Mesalazine enteric-coated sustained-release tablet and preparation process thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a mesalazine enteric-coated sustained-release tablet and a preparation process thereof. The preparation method comprises the following steps: S1, uniformly mixing mesalazine, a pH regulator, modified hydroxypropyl methyl cellulose, a filler and an adhesive, carrying out wet granulation, drying, carrying out size stabilization, adding a lubricant and a flow aid, uniformly mixing, and tabletting to obtain a tablet core; s2, uniformly mixing hydroxypropyl methyl cellulose and deionized water to obtain an isolation coating solution; spraying the isolation coating liquid onto the tablet core to form an isolation coating layer so as to obtain an isolation coating tablet core; s3, uniformly mixing a methacrylic acid-ethyl acrylate copolymer dispersion liquid, a modified polyacrylate emulsion, an ethanol water solution, Tween 80, a plasticizer and talcum powder to obtain an enteric coating liquid; and spraying the enteric coating liquid onto the isolation coating tablet core to form an enteric coating layer, thereby obtaining the mesalazine enteric sustained-release tablet.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, in particular to a mesalazine enteric-coated sustained-release tablet and a preparation process thereof. Background Art

[0002] Mesalazine, also known as 5-aminosalicylic acid, is a commonly used anti-inflammatory drug, mainly used to treat inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Mesalazine has an anti-inflammatory effect by inhibiting the synthesis of prostaglandins and the formation of leukotrienes.

[0003] Traditional mesalazine dosage forms mainly include tablets, capsules and enema solutions. Mesalazine enteric-coated sustained-release tablets are an improved drug preparation that aims to release the drug in specific parts of the intestine (such as the colon) through enteric coating and sustained-release technology, thereby increasing the local concentration and therapeutic effect of the drug. However, the existing technology has the following problems: 1. Low bioavailability: After oral administration, mesalazine is partially destroyed in gastric acid, resulting in reduced bioavailability.

[0004] 2. Short duration of action: Traditional dosage forms release drugs quickly and cannot maintain effective blood drug concentrations for a long time, requiring frequent dosing.

[0005] 3. Severe irritation to the gastrointestinal tract: Mesalazine has a certain degree of irritation to the gastrointestinal tract, and traditional dosage forms may increase the incidence of adverse reactions.

[0006] Therefore, we propose a mesalazine enteric-coated sustained-release tablet and a preparation process thereof. Summary of the invention

[0007] The object of the present invention is to provide a mesalazine enteric-coated sustained-release tablet and a preparation process thereof, so as to solve the problems raised in the prior art.

[0008] To achieve the above object, the present invention provides the following technical solutions: A preparation process of mesalazine enteric-coated sustained-release tablets comprises the following steps: Step S1: mixing mesalazine, pH adjuster, modified hydroxypropyl methylcellulose, filler and binder uniformly, wet granulating, drying, granulating, adding lubricant and glidant, mixing uniformly, tableting to obtain tablet cores; Step S2: mixing hydroxypropyl methylcellulose and deionized water evenly to obtain an isolation coating liquid; spraying the isolation coating liquid onto the tablet core to form an isolation coating layer to obtain an isolation coated tablet core; Step S3: uniformly mixing the methacrylic acid-ethyl acrylate copolymer dispersion, the modified polyacrylate emulsion, the ethanol aqueous solution, Tween 80, the plasticizer and the talcum powder to obtain an enteric coating solution; spraying the enteric coating solution onto the isolation coating tablet core to form an enteric coating layer to obtain mesalazine enteric sustained-release tablets.

[0009] Furthermore, the tablet core is composed of the following components in parts by weight: 450-550 parts of mesalamine, 50-170 parts of pH adjuster, 30-80 parts of filler, 10-40 parts of modified hydroxypropyl methylcellulose, 10-30 parts of binder, 3-10 parts of glidant, and 5-20 parts of lubricant.

[0010] Furthermore, the preparation method of the modified hydroxypropyl methylcellulose is as follows: Step (1): uniformly mixing a hydroxypropyl methylcellulose aqueous solution and sodium periodate, adjusting the pH to 2-6, heating to 30-50° C., reacting for 3-5 hours under light-shielding conditions, dialyzing, and drying to obtain dialdehyde hydroxypropyl methylcellulose; Step (2): uniformly mixing the ethylene glycol chitosan aqueous solution and the octenyl succinic anhydride ethanol aqueous solution, adjusting the pH to 8.3-8.5, reacting at 30-40° C. for 22-24 hours, dialyzing and drying to obtain ethylene glycol chitosan containing double bonds; Step (3): prepare a dialdehyde hydroxypropyl methylcellulose aqueous solution, add a mixed solution of polylactic acid-polyethylene glycol-amino and tetrahydrofuran, adjust the pH to 3-5, react at 25-35°C for 12-18 hours, then add double bond ethylene glycol chitosan and continue to react for 22-24 hours, remove the organic solvent, dialyze and dry to obtain modified hydroxypropyl methylcellulose.

