 60°C for 2 h (moisture ≤0.5%), and cooled for standby. The filler is passed through a 100 mesh sieve; the binder is prepared into a 12% (w / v) solution with purified water, stirred and dissolved, and then placed for 30 min to remove bubbles for standby.

[0030] (2) Treatment of sustained-release material: Hydroxypropyl methylcellulose was spread on a low-temperature plasma treatment instrument with the following parameters: vacuum degree 0.05MPa, power 80W, time 60s, and gas argon and oxygen (4:1). After treatment, it was sealed and stored. Propylene carbonate was added to a high-speed shear disperser, and corn gluten was added under stirring at 1500r / min. The dispersion was sheared and dispersed at 45℃ for 30min to form a dispersion. The treated hydroxypropyl methylcellulose was added to purified water and stirred at 800r / min to form a suspension. The temperature was raised to 50℃, and the dispersion was added dropwise at 5mL / min. The reaction was continued by stirring for 1h. The mixture was freeze-dried (pre-freezing at -40℃ for 2h, vacuum sublimation drying for 12h), pulverized and passed through a 100-mesh sieve to obtain the sustained-release matrix for later use.

[0031] (3) Wet mixing and granulation: Metformin hydrochloride, slow-release matrix and filler are put into a wet mixing granulator and dry-mixed at 300r / min for 10min; the binder is sprayed at 600r / min stirring and 1500r / min cutter speed and granulated for 8-10min.

[0032] (4) Fluidized bed drying: inlet air temperature 45℃, outlet air temperature ≤30℃, air velocity 1.2-1.5m / s, dry to moisture content 1.0%-1.5%, and cool to room temperature.

[0033] (5) Granulation and mixing: Granulate through a 16-mesh sieve, add lubricant in a three-dimensional mixer, and mix at 25 r / min for 15 min.

[0034] (6) Tableting: Hardness (4-6 kgf), brittleness (≤0.5%).

[0035] Example 4: Metformin Hydrochloride Extended-Release Coated Tablets Based on the metformin hydrochloride sustained-release tablets of Example 1, a film coating was performed: (1) Preparation of coating solution: Take 10g of gastric-soluble film coating premix, add 80mL of purified water, stir to dissolve and shear to disperse for 15min, let stand to degas for 20min, and obtain a uniform 11.1% (w / v) coating solution.

[0036] (2) Coating operation: Put the uncoated tablets into a high-efficiency coating machine, set the inlet air temperature to 60℃, the outlet air temperature to 35-40℃, the pot rotation speed to 30r / min, and the spraying rate to 3mL / min, and spray coating until the uncoated tablets gain 3%-4% of their weight.

[0037] (3) Drying and curing: After coating is completed, keep the air inlet temperature at 50℃ and the pot rotation speed at 20r / min, continue drying for 30min, and discharge the material after cooling to room temperature.

[0038] Release behavior: 16.1% cumulative release rate at 0.5h and 98.5% cumulative release rate at 24h, with no burst release phenomenon. Stability: After 6 months of accelerated testing (40℃, RH75%), the similarity factor (f2) between the release curve and the initial sample reached 89.2, with no cracking or peeling of the coating layer, and the sustained-release performance was stable.

[0039] Comparative Example 1: Metformin Hydrochloride Extended-Release Tablets formula: Preparation method: (1) Pretreatment of raw materials and auxiliary materials: Metformin hydrochloride was ultra-finely pulverized and passed through a 120-mesh sieve, vacuum dried at 60℃ for 2 hours (moisture content ≤0.5%), and cooled for later use. The filler was passed through a 100-mesh sieve; the binder was prepared into a 10% (w / v) solution with purified water, stirred to dissolve, and then allowed to stand for 30 minutes to remove bubbles for later use.

[0040] (2) Treatment of slow-release material: Add propylene carbonate to a high-speed shear disperser, add corn gluten while stirring at 1500 r / min, shear disperse at 45℃ for 30 min to form a dispersion, freeze dry (pre-freeze at -40℃ / 2h, vacuum sublimation drying for 12h), pulverize and pass through a 100-mesh sieve to obtain the slow-release matrix for later use.

[0041] (3) Wet mixing and granulation: Metformin hydrochloride, slow-release matrix and filler are put into a wet mixing granulator and dry-mixed at 300r / min for 10min; the binder is sprayed at 600r / min stirring and 1500r / min cutter speed and granulated for 8-10min.

[0042] (4) Fluidized bed drying: inlet air temperature 45℃, outlet air temperature ≤30℃, air velocity 1.2-1.5m / s, dry to moisture content 1.0%-1.5%, and cool to room temperature.

