Sodium rabeprazole enteric-coated tablet and preparation method thereof

Abstract

The invention discloses a rabeprazole sodium enteric-coated tablet and a preparation method thereof, and relates to the technical field of pharmaceutical preparations. The rabeprazole sodium enteric-coated tablet is sequentially provided with a medicine core layer, an enteric-coated layer and a gastric-soluble layer from inside to outside. The medicine core layer is obtained by mixing, granulating and tabletting the following raw material components: rabeprazole sodium, an adhesive, a filler, a stabilizer, a disintegrating agent, a lubricant and absolute ethyl alcohol; the enteric-coated layer is obtained by atomizing and spraying an enteric-coated coating solution and is prepared from the following raw material components: modified starch, a plasticizer, enteric-coated acrylic resin, talcum powder and an ethanol water solution; the gastric-soluble layer is obtained by atomizing and spraying a gastric-soluble coating solution, and is prepared from the following raw material components: chitosan, a plasticizer, an auxiliary flexibilizer and an acetic acid aqueous solution. According to the rabeprazole sodium enteric-coated tablet, the medicine core layer is protected through the enteric-coated layer and the gastric-coated layer, the overall stability of the rabeprazole sodium enteric-coated tablet is greatly improved, and the efficacy utilization rate of rabeprazole sodium is increased.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a rabeprazole sodium enteric-coated tablet and its preparation method. Background Technology

[0002] Peptic ulcers are a common and frequently occurring disease with a low mortality rate, but they cause significant suffering to patients. Peptic ulcers are well-defined mucosal diseases that can penetrate the mucosal basal layer. They occur in areas of the gastrointestinal tract that come into contact with gastric juices, and can be found in the lesser curvature of the stomach, pyloric canal, duodenal bulb, and lower esophagus. The vast majority are located in the stomach and duodenum, and are referred to as gastric and duodenal ulcers.

[0003] Acid-suppressing agents have become the main drugs for treating peptic ulcers, especially proton pump inhibitors (PPIs), such as omeprazole, rabeprazole sodium, and yantoprazole. PPIs have a stronger and longer-lasting acid-suppressing effect. Rabeprazole sodium is a reversible PPI with antisecretory activity. In vitro, its antisecretory activity is 2 to 10 times stronger than omeprazole. Orally, it is rapidly activated in vivo and binds to the proton pump to exert its acid-suppressing effect. Rabeprazole sodium is extremely unstable under acidic conditions, so it needs to be prepared as an enteric-coated formulation to disintegrate and be absorbed in the intestine to exert its therapeutic effect. However, the dissolution rate of the tablet cores in rabeprazole sodium coated tablets or enteric-coated tablets provided by current technology is poor, resulting in low bioavailability of rabeprazole sodium.

[0004] Based on this, the present invention will provide a rabeprazole sodium enteric-coated tablet with stable quality and high bioavailability, which is of great significance. Summary of the Invention

[0005] The purpose of this invention is to provide a rabeprazole sodium enteric-coated tablet and its preparation method, so as 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 rabeprazole sodium enteric-coated tablets includes the following steps: S1: Preparation of the drug core layer: S11: Add the adhesive to anhydrous ethanol and stir to mix evenly to obtain an adhesive solution; S12: After mixing rabeprazole sodium, filler, stabilizer and disintegrant evenly, add binder solution, continue mixing, and finally granulate, vacuum dry and sieve to obtain rabeprazole sodium pills. S13: Rabeprazole sodium pills and lubricant are stirred and mixed evenly, and then compressed into tablets to obtain the core layer; S2: Enteric coating: S21: (1) Add starch to deionized water, stir and heat to 40~60℃, and add sodium hydroxide aqueous solution to adjust pH to 8~9. After stirring and mixing for 4~8h, a deprotonated starch solution is obtained; (2) Add 2-bromo-1-dodecene to N,N-dimethylformamide, stir and mix evenly to obtain a 2-bromo-1-dodecene solution; (3) Add the 2-bromo-1-dodecene solution to the deprotonated starch solution, stir and react at room temperature for 4~8h, add excess deionized water to stop the reaction, extract and collect the organic phase, and then distill under reduced pressure to obtain modified starch; The mass ratio of starch to 2-bromo-1-dodecene is 10:(0.5~1); S22: Add modified starch, plasticizer, enteric acrylic resin, and talc to a 95wt% ethanol aqueous solution, stir and mix evenly to obtain an enteric coating solution; S23: After preheating the drug core layer to 35~45℃, place it in a coating pan, then atomize and spray the enteric coating solution onto the drug core layer. After vacuum drying, an enteric layer is formed, and rabeprazole sodium enteric-coated tablets are obtained.

[0007] Furthermore, the core layer comprises the following raw material components: by weight ratio, 10-20 parts of rabeprazole sodium, 6-10 parts of binder, 25-35 parts of filler, 25-35 parts of stabilizer, 6-10 parts of disintegrant, 1-1.5 parts of lubricant, and 20-25 parts of anhydrous ethanol.

[0008] Furthermore, the adhesive is povidone K30; the filler is microcrystalline cellulose; the stabilizer is magnesium oxide; the disintegrant is cross-linked povidone; and the lubricant is magnesium stearate.

[0009] Furthermore, the enteric coating solution comprises the following raw material components: by weight, 4-8 parts modified starch, 4-8 parts plasticizer, 30 parts enteric acrylic resin, 10-15 parts talc, and 600-750 parts ethanol aqueous solution.

[0010] Furthermore, the plasticizer is triethyl citrate; the enteric acrylic resin is Eudragit L100.

[0011] Furthermore, the enteric coating increases the weight by 5-8 wt%.

[0012] Furthermore, in S1, the parameters for vacuum drying are: vacuum degree of 10. -1 ~10 -3 Pa, drying temperature is 50~60℃, drying until the core layer contains ≤2wt% anhydrous ethanol.