[0011] In the above technical solution, sodium periodate (NaIO 4 ) was used to oxidize hydroxypropyl methylcellulose (HPMC), and the hydroxyl groups at the C2 and C3 positions of its molecular chain were oxidized to aldehyde groups to obtain dialdehyde hydroxypropyl methylcellulose; then, octenyl succinic anhydride was used to partially hydrophobically modify the water-soluble glycol chitosan (GC), and double bonds and hydrophobic groups were introduced to form an amphiphilic derivative, namely, glycol chitosan containing double bonds; finally, the aldehyde groups in dialdehyde hydroxypropyl methylcellulose were reacted with amino groups, and glycol chitosan containing double bonds and polylactic acid-polyethylene glycol-amino groups were respectively grafted to the two ends of dialdehyde hydroxypropyl methylcellulose to obtain modified hydroxypropyl methylcellulose.

[0012] Furthermore, in step (1), the concentration of the hydroxypropyl methylcellulose aqueous solution is 1-3 wt %.

[0013] Furthermore, in the step (1), the mass ratio of hydroxypropyl methylcellulose to sodium periodate is 1:(0.04-0.20).

[0014] Furthermore, in step (2), the concentration of the ethylene glycol chitosan aqueous solution is 1-3wt%, Furthermore, in step (2), the concentration of the octenyl succinic anhydride ethanol aqueous solution is 10-12 wt %, and the amount thereof is 0.1-0.2 times the mass of the ethylene glycol chitosan aqueous solution.

[0015] Furthermore, in step (3), the concentration of the dialdehyde hydroxypropyl methylcellulose aqueous solution is 10-20 wt %.

[0016] Furthermore, in the step (3), the mass ratio of polylactic acid-polyethylene glycol-amino to tetrahydrofuran is 1:(2-4).

[0017] Furthermore, in step (3), the molar ratio of the aldehyde group in the aqueous solution of dialdehyde hydroxypropyl methylcellulose to the amino group in the polylactic acid-polyethylene glycol-amino group is 1:(0.4-0.6).

[0018] Furthermore, in the step (3), the mass of the double-bond glycol chitosan is 1-2 times the mass of the dialdehyde hydroxypropyl methylcellulose.

[0019] Furthermore, the pH regulator is one or more of calcium carbonate, sodium carbonate, glycine, and a glycine-sodium carbonate complex.

[0020] Furthermore, the glidant is colloidal silicon dioxide.

[0021] Furthermore, the adhesive is povidone.

[0022] Furthermore, the filler is one or more of starch, lactose, mannitol and microcrystalline cellulose.

[0023] Furthermore, the lubricant is magnesium stearate.

[0024] Furthermore, in the isolation coating liquid, the mass ratio of hydroxypropyl methylcellulose to deionized water is 1:(9-10).

[0025] Furthermore, the enteric coating liquid is composed of the following components in parts by weight: 50-70 parts of methacrylic acid-ethyl acrylate copolymer dispersion, 800-1000 parts of ethanol aqueous solution, 20-40 parts of Tween 80, 20-30 parts of modified polyacrylate emulsion, 5-15 parts of plasticizer, and 5-10 parts of talc.

[0026] Furthermore, the preparation of the modified polyacrylate emulsion comprises the following steps: Ammonium persulfate, sodium dodecyl sulfate, Tween 80, dodecyl mercaptan and deionized water are mixed and uniformly mixed, nitrogen is introduced, methacrylic acid, hydroxyethyl methacrylate, ethyl acrylate, methyl methacrylate and modified hydroxypropyl methylcellulose are added, stirred uniformly, reacted at 70-80° C. for 4-6 hours, the pH is adjusted to 7-8, and the material is filtered and purified to obtain a modified polyacrylate emulsion.

[0027] Furthermore, the modified polyacrylate emulsion is composed of the following components in parts by weight: 0.4-0.5 parts of sodium lauryl sulfate, 1.2-1.5 parts of Tween 80, 0.2-0.3 parts of dodecyl mercaptan, 60-70 parts of deionized water, 10-15 parts of methacrylic acid, 4-6 parts of hydroxyethyl methacrylate, 10-15 parts of ethyl acrylate, 2-4 parts of methyl methacrylate, 5-10 parts of modified hydroxypropyl methylcellulose, and 0.1-0.3 parts of ammonium persulfate.