[0043] (5) Granulation and mixing: Granulate through a 16-mesh sieve, add lubricant in a three-dimensional mixer, and mix at 25 r / min for 15 min.

[0044] (6) Tableting: Hardness (4-6 kgf), brittleness (≤0.5%).

[0045] Comparative Example 2: Metformin Hydrochloride Extended-Release Tablets formula: Preparation method: (1) Pretreatment of raw materials and auxiliary materials: Metformin hydrochloride was ultra-finely pulverized and passed through a 120-mesh sieve, vacuum dried at 60℃ for 2 hours (moisture content ≤0.5%), and cooled for later use. The filler was passed through a 100-mesh sieve; the binder was prepared into a 10% (w / v) solution with purified water, stirred to dissolve, and then allowed to stand for 30 minutes to remove bubbles for later use.

[0046] (2) Treatment of sustained-release material: Hydroxypropyl methylcellulose was spread on a low-temperature plasma treatment instrument with the following parameters: vacuum degree 0.05MPa, power 80W, time 60s, and gas argon and oxygen (4:1). Purified water was added and the mixture was stirred at 800r / min to form a suspension. The temperature was raised to 50℃, corn gluten was added, and the mixture was stirred and reacted for 1h to form a suspension. The suspension was then freeze-dried (pre-freezing at -40℃ for 2h, followed by vacuum sublimation drying for 12h), pulverized, and passed through a 100-mesh sieve to obtain the sustained-release matrix for later use.

[0047] (3) Wet mixing and granulation: Metformin hydrochloride, slow-release matrix and filler are put into a wet mixing granulator and dry-mixed at 300r / min for 10min; the binder is sprayed at 600r / min stirring and 1500r / min cutter speed and granulated for 8-10min.

[0048] (4) Fluidized bed drying: inlet air temperature 45℃, outlet air temperature ≤30℃, air velocity 1.2-1.5m / s, dry to moisture content 1.0%-1.5%, and cool to room temperature.

[0049] (5) Granulation and mixing: Granulate through a 16-mesh sieve, add lubricant in a three-dimensional mixer, and mix at 25 r / min for 15 min.

[0050] (6) Tableting: Hardness (4-6 kgf), brittleness (≤0.5%).

[0051] Comparative Example 3: Metformin Hydrochloride Extended-Release Tablets formula: Preparation method: (1) Pretreatment of raw materials and auxiliary materials: Metformin hydrochloride was ultra-finely pulverized and passed through a 120-mesh sieve, vacuum dried at 60℃ for 2 hours (moisture content ≤0.5%), and cooled for later use. The filler was passed through a 100-mesh sieve; the binder was prepared into a 10% (w / v) solution with purified water, stirred to dissolve, and then allowed to stand for 30 minutes to remove bubbles for later use.

[0052] (2) Treatment of sustained-release material: Hydroxypropyl methylcellulose was spread on a low-temperature plasma treatment instrument with the following parameters: vacuum degree 0.05MPa, power 80W, time 60s, and gas argon and oxygen (4:1). Purified water was added and the mixture was stirred at 800r / min to form a suspension. The temperature was raised to 50℃, propylene carbonate was added, and the mixture was stirred for 1h. The mixture was then freeze-dried (pre-freezing at -40℃ for 2h, followed by vacuum sublimation drying for 12h), pulverized, and passed through a 100-mesh sieve to obtain the sustained-release matrix for later use.

[0053] (3) Wet mixing and granulation: Metformin hydrochloride, slow-release matrix and filler are put into a wet mixing granulator and dry-mixed at 300r / min for 10min; the binder is sprayed at 600r / min stirring and 1500r / min cutter speed and granulated for 8-10min.

[0054] (4) Fluidized bed drying: inlet air temperature 45℃, outlet air temperature ≤30℃, air velocity 1.2-1.5m / s, dry to moisture content 1.0%-1.5%, and cool to room temperature.

[0055] (5) Granulation and mixing: Granulate through a 16-mesh sieve, add lubricant in a three-dimensional mixer, and mix at 25 r / min for 15 min.

[0056] (6) Tableting: Hardness (4-6 kgf), brittleness (≤0.5%).

[0057] Comparative Example 4: Metformin Hydrochloride Extended-Release Tablets formula: Preparation method: (1) Pretreatment of raw materials and auxiliary materials: Metformin hydrochloride was ultra-finely pulverized and passed through a 120-mesh sieve, vacuum dried at 60℃ for 2 hours (moisture content ≤0.5%), and cooled for later use. The filler was passed through a 100-mesh sieve; the binder was prepared into a 10% (w / v) solution with purified water, stirred to dissolve, and then allowed to stand for 30 minutes to remove bubbles for later use.