[0013] Furthermore, in S2, the parameters for vacuum drying are: vacuum degree of 10. -1 ~10 -3 Pa, drying temperature is 50~60℃, drying time is 30~90min.

[0014] Furthermore, in S2, the parameters for atomization spraying are: atomization pressure of 0.15~0.3MPa, spraying temperature of 50~60℃, spraying speed of 2~5mL / min, and coating pan rotation speed of 10~15r / min.

[0015] Furthermore, the rabeprazole sodium enteric-coated tablets also include a gastric coating layer; the gastric coating layer is obtained by atomizing and spraying a gastric coating solution, specifically step S3 is as follows: S31: (1) Add chitosan to a 2wt% aqueous acetic acid solution, stir and heat to 60~70℃ to obtain a chitosan solution; (2) Add plasticizer and auxiliary toughening agent to the chitosan solution, stir and mix evenly to obtain a gastric coating solution; S32: After the enteric coating layer is preheated to 35~45℃, it is placed in a coating pan, and then the gastric coating solution is atomized and sprayed onto the enteric coating layer. After vacuum drying, the gastric coating layer is formed, and rabeprazole sodium enteric-coated tablets are obtained.

[0016] Furthermore, the gastric coating solution comprises the following raw material components: by weight, 6-12 parts chitosan, 2-4 parts plasticizer, 0.5-1 part auxiliary toughening agent, and 1000 parts aqueous acetic acid solution.

[0017] Furthermore, the degree of deacetylation of the chitosan is ≥70%.

[0018] Furthermore, the plasticizer is triethyl citrate; the auxiliary toughening agent is glycerol.

[0019] Furthermore, the gastric coating increases in weight by 2-5 wt%.

[0020] Furthermore, in S3, the atomization spraying and vacuum drying parameters in the gastric coating process are the same as in S2.

[0021] Compared with the prior art, the beneficial effects achieved by the present invention are: (1) The enteric layer formed by traditional enteric acrylic resin is not dense and has microscopic defects. When the enteric tablet enters the stomach, a small amount of acid and water will slowly seep into the core layer, causing partial degradation of rabeprazole sodium, which in turn leads to a reduction in efficacy. Therefore, this invention prepares a hydrophobic modified starch with long carbon unsaturated segments by deprotonating starch under weakly alkaline conditions and then introducing 2-bromo-1-dodecene onto the starch through nucleophilic substitution. In this invention, the modified starch replaces part of the enteric-coated acrylic resin. Because the modified starch has good compatibility with the enteric-coated acrylic resin, the prepared enteric coating solution is of uniform quality. After atomization spraying, the modified starch can interpenetrate between the enteric-coated acrylic resin, replenishing the hydrophilic micropores in the enteric-coated acrylic resin film, promoting film formation, and effectively improving the water and acid permeability resistance of the enteric layer, thus better protecting the drug in the enteric tablet and exerting better efficacy. On the other hand, the modified starch contains unsaturated double bonds, and partial cross-linking reactions occur during the formation of the enteric layer, which can enhance the density of the enteric layer to a certain extent. However, the modified starch should not be used excessively, as excessive use will cause the enteric layer to be unstable in gastric acid.

[0022] (2) In this invention, it is considered that if only the enteric coating layer is used to coat the drug core layer to prepare rabeprazole sodium enteric-coated tablets, during oral administration, the oral cavity contains amylase, and the enteric coating layer contains starch. Even if it is only for a very short time, it will cause some damage to the enteric coating layer, thereby reducing the stability of rabeprazole sodium enteric-coated tablets. Therefore, the present invention designs to further atomize and spray a gastric coating layer on the outside of the enteric coating layer. The main component of the gastric coating layer is chitosan. Chitosan has a certain degree of hydrophobicity and only dissolves under acidic conditions. During oral administration, it can protect the enteric-coated tablets. After entering the stomach, under the action of gastric acid, it will degrade, exposing the enteric coating layer and greatly enhancing the stability of rabeprazole sodium enteric-coated tablets. Since the higher the degree of deacetylation of chitosan, the higher its hydrophobicity, it is also more likely to be acid-degraded. In order to ensure the hydrophobicity of the gastric coating layer, the degree of deacetylation of chitosan should be ≥70%.

[0023] (3) In this invention, the enteric coating layer and the gastric coating layer are used to protect the drug core layer, which greatly improves the overall stability of rabeprazole sodium enteric-coated tablets and improves the efficacy utilization rate of rabeprazole sodium. Detailed Implementation

[0024] 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.

[0025] 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, povidone K30, crospovidone (catalog number 181-9132-1252), magnesium oxide (catalog number 180-9270-5451), magnesium stearate, triethyl citrate, and glycerin were all purchased from Xi'an Jinxiang Pharmaceutical Excipients Co., Ltd. 2-Bromo-1-dodecene, CAS No. 74571-85-0, was purchased from Beijing Bailingwei Technology Co., Ltd. Enteric-coated acrylic resin, model Eudragit L100; chitosan, with a degree of deacetylation of 60% and 80%, purchased from Shanghai Changwei Pharmaceutical Excipients Technology Co., Ltd. The starch-degrading enzyme was α-amylase with a purity of 10000 u / g, purchased from Aladdin Reagent Co., Ltd.; all other raw materials were commercially available; each of the following parts by weight is 10g.

[0026] Example 1: A method for preparing rabeprazole sodium enteric-coated tablets: S1: Preparation of the drug core layer: S11: Add 8 parts of povidone K30 to 25 parts of anhydrous ethanol, stir and mix evenly to obtain an adhesive solution; S12: Mix 20 parts rabeprazole sodium, 30 parts microcrystalline cellulose, 30 parts magnesium oxide, and 8 parts crospovidone until homogeneous. Then add the binder solution and continue mixing for 15 minutes. Finally, granulate and vacuum dry (vacuum degree 10). -2 Pa, drying temperature is 55℃, dried until the core layer contains ≤2wt% anhydrous ethanol), passed through a 24-mesh sieve, to obtain 10,000 rabeprazole sodium pills, that is, each rabeprazole sodium pill contains 20mg of rabeprazole sodium; S13: The rabeprazole sodium pills prepared in S12 and 1.2 parts of magnesium stearate are stirred and mixed evenly, and then compressed into tablets to obtain the core layer; S2: Enteric coating: S21: (1) Add 10 parts of starch to 100 parts of deionized water, stir and heat to 50°C, and add 5 wt% sodium hydroxide aqueous solution to adjust the pH to 8.5. After stirring and mixing for 6 hours, a deprotonated starch solution is obtained; (2) Add 0.85 parts of 2-bromo-1-dodecene to 10 parts of N,N-dimethylformamide, stir and mix evenly to obtain a 2-bromo-1-dodecene solution; (3) Add the 2-bromo-1-dodecene solution to the deprotonated starch solution, stir and react at room temperature for 6 hours, add excess deionized water to stop the reaction, extract and collect the organic phase, and then distill under reduced pressure to obtain modified starch; S22: Add 6 parts modified starch, 6 parts triethyl citrate, 30 parts enteric acrylic resin Eudragit L100, and 12.5 parts talc to 650 parts 95wt% ethanol aqueous solution, stir and mix evenly to obtain enteric coating solution. S23: After preheating the drug core layer to 40℃, place it in a coating pan, then atomize and spray the enteric coating solution (atomization pressure 0.2MPa, spraying temperature 55℃, spraying speed 4mL / min, coating pan rotation speed 15r / min) onto the drug core layer, and then vacuum dry (vacuum degree 10). -2 (Pa, drying temperature 55℃, drying time 90min), forming an enteric coating layer, controlling the weight gain 6±0.1wt%; to obtain rabeprazole sodium enteric-coated tablets.

[0027] Example 2: A method for preparing rabeprazole sodium enteric-coated tablets: S1: Preparation of the drug core layer: S11: Add 8 parts of povidone K30 to 25 parts of anhydrous ethanol, stir and mix evenly to obtain an adhesive solution; S12: Mix 20 parts rabeprazole sodium, 30 parts microcrystalline cellulose, 30 parts magnesium oxide, and 8 parts crospovidone until homogeneous. Then add the binder solution and continue mixing for 15 minutes. Finally, granulate and vacuum dry (vacuum degree 10). -2 Pa, drying temperature is 55℃, dried until the core layer contains ≤2wt% anhydrous ethanol), passed through a 24-mesh sieve, to obtain 10,000 rabeprazole sodium pills, that is, each rabeprazole sodium pill contains 20mg of rabeprazole sodium; S13: The rabeprazole sodium pills prepared in S12 and 1.2 parts of magnesium stearate are stirred and mixed evenly, and then compressed into tablets to obtain the core layer. S2: Enteric coating: S21: (1) Add 10 parts of starch to 100 parts of deionized water, stir and heat to 50°C, and add 5 wt% sodium hydroxide aqueous solution to adjust the pH to 8.5. After stirring and mixing for 6 hours, a deprotonated starch solution is obtained; (2) Add 0.85 parts of 2-bromo-1-dodecene to 10 parts of N,N-dimethylformamide, stir and mix evenly to obtain a 2-bromo-1-dodecene solution; (3) Add the 2-bromo-1-dodecene solution to the deprotonated starch solution, stir and react at room temperature for 6 hours, add excess deionized water to stop the reaction, extract and collect the organic phase, and then distill under reduced pressure to obtain modified starch; S22: Add 4 parts modified starch, 6 parts triethyl citrate, 30 parts enteric acrylic resin Eudragit L100, and 12.5 parts talc to 650 parts 95wt% ethanol aqueous solution, stir and mix evenly to obtain enteric coating solution. S23: After preheating the drug core layer to 40℃, place it in a coating pan, then atomize and spray the enteric coating solution (atomization pressure 0.2MPa, spraying temperature 55℃, spraying speed 4mL / min, coating pan rotation speed 15r / min) onto the drug core layer, and then vacuum dry (vacuum degree 10). -2 (Pa, drying temperature 55℃, drying time 90min), forming an enteric coating layer, controlling the weight gain 6±0.1wt%, to obtain rabeprazole sodium enteric-coated tablets.

[0028] Example 3: A method for preparing rabeprazole sodium enteric-coated tablets: S1: Preparation of the drug core layer: S11: Add 8 parts of povidone K30 to 25 parts of anhydrous ethanol, stir and mix evenly to obtain an adhesive solution; S12: Mix 20 parts rabeprazole sodium, 30 parts microcrystalline cellulose, 30 parts magnesium oxide, and 8 parts crospovidone until homogeneous. Then add the binder solution and continue mixing for 15 minutes. Finally, granulate and vacuum dry (vacuum degree 10). -2 Pa, drying temperature is 55℃, dried until the core layer contains ≤2wt% anhydrous ethanol), passed through a 24-mesh sieve, to obtain 10,000 rabeprazole sodium pills, that is, each rabeprazole sodium pill contains 20mg of rabeprazole sodium; S13: The rabeprazole sodium pills prepared in S12 and 1.2 parts of magnesium stearate are stirred and mixed evenly, and then compressed into tablets to obtain the core layer; S2: Enteric coating: S21: (1) Add 10 parts of starch to 100 parts of deionized water, stir and heat to 50°C, and add 5 wt% sodium hydroxide aqueous solution to adjust the pH to 8.5. After stirring and mixing for 6 hours, a deprotonated starch solution is obtained; (2) Add 0.85 parts of 2-bromo-1-dodecene to 10 parts of N,N-dimethylformamide, stir and mix evenly to obtain a 2-bromo-1-dodecene solution; (3) Add the 2-bromo-1-dodecene solution to the deprotonated starch solution, stir and react at room temperature for 6 hours, add excess deionized water to stop the reaction, extract and collect the organic phase, and then distill under reduced pressure to obtain modified starch; S22: Add 8 parts modified starch, 6 parts triethyl citrate, 30 parts enteric acrylic resin Eudragit L100, and 12.5 parts talc to 650 parts 95wt% ethanol aqueous solution, stir and mix evenly to obtain enteric coating solution. S23: After preheating the drug core layer to 40℃, place it in a coating pan, then atomize and spray the enteric coating solution (atomization pressure 0.2MPa, spraying temperature 55℃, spraying speed 4mL / min, coating pan rotation speed 15r / min) onto the drug core layer, and then vacuum dry (vacuum degree 10). -2 (Pa, drying temperature 55℃, drying time 90min), forming an enteric coating layer, controlling the weight gain 6±0.1wt%, to obtain rabeprazole sodium enteric-coated tablets.

[0029] Example 4: A method for preparing rabeprazole sodium enteric-coated tablets: S1: Preparation of the drug core layer: S11: Add 8 parts of povidone K30 to 25 parts of anhydrous ethanol, stir and mix evenly to obtain an adhesive solution; S12: Mix 10 parts rabeprazole sodium, 30 parts microcrystalline cellulose, 30 parts magnesium oxide, and 8 parts crospovidone until homogeneous. Then add the binder solution and continue mixing for 15 minutes. Finally, granulate and vacuum dry (vacuum degree 10). -2 Pa, drying temperature is 55℃, dried until the core layer contains ≤2wt% anhydrous ethanol), passed through a 24-mesh sieve, to obtain 10,000 rabeprazole sodium pills, that is, each rabeprazole sodium pill contains 10mg of rabeprazole sodium; S13: The rabeprazole sodium pills prepared in S12 and 1.2 parts of magnesium stearate are stirred and mixed evenly, and then compressed into tablets to obtain the core layer. S2: Enteric coating: S21: (1) Add 10 parts of starch to 100 parts of deionized water, stir and heat to 50°C, and add 5 wt% sodium hydroxide aqueous solution to adjust the pH to 8.5. After stirring and mixing for 6 hours, a deprotonated starch solution is obtained; (2) Add 0.85 parts of 2-bromo-1-dodecene to 10 parts of N,N-dimethylformamide, stir and mix evenly to obtain a 2-bromo-1-dodecene solution; (3) Add the 2-bromo-1-dodecene solution to the deprotonated starch solution, stir and react at room temperature for 6 hours, add excess deionized water to stop the reaction, extract and collect the organic phase, and then distill under reduced pressure to obtain modified starch; S22: Add 6 parts modified starch, 6 parts triethyl citrate, 30 parts enteric acrylic resin Eudragit L100, and 12.5 parts talc to 650 parts 95wt% ethanol aqueous solution, stir and mix evenly to obtain enteric coating solution. S23: After preheating the drug core layer to 40℃, place it in a coating pan, then atomize and spray the enteric coating solution (atomization pressure 0.2MPa, spraying temperature 55℃, spraying speed 4mL / min, coating pan rotation speed 15r / min) onto the drug core layer, and then vacuum dry (vacuum degree 10). -2 (Pa, drying temperature 55℃, drying time 90min), forming an enteric coating layer, controlling the weight gain 6±0.1wt%; to obtain rabeprazole sodium enteric-coated tablets.

[0030] The following is a control experiment based on Example 1, with comparative examples 1 and 2 set up as follows: Comparative Example 1: Comparative Example 1 is based on Example 1, with the following adjustment: no modification treatment is performed on the starch, while other processes remain unchanged. Specifically: A method for preparing rabeprazole sodium enteric-coated tablets: S1: Preparation of the drug core layer: S11: Add 8 parts of povidone K30 to 25 parts of anhydrous ethanol, stir and mix evenly to obtain an adhesive solution; S12: Mix 20 parts rabeprazole sodium, 30 parts microcrystalline cellulose, 30 parts magnesium oxide, and 8 parts crospovidone until homogeneous. Then add the binder solution and continue mixing for 15 minutes. Finally, granulate and vacuum dry (vacuum degree 10). -2 Pa, drying temperature is 55℃, dried until the core layer contains ≤2wt% anhydrous ethanol), passed through a 24-mesh sieve, to obtain 10,000 rabeprazole sodium pills, that is, each rabeprazole sodium pill contains 20mg of rabeprazole sodium; S13: The rabeprazole sodium pills prepared in S12 and 1.2 parts of magnesium stearate are stirred and mixed evenly, and then compressed into tablets to obtain the core layer. S2: Enteric coating: S21: Add 6 parts starch, 6 parts triethyl citrate, 30 parts enteric acrylic resin Eudragit L100, and 12.5 parts talc to 650 parts 95wt% ethanol aqueous solution, stir and mix evenly to obtain enteric coating solution. S22: After preheating the drug core layer to 40℃, place it in a coating pan, then atomize and spray the enteric coating solution (atomization pressure 0.2MPa, spraying temperature 55℃, spraying speed 4mL / min, coating pan rotation speed 15r / min) onto the drug core layer, and then vacuum dry (vacuum degree 10). -2 (Pa, drying temperature 55℃, drying time 90min), forming an enteric coating layer, controlling the weight gain 6±0.1wt%, to obtain rabeprazole sodium enteric-coated tablets.

[0031] Comparative Example 2: Comparative Example 2 is based on Example 1, with the following adjustments: no modified starch was added, and all modified starch was replaced with enteric acrylic resin Eudragit L100. Other processes remained unchanged. Specifically: A method for preparing rabeprazole sodium enteric-coated tablets: S1: Preparation of the drug core layer: S11: Add 8 parts of povidone K30 to 25 parts of anhydrous ethanol, stir and mix evenly to obtain an adhesive solution; S12: Mix 20 parts rabeprazole sodium, 30 parts microcrystalline cellulose, 30 parts magnesium oxide, and 8 parts crospovidone until homogeneous. Then add the binder solution and continue mixing for 15 minutes. Finally, granulate and vacuum dry (vacuum degree 10). -2 Pa, drying temperature is 55℃, dried until the core layer contains ≤2wt% anhydrous ethanol), passed through a 24-mesh sieve, to obtain 10,000 rabeprazole sodium pills, that is, each rabeprazole sodium pill contains 20mg of rabeprazole sodium; S13: The rabeprazole sodium pills prepared in S12 and 1.2 parts of magnesium stearate are stirred and mixed evenly, and then compressed into tablets to obtain the core layer; S2: Enteric coating: S21: Add 6 parts of triethyl citrate, 36 parts of enteric acrylic resin Eudragit L100, and 12.5 parts of talc to 650 parts of 95wt% ethanol aqueous solution, stir and mix evenly to obtain enteric coating solution; S22: After preheating the drug core layer to 40℃, place it in a coating pan, then atomize and spray the enteric coating solution (atomization pressure 0.2MPa, spraying temperature 55℃, spraying speed 4mL / min, coating pan rotation speed 15r / min) onto the drug core layer, and then vacuum dry (vacuum degree 10). -2 (Pa, drying temperature 55℃, drying time 90min), forming an enteric coating layer, controlling the weight gain 6±0.1wt%, to obtain rabeprazole sodium enteric-coated tablets.

[0032] Performance Test 1: According to the "Guidelines for the Determination and Comparison of Dissolution Curves of Common Oral Solid Dosage Forms," ​​the in vitro dissolution performance of rabeprazole sodium enteric-coated tablets prepared in Examples 1-4 and Comparative Examples 1-2 of this invention, as well as commercially available rabeprazole sodium enteric-coated tablets (20mg) from the brand Shutaide, was tested in dissolution media at different pH values. The specific test methods are as follows: 1. Prepare a dissolution medium with the following pH: (1) Dissolution medium with pH=1.2: Take 7.65 mL of hydrochloric acid, dilute with deionized water to 1000 mL, shake well to obtain a dissolution medium with pH=1.2; (2) Dissolution medium with pH=6.0: Take 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution and mix with 28 mL of 0.2 mol / L sodium hydroxide solution, add deionized water to dilute to 1000 mL, shake well to obtain dissolution medium with pH=6.0; The potassium dihydrogen phosphate solution is prepared as follows: 27.22 g of potassium dihydrogen phosphate is dissolved and diluted with deionized water to 1000 mL to obtain a 0.2 mol / L potassium dihydrogen phosphate solution; the sodium hydroxide solution is prepared as follows: 8.00 g of sodium hydroxide is dissolved and diluted with deionized water to 1000 mL to obtain a 0.2 mol / L sodium hydroxide solution. (3) Dissolution medium with pH=6.8: Take 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution and mix with 112 mL of 0.2 mol / L sodium hydroxide solution, add deionized water to dilute to 1000 mL, shake well to obtain dissolution medium with pH=6.8; (4) Dissolution medium with pH=7.0: Take 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution and mix with 145.5 mL of 0.2 mol / L sodium hydroxide solution, add deionized water to dilute to 1000 mL, shake well to obtain dissolution medium with pH=7.0; (5) Dissolution medium with pH=8.0: Take 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution and mix with 230.5 mL of 0.2 mol / L sodium hydroxide solution, add deionized water to dilute to 1000 mL, shake well, and obtain the dissolution medium with pH=8.0; 2. After heating each dissolution medium to 37.5℃ in a water bath, the dissolution rate was tested using the basket method: Rabeprazole sodium enteric-coated tablets corresponding to each example were placed in a rotating basket and placed in dissolution media of different pH values. The baskets were then treated at a speed of 100 r / min for 120 min. The baskets were then removed, and the remaining amount of rabeprazole sodium was measured. The dissolution rate (%) of rabeprazole sodium enteric-coated tablets in each pH dissolution medium was indirectly calculated.

[0033] The specific test results are shown in Table 1 below: Table 1

[0034] Results Analysis: Comparing Examples 1-3 and commercially available brands in Table 1 above, we can see that: (1) In the dissolution medium with pH=1.2, Example 1 has a lower dissolution rate compared with other examples, which indicates that it has better stability under acidic conditions; while in Example 3, the modified starch content of the enteric coating is too high, and the stability of the enteric coating is poor under the action of gastric acid. Therefore, Example 3 has a higher dissolution rate. (2) In the dissolution medium at pH=6.0, since the modified starch content in Example 3 is relatively high, the enteric coating obtained by atomization spraying is more dense. Therefore, the dissolution rate of Example 3 is the lowest at this time. In contrast, the modified starch content in Example 2 is relatively low, and the quality of the enteric coating formed is poor. Therefore, the dissolution rate of Example 2 is the highest at this time. (3) In the dissolution media with pH=6.8, 7.0 and 8.0, it can be seen that the dissolution rate of Example 2 is less than that of Example 1 and Example 3. However, the dissolution rates of Example 1 and Example 3 tend to be similar as the pH of the dissolution medium increases, and there is no significant difference.

[0035] (4) However, it should be noted that the stability of rabeprazole sodium dissolved at pH ≤ 6.0 is insufficient and it will degrade. That is, the rabeprazole sodium dissolved at this time cannot exert its maximum effect in the human body. The actual effective effect in the human body should be exerted by rabeprazole sodium dissolved at pH > 6.0. Based on cost considerations, and combined with the dissolution rate of Examples 1 and 3 in Table 1 above in dissolution media at pH=1.2 and pH=6.0, and considering the actual situation of human body structure, Example 1 is the optimal example. (5) Further comparison of Example 1 and commercially available brands shows that in a dissolution medium with pH ≤ 6.0, Example 1 of the present invention has a lower dissolution rate and better stability; in a dissolution medium with pH > 6.0, Example 1 of the present invention has a higher dissolution rate and higher drug utilization rate. Therefore, the rabeprazole sodium enteric-coated tablets prepared in Example 1 of the present invention have better performance than commercially available brands. (6) Except for the content of rabeprazole sodium, there are no other differences between Example 4 (10mg per tablet) and Example 1 (20mg per tablet). The final test data are similar, and Example 4 also has excellent performance.

[0036] Furthermore, comparing Example 1 with Comparative Examples 1 and 2, it can be seen that: (7) Comparative Example 1 did not modify the starch, so it lacked hydrophobicity and had insufficient affinity for enteric acrylic resin, resulting in poor quality of the enteric coating. Therefore, in dissolution media with pH=1.2 and pH=6.0, the dissolution rate of rabeprazole sodium enteric-coated tablets prepared in Comparative Example 1 was significantly greater than that in Example 1. In dissolution media with pH=6.8, pH=7.0 and pH=8.0, due to the hydrophilicity of starch and the poor quality of the enteric coating itself, the dissolution rate was even better than that in Example 1. (8) In Comparative Example 2, since no modified starch was added, the performance of the enteric coating layer was significantly worse than that in Example 1, and therefore the dissolution rate in dissolution media at various pH values ​​decreased.

[0037] Based on the results of the above performance test 1, and further based on Examples 1 and 4, a gastric coating layer was atomized and sprayed onto the rabeprazole sodium enteric-coated tablets prepared in Examples 1 and 4, respectively, to set up Examples 5 and 6; and based on Example 5, a control experiment was further conducted, setting up Comparative Example 3, as follows: Example 5: A method for preparing rabeprazole sodium enteric-coated tablets: S1: Preparation of the drug core layer: S11: Add 8 parts of povidone K30 to 25 parts of anhydrous ethanol, stir and mix evenly to obtain an adhesive solution; S12: Mix 20 parts rabeprazole sodium, 30 parts microcrystalline cellulose, 30 parts magnesium oxide, and 8 parts crospovidone evenly. Then add the binder solution and continue mixing. Finally, granulate and vacuum dry (vacuum degree 10). -2 Pa, drying temperature is 55℃, dried until the core layer contains ≤2wt% anhydrous ethanol), passed through a 24-mesh sieve, to obtain 10,000 rabeprazole sodium pills, that is, each rabeprazole sodium pill contains 20mg of rabeprazole sodium; S13: The rabeprazole sodium pills prepared in S12 and 1.2 parts of magnesium stearate are stirred and mixed evenly, and then compressed into tablets to obtain the core layer; S2: Enteric coating: S21: (1) Add 10 parts of starch to 100 parts of deionized water, stir and heat to 50°C, and add 5 wt% sodium hydroxide aqueous solution to adjust the pH to 8.5. After stirring and mixing for 6 hours, a deprotonated starch solution is obtained; (2) Add 0.85 parts of 2-bromo-1-dodecene to 10 parts of N,N-dimethylformamide, stir and mix evenly to obtain a 2-bromo-1-dodecene solution; (3) Add the 2-bromo-1-dodecene solution to the deprotonated starch solution, stir and react at room temperature for 6 hours, add excess deionized water to stop the reaction, extract and collect the organic phase, and then distill under reduced pressure to obtain modified starch; S22: Add 6 parts modified starch, 6 parts triethyl citrate, 30 parts enteric acrylic resin Eudragit L100, and 12.5 parts talc to 650 parts 95wt% ethanol aqueous solution, stir and mix evenly to obtain enteric coating solution. S23: After preheating the drug core layer to 40℃, place it in a coating pan, then atomize and spray the enteric coating solution (atomization pressure 0.2MPa, spraying temperature 55℃, spraying speed 4mL / min, coating pan rotation speed 15r / min) onto the drug core layer, and then vacuum dry (vacuum degree 10). -2 (Pa, drying temperature 55℃, drying time 90min), forming an enteric coating, controlling weight gain 6±0.1wt%; S3: Gastric lysate coating: S31: (1) Add 10 parts of chitosan with a degree of deacetylation of 80% to a 2wt% acetic acid solution, stir and heat to 65℃ to obtain a chitosan solution; (2) Add 3 parts of triethyl citrate and 0.8 parts of glycerol to the chitosan solution, stir and mix evenly to obtain a gastric coating solution; S32: After preheating the enteric coating layer to 40℃, place it in a coating pan, then atomize and spray the enteric coating solution (atomization pressure 0.2MPa, spraying temperature 55℃, spraying speed 4mL / min, coating pan rotation speed 15r / min) onto the enteric coating layer, and then vacuum dry (vacuum degree 10). -2 (Pa, drying temperature 55℃, drying time 90min), forming a gastric lysate, controlling the weight gain to 3±0.1wt%, to obtain rabeprazole sodium enteric-coated tablets.