[0028] Furthermore, the plasticizer is one or more of triethyl citrate, polyethylene glycol 6000, tributyl citrate, and dibutyl sebacate.

[0029] Furthermore, the concentration of the ethanol aqueous solution is 80-90wt%.

[0030] Compared with the prior art, the present invention has the following beneficial effects: 1. A mesalazine enteric-coated sustained-release tablet and a preparation process thereof of the present invention are characterized in that dialdehyde hydroxypropyl methylcellulose and double-bond glycol chitosan are respectively grafted to both ends of dialdehyde hydroxypropyl methylcellulose to obtain amphiphilic modified hydroxypropyl methylcellulose, which can not only be well dispersed in an aqueous phase, but also its hydrophobic property ensures that the drug is not easily dissolved in the stomach and is released in the intestine, effectively protecting the gastric mucosa from irritation, and can also be mixed with other film-forming materials for use, and can effectively adjust the release rate of the drug to achieve a sustained-release effect; by compounding double-bond glycol chitosan and polylactic acid-polyethylene glycol-amino, the synergistic effect between the materials can be brought into play, and the sustained-release performance of the material can be effectively improved, and the drug loading capacity and biocompatibility of the drug can be enhanced; in addition, the introduction of double bonds also provides the possibility for subsequent cross-linking reactions, and enhances the mechanical properties and structural stability of the material.

[0031] 2. The invention discloses a mesalazine enteric-coated sustained-release tablet and a preparation process thereof. The invention introduces modified hydroxypropyl methylcellulose into a modified polyacrylate emulsion, thereby significantly improving affinity with a methacrylic acid-ethyl acrylate copolymer dispersion, promoting uniform dispersion of emulsion particles, and thus improving stability and film-forming property of the coating solution. The methacrylic acid-ethyl acrylate copolymer dispersion and the modified polyacrylate emulsion are used as main components of the coating solution, and an ethanol aqueous solution, Tween 80 and a plasticizer are used in combination to prepare an enteric coating solution, which can effectively prevent degradation of the drug in a gastric acid environment, slow down the release rate of the drug in the intestine, help prolong the release time of the drug in the body, and improve bioavailability. DETAILED DESCRIPTION

[0032] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0033] In this example, hydroxypropyl methylcellulose: K100M, from Xi'an Jinxiang Pharmaceutical Excipients Co., Ltd.; ethylene glycol chitosan: model S41671, from Shanghai Yuanye Biotechnology Co., Ltd.; polylactic acid-polyethylene glycol-amino: PLA-PEG-NH 2 , from Xi'an Qiyue Biotechnology Co., Ltd.; methacrylic acid-ethyl acrylate copolymer dispersion: 30%, model L30D-55, from Xi'an Jinxiang Pharmaceutical Excipients Co., Ltd.; pH adjuster: glycine, pharmaceutical grade, from Wuxi Bikang Bioengineering Co., Ltd.; filler: microcrystalline cellulose, model 101, from JRS; binder: povidone, model PVP-K15; lubricant: magnesium stearate, model 767514, from Shanghai McLean Biochemical Technology Co., Ltd.; glidant: colloidal silicon dioxide, model A200, from Evonik; mesalazine: model A823148, from Shanghai McLean Biochemical Technology Co., Ltd.; plasticizer: polyethylene glycol 6000, from Nanjing Will; talc: item number tz0078, from Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.