[0058] (2) Treatment of sustained-release material: Methylcellulose was spread on a low-temperature plasma treatment instrument with the following parameters: vacuum degree 0.05MPa, power 80W, time 60s, and gas argon and oxygen (4:1). After treatment, it was sealed and stored. Propylene carbonate was added to a high-speed shear disperser, and corn gluten was added under stirring at 1500r / min. The mixture was sheared and dispersed at 45℃ for 30min to form a dispersion. The treated methylcellulose was added to purified water and stirred at 800r / min to form a suspension. The temperature was raised to 50℃, and the dispersion was added dropwise at 5mL / min. The reaction was continued by stirring for 1h. The mixture was freeze-dried (pre-freezing at -40℃ for 2h, vacuum sublimation drying for 12h), pulverized and passed through a 100-mesh sieve to obtain the sustained-release matrix for later use.

[0059] (3) Wet mixing and granulation: Metformin hydrochloride, slow-release matrix and filler are put into a wet mixing granulator and dry-mixed at 300r / min for 10min; the binder is sprayed at 600r / min stirring and 1500r / min cutter speed and granulated for 8-10min.

[0060] (4) Fluidized bed drying: inlet air temperature 45℃, outlet air temperature ≤30℃, air velocity 1.2-1.5m / s, dry to moisture content 1.0%-1.5%, and cool to room temperature.

[0061] (5) Granulation and mixing: Granulate through a 16-mesh sieve, add lubricant in a three-dimensional mixer, and mix at 25 r / min for 15 min.

[0062] (6) Tableting: Hardness (4-6 kgf), brittleness (≤0.5%).

[0063] Comparative Example 5: Metformin Hydrochloride Extended-Release Tablets formula: Preparation method: (1) Pretreatment of raw materials and auxiliary materials: Metformin hydrochloride was ultra-finely pulverized and passed through a 120-mesh sieve, vacuum dried at 60℃ for 2 hours (moisture content ≤0.5%), and cooled for later use. The filler was passed through a 100-mesh sieve; the binder was prepared into a 10% (w / v) solution with purified water, stirred to dissolve, and then allowed to stand for 30 minutes to remove bubbles for later use.

[0064] (2) Treatment of sustained-release material: Hydroxypropyl methylcellulose was spread on a low-temperature plasma treatment instrument with the following parameters: vacuum degree 0.05MPa, power 80W, time 60s, and gas argon and oxygen (4:1). After treatment, it was sealed and stored. Propylene glycol was added to a high-speed shear disperser, and corn gluten was added under stirring at 1500r / min. The mixture was sheared and dispersed at 45℃ for 30min. The treated hydroxypropyl methylcellulose was added to purified water and stirred at 800r / min to form a suspension. The temperature was raised to 50℃, and the dispersion was added dropwise at 5mL / min. The reaction was continued by stirring for 1h. The mixture was freeze-dried (pre-freezing at -40℃ for 2h, vacuum sublimation drying for 12h), pulverized and passed through a 100-mesh sieve to obtain the sustained-release matrix for later use.

[0065] (3) Wet mixing and granulation: Metformin hydrochloride, slow-release matrix and filler are put into a wet mixing granulator and dry-mixed at 300r / min for 10min; the binder is sprayed at 600r / min stirring and 1500r / min cutter speed and granulated for 8-10min.

[0066] (4) Fluidized bed drying: inlet air temperature 45℃, outlet air temperature ≤30℃, air velocity 1.2-1.5m / s, dry to moisture content 1.0%-1.5%, and cool to room temperature.

[0067] (5) Granulation and mixing: Granulate through a 16-mesh sieve, add lubricant in a three-dimensional mixer, and mix at 25 r / min for 15 min.

[0068] (6) Tableting: Hardness (4-6 kgf), brittleness (≤0.5%).

[0069] Comparative Example 6: Metformin Hydrochloride Extended-Release Tablets formula: Preparation method: (1) Pretreatment of raw materials and auxiliary materials: Metformin hydrochloride was ultra-finely pulverized and passed through a 120-mesh sieve, vacuum dried at 60℃ for 2 hours (moisture content ≤0.5%), and cooled for later use. The filler was passed through a 100-mesh sieve; the binder was prepared into a 10% (w / v) solution with purified water, stirred to dissolve, and then allowed to stand for 30 minutes to remove bubbles for later use.

[0070] (2) Treatment of sustained-release material: Hydroxypropyl methylcellulose was spread on a low-temperature plasma treatment instrument with the following parameters: vacuum degree 0.05MPa, power 80W, time 60s, and gas argon and oxygen (4:1). After treatment, it was sealed and stored. Propylene carbonate was added to a high-speed shear disperser, and chitosan was added under stirring at 1500r / min. The mixture was sheared and dispersed at 45℃ for 30min. The treated hydroxypropyl methylcellulose was added to purified water and stirred at 800r / min to form a suspension. The temperature was raised to 50℃, and the dispersion was added dropwise at 5mL / min. The reaction was continued by stirring for 1h. The mixture was freeze-dried (pre-freezing at -40℃ for 2h, and vacuum sublimation drying for 12h), pulverized and passed through a 100-mesh sieve to obtain the sustained-release matrix for later use.

[0071] (3) Wet mixing and granulation: Metformin hydrochloride, slow-release matrix and filler are put into a wet mixing granulator and dry-mixed at 300r / min for 10min; the binder is sprayed at 600r / min stirring and 1500r / min cutter speed and granulated for 8-10min.

[0072] (4) Fluidized bed drying: inlet air temperature 45℃, outlet air temperature ≤30℃, air velocity 1.2-1.5m / s, dry to moisture content 1.0%-1.5%, and cool to room temperature.

[0073] (5) Granulation and mixing: Granulate through a 16-mesh sieve, add lubricant in a three-dimensional mixer, and mix at 25 r / min for 15 min.

[0074] (6) Tableting: Hardness (4-6 kgf), brittleness (≤0.5%).

[0075] Comparative Example 7: Metformin Hydrochloride Extended-Release Tablets formula: Preparation method: (1) Pretreatment of raw materials and auxiliary materials: Metformin hydrochloride was ultra-finely pulverized and passed through a 120-mesh sieve, vacuum dried at 60℃ for 2 hours (moisture content ≤0.5%), and cooled for later use. The filler was passed through a 100-mesh sieve; the binder was prepared into a 10% (w / v) solution with purified water, stirred to dissolve, and then allowed to stand for 30 minutes to remove bubbles for later use.

[0076] (2) Treatment of sustained-release material: Hydroxypropyl methylcellulose is mixed with propylene carbonate and corn gluten, purified water is added, the mixture is stirred and reacted for 1 hour, then freeze-dried (pre-freeze at -40℃ for 2 hours, vacuum sublimation drying for 12 hours), pulverized and passed through a 100-mesh sieve to obtain a sustained-release matrix for later use.

[0077] (3) Wet mixing and granulation: Metformin hydrochloride, slow-release matrix and filler are put into a wet mixing granulator and dry-mixed at 300r / min for 10min; the binder is sprayed at 600r / min stirring and 1500r / min cutter speed and granulated for 8-10min.

[0078] (4) Fluidized bed drying: inlet air temperature 45℃, outlet air temperature ≤30℃, air velocity 1.2-1.5m / s, dry to moisture content 1.0%-1.5%, and cool to room temperature.

[0079] (5) Granulation and mixing: Granulate through a 16-mesh sieve, add lubricant in a three-dimensional mixer, and mix at 25 r / min for 15 min.

[0080] (6) Tableting: Hardness (4-6 kgf), brittleness (≤0.5%).

[0081] Commercially available preparation: National Drug Approval Number H20227043 Metformin hydrochloride extended-release tablets sustained-release effect The in vitro sustained-release behavior of Examples 1-3, Comparative Examples 1-7 and the commercially available formulation (National Drug Approval Number H20227043) was investigated, and the stability of the sustained-release effect at the beginning and after 6 months in accelerated testing (40°C, RH 75%) was evaluated.

[0082] Experimental conditions Release medium: 900 mL of 0.1 mol / L hydrochloric acid solution for 0-2 h, then switched to 900 mL of pH 6.8 phosphate buffer solution after 2 h (keeping the medium volume constant throughout); stirring speed: 50 rpm; medium temperature: 37℃±0.5℃; sampling time points: 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h; accelerated test conditions: after treating each sample according to the "sealed packaging" requirements, place them in a constant temperature and humidity chamber at 40℃±2℃ and RH 75%±5% for 6 months. Experimental steps Release rate determination: Take 6 tablets of each sample and place them into the dissolution vessel of the dissolution apparatus. Start the test according to the set conditions. Take 10 mL of sample at each time point and add 10 mL of an equal volume of isothermal release medium (ensuring the medium volume remains constant). Sample processing: Immediately filter the taken samples through a 0.45 μm microporous membrane, discard 5 mL of the initial filtrate, and use the subsequent filtrate as the test solution. HPLC detection: Refer to the metformin hydrochloride release rate detection method in the Chinese Pharmacopoeia to determine the peak area of ​​the test solution, and calculate the cumulative release rate at each time point using the external standard method. The similarity factor (f2) is used to evaluate the similarity of the release curves before and after acceleration.

