Preparation process of mesalazine enteric-coated sustained-release granules

Abstract

The present invention relates to the field of pharmaceutical preparations, and specifically to a preparation process of mesalazine enteric-coated sustained-release granules. The present invention discloses a preparation process of mesalazine enteric-coated sustained-release granules, which uses octenyl succinic anhydride modified starch to prepare hydrophobic starch; uses chitosan quaternary ammonium salt and starch as raw materials to prepare chitosan quaternary ammonium salt modified starch; mixes hydrophobic starch, starch and polyvinyl alcohol to prepare an adhesive slurry; loads mesalazine with chitosan quaternary ammonium salt modified starch, and then adds the adhesive slurry to extrude, spheronize and dry to obtain spherical dry pellets; coats the spherical dry pellets to obtain mesalazine enteric-coated sustained-release granules.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly to a preparation process of mesalazine enteric-coated sustained-release granules. Background Art

[0002] Mesalazine is a drug for treating ulcerative colitis. Its therapeutic effect on the disease is independent of its concentration in the systemic circulation and is only related to the concentration of mesalazine at the intestinal inflammation site. It can only have a better therapeutic effect when maintaining a high concentration in the intestine. Therefore, mesalazine is usually formulated into a colon-targeted dosage form.

[0003] After oral administration of mesalazine sustained-release granules, if the drug release rate is too fast, the rapidly released mesalazine will be quickly absorbed by the human body and enter the systemic circulation, thereby reducing its concentration at the intestinal inflammation site and decreasing the therapeutic effect. Therefore, it is highly necessary to provide a mesalazine enteric-coated sustained-release granule with a function of delaying drug release. Summary of the Invention

[0004] The purpose of the present invention is to provide a preparation process of mesalazine enteric-coated sustained-release granules to solve the problems raised in the above background art.

[0005] To solve the above technical problems, the present invention provides the following technical solution: A preparation process of mesalazine enteric-coated sustained-release granules, comprising the following steps:

[0006] Step 1:

[0007] Disperse starch in deionized water, stir and add sodium hydroxide solution to obtain a starch dispersion with a pH value of 7.5 - 8; disperse octenyl succinic anhydride in absolute ethanol to obtain an octenyl succinic anhydride dispersion; add the octenyl succinic anhydride dispersion to the starch dispersion in three equal portions, and after each addition, control the pH value of the system to remain at 7.5 - 8 with sodium hydroxide solution and react for 15 - 20 min; after the reaction is completed, perform centrifugal separation on the reaction solution, remove the supernatant, wash the precipitate with a citric acid solution with a pH value of 4 - 4.5 and deionized water respectively, and vacuum dry to obtain hydrophobic starch;

[0008] Step 2:

[0009] Disperse starch in deionized water to obtain a starch dispersion; add chitosan quaternary ammonium salt and sodium sulfate, adjust the pH value to 9 - 9.5 with sodium hydroxide solution, then add epichlorohydrin to the reaction system, heat up to 40 - 55 °C, react for 4 - 6 h, adjust the pH value of the reaction solution to 7.0, cool, filter, wash, dry, and pulverize to obtain chitosan quaternary ammonium salt-modified starch;

[0010] Step 3:

[0011] S1: Take hydrophobic starch, starch, and polyvinyl alcohol and mix them to obtain a mixture; add deionized water to the mixture, stir and gelatinize at 60 - 70 °C for 30 - 40 min, and cool down to obtain an adhesive slurry;

[0012] S2: Sieve mesalazine and chitosan quaternary ammonium salt modified starch, disperse the sieved mesalazine and chitosan quaternary ammonium salt modified starch in dichloromethane to obtain an oil phase; after stirring for 30 - 60 min, add the adhesive slurry and magnesium stearate, continue to stir for 10 - 20 min, then add polyethylene glycol and silicon dioxide and stir to make a soft material. Extrude the soft material into strip-shaped soft materials using an extrusion spheronizer and roll them into spherical wet pills. Vacuum dry the wet pills at 50 - 60 °C and sieve to obtain spherical dry pills;

[0013] S3: Disperse 1.5 - 2 parts of polyacrylic resin Eudragit s100 and 0.1 - 0.3 parts of ethyl cellulose in a 95% ethanol solution by mass concentration, add 2 - 2.5 parts of triethyl citrate to make a coating solution; coat the spherical dry pills and vacuum dry at 40 - 50 °C to obtain mesalazine enteric-coated sustained-release granules.