[0034] Unless otherwise specified, the following parts are all parts by mass and percentage by mass; Example 1: A preparation process of mesalazine enteric-coated sustained-release tablets, comprising the following process: Step S1: 450 parts of mesalazine, 50 parts of pH regulator, 10 parts of modified hydroxypropyl methylcellulose, 30 parts of filler, and 10 parts of binder are mixed evenly, and 110 parts of 90% ethanol aqueous solution are added for wet granulation (stirring speed 500 rpm, cutter speed 1500 rpm, granulation time 60 s), dried (drying temperature 60°C, moisture controlled at 2%), granulated, passed through a 1.2 mm sieve, and then 5 parts of lubricant and 3 parts of flow aid are added, mixed evenly, and tableted to obtain tablet cores; Step S2: Mix hydroxypropyl methylcellulose and deionized water in a mass ratio of 1:9 to obtain an isolation coating solution; spray the isolation coating solution onto the tablet core to form an isolation coating layer (the parameters of the fluidized bed coating are as follows: inlet air temperature 50°C, air volume 100m 3 / h, material temperature 30°C, peristaltic pump speed 5rpm, coating weight gain 3%), to obtain isolation coated tablet cores; Step S3: 50 parts of methacrylic acid-ethyl acrylate copolymer dispersion, 20 parts of modified polyacrylate emulsion, 800 parts of 80wt% ethanol aqueous solution, 20 parts of Tween 80, 5 parts of plasticizer and 5 parts of talc are mixed uniformly to obtain an enteric coating liquid; the enteric coating liquid is sprayed onto the isolation coating core to form an enteric coating layer (the parameters of the fluidized bed coating are as follows: inlet air temperature 35°C, air volume 110m 3 / h, material temperature 30°C, peristaltic pump speed 20rpm, coating weight gain 5%), to obtain mesalazine enteric-coated sustained-release tablets; The preparation method of modified hydroxypropyl methylcellulose is as follows: Step (1): uniformly mixing a 1 wt % hydroxypropyl methylcellulose aqueous solution and sodium periodate, adjusting the pH to 2, heating to 30° C., reacting for 3 h under light-shielding conditions, dialyzing, and drying to obtain dialdehyde hydroxypropyl methylcellulose; the mass ratio of hydroxypropyl methylcellulose to sodium periodate is 1:0.04; Step (2): 1 wt% ethylene glycol chitosan aqueous solution and 10 wt% octenyl succinic anhydride ethanol aqueous solution are mixed uniformly in a mass ratio of 1:0.2, the pH is adjusted to 8.3, the mixture is reacted at 30°C for 22 hours, and after dialyzing and drying, ethylene glycol chitosan containing double bonds is obtained; Step (3): preparing 200 parts of a 10 wt% aqueous solution of dialdehyde hydroxypropyl methylcellulose, adding a mixed solution of polylactic acid-polyethylene glycol-amino and tetrahydrofuran in a mass ratio of 1:2, mixing, adjusting the pH to 3, reacting at 25°C for 12 hours, then adding 20 parts of double bond glycol chitosan, mixing, continuing the reaction for 22 hours, removing the organic solvent, dialyzing, and drying to obtain modified hydroxypropyl methylcellulose; the molar ratio of aldehyde groups in the aqueous solution of dialdehyde hydroxypropyl methylcellulose to amino groups in polylactic acid-polyethylene glycol-amino is 1:0.4; The preparation of modified polyacrylate emulsion comprises the following steps: Ammonium persulfate, sodium dodecyl sulfate, Tween 80, dodecyl mercaptan and deionized water were mixed and uniformly mixed, nitrogen was introduced, methacrylic acid, hydroxyethyl methacrylate, ethyl acrylate, methyl methacrylate and modified hydroxypropyl methylcellulose were added, stirred uniformly, reacted at 70° C. for 4 h, the pH was adjusted to 7, and the material was filtered and purified to obtain a modified polyacrylate emulsion; The modified polyacrylate emulsion is composed of the following components in parts by weight: 0.4 parts of sodium lauryl sulfate, 1.2 parts of Tween 80, 0.2 parts of dodecyl mercaptan, 60 parts of deionized water, 10 parts of methacrylic acid, 4 parts of hydroxyethyl methacrylate, 10 parts of ethyl acrylate, 2 parts of methyl methacrylate, 5 parts of modified hydroxypropyl methylcellulose, and 0.1 parts of ammonium persulfate.