[0083] Table 1. Sustained-release effect of initial samples Table 1 shows that the metformin hydrochloride extended-release tablets in Examples 1-3 had stable initial release without burst release, while the metformin hydrochloride extended-release tablets in Comparative Examples 1-7 and commercially available metformin hydrochloride extended-release tablets had a risk of burst release or insufficient release controllability.

[0084] Table 2. Effect of sustained release on samples after 6 months of acceleration Table 2 shows that the metformin hydrochloride sustained-release tablets of Examples 1-3 have excellent stability, and the f2 value of the metformin hydrochloride sustained-release tablets of Examples 1-3 is higher than the standard (f2≥50), which can ensure the therapeutic effect. The f2 values ​​of the metformin hydrochloride sustained-release tablets of Comparative Examples 1-7 and commercially available formulations are 47.2-55.9, and some are even lower than 50, indicating a significant change in sustained-release performance.

Claims

1. A metformin hydrochloride sustained-release tablet, characterized in that, The formulation of the metformin hydrochloride sustained-release tablets is as follows: metformin hydrochloride, sustained-release material, filler, binder, and lubricant. The sustained-release material is a combination of hydroxypropyl methylcellulose, propylene carbonate, and zein.

2. The metformin hydrochloride sustained-release tablet according to claim 1, characterized in that, The formulation of the metformin hydrochloride sustained-release tablets, by weight, is as follows: 500 parts metformin hydrochloride, 45-90 parts sustained-release material, 40-100 parts filler, 4-8 parts binder, and 0.5-2 parts lubricant.

3. The metformin hydrochloride sustained-release tablet according to claim 1, characterized in that, The sustained-release material is: 30-60 parts of hydroxypropyl methylcellulose, 10-20 parts of propylene carbonate, and 5-10 parts of corn gluten.

4. The metformin hydrochloride sustained-release tablet according to claim 1, characterized in that, The filler is selected from at least one of microcrystalline cellulose, lactose, dicalcium phosphate, mannitol, starch, and dextrin.

5. The metformin hydrochloride sustained-release tablet according to claim 1, characterized in that, The adhesive is selected from at least one of sodium carboxymethyl cellulose, gelatin, and povidone K30.

6. The metformin hydrochloride sustained-release tablet according to claim 1, characterized in that, The lubricant is selected from at least one of magnesium stearate, micronized silica gel, and sodium stearate fumarate.

7. The metformin hydrochloride sustained-release tablet according to claim 1, characterized in that, The formulation of the metformin hydrochloride sustained-release tablets also contains 8-12 parts of film coating material, wherein the film coating material is a gastric-soluble film coating premix.

8. A method for preparing the metformin hydrochloride sustained-release tablets according to claim 1, characterized in that, The preparation method includes the following steps: (1) Pretreatment of raw materials and auxiliary materials: Metformin hydrochloride is crushed, sieved and dried; adhesive is prepared into a 5-12% (w / v) solution with purified water; (2) Treatment of sustained-release material: Hydroxypropyl methylcellulose was treated with a low-temperature plasma treatment instrument, purified water was added, the temperature was raised to 50°C, a dispersion formed by mixing propylene carbonate and corn gluten was added dropwise, stirred, freeze-dried, pulverized and sieved to obtain a sustained-release matrix; (3) Wet mixing and granulation: Metformin hydrochloride, slow-release matrix and filler are dry mixed, adhesive is sprayed and granulation is performed; (4) Fluidized bed drying; (5) Granulation and mixing: Granulate, add lubricant, and mix; (6) Tableting.

9. The preparation method according to claim 8, characterized in that, The parameters for processing hydroxypropyl methylcellulose using a low-temperature plasma treatment instrument are: vacuum degree 0.05MPa, power 80W, time 60s, and gas is argon and oxygen (4:1).

10. The preparation method according to claim 8, characterized in that, The freeze-drying steps are as follows: pre-freezing at -40℃ for 2 hours, followed by vacuum sublimation drying for 12 hours.

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