[0014] Further, in step 1, octenyl succinic anhydride reacts with starch in a mass ratio of (2 - 3):100.

[0015] Further, in step 2, the dosages of each component, by weight, are 6 - 10 parts of starch, 100 parts of deionized water, 0.15 - 0.22 parts of chitosan quaternary ammonium salt, 0.3 - 0.4 parts of sodium sulfate, and 7 - 9 parts of epichlorohydrin.

[0016] Further, in S1, in the mixture, the mass ratio of hydrophobic starch, starch, and polyvinyl alcohol is (0.8 - 1):1:1.

[0017] Further, in S1, in the adhesive slurry, the content of each component, by weight, is 10 - 15 parts of the mixture and 100 parts of deionized water.

[0018] Further, in S2, mesalazine and chitosan quaternary ammonium salt modified starch are respectively sieved through a 100 - 150 mesh sieve.

[0019] Further, in S2, the particle size of the spherical wet pills is 1 - 1.5 mm.

[0020] Further, in S2, in the spherical dry pills, the content of each component, by weight percentage, is 70 - 75% mesalazine, 15 - 20% chitosan quaternary ammonium salt modified starch, 5 - 10% polyethylene glycol, 1 - 5% silicon dioxide, and 1 - 5% magnesium stearate.

[0021] Further, in S3, in the coating solution, the mass ratio of polyacrylic acid resin Eudragit s100, ethyl cellulose, and triethyl citrate is (1.5 - 2):(0.1 - 0.3):(2 - 2.5).

[0022] Compared with the prior art, the beneficial effects achieved by the present invention are as follows: The present invention provides a preparation process for mesalazine enteric-coated sustained-release granules. The coating layer of the sustained-release granules is affected by the pH value of the environmental medium and is basically insoluble in the acidic environment of the stomach, and the release amount of the active drug < 2%. In the intestine, the drug can be continuously and slowly released, which plays a role in controlling the release position and release rate of the drug.

[0023] In the present invention, the inventor modified starch in two ways. Starch was modified with quaternary ammonium salt of chitosan. The quaternary ammonium salt of chitosan was grafted onto the starch granules through chemical bonds and crosslinked to form a three-dimensional network structure, forming "pits" on the surface of the starch granules, increasing the specific surface area of the starch, and improving the adsorption amount of mesalazine. At the same time, the modified starch also has a certain emulsifying effect in the emulsion, so the stability of the emulsion is higher.

[0024] In the present invention, starch was also modified with octenyl succinic anhydride to obtain hydrophobic starch. The hydrophobic starch was mixed with starch and polyvinyl alcohol to prepare an adhesive slurry. The adhesive can form a tight bond between the starch granules loaded with the drug, enhancing the agglomeration of the granules. The adhesive added with hydrophobic starch can, on the one hand, reduce the viscosity of the slurry, facilitate extrusion molding during the preparation of the soft material, avoid the soft material from adhering to the equipment, and prevent problems such as the soft material sticking to the wall and uneven molding. On the other hand, the hydrophobic chain segments and the remaining hydrophilic chain segments can improve the stability of the emulsion after addition and increase the binding efficiency between the granules. In addition, when adding the adhesive slurry, the adhesive and magnesium stearate need to be added first, and other additives are added after a period of time to avoid the additive particles from being dispersed among the starch granules loaded with the drug, avoid uneven drug concentration in the prepared granules, and improve the overall stability of the efficacy of the sustained-release granules. Specific embodiments

[0025] Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0026] The materials used in the present invention and their sources: Polyacrylic acid resin Eudragit s100 comes from Shanghai Changwei Pharmaceutical Excipient Technology Co., Ltd.; the starch is edible corn starch from Shandong Shouguang Jueneng Golden Corn Development Co., Ltd.; the quaternary ammonium salt of chitosan comes from Hubei Chang'ao Pharmaceutical Co., Ltd., food grade; ethyl cellulose comes from Hubei Nuona Technology Co., Ltd., pharmaceutical grade.