[0035] Example 2: A preparation process of mesalazine enteric-coated sustained-release tablets, comprising the following process: Step S1: 500 parts of mesalazine, 100 parts of pH regulator, 30 parts of modified hydroxypropyl methylcellulose, 50 parts of filler, and 20 parts of binder are mixed evenly, 150 parts of 90% ethanol aqueous solution are added for wet granulation (stirring speed 500 rpm, cutter speed 1500 rpm, granulation time 60 s), drying (drying temperature 65°C, moisture controlled at 2.5%), granulation, passing through a 1.2 mm sieve, and then adding 10 parts of lubricant and 5 parts of flow aid, mixing evenly, and tableting to obtain tablet cores; Step S2: Mix hydroxypropyl methylcellulose and deionized water in a mass ratio of 1:9.5 to obtain an isolation coating solution; spray the isolation coating solution onto the tablet core to form an isolation coating layer (the parameters of the fluidized bed coating are as follows: inlet air temperature 55°C, air volume 110m 3 / h, material temperature 35°C, peristaltic pump speed 10rpm, coating weight gain 5%), to obtain isolation coated tablet cores; Step S3: 60 parts of methacrylic acid-ethyl acrylate copolymer dispersion, 25 parts of modified polyacrylate emulsion, 900 parts of 85wt% ethanol aqueous solution, 30 parts of Tween 80, 10 parts of plasticizer and 8 parts of talc are mixed uniformly to obtain an enteric coating liquid; the enteric coating liquid is sprayed onto the isolation coating core to form an enteric coating layer (the parameters of the fluidized bed coating are as follows: inlet air temperature 40°C, air volume 120 m 3 / h, material temperature 35°C, peristaltic pump speed 30rpm, coating weight gain 8%), to obtain mesalazine enteric-coated sustained-release tablets; The preparation method of modified hydroxypropyl methylcellulose is as follows: Step (1): uniformly mixing a 2 wt % hydroxypropyl methylcellulose aqueous solution and sodium periodate, adjusting the pH to 4, heating to 40° C., reacting for 4 hours under light-shielding conditions, dialyzing, and drying to obtain dialdehyde hydroxypropyl methylcellulose; the mass ratio of hydroxypropyl methylcellulose to sodium periodate is 1:0.1; Step (2): 2 wt% ethylene glycol chitosan aqueous solution and 11 wt% octenyl succinic anhydride ethanol aqueous solution were mixed uniformly in a mass ratio of 1:0.15, the pH was adjusted to 8.4, the mixture was reacted at 35°C for 23 hours, and after dialyzing and drying, ethylene glycol chitosan containing double bonds was obtained; Step (3): preparing 280 parts of a 15 wt% aqueous solution of dialdehyde hydroxypropyl methylcellulose, adding a mixed solution of polylactic acid-polyethylene glycol-amino and tetrahydrofuran in a mass ratio of 1:3, mixing, adjusting the pH to 4, reacting at 30°C for 16 hours, then adding 63 parts of double bond ethylene glycol chitosan, mixing, continuing the reaction for 23 hours, removing the organic solvent, dialyzing, and drying to obtain modified hydroxypropyl methylcellulose; the molar ratio of aldehyde groups in the aqueous solution of dialdehyde hydroxypropyl methylcellulose to amino groups in polylactic acid-polyethylene glycol-amino is 1:0.5; The preparation of modified polyacrylate emulsion comprises the following steps: Ammonium persulfate, sodium dodecyl sulfate, Tween 80, dodecyl mercaptan and deionized water were mixed and uniformly mixed, nitrogen was introduced, methacrylic acid, hydroxyethyl methacrylate, ethyl acrylate, methyl methacrylate and modified hydroxypropyl methylcellulose were added, stirred uniformly, reacted at 75° C. for 5 h, the pH was adjusted to 7.5, and the material was filtered and purified to obtain a modified polyacrylate emulsion; The modified polyacrylate emulsion is composed of the following components in parts by weight: 0.45 parts of sodium lauryl sulfate, 1.4 parts of Tween 80, 0.25 parts of dodecyl mercaptan, 65 parts of deionized water, 12 parts of methacrylic acid, 5 parts of hydroxyethyl methacrylate, 12 parts of ethyl acrylate, 3 parts of methyl methacrylate, 8 parts of modified hydroxypropyl methylcellulose, and 0.2 parts of ammonium persulfate.

[0036] Example 3: A process for preparing mesalazine enteric-coated sustained-release tablets, comprising the following process: Step S1: 550 parts of mesalazine, 170 parts of pH regulator, 40 parts of modified hydroxypropyl methylcellulose, 80 parts of filler, and 30 parts of binder are mixed evenly, and 217.5 parts of 90% ethanol aqueous solution are added for wet granulation (stirring speed 500 rpm, cutter speed 1500 rpm, granulation time 60 s), dried (drying temperature 70°C, moisture controlled at 3%), granulated, passed through a 1.2 mm sieve, and then 20 parts of lubricant and 10 parts of flow aid are added, mixed evenly, and tableted to obtain tablet cores; Step S2: Mix hydroxypropyl methylcellulose and deionized water in a mass ratio of 1:10 to obtain an isolation coating solution; spray the isolation coating solution onto the tablet core to form an isolation coating layer (the parameters of the fluidized bed coating are as follows: inlet air temperature 60°C, air volume 120m 3 / h, material temperature 40°C, peristaltic pump speed 20rpm, coating weight gain 8%), to obtain isolation coated tablet cores; Step S3: 70 parts of methacrylic acid-ethyl acrylate copolymer dispersion, 30 parts of modified polyacrylate emulsion, 1000 parts of 90wt% ethanol aqueous solution, 40 parts of Tween 80, 15 parts of plasticizer and 10 parts of talc are mixed uniformly to obtain an enteric coating liquid; the enteric coating liquid is sprayed onