Preparation method of metformin hydrochloride tablet with high stability

Abstract

The application discloses a preparation method of metformin hydrochloride tablets with high stability, and relates to the technical field of pharmaceutical preparations.The preparation method comprises the following steps: S1, modifying treatment is performed on starch by using whey protein, soybean lecithin and glycerol monostearate to obtain starch modification; S2, the starch modification, microcrystalline cellulose and calcium hydrogen phosphate are mixed and compounded to obtain a filler; S3, metformin hydrochloride, the filler, a lubricant, a binder, a disintegrant and an anti-hygroscopic agent are uniformly mixed, low-temperature crushing is performed, and tabletting is carried out to obtain metformin hydrochloride dry tablets; S4, enteric acrylic resin, the starch modification, an opacifying agent and a plasticizer are added into a solvent, and stirring, mixing and uniformity are carried out to obtain an enteric coating solution; and S5, after preheating of the metformin hydrochloride dry tablets, the enteric coating solution is atomized and sprayed onto the surface of the metformin hydrochloride dry tablets, and vacuum drying is carried out to obtain metformin hydrochloride tablets with high stability.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically a method for preparing highly stable metformin hydrochloride tablets. Background Technology

[0002] Metformin hydrochloride is a first-line drug for the treatment of type 2 diabetes and is widely used in clinical practice. However, the raw material of metformin hydrochloride has poor stability and is prone to degradation under light, resulting in reduced efficacy; at the same time, it has strong hygroscopicity and is prone to clumping in high humidity environments.

[0003] Current technologies for preparing metformin hydrochloride tablets primarily employ wet granulation or direct powder compression processes. Wet granulation introduces moisture and heat during production, which accelerates the degradation of metformin hydrochloride, leading to increased impurity levels during storage. While direct powder compression avoids the damp-heat process, it places extremely high demands on the flowability and compressibility of raw materials and excipients, and similarly struggles to address the issue of moisture absorption and degradation during long-term storage.

[0004] Therefore, developing a preparation method that can effectively inhibit the degradation of metformin hydrochloride and significantly improve product stability is of great significance for ensuring the safety and efficacy of clinical medication. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing highly stable metformin hydrochloride tablets to solve the problems mentioned in the background art.

[0006] To solve the above-mentioned technical problems, the present invention provides the following technical solution: A method for preparing highly stable metformin hydrochloride tablets includes the following steps: S1: Starch was modified by using whey protein, soybean lecithin, and glyceryl monostearate to obtain a modified starch product; S2: Mix and compound starch-modified material, microcrystalline cellulose, and dicalcium phosphate according to the formula ratio to obtain a filler; S3: According to the formula ratio, mix metformin hydrochloride, filler, lubricant, binder, disintegrant and antihygroscopic agent evenly, then pulverize at low temperature and compress into tablets to obtain metformin hydrochloride dry tablets. S4: Add enteric-coated acrylic resin, starch modifier, plasticizer, and opacifier to the solvent according to the formula ratio, stir and mix evenly to obtain enteric coating solution; S5: After preheating the metformin hydrochloride dry tablets, the enteric coating solution is atomized and sprayed onto the surface of the metformin hydrochloride dry tablets, and then vacuum dried to obtain highly stable metformin hydrochloride tablets.

[0007] Furthermore, the metformin hydrochloride dry tablets comprise the following raw material components: based on 1000 tablets, 250-850g of metformin hydrochloride, 100-300g of filler, 5-15g of lubricant, 20-80g of binder, 30-100g of disintegrant, and 5-10g of antihyperabsorbent.

[0008] Furthermore, the filler is obtained by mixing and compounding starch-modified material, microcrystalline cellulose, and dicalcium phosphate in a mass ratio of (3~5):(2~3):(1~2).

[0009] Further, the preparation method of the starch modified product is as follows: (1) Add starch to purified water and stir and disperse at a stirring speed of 300~500 rpm for 5~15 min to obtain a starch suspension; (2) Add whey protein to the starch suspension and stir and disperse at a stirring speed of 300~500 rpm for 5~15 min, then stir and heat at 65~75℃ at a stirring speed of 500~800 rpm for 10~30 min; (3) Add soybean lecithin and glyceryl monostearate to (2), stir and heat at a stirring speed of 500~800 rpm for 5~15 min, cool to room temperature, place in an environment of 4±1℃ and stand overnight, filter, freeze dry to a water content of <2% to obtain the starch modified product.

[0010] Further, the mass ratio of starch, whey protein, soy lecithin, glyceryl monostearate, and purified water is (1~2):(0.1~0.2):(0.05~0.1):(0.05~0.1):(8~12).

[0011] Furthermore, the starch includes, but is not limited to, one or more combinations of corn starch, potato starch, and tapioca starch.