[0027] Example 1: A preparation process of mesalazine enteric-coated sustained-release granules, comprising the following steps:

[0028] Step 1:

[0029] Disperse starch in deionized water, stir and add sodium hydroxide solution to obtain a starch dispersion with a pH value of 7.5; disperse octenyl succinic anhydride in absolute ethanol to obtain an octenyl succinic anhydride dispersion; add the octenyl succinic anhydride dispersion to the starch dispersion in three equal portions, and after each addition, control the pH value of the system to remain at 7.5 with sodium hydroxide solution and react for 15 min; after the reaction is completed, centrifuge the reactant solution to remove the supernatant, wash the precipitate with citric acid solution with a pH value of 4 and deionized water respectively, and vacuum dry to obtain hydrophobic starch; wherein, octenyl succinic anhydride reacts with starch at a mass ratio of 3:100;

[0030] Step 2:

[0031] Disperse 8 g of starch in 100 g of deionized water to obtain a starch dispersion; add 0.2 g of quaternary ammonium salt of chitosan and 0.35 g of sodium sulfate, adjust the pH value to 9 with sodium hydroxide solution, then add 7 g of epichlorohydrin to the reaction system, raise the temperature to 45 °C, react for 4 h, adjust the pH value of the reaction solution to 7.0, cool, filter, wash, dry and crush to obtain quaternary ammonium salt of chitosan-modified starch;

[0032] Step 3:

[0033] S1: Take hydrophobic starch, starch, and polyvinyl alcohol and mix them in a mass ratio of 1:1:1 to obtain a mixture. Add 100 g of deionized water to 13 g of the mixture, stir and gelatinize at 60 °C for 30 min, and cool down to obtain an adhesive slurry;

[0034] S2: Pass mesalazine and quaternary ammonium salt of chitosan-modified starch through a 100-mesh sieve respectively, disperse the sieved mesalazine and quaternary ammonium salt of chitosan-modified starch in dichloromethane to obtain an oil phase; after stirring for 30 min, add the adhesive slurry and magnesium stearate, continue to stir for 10 min, then add polyethylene glycol and silicon dioxide and stir to make a soft material. Extrude the soft material into strip-shaped soft materials with an extrusion rounder and roll them into spherical wet pills with a particle size of 1 mm. Vacuum dry the wet pills at 50 °C and screen to obtain spherical dry pills; in the spherical dry pills, the content of each component, by weight percentage, is 70% mesalazine, 20% quaternary ammonium salt of chitosan-modified starch, 8% polyethylene glycol, 1% silicon dioxide, and 1% magnesium stearate;

[0035] S3: Disperse 1.8 g of polyacrylic acid resin Eudragit s100 and 0.2 g of ethyl cellulose in a 95% ethanol solution by mass concentration, add 2 g of triethyl citrate, and prepare a coating solution; after coating the spherical dry pellets, perform vacuum drying at 40 °C to obtain mesalazine enteric-coated sustained-release granules.

[0036] Example 2: A preparation process of mesalazine enteric-coated sustained-release granules, comprising the following steps:

[0037] Step 1:

[0038] Disperse starch in deionized water, stir and add sodium hydroxide solution to obtain a starch dispersion with a pH value of 7.8; disperse octenyl succinic anhydride in absolute ethanol to obtain an octenyl succinic anhydride dispersion; add the octenyl succinic anhydride dispersion to the starch dispersion in three equal portions, and after each addition, control the pH value of the system to remain at 7.5 with sodium hydroxide solution and react for 18 min; after the reaction is completed, perform centrifugal separation on the reaction solution, remove the supernatant, wash the precipitate with a citric acid solution with a pH value of 4.3 and deionized water respectively, and perform vacuum drying to obtain hydrophobic starch; wherein, octenyl succinic anhydride reacts with starch at a mass ratio of 3:100;

[0039] Step 2:

[0040] Disperse 8 g of starch in 100 g of deionized water to obtain a starch dispersion; add 0.2 g of quaternary ammonium salt of chitosan and 0.35 g of sodium sulfate, adjust the pH value to 9.3 with sodium hydroxide solution, then add 7 g of epichlorohydrin to the reaction system, raise the temperature to 40 °C, react for 5 h, adjust the pH value of the reaction solution to 7.0, cool, filter, wash, dry, and pulverize to obtain quaternary ammonium salt of chitosan-modified starch;

[0041] Step 3:

[0042] S1: Take hydrophobic starch, starch, and polyvinyl alcohol and mix them in a mass ratio of 1:1:1 to obtain a mixture. Add 100 g of deionized water to 13 g of the mixture, stir and gelatinize at 65 °C for 35 min, and cool down to obtain an adhesive slurry;

[0043] S2: Sieving mesalazine and quaternary ammonium salt modified chitosan starch through a 120-mesh sieve respectively, and dispersing the sieved mesalazine and quaternary ammonium salt modified chitosan starch in dichloromethane to obtain an oil phase; after stirring for 45 min, adding a binder slurry and magnesium stearate, continuing to stir for 15 min, then adding polyethylene glycol and silicon dioxide and stirring to make a soft material, extruding the soft material into strip-shaped soft materials by an extrusion spheronizer, and spheronizing them into spherical wet pills with a particle size of 1.2 mm, drying the wet pills in vacuum at 55 °C, and screening to obtain spherical dry pills; in the said spherical dry pills, the content of each component, by weight percentage, is 70% mesalazine, 20% quaternary ammonium salt modified chitosan starch, 8% polyethylene glycol, 1% silicon dioxide, and 1% magnesium stearate;

[0044] S3: Dissolving 1.8 g of polyacrylic resin Eudragit s100 and 0.2 g of ethyl cellulose in an ethanol solution with a mass concentration of 95%, adding 2 g of triethyl citrate, and making a coating solution; coating the spherical dry pills and drying in vacuum at 45 °C to obtain mesalazine enteric-coated sustained-release granules.

[0045] Example 3: A preparation process of mesalazine enteric-coated sustained-release granules, comprising the following steps:

[0046] Step 1:

[0047] Dispersing starch in deionized water, stirring and adding a sodium hydroxide solution to obtain a starch dispersion with a pH value of 8; dispersing octenyl succinic anhydride in absolute ethanol to obtain an octenyl succinic anhydride dispersion; adding the octenyl succinic anhydride dispersion to the starch dispersion, adding it in three equal amounts, and controlling the pH value of the system to remain at 8 with a sodium hydroxide solution and reacting for 20 min after each addition; after the reaction is completed, centrifuging the reactant solution to remove the supernatant, washing the precipitate with a citric acid solution with a pH value of 4.5 and deionized water respectively, and drying in vacuum to obtain hydrophobic starch; wherein, octenyl succinic anhydride reacts with starch in a mass ratio of 3:100;

[0048] Step 2:

[0049] Dispersing 8 g of starch in 100 g of deionized water to obtain a starch dispersion; adding 0.2 g of quaternary ammonium salt of chitosan and 0.35 g of sodium sulfate, adjusting the pH value to 9.5 with a sodium hydroxide solution, then adding 7 g of epichlorohydrin to the reaction system, heating to 55 °C, reacting for 6 h, adjusting the pH value of the reaction solution to 7.0, cooling, filtering, washing, drying, and pulverizing to obtain quaternary ammonium salt modified chitosan starch;

[0050] Step 3:

[0051] S1: Mix waxy starch, starch, and polyvinyl alcohol in a mass ratio of 1:1:1 to obtain a mixture. Add 100 g of deionized water to 13 g of the mixture, and stir and gelatinize at 65 °C for 35 min. Then cool down to obtain the binder slurry.