[0038] Example 6: A method for preparing rabeprazole sodium enteric-coated tablets: S1: Preparation of the drug core layer: S11: Add 8 parts of povidone K30 to 25 parts of anhydrous ethanol, stir and mix evenly to obtain an adhesive solution; S12: Mix 10 parts rabeprazole sodium, 30 parts microcrystalline cellulose, 30 parts magnesium oxide, and 8 parts crospovidone evenly. Then add the binder solution and continue mixing. Finally, granulate and vacuum dry (vacuum degree 10). -2 Pa, drying temperature is 55℃, dried until the core layer contains ≤2wt% anhydrous ethanol), passed through a 24-mesh sieve, to obtain 10,000 rabeprazole sodium pills, that is, each rabeprazole sodium pill contains 10mg of rabeprazole sodium; S13: The rabeprazole sodium pills prepared in S12 and 1.2 parts of magnesium stearate are stirred and mixed evenly, and then compressed into tablets to obtain the core layer. S2: Enteric coating: S21: (1) Add 10 parts of starch to 100 parts of deionized water, stir and heat to 50°C, and add 5 wt% sodium hydroxide aqueous solution to adjust the pH to 8.5. After stirring and mixing for 6 hours, a deprotonated starch solution is obtained; (2) Add 0.85 parts of 2-bromo-1-dodecene to 10 parts of N,N-dimethylformamide, stir and mix evenly to obtain a 2-bromo-1-dodecene solution; (3) Add the 2-bromo-1-dodecene solution to the deprotonated starch solution, stir and react at room temperature for 6 hours, add excess deionized water to stop the reaction, extract and collect the organic phase, and then distill under reduced pressure to obtain modified starch; S22: Add 6 parts modified starch, 6 parts triethyl citrate, 30 parts enteric acrylic resin Eudragit L100, and 12.5 parts talc to 650 parts 95wt% ethanol aqueous solution, stir and mix evenly to obtain enteric coating solution. S23: After preheating the drug core layer to 40℃, place it in a coating pan, then atomize and spray the enteric coating solution (atomization pressure 0.2MPa, spraying temperature 55℃, spraying speed 4mL / min, coating pan rotation speed 15r / min) onto the drug core layer, and then vacuum dry (vacuum degree 10). -2 (Pa, drying temperature 55℃, drying time 90min), forming an enteric coating, controlling weight gain 6±0.1wt%; S3: Gastric lysate coating: S31: (1) Add 10 parts of chitosan with a degree of deacetylation of 80% to a 2wt% acetic acid solution, stir and heat to 65℃ to obtain a chitosan solution; (2) Add 3 parts of triethyl citrate and 0.8 parts of glycerol to the chitosan solution, stir and mix evenly to obtain a gastric coating solution; S32: After preheating the enteric coating layer to 40℃, place it in a coating pan, then atomize and spray the enteric coating solution (atomization pressure 0.2MPa, spraying temperature 55℃, spraying speed 4mL / min, coating pan rotation speed 15r / min) onto the enteric coating layer, and then vacuum dry (vacuum degree 10). -2 (Pa, drying temperature 55℃, drying time 90min), forming a gastric lysate, controlling the weight gain to 3±0.1wt%, to obtain rabeprazole sodium enteric-coated tablets.

[0039] Comparative Example 3: Comparative Example 3 is based on Example 5, with the following adjustment: the degree of deacetylation of chitosan was set to 60%, while other processes remained unchanged. Specifically: A method for preparing rabeprazole sodium enteric-coated tablets: S1: Preparation of the drug core layer: S11: Add 8 parts of povidone K30 to 25 parts of anhydrous ethanol, stir and mix evenly to obtain an adhesive solution; S12: Mix 20 parts rabeprazole sodium, 30 parts microcrystalline cellulose, 30 parts magnesium oxide, and 8 parts crospovidone evenly. Then add the binder solution and continue mixing. Finally, granulate and vacuum dry (vacuum degree 10). -2 Pa, drying temperature is 55℃, dried until the core layer contains ≤2wt% anhydrous ethanol), passed through a 24-mesh sieve, to obtain 10,000 rabeprazole sodium pills, that is, each rabeprazole sodium pill contains 20mg of rabeprazole sodium; S13: The rabeprazole sodium pills prepared in S12 and 1.2 parts of magnesium stearate are stirred and mixed evenly, and then compressed into tablets to obtain the core layer; S2: Enteric coating: S21: (1) Add 10 parts of starch to 100 parts of deionized water, stir and heat to 50°C, and add 5 wt% sodium hydroxide aqueous solution to adjust the pH to 8.5. After stirring and mixing for 6 hours, a deprotonated starch solution is obtained; (2) Add 0.85 parts of 2-bromo-1-dodecene to 10 parts of N,N-dimethylformamide, stir and mix evenly to obtain a 2-bromo-1-dodecene solution; (3) Add the 2-bromo-1-dodecene solution to the deprotonated starch solution, stir and react at room temperature for 6 hours, add excess deionized water to stop the reaction, extract and collect the organic phase, and then distill under reduced pressure to obtain modified starch; S22: Add 8 parts modified starch, 6 parts triethyl citrate, 30 parts enteric acrylic resin Eudragit L100, and 12.5 parts talc to 650 parts 95wt% ethanol aqueous solution, stir and mix evenly to obtain enteric coating solution. S23: After preheating the drug core layer to 40℃, place it in a coating pan, then atomize and spray the enteric coating solution (atomization pressure 0.2MPa, spraying temperature 55℃, spraying speed 4mL / min, coating pan rotation speed 15r / min) onto the drug core layer, and then vacuum dry (vacuum degree 10). -2 (Pa, drying temperature 55℃, drying time 90min), forming an enteric coating, controlling weight gain 6±0.1wt%; S3: Gastric lysate coating: S31: (1) Add 10 parts of chitosan with a degree of deacetylation of 60% to a 2wt% acetic acid solution, stir and heat to 65℃ to obtain a chitosan solution; (2) Add 3 parts of triethyl citrate and 0.8 parts of glycerol to the chitosan solution, stir and mix evenly to obtain a gastric coating solution; S32: After preheating the enteric coating layer to 40℃, place it in a coating pan, then atomize and spray the enteric coating solution (atomization pressure 0.2MPa, spraying temperature 55℃, spraying speed 4mL / min, coating pan rotation speed 15r / min) onto the enteric coating layer, and then vacuum dry (vacuum degree 10). -2 (Pa, drying temperature 55℃, drying time 90min), forming a gastric lysate, controlling the weight gain to 3±0.1wt%, to obtain rabeprazole sodium enteric-coated tablets.

[0040] Performance Test 2: The rabeprazole sodium enteric-coated tablets corresponding to Examples 1, 5, 6, and Comparative Example 3 were placed in a rotating basket and immersed in a 2wt% amylase aqueous solution at 37.5℃ for 15 seconds, then removed; then immersed in deionized water at 37.5℃ for 5 seconds, then removed; finally placed in a dissolution medium at pH=1.2 at 37.5℃ for 120 minutes at a speed of 100 r / min, the rotating basket was removed, and the remaining amount of rabeprazole sodium was measured to indirectly calculate the dissolution rate (%) of rabeprazole sodium enteric-coated tablets in each pH dissolution medium.

[0041] The specific test results are shown in Table 2 below: Table 2

[0042] Results Analysis: Comparing the data from Examples 1, 5, 6, and Comparative Example 3 in Table 2 above, we can see that: (1) In Example 1, the lack of a gastric soluble layer resulted in the destruction of the enteric soluble layer in the aqueous solution of starch-degrading enzyme, which in turn led to a higher dissolution rate in the dissolution medium at pH=1.2, i.e., poorer stability. (2) In Comparative Example 3, due to the low degree of deacetylation of chitosan, its hydrophobicity is poor. As a result, during the process of immersing in the aqueous solution of starch-degrading enzyme, some of the aqueous solution of starch-degrading enzyme is immersed into the enteric layer, which causes slight damage to the enteric layer of Comparative Example 3. As a result, in the dissolution medium of pH=1.2, its dissolution rate is higher than that of Example 5, but still better than that of Example 1.

[0043] (3) Similarly, except for the content of rabeprazole sodium, there are no other parameter differences between Examples 5 and 6, and the final experimental data are similar.

[0044] In summary, the enteric coating and gastric coating layers of this invention protect the core layer of rabeprazole sodium, greatly improving the overall stability of rabeprazole sodium enteric-coated tablets and increasing the efficacy of rabeprazole sodium.

[0045] 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 rabeprazole sodium enteric-coated tablets, characterized in that: Includes the following steps: S1: Preparation of the drug core layer: S11: Add the adhesive to anhydrous ethanol and stir to mix evenly to obtain an adhesive solution; S12: After mixing rabeprazole sodium, filler, stabilizer and disintegrant evenly, add binder solution, continue mixing, and finally granulate, vacuum dry and sieve to obtain rabeprazole sodium pills. S13: Rabeprazole sodium pills and lubricant are stirred and mixed evenly, and then compressed into tablets to obtain the core layer; S2: Enteric coating: S21: (1) Add starch to deionized water, stir and heat to 40~60℃, and add sodium hydroxide aqueous solution to adjust pH to 8~9. After stirring and mixing for 4~8h, a deprotonated starch solution is obtained; (2) Add 2-bromo-1-dodecene to N,N-dimethylformamide, stir and mix evenly to obtain a 2-bromo-1-dodecene solution; (3) Add the 2-bromo-1-dodecene solution to the deprotonated starch solution, stir and react at room temperature for 4~8h, add excess deionized water to stop the reaction, extract and collect the organic phase, and then distill under reduced pressure to obtain modified starch; S22: Add modified starch, plasticizer, enteric acrylic resin, and talc to a 95wt% ethanol aqueous solution, stir and mix evenly to obtain an enteric coating solution; S23: After the drug core layer is preheated, it is placed in a coating pan, and then the enteric coating solution is atomized and sprayed onto the drug core layer. After vacuum drying, an enteric layer is formed to obtain rabeprazole sodium enteric-coated tablets. The enteric coating solution comprises the following raw material components: by weight, 4-8 parts modified starch, 4-8 parts plasticizer, 30 parts enteric acrylic resin, 10-15 parts talc, and 600-750 parts ethanol aqueous solution.

2. The method for preparing rabeprazole sodium enteric-coated tablets according to claim 1, characterized in that: The core layer comprises the following raw material components: by weight ratio, 10-20 parts of rabeprazole sodium, 6-10 parts of binder, 25-35 parts of filler, 25-35 parts of stabilizer, 6-10 parts of disintegrant, 1-1.5 parts of lubricant, and 20-25 parts of anhydrous ethanol.

3. The method for preparing rabeprazole sodium enteric-coated tablets according to claim 2, characterized in that: The adhesive is polyvinylpyrrolidone K30; the filler is microcrystalline cellulose; the stabilizer is magnesium oxide; the disintegrant is cross-linked polyvinylpyrrolidone; and the lubricant is magnesium stearate.

4. The method for preparing rabeprazole sodium enteric-coated tablets according to claim 1, characterized in that: The plasticizer is triethyl citrate; the enteric acrylic resin is Eudragit L100.

5. The method for preparing rabeprazole sodium enteric-coated tablets according to claim 1, characterized in that: The mass ratio of starch to 2-bromo-1-dodecene is 10:(0.5~1).

6. The method for preparing rabeprazole sodium enteric-coated tablets according to claim 1, characterized in that: The rabeprazole sodium enteric-coated tablets also include a gastric coating layer, which is obtained by atomizing and spraying a gastric coating solution. Specific step S3 is: gastric lysate coating: S31: (1) Add chitosan to a 2wt% aqueous acetic acid solution, stir and heat to 60~70℃ to obtain a chitosan solution; (2) Add plasticizer and auxiliary toughening agent to the chitosan solution, stir and mix evenly to obtain a gastric coating solution; S32: After the enteric coating layer is preheated to 35~45℃, it is placed in a coating pan, and then the gastric coating solution is atomized and sprayed onto the enteric coating layer. After vacuum drying, the gastric coating layer is formed, and rabeprazole sodium enteric-coated tablets are obtained.

7. The method for preparing rabeprazole sodium enteric-coated tablets according to claim 6, characterized in that: The gastric coating solution comprises the following raw material components: by weight, 6-12 parts chitosan, 2-4 parts plasticizer, 0.5-1 part auxiliary toughening agent, and 1000 parts aqueous acetic acid solution.

8. The method for preparing rabeprazole sodium enteric-coated tablets according to claim 7, characterized in that: The degree of deacetylation of the chitosan is ≥70%.

9. The method for preparing rabeprazole sodium enteric-coated tablets according to claim 7, characterized in that: The plasticizer is triethyl citrate; the auxiliary toughening agent is glycerol.

10. The rabeprazole sodium enteric-coated tablets prepared according to any one of claims 1 to 9, characterized in that: The rabeprazole sodium enteric-coated tablets are composed of a core layer, an enteric layer, and a gastric coating layer from the inside out; wherein, the enteric coating layer increases the weight by 5-8 wt%; and the gastric coating layer increases the weight by 2-5 wt%.

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