[0012] In this invention, the modified starch is obtained by modifying whey protein, soy lecithin, and glyceryl monostearate. All three contain hydrophilic and hydrophobic groups. At 65-75°C, starch gelatinization exposes more active binding sites, while whey protein denaturation exposes both hydrophilic and hydrophobic groups. At this time, the hydrophilic groups of whey protein, soy lecithin, and glyceryl monostearate can form a cross-linked network structure with the polar groups such as -OH on starch through hydrogen bonding, while the hydrophobic groups of the three can interact through van der Waals forces. Subsequent low-temperature static setting allows the cross-linked network system to recombine and bind, thereby inhibiting starch retrogradation and ultimately obtaining a tightly bound and stable modified starch.

[0013] Furthermore, the lubricant is a fatty acid salt, including but not limited to one or more combinations of sodium stearate, magnesium stearate, and calcium stearate.

[0014] In this invention, sodium stearate fumarate is preferred as a lubricant because it has stronger hydrophobic properties, can better block moisture, and better enhance the stability of metformin hydrochloride tablets.

[0015] Furthermore, the adhesive is polyvinylpyrrolidone.

[0016] Furthermore, the disintegrant is crospovidone.

[0017] Furthermore, the moisture-absorbing agent is an inorganic adsorbent material, including but not limited to one or more combinations of colloidal silica, magnesium aluminum silicate, and talc.

[0018] In this invention, colloidal silica is preferred as an anti-hygroscopic agent. It has stable adsorption and high adsorption efficiency. It can work together with the aforementioned lubricant and starch modifier to play a hydrophobic role, thereby improving the stability of metformin hydrochloride tablets.

[0019] Furthermore, the process parameters for the low-temperature pulverization are: temperature -20~0℃, pulverization to 100~150μm.

[0020] Furthermore, the enteric coating solution comprises the following raw material components: by weight, 10-15 parts enteric acrylic resin, 1-2 parts starch modifier, 1-2 parts opacifier, 1.5-2.5 parts plasticizer, and 100 parts solvent.

[0021] Furthermore, the plasticizer is triethyl citrate.

[0022] Furthermore, the light-blocking agent is titanium dioxide.

[0023] Furthermore, the solvent is obtained by mixing ethanol and ethyl acetate in a volume ratio of (8~9):(1~2).

[0024] Furthermore, the preheating temperature is 40~60℃.

[0025] Furthermore, the parameters for the atomization spraying are: atomization pressure of 0.2~0.3MPa, spraying temperature of 40~60℃, spraying speed of 3~5mL / min, and coating pan rotation speed of 10~15r / min.

[0026] Furthermore, the parameters for the vacuum drying are: vacuum degree of 10. -1 ~10 -3 Pa, drying temperature is 40~60℃, drying time is 1~2h.

[0027] Furthermore, the metformin hydrochloride dry tablets gain 2-5 wt% weight after coating.

[0028] Compared with the prior art, the beneficial effects achieved by the present invention are: (1) In this invention, the starch-modified material can tightly bind metformin hydrochloride through a hydrogen bond network of starch-whey protein-soy lecithin-glyceryl monostearate, providing plasticity and rigidity during tableting and avoiding the problems of poor molding stability and easy cracking of dry metformin hydrochloride tablets. In addition, the hydrophobic binding groups of the starch-modified material can enhance the hydrophobicity of metformin hydrochloride and enhance its moisture resistance. This invention further adds microcrystalline cellulose, dicalcium phosphate and starch-modified material to form a filler; microcrystalline cellulose can synergistically enhance the compressibility of the tablet with starch-modified material, and dicalcium phosphate has high stability and can further synergistically improve the sensitivity of metformin hydrochloride to moisture with starch-modified material. Finally, under the synergistic effect of the three, the molding stability and efficacy stability of metformin hydrochloride tablets are improved.

[0029] (2) In this invention, the raw materials are pulverized by low temperature. Low temperature can avoid the thermal degradation of metformin hydrochloride during the pulverization process and ensure the stability of metformin hydrochloride tablets during preparation.

[0030] (3) In order to enhance the storage performance and bioavailability of metformin hydrochloride tablets, the present invention employs enteric-coated acrylic resin for coating. After coating, the enteric coating layer can enhance the moisture resistance of metformin hydrochloride tablets to a certain extent, which helps to enhance their storage performance. It can also prevent the direct release of metformin hydrochloride tablets into the stomach, which would result in a short residence time of the active pharmaceutical ingredient in the intestines and low bioavailability of metformin hydrochloride. Considering that using only enteric-coated acrylic resin for coating would result in a brittle coating layer that is prone to cracking due to temperature, vibration, or other issues, a plasticizer is further added to improve this. The formulation further incorporates starch modifiers and light-blocking agents. The starch modifiers increase the viscosity of the enteric coating solution, thereby enhancing atomized spraying processability. They also synergistically enhance the plasticity of the enteric coating layer with the plasticizer, and strengthen the adhesion between the enteric coating layer and the metformin hydrochloride dry tablets. The light-blocking agent provides light protection, enhancing the metformin hydrochloride tablets' resistance to photodegradation. The solvent in the formulation is prepared by mixing ethanol and ethyl acetate, preventing water ingress and maximizing the stability of the metformin hydrochloride tablets' efficacy.