[0052] S2: Pass mesalazine and quaternary ammonium salt modified chitosan starch through a 150-mesh sieve respectively. Disperse the sieved mesalazine and quaternary ammonium salt modified chitosan starch in dichloromethane to obtain the oil phase. After stirring for 45 min, add the binder slurry and magnesium stearate, and continue stirring for 15 min. Then add polyethylene glycol and silicon dioxide and stir to make the soft material. Extrude the soft material into strip-shaped soft material using an extrusion spheronizer, and roll it into spherical wet pills with a particle size of 1.2 mm. Vacuum dry the wet pills at 60 °C and screen to obtain spherical dry pills. In the spherical dry pills, the content of each component, by weight percentage, is 70% mesalazine, 20% quaternary ammonium salt modified chitosan starch, 8% polyethylene glycol, 1% silicon dioxide, and 1% magnesium stearate.

[0053] S3: Disperse 1.8 g of polyacrylic resin Eudragit s100 and 0.2 g of ethyl cellulose in a 95% ethanol solution by mass concentration, add 2 g of triethyl citrate, and make the coating solution. After coating the spherical dry pills, vacuum dry at 50 °C to obtain mesalazine enteric-coated sustained-release granules.

[0054] Comparative Example 1: Do not add waxy starch to the binder slurry, and the other parameters are the same as in Example 1.

[0055] Step 1:

[0056] Disperse 8 g of starch in 100 g of deionized water to obtain a starch dispersion. Add 0.2 g of quaternary ammonium salt modified chitosan and 0.35 g of sodium sulfate, adjust the pH value to 9 with sodium hydroxide solution, then add 7 g of epichlorohydrin to the reaction system, raise the temperature to 45 °C, react for 4 h, adjust the pH value of the reaction solution to 7.0, cool, filter, wash, dry, and pulverize to obtain quaternary ammonium salt modified chitosan starch.

[0057] Step 2:

[0058] S1: Mix starch and polyvinyl alcohol in a mass ratio of 1:1 to obtain a mixture. Add 100 g of deionized water to 13 g of the mixture, and stir and gelatinize at 60 °C for 30 min. Then cool down to obtain the binder slurry.

[0059] S2: Pass mesalazine and quaternary ammonium salt modified chitosan starch through a 100-mesh sieve respectively. Disperse the sieved mesalazine and quaternary ammonium salt modified chitosan starch in dichloromethane to obtain an oil phase. After stirring for 30 min, add the binder slurry and magnesium stearate. Continue stirring for 10 min, then add polyethylene glycol and silicon dioxide and stir to make a soft material. Extrude the soft material into strip-shaped soft materials using an extrusion spheronizer and spheronize them into spherical wet pills with a particle size of 1 mm. Vacuum dry the wet pills at 50 °C and screen to obtain spherical dry pills. In the spherical dry pills, the content of each component, by weight percentage, is 70% mesalazine, 20% quaternary ammonium salt modified chitosan starch, 8% polyethylene glycol, 1% silicon dioxide, and 1% magnesium stearate.

[0060] S3: Disperse 1.8 g of polyacrylic resin Eudragit s100 and 0.2 g of ethyl cellulose in a 95% ethanol solution by mass concentration, add 2 g of triethyl citrate to make a coating solution. After coating the spherical dry pills, vacuum dry them at 40 °C to obtain mesalazine enteric-coated sustained-release granules.

[0061] Comparative Example 2: Use microcrystalline cellulose instead of quaternary ammonium salt modified chitosan starch, and the other parameters are the same as those in Example 2.

[0062] Step 1:

[0063] Disperse starch in deionized water, stir and add sodium hydroxide solution to obtain a starch dispersion with a pH value of 7.8. Disperse octenyl succinic anhydride in absolute ethanol to obtain an octenyl succinic anhydride dispersion. Add the octenyl succinic anhydride dispersion to the starch dispersion in three equal portions. After each addition, use sodium hydroxide solution to control the pH value of the system to remain at 7.5 and react for 18 min. After the reaction is completed, centrifuge the reactant solution to remove the supernatant, and wash the precipitate with citric acid solution with a pH value of 4.3 and deionized water respectively, and vacuum dry to obtain hydrophobic starch. Among them, octenyl succinic anhydride reacts with starch at a mass ratio of 3:100.

[0064] Step 2:

[0065] S1: Take hydrophobic starch, starch, and polyvinyl alcohol and mix them in a mass ratio of 1:1:1 to obtain a mixture. Add 100 g of deionized water to 13 g of the mixture and stir and gelatinize at 65 °C for 35 min, then cool down to obtain a binder slurry.

[0066] S2: Pass mesalazine and microcrystalline cellulose through a 120-mesh sieve respectively. Disperse the sieved mesalazine and microcrystalline cellulose in dichloromethane to obtain an oil phase. After stirring for 45 min, add the binder slurry and magnesium stearate. Continue stirring for 15 min, then add polyethylene glycol and silicon dioxide and stir to make a soft material. Extrude the soft material into strip-shaped soft materials using an extrusion spheronizer and spheronize them into spherical wet pills with a particle size of 1.2 mm. Vacuum dry the wet pills at 55 °C and screen to obtain spherical dry pills. In the said spherical dry pills, the content of each component, by weight percentage, is 70% mesalazine, 20% microcrystalline cellulose, 8% polyethylene glycol, 1% silicon dioxide, and 1% magnesium stearate.

[0067] S3: Disperse 1.8 g of polyacrylic resin Eudragit s100 and 0.2 g of ethyl cellulose in a 95% ethanol solution by mass concentration, add 2 g of triethyl citrate, and make a coating solution. After coating the spherical dry pills, vacuum dry them at 45 °C to obtain mesalazine enteric-coated sustained-release granules.

[0068] Comparative Example 3: Add the binder slurry, magnesium stearate, polyethylene glycol, and silicon dioxide to prepare the soft material simultaneously.

[0069] Step 1:

[0070] Disperse starch in deionized water, stir and add sodium hydroxide solution to obtain a starch dispersion with a pH value of 8. Disperse octenyl succinic anhydride in absolute ethanol to obtain an octenyl succinic anhydride dispersion. Add the octenyl succinic anhydride dispersion to the starch dispersion in three equal portions. After each addition, use sodium hydroxide solution to control the pH value of the system to remain at 8 and react for 20 min. After the reaction is completed, centrifuge the reactant solution to remove the supernatant. Wash the precipitate with a citric acid solution with a pH value of 4.5 and deionized water respectively, and vacuum dry to obtain hydrophobic starch. Among them, octenyl succinic anhydride reacts with starch in a mass ratio of 3:100.

[0071] Step 2:

[0072] Disperse 8 g of starch in 100 g of deionized water to obtain a starch dispersion. Add 0.2 g of quaternary ammonium salt of chitosan and 0.35 g of sodium sulfate. After adjusting the pH value to 9.5 with sodium hydroxide solution, add 7 g of epichlorohydrin to the reaction system, heat up to 55 °C, react for 6 h, adjust the pH value of the reaction solution to 7.0, cool, filter, wash, dry, and pulverize to obtain quaternary ammonium salt of chitosan-modified starch.

[0073] Step 3:

[0074] S1: Take tapioca starch, starch, and polyvinyl alcohol and mix them in a mass ratio of 1:1:1 to obtain a mixture. Add 100 g of deionized water to 13 g of the mixture, stir and gelatinize at 65 °C for 35 min, and cool down to obtain an adhesive slurry.

[0075] S2: Pass mesalazine and chitosan quaternary ammonium salt modified starch through a 150-mesh sieve respectively. Disperse the sieved mesalazine and chitosan quaternary ammonium salt modified starch in dichloromethane to obtain an oil phase. After stirring for 45 min, add the adhesive slurry, magnesium stearate, polyethylene glycol, and silicon dioxide and stir to make a soft material. Use an extrusion spheronizer to extrude the soft material into strip-shaped soft materials, and then spheronize them into spherical wet pellets with a particle size of 1.2 mm. Vacuum dry the wet pellets at 60 °C and screen to obtain spherical dry pellets. In the spherical dry pellets, the content of each component, by weight percentage, is 70% mesalazine, 20% chitosan quaternary ammonium salt modified starch, 8% polyethylene glycol, 1% silicon dioxide, and 1% magnesium stearate.

[0076] S3: Disperse 1.8 g of polyacrylic resin Eudragit s100 and 0.2 g of ethyl cellulose in an ethanol solution with a mass concentration of 95%, and add 2 g of triethyl citrate to make a coating solution. After coating the spherical dry pellets, vacuum dry at 50 °C to obtain mesalazine enteric-coated sustained-release granules.

[0077] Experiment: Test the mesalazine enteric-coated sustained-release granules prepared in Examples 1 to 3 and Comparative Examples 1 to 3.

[0078] Drug loading: Disperse the samples in 10 mL of absolute ethanol respectively and completely swell at 37 °C for 24 h. Crush the swollen samples and centrifuge at 15000 rpm, collect the supernatant, and detect 5-aminosalicylic acid by HPLC. Drug loading rate (%) = amount of 5-aminosalicylic acid / amount of mesalazine sustained-release granules × 100%.

[0079] Sustained release degree: The release degree was measured. Using the first method device of the dissolution test method (the first method, basket method, Appendix XC, Part II, Chinese Pharmacopoeia 2010 Edition), using 900 mL of 0.1 mol / L HCl and phosphate buffer solution with a pH value of 6.8 as the release media respectively, simulate the human gastrointestinal tract to change the pH media to measure the release degree. First, put the sample into 0.1 mol / L HCl for 2 h, with a rotation speed of 100 rpm and a temperature of 37 °C, then change to phosphate buffer solution with a pH value of 6.8 for 3 h, and complete the change of media within 5 min. Sampling is carried out every 15 min, and at the same time, an equal amount of the same-temperature media is supplemented. Filter with a 0.45 μm microporous filter membrane, take an appropriate amount of the subsequent filtrate, after dilution, according to the ultraviolet-visible spectrophotometry (Appendix IVA, Part II, Chinese Pharmacopoeia 2010 Edition), measure the absorbance and calculate the release degree. The experimental results are shown in Table 1.

[0080] Table 1. Performance test results of mesalazine enteric-coated sustained-release granules

[0081]

[0082] Conclusion: The data of Examples 1-3 show that the sustained-release granules prepared by the present invention have good performance, the release amount in 2 hours in the medium simulating the gastric environment is <2%, while the release amount in 3 hours in the medium simulating the intestinal environment is about 50%, and precise drug delivery can be achieved. The data of Example 1 and Comparative Example 1 show that after adding hydrophobic starch, the release time of the sustained-release granules in the intestinal environment is longer. The data of Example 2 and Comparative Example 2 show that using quaternary ammonium salt-modified chitosan starch as a carrier can load more active ingredients. The data of Example 3 and Comparative Example 3 show that after directly blending the binder slurry, magnesium stearate and other additives to prepare the soft material, the drug loading amount is reduced and the sustained-release effect is poor.

[0083] Finally, it should be noted that the above are only the 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 perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A preparation process of mesalazine enteric-coated sustained-release granules, characterized in that: It includes the following steps: Step 1: Disperse starch in deionized water, stir and add sodium hydroxide solution to obtain a starch dispersion with a pH value of 7.5 - 8; disperse octenyl succinic anhydride in absolute ethanol to obtain an octenyl succinic anhydride dispersion; add the octenyl succinic anhydride dispersion to the starch dispersion in three equal portions, and after each addition, use sodium hydroxide solution to control the pH value of the system to remain at 7.5 - 8 and react for 15 - 20 min; after the reaction is completed, centrifuge the reactant solution, remove the supernatant, wash the precipitate with a citric acid solution with a pH value of 4 - 4.5 and deionized water respectively, and vacuum dry to obtain hydrophobic starch; Step 2: Disperse starch in deionized water to obtain a starch dispersion; add chitosan quaternary ammonium salt and sodium sulfate, adjust the pH value to 9 - 9.5 with sodium hydroxide solution, then add epichlorohydrin to the reaction system, heat up to 40 - 55 °C, react for 4 - 6 h, adjust the pH value of the reaction solution to 7.0, cool, filter, wash, dry, and pulverize to obtain chitosan quaternary ammonium salt modified starch; Step 3: S1: Take hydrophobic starch, starch, and polyvinyl alcohol and mix them to obtain a mixture; add deionized water to the mixture, stir and gelatinize at 60 - 70 °C for 30 - 40 min, and cool down to obtain an adhesive slurry; S2: Sieve mesalazine and chitosan quaternary ammonium salt modified starch, disperse the sieved mesalazine and chitosan quaternary ammonium salt modified starch in dichloromethane to obtain an oil phase; after stirring for 30 - 60 min, add the adhesive slurry and magnesium stearate, continue to stir for 10 - 20 min, then add polyethylene glycol and silicon dioxide and stir to make a soft material, use an extrusion - spheronization machine to extrude it into strip - shaped soft materials, and spheronize them into spherical wet pills, vacuum dry the wet pills at 50 - 60 °C, and sieve to obtain spherical dry pills; S3: Disperse 1.5 - 2 parts by weight of polyacrylic resin Eudragit s100 and 0.1 - 0.3 parts by weight of ethyl cellulose in a 95% ethanol solution by mass concentration, add 2 - 2.5 parts by weight of triethyl citrate to make a coating solution; coat the spherical dry pills and vacuum dry at 40 - 50 °C to obtain mesalazine enteric - coated sustained - release granules; In S2, in the spherical dry pills, the content of each component, by weight percentage, is 70 - 75% mesalazine, 15 - 20% chitosan quaternary ammonium salt modified starch, 5 - 10% polyethylene glycol, 1 - 5% silicon dioxide, 1 - 5% magnesium stearate; In Step 2, the dosage of each component, by weight parts, is 6 - 10 parts of starch, 100 parts of deionized water, 0.15 - 0.22 parts of chitosan quaternary ammonium salt, 0.3 - 0.4 parts of sodium sulfate, 7 - 9 parts of epichlorohydrin.

2. The preparation process of a mesalazine enteric-coated sustained-release granule according to claim 1, wherein: In Step 1, octenyl succinic anhydride reacts with starch in a mass ratio of (2 - 3):

100.

3. The preparation process of a mesalazine enteric-coated sustained-release granule according to claim 1, characterized in that: In S1, in the mixture, hydrophobic starch, starch, and polyvinyl alcohol are in a mass ratio of (0.8 - 1):1:

1.

4. The preparation process of a mesalazine enteric-coated sustained-release granule according to claim 1, wherein: In S1, in the adhesive slurry, the content of each component, by weight parts, is 10 - 15 parts of the mixture and 100 parts of deionized water.

5. The preparation process of a mesalazine enteric-coated sustained-release granule according to claim 1, characterized in that: In S2, mesalazine and chitosan quaternary ammonium salt modified starch are respectively sieved through a 100 - 150 - mesh sieve.

6. The preparation process of a mesalazine enteric-coated sustained-release granule according to claim 1, characterized in that: In S2, the particle size of the spherical wet pills is 1 - 1.5 mm.

7. Mesalazine enteric-coated sustained-release granules prepared by the preparation process according to any one of claims 1 - 6.

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