[0031] (4) After coating, the storage performance of metformin hydrochloride tablets is greatly enhanced, and the efficacy can be maintained for a long time. When metformin hydrochloride tablets are taken, the presence of the enteric coating layer greatly protects the metformin hydrochloride tablets in the stomach, avoiding direct contact between the drug and the gastric mucosa and causing gastric irritation. When it enters the intestine, the enteric coating layer dissolves, exposing the drug core layer. Due to the tight binding of the starch modifier, the starch is slowly hydrolyzed and absorbed under the action of amylase, and metformin hydrochloride also begins to be slowly released and absorbed. During this period, whey protein and soy lecithin are also absorbed, which can improve the intestinal mucosa and enhance the absorption efficiency of metformin hydrochloride, ultimately achieving the targeted delivery and high absorption effect of "gastric retention-intestinal slow release".

[0032] In summary, this invention, through synergistic innovation in starch modification, filler compounding, and coating treatment, solves the problems of easy degradation of active pharmaceutical ingredients, short storage time, and low bioavailability during the processing of metformin hydrochloride tablets. Ultimately, it yields highly stable metformin hydrochloride tablets with stable molding, good storage performance, and high bioavailability, which have great clinical application value. Detailed Implementation

[0033] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0034] It should be noted that the following quantities are by weight, and there are no special restrictions on the suppliers of all raw materials involved in this invention. Exemplary examples include: In the following examples, whey protein (CAS No. 9013-90-5), soybean lecithin (CAS No. 8030-76-0), titanium dioxide (particle size 15~100nm), enteric-coated acrylic resin (Eudragit L100), glyceryl monostearate, microcrystalline cellulose, dicalcium phosphate, sodium stearate fumarate, povidone K30, crospovidone, colloidal silica, triethyl citrate, and ethyl acetate were all commercially available with a purity >99%. Each serving is 10g.

[0035] Preparatory steps: The solvent is prepared by mixing ethanol and ethyl acetate in a volume ratio of 9:1.

[0036] Example 1: A method for preparing highly stable metformin hydrochloride tablets: S1: Preparation of starch-modified product: (1) Add corn starch to purified water and stir at 400 rpm for 10 min to obtain starch suspension; (2) Add whey protein to starch suspension and stir at 400 rpm for 10 min, then stir and heat at 70℃ at 650 rpm for 20 min; (3) Add soybean lecithin and glyceryl monostearate to (2), stir and heat at 650 rpm for 10 min, cool to room temperature, stand overnight at 4±1℃, filter, freeze dry to water content <2% to obtain starch-modified product; wherein, the mass ratio of corn starch, whey protein, soybean lecithin, glyceryl monostearate, and purified water is 1.5:0.15:0.075:0.075:10; S2: The starch-modified material, microcrystalline cellulose, and dicalcium phosphate are mixed and compounded in a mass ratio of 4:2.5:1.5 to obtain the filler; S3: Add metformin hydrochloride, filler, sodium stearate fumarate, povidone K30, cross-linked povidone, and colloidal silica into a mixer, mix evenly, then pulverize at -20℃ to 100μm, compress into tablets, and obtain metformin hydrochloride dry tablets. Metformin hydrochloride dry tablets contain the following raw material components: based on 1000 tablets, 500g of metformin hydrochloride, 200g of filler, 10g of sodium stearate fumarate, 50g of povidone K30, 65g of cross-linked povidone, and 7.5g of colloidal silica. S4: Add Eudragit L100 enteric acrylic resin, starch modifier, triethyl citrate, and titanium dioxide to the solvent and stir to mix evenly to obtain the enteric coating solution; The enteric coating solution comprises the following raw material components: by weight, 12.5 parts of Eudragit L100 enteric acrylic resin, 1.5 parts of starch modifier, 1.5 parts of titanium dioxide, 2 parts of triethyl citrate, and 100 parts of solvent; S5: After preheating the metformin hydrochloride dry tablets to 50℃, transfer them to a coating pan. Atomize and spray the enteric coating solution onto the surface of the metformin hydrochloride dry tablets using parameters of 0.25MPa atomization pressure, 50℃ spraying temperature, 4mL / min spraying speed, and 13r / min rotation speed. Then, apply the coating solution under a vacuum of 10... -2 High-stability metformin hydrochloride tablets were obtained by vacuum drying at 50℃ for 1.5 h, with a coating weight gain of 3.5 ± 0.5 wt%.

[0037] Example 2: A method for preparing highly stable metformin hydrochloride tablets: Example 2 is based on Example 1, but with the following adjustment: the mixing ratio of the filler is changed from 4:2.5:1.5 to 3:2.5:1.5; other processes remain unchanged, specifically: S1: Preparation of starch-modified product: (1) Add corn starch to purified water and stir at 400 rpm for 10 min to obtain starch suspension; (2) Add whey protein to starch suspension and stir at 400 rpm for 10 min, then stir and heat at 70℃ at 650 rpm for 20 min; (3) Add soybean lecithin and glyceryl monostearate to (2), stir and heat at 650 rpm for 10 min, cool to room temperature, stand overnight at 4±1℃, filter, freeze dry to water content <2% to obtain starch-modified product; wherein, the mass ratio of corn starch, whey protein, soybean lecithin, glyceryl monostearate, and purified water is 1.5:0.15:0.075:0.075:10; S2: Mix starch-modified material, microcrystalline cellulose, and dicalcium phosphate in a mass ratio of 3:2.5:1.5 to obtain a filler; S3: Add metformin hydrochloride, filler, sodium stearate fumarate, povidone K30, cross-linked povidone, and colloidal silica into a mixer, mix evenly, then pulverize at -20℃ to 100μm, compress into tablets, and obtain metformin hydrochloride dry tablets. Metformin hydrochloride dry tablets contain the following raw material components: based on 1000 tablets, 500g of metformin hydrochloride, 200g of filler, 10g of sodium stearate fumarate, 50g of povidone K30, 65g of cross-linked povidone, and 7.5g of colloidal silica. S4: Add Eudragit L100 enteric acrylic resin, starch modifier, triethyl citrate, and titanium dioxide to the solvent and stir to mix evenly to obtain the enteric coating solution; The enteric coating solution comprises the following raw material components: by weight, 12.5 parts of Eudragit L100 enteric acrylic resin, 1.5 parts of starch modifier, 1.5 parts of titanium dioxide, 2 parts of triethyl citrate, and 100 parts of solvent; S5: After preheating the metformin hydrochloride dry tablets to 50℃, transfer them to a coating pan. Atomize and spray the enteric coating solution onto the surface of the metformin hydrochloride dry tablets using parameters of 0.25MPa atomization pressure, 50℃ spraying temperature, 4mL / min spraying speed, and 13r / min rotation speed. Then, apply the coating solution under a vacuum of 10... -2 High-stability metformin hydrochloride tablets were obtained by vacuum drying at 50℃ for 1.5 h, with a coating weight gain of 3.5 ± 0.5 wt%.

[0038] Example 3: A method for preparing highly stable metformin hydrochloride tablets: Example 3 is based on Example 1, but with the following adjustment: the mixing ratio of the filler is changed from 4:2.5:1.5 to 5:2.5:1.5; other processes remain unchanged, specifically: S1: Preparation of starch-modified product: (1) Add corn starch to purified water and stir at 400 rpm for 10 min to obtain starch suspension; (2) Add whey protein to starch suspension and stir at 400 rpm for 10 min, then stir and heat at 70℃ at 650 rpm for 20 min; (3) Add soybean lecithin and glyceryl monostearate to (2), stir and heat at 650 rpm for 10 min, cool to room temperature, stand overnight at 4±1℃, filter, freeze dry to water content <2% to obtain starch-modified product; wherein, the mass ratio of corn starch, whey protein, soybean lecithin, glyceryl monostearate, and purified water is 1.5:0.15:0.075:0.075:10; S2: Mix starch-modified material, microcrystalline cellulose, and dicalcium phosphate in a mass ratio of 5:2.5:1.5 to obtain a filler; S3: Add metformin hydrochloride, filler, sodium stearate fumarate, povidone K30, cross-linked povidone, and colloidal silica into a mixer, mix evenly, then pulverize at -20℃ to 100μm, compress into tablets, and obtain metformin hydrochloride dry tablets. Metformin hydrochloride dry tablets contain the following raw material components: based on 1000 tablets, 500g of metformin hydrochloride, 200g of filler, 10g of sodium stearate fumarate, 50g of povidone K30, 65g of cross-linked povidone, and 7.5g of colloidal silica. S4: Add Eudragit L100 enteric acrylic resin, starch modifier, triethyl citrate, and titanium dioxide to the solvent and stir to mix evenly to obtain the enteric coating solution; The enteric coating solution comprises the following raw material components: by weight, 12.5 parts of Eudragit L100 enteric acrylic resin, 1.5 parts of starch modifier, 1.5 parts of titanium dioxide, 2 parts of triethyl citrate, and 100 parts of solvent; S5: After preheating the metformin hydrochloride dry tablets to 50℃, transfer them to a coating pan. Atomize and spray the enteric coating solution onto the surface of the metformin hydrochloride dry tablets using parameters of 0.25MPa atomization pressure, 50℃ spraying temperature, 4mL / min spraying speed, and 13r / min rotation speed. Then, apply the coating solution under a vacuum of 10... -2High-stability metformin hydrochloride tablets were obtained by vacuum drying at 50℃ for 1.5 h, with a coating weight gain of 3.5 ± 0.5 wt%.

[0039] Example 4: A method for preparing highly stable metformin hydrochloride tablets: Example 4 is based on Example 1, with the following adjustment: the amount of starch modifier in the enteric coating solution is reduced from 1.5 parts to 1 part; other processes remain unchanged. Specifically: S1: Preparation of starch-modified product: (1) Add corn starch to purified water and stir at 400 rpm for 10 min to obtain starch suspension; (2) Add whey protein to starch suspension and stir at 400 rpm for 10 min, then stir and heat at 70℃ at 650 rpm for 20 min; (3) Add soybean lecithin and glyceryl monostearate to (2), stir and heat at 650 rpm for 10 min, cool to room temperature, stand overnight at 4±1℃, filter, freeze dry to water content <2% to obtain starch-modified product; wherein, the mass ratio of corn starch, whey protein, soybean lecithin, glyceryl monostearate, and purified water is 1.5:0.15:0.075:0.075:10; S2: The starch-modified material, microcrystalline cellulose, and dicalcium phosphate are mixed and compounded in a mass ratio of 4:2.5:1.5 to obtain the filler; S3: Add metformin hydrochloride, filler, sodium stearate fumarate, povidone K30, cross-linked povidone, and colloidal silica into a mixer, mix evenly, then pulverize at -20℃ to 100μm, compress into tablets, and obtain metformin hydrochloride dry tablets. Metformin hydrochloride dry tablets contain the following raw material components: based on 1000 tablets, 500g of metformin hydrochloride, 200g of filler, 10g of sodium stearate fumarate, 50g of povidone K30, 65g of cross-linked povidone, and 7.5g of colloidal silica. S4: Add Eudragit L100 enteric acrylic resin, starch modifier, triethyl citrate, and titanium dioxide to the solvent and stir to mix evenly to obtain the enteric coating solution; The enteric coating solution comprises the following raw material components: by weight, 12.5 parts of Eudragit L100 enteric acrylic resin, 1 part of starch modifier, 1.5 parts of titanium dioxide, 2 parts of triethyl citrate, and 100 parts of solvent; S5: After preheating the metformin hydrochloride dry tablets to 50℃, transfer them to a coating pan. Atomize and spray the enteric coating solution onto the surface of the metformin hydrochloride dry tablets using parameters of 0.25MPa atomization pressure, 50℃ spraying temperature, 4mL / min spraying speed, and 13r / min rotation speed. Then, apply the coating solution under a vacuum of 10... -2 High-stability metformin hydrochloride tablets were obtained by vacuum drying at 50℃ for 1.5 h, with a coating weight gain of 3.5 ± 0.5 wt%.

[0040] Example 5: A method for preparing highly stable metformin hydrochloride tablets: Example 5 is based on Example 1, with the following adjustment: the amount of starch modifier in the enteric coating solution is adjusted from 1.5 parts to 2 parts; other processes remain unchanged, specifically: S1: Preparation of starch-modified product: (1) Add corn starch to purified water and stir at 400 rpm for 10 min to obtain starch suspension; (2) Add whey protein to starch suspension and stir at 400 rpm for 10 min, then stir and heat at 70℃ at 650 rpm for 20 min; (3) Add soybean lecithin and glyceryl monostearate to (2), stir and heat at 650 rpm for 10 min, cool to room temperature, stand overnight at 4±1℃, filter, freeze dry to water content <2% to obtain starch-modified product; wherein, the mass ratio of corn starch, whey protein, soybean lecithin, glyceryl monostearate, and purified water is 1.5:0.15:0.075:0.075:10; S2: The starch-modified material, microcrystalline cellulose, and dicalcium phosphate are mixed and compounded in a mass ratio of 4:2.5:1.5 to obtain the filler; S3: Add metformin hydrochloride, filler, sodium stearate fumarate, povidone K30, cross-linked povidone, and colloidal silica into a mixer, mix evenly, then pulverize at -20℃ to 100μm, compress into tablets, and obtain metformin hydrochloride dry tablets. Metformin hydrochloride dry tablets contain the following raw material components: based on 1000 tablets, 500g of metformin hydrochloride, 200g of filler, 10g of sodium stearate fumarate, 50g of povidone K30, 65g of cross-linked povidone, and 7.5g of colloidal silica. S4: Add Eudragit L100 enteric acrylic resin, starch modifier, triethyl citrate, and titanium dioxide to the solvent and stir to mix evenly to obtain the enteric coating solution; The enteric coating solution comprises the following raw material components: by weight, 12.5 parts of Eudragit L100 enteric acrylic resin, 2 parts of starch modifier, 1.5 parts of titanium dioxide, 2 parts of triethyl citrate, and 100 parts of solvent; S5: After preheating the metformin hydrochloride dry tablets to 50℃, transfer them to a coating pan. Atomize and spray the enteric coating solution onto the surface of the metformin hydrochloride dry tablets using parameters of 0.25MPa atomization pressure, 50℃ spraying temperature, 4mL / min spraying speed, and 13r / min rotation speed. Then, apply the coating solution under a vacuum of 10... -2 High-stability metformin hydrochloride tablets were obtained by vacuum drying at 50℃ for 1.5 h, with a coating weight gain of 3.5 ± 0.5 wt%.

[0041] The following is a control experiment based on Example 1, with comparative examples 1 to 5, as detailed below: Comparative Example 1: A method for preparing highly stable metformin hydrochloride tablets: Comparative Example 1 is based on Example 1, with the following adjustment: no modification treatment is performed on the corn starch, while other processes remain unchanged. Specifically: S1: Corn starch, microcrystalline cellulose, and dicalcium phosphate are mixed and compounded in a mass ratio of 4:2.5:1.5 to obtain a filler; S2: Add metformin hydrochloride, filler, sodium stearate fumarate, povidone K30, cross-linked povidone, and colloidal silica into a mixer, mix evenly, then pulverize at -20℃ to 100μm, compress into tablets, and obtain metformin hydrochloride dry tablets. Metformin hydrochloride dry tablets contain the following raw material components: based on 1000 tablets, 500g of metformin hydrochloride, 200g of filler, 10g of sodium stearate fumarate, 50g of povidone K30, 65g of cross-linked povidone, and 7.5g of colloidal silica. S3: Add Eudragit L100 enteric acrylic resin, corn starch, triethyl citrate, and titanium dioxide to the solvent and stir to mix evenly to obtain the enteric coating solution; The enteric coating solution comprises the following raw material components: by weight, 12.5 parts of Eudragit L100 enteric acrylic resin, 1.5 parts of corn starch, 1.5 parts of titanium dioxide, 2 parts of triethyl citrate, and 100 parts of solvent; S4: After preheating the metformin hydrochloride dry tablets to 50℃, transfer them to a coating pan. Atomize and spray the enteric coating solution onto the surface of the metformin hydrochloride dry tablets using parameters of 0.25MPa atomization pressure, 50℃ spraying temperature, 4mL / min spraying speed, and 13r / min rotation speed. Then, apply the coating solution under a vacuum of 10... -2High-stability metformin hydrochloride tablets were obtained by vacuum drying at 50℃ for 1.5 h, with a coating weight gain of 3.5 ± 0.5 wt%.

[0042] Comparative Example 2: A method for preparing highly stable metformin hydrochloride tablets: Comparative Example 2 is based on Example 1, with the following adjustment: only starch-modified material is used as a filler, while other processes remain unchanged. Specifically: S1: Preparation of starch-modified product: (1) Add corn starch to purified water and stir at 400 rpm for 10 min to obtain starch suspension; (2) Add whey protein to starch suspension and stir at 400 rpm for 10 min, then stir and heat at 70℃ at 650 rpm for 20 min; (3) Add soybean lecithin and glyceryl monostearate to (2), stir and heat at 650 rpm for 10 min, cool to room temperature, stand overnight at 4±1℃, filter, freeze dry to water content <2% to obtain starch-modified product; wherein, the mass ratio of corn starch, whey protein, soybean lecithin, glyceryl monostearate, and purified water is 1.5:0.15:0.075:0.075:10; S2: Add metformin hydrochloride, starch modifier, sodium stearate fumarate, povidone K30, cross-linked povidone, and colloidal silica into a mixer, mix evenly, then pulverize at -20℃ to 100μm, compress into tablets, and obtain metformin hydrochloride dry tablets. Metformin hydrochloride dry tablets contain the following raw material components: based on 1000 tablets, 500g of metformin hydrochloride, 200g of starch modifier, 10g of sodium stearate fumarate, 50g of povidone K30, 65g of cross-linked povidone, and 7.5g of colloidal silica. S3: Add Eudragit L100 enteric acrylic resin, starch modifier, triethyl citrate, and titanium dioxide to the solvent and stir to mix evenly to obtain the enteric coating solution; The enteric coating solution comprises the following raw material components: by weight, 12.5 parts of Eudragit L100 enteric acrylic resin, 1.5 parts of starch modifier, 1.5 parts of titanium dioxide, 2 parts of triethyl citrate, and 100 parts of solvent; S4: After preheating the metformin hydrochloride dry tablets to 50℃, transfer them to a coating pan. Atomize and spray the enteric coating solution onto the surface of the metformin hydrochloride dry tablets using parameters of 0.25MPa atomization pressure, 50℃ spraying temperature, 4mL / min spraying speed, and 13r / min rotation speed. Then, apply the coating solution under a vacuum of 10... -2High-stability metformin hydrochloride tablets were obtained by vacuum drying at 50℃ for 1.5 h, with a coating weight gain of 3.5 ± 0.5 wt%.

[0043] Comparative Example 3: A method for preparing highly stable metformin hydrochloride tablets: Comparative Example 3 is based on Example 1, with the following adjustment: no starch modifier is added to the enteric coating solution, while other processes remain unchanged. Specifically: S1: Preparation of starch-modified product: (1) Add corn starch to purified water and stir at 400 rpm for 10 min to obtain starch suspension; (2) Add whey protein to starch suspension and stir at 400 rpm for 10 min, then stir and heat at 70℃ at 650 rpm for 20 min; (3) Add soybean lecithin and glyceryl monostearate to (2), stir and heat at 650 rpm for 10 min, cool to room temperature, stand overnight at 4±1℃, filter, freeze dry to water content <2% to obtain starch-modified product; wherein, the mass ratio of corn starch, whey protein, soybean lecithin, glyceryl monostearate, and purified water is 1.5:0.15:0.075:0.075:10; S2: The starch-modified material, microcrystalline cellulose, and dicalcium phosphate are mixed and compounded in a mass ratio of 4:2.5:1.5 to obtain the filler; S3: Add metformin hydrochloride, filler, sodium stearate fumarate, povidone K30, cross-linked povidone, and colloidal silica into a mixer, mix evenly, then pulverize at -20℃ to 100μm, compress into tablets, and obtain metformin hydrochloride dry tablets. Metformin hydrochloride dry tablets contain the following raw material components: based on 1000 tablets, 500g of metformin hydrochloride, 200g of filler, 10g of sodium stearate fumarate, 50g of povidone K30, 65g of cross-linked povidone, and 7.5g of colloidal silica. S4: Add Eudragit L100 enteric acrylic resin, triethyl citrate, and titanium dioxide to the solvent and stir to mix evenly to obtain the enteric coating solution; The enteric coating solution comprises the following raw material components: by weight, 12.5 parts of Eudragit L100 enteric acrylic resin, 1.5 parts of titanium dioxide, 2 parts of triethyl citrate, and 100 parts of solvent; S5: After preheating the metformin hydrochloride dry tablets to 50℃, transfer them to a coating pan. Atomize and spray the enteric coating solution onto the surface of the metformin hydrochloride dry tablets using parameters of 0.25MPa atomization pressure, 50℃ spraying temperature, 4mL / min spraying speed, and 13r / min rotation speed. Then, apply the coating solution under a vacuum of 10... -2High-stability metformin hydrochloride tablets were obtained by vacuum drying at 50℃ for 1.5 h, with a coating weight gain of 3.5 ± 0.5 wt%.

[0044] Comparative Example 4: A method for preparing highly stable metformin hydrochloride tablets: Comparative Example 4 is based on Example 1, with the following adjustment: no coating treatment is performed, while other processes remain unchanged. Specifically: S1: Preparation of starch-modified product: (1) Add corn starch to purified water and stir at 400 rpm for 10 min to obtain starch suspension; (2) Add whey protein to starch suspension and stir at 400 rpm for 10 min, then stir and heat at 70℃ at 650 rpm for 20 min; (3) Add soybean lecithin and glyceryl monostearate to (2), stir and heat at 650 rpm for 10 min, cool to room temperature, stand overnight at 4±1℃, filter, freeze dry to water content <2% to obtain starch-modified product; wherein, the mass ratio of corn starch, whey protein, soybean lecithin, glyceryl monostearate, and purified water is 1.5:0.15:0.075:0.075:10; S2: The starch-modified material, microcrystalline cellulose, and dicalcium phosphate are mixed and compounded in a mass ratio of 4:2.5:1.5 to obtain the filler; S3: Add metformin hydrochloride, filler, sodium stearate fumarate, povidone K30, cross-linked povidone, and colloidal silica into a mixer, mix evenly, then pulverize at -20℃ to 100μm, compress into tablets, and obtain highly stable metformin hydrochloride tablets. Metformin hydrochloride dry tablets contain the following raw material components: based on 1000 tablets, 500g of metformin hydrochloride, 200g of filler, 10g of sodium stearate fumarate, 50g of povidone K30, 65g of cross-linked povidone, and 7.5g of colloidal silica.

[0045] Performance testing: The metformin hydrochloride tablets prepared in Examples 1-5 and Comparative Examples 1-4 of this invention were compared with commercially available metformin hydrochloride tablets (brand: Tianan, batch number: National Drug Approval Number H20073382, specification: 0.5g per tablet) for relevant performance tests, as follows: 1. Visual inspection: 100 metformin hydrochloride dry tablets were randomly selected from each group of cases to observe whether there were defects such as cracks in their appearance, and the pass rate (%) was calculated. 2. Dissolution performance test: Dissolution test was conducted using the basket method: (1) Dissolution media with pH=1.2, pH=6.0, pH=6.8 and pH=7.0 were prepared according to the standard of "Guidelines for Determination and Comparison of Dissolution Curves of Ordinary Oral Solid Dosage Forms"; (2) 900 mL of dissolution media of each pH was taken and heated to 37.5℃ in a water bath. Six tablets of metformin hydrochloride tablets corresponding to each example were then placed in a rotating basket and placed in dissolution media of different pH values. The dissolution test was conducted at a rotation speed of 100 r / min. During the test, 1 mL of solution was taken every 30 min and an equal amount of constant temperature and pH dissolution media was added in time. The dissolution rate (%) was measured at 30 min, 60 min, 90 min and 120 min. 3. Storage performance: Several metformin hydrochloride tablets were randomly selected from each group of examples and stored at 30°C and RH 65% for 6 months. Then, their dissolution performance in a dissolution medium with pH=6.8 was tested.

[0046] The test results are shown in Tables 1 and 2 below: Table 1

[0047]

[0048] Table 2

[0049] Results Analysis: The data in Tables 1 and 2 above show that this invention, through synergistic innovation in starch modification, filler compounding, and coating treatment, solves the problems of easy degradation of active pharmaceutical ingredients, short storage time, and low bioavailability during the processing of metformin hydrochloride tablets. Ultimately, it obtains highly stable metformin hydrochloride tablets with stable molding, good storage performance, and high bioavailability, achieving the targeted delivery and high absorption effect of metformin hydrochloride tablets through "gastric retention-intestinal slow release".

[0050] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing highly stable metformin hydrochloride tablets, characterized in that: Includes the following steps: S1: Starch was modified by using whey protein, soybean lecithin, and glyceryl monostearate to obtain a modified starch product; S2: Mix and compound starch-modified material, microcrystalline cellulose, and dicalcium phosphate to obtain a filler; S3: After mixing metformin hydrochloride, filler, lubricant, binder, disintegrant, and antihygroscopic agent evenly, the mixture is pulverized at low temperature and compressed into tablets to obtain metformin hydrochloride dry tablets. S4: Add enteric-coated acrylic resin, starch modifier, opacifier, and plasticizer to the solvent, stir and mix evenly to obtain enteric coating solution; S5: After preheating the metformin hydrochloride dry tablets, the enteric coating solution is atomized and sprayed onto the surface of the metformin hydrochloride dry tablets, and then vacuum dried to obtain highly stable metformin hydrochloride tablets. Metformin hydrochloride dry tablets include the following raw material components: based on 1000 tablets, 250~850g of metformin hydrochloride, 100~300g of filler, 5~15g of lubricant, 20~80g of binder, 30~100g of disintegrant, and 5~10g of antihyperabsorbent; The enteric coating solution comprises the following raw material components: by weight, 10-15 parts enteric acrylic resin, 1-2 parts starch modifier, 1-2 parts opacifier, 1.5-2.5 parts plasticizer, and 100 parts solvent.

2. The method for preparing a highly stable metformin hydrochloride tablet according to claim 1, characterized in that: The method for preparing the starch-modified material is as follows: (1) Add starch to purified water and stir at 300-500 rpm for 5-15 min to obtain starch suspension; (2) Add whey protein to starch suspension, stir and disperse at 300-500 rpm for 5-15 min, then heat at 65-75℃ at 500-800 rpm for 10-30 min. (3) Add soybean lecithin and glyceryl monostearate to (2), stir and heat at a stirring speed of 500~800 rpm for 5~15 min, cool to room temperature, let stand overnight at 4±1℃, filter, freeze dry to water content <2%, and obtain starch modified product. The mass ratio of starch, whey protein, soy lecithin, glyceryl monostearate, and purified water is (1~2):(0.1~0.2):(0.05~0.1):(0.05~0.1):(8~12).

3. The method for preparing a highly stable metformin hydrochloride tablet according to claim 1, characterized in that: The filler is obtained by mixing and compounding starch-modified material, microcrystalline cellulose, and dicalcium phosphate in a mass ratio of (3~5):(2~3):(1~2).

4. The method for preparing a highly stable metformin hydrochloride tablet according to claim 1, characterized in that: The process parameters for the low-temperature pulverization are: temperature -20~0℃, pulverization to 100~150μm.

5. The method for preparing a highly stable metformin hydrochloride tablet according to claim 1, characterized in that: The solvent is obtained by mixing ethanol and ethyl acetate in a volume ratio of (8~9):(1~2).

6. The method for preparing a highly stable metformin hydrochloride tablet according to claim 1, characterized in that: The lubricant is a fatty acid salt, including one or more of sodium stearate, magnesium stearate, and calcium stearate. The moisture-absorbing agent is an inorganic adsorbent material, including one or more of colloidal silica, magnesium aluminum silicate, and talc.

7. The method for preparing a highly stable metformin hydrochloride tablet according to claim 1, characterized in that: The preheating temperature is 40~60℃; The parameters for atomized spraying are: atomization pressure of 0.2~0.3MPa, spraying temperature of 40~60℃, spraying speed of 3~5mL / min, and coating pan rotation speed of 10~15r / min; The parameters for vacuum drying are: vacuum degree of 10. -1 ~10 -3 Pa, drying temperature is 40~60℃, drying time is 1~2h.

8. The method for preparing a highly stable metformin hydrochloride tablet according to claim 1, characterized in that: The metformin hydrochloride dry tablets, after coating, have a weight gain of 2-5 wt%.

9. A highly stable metformin hydrochloride tablet, characterized in that: It is prepared by the preparation method according to any one of claims 1 to 8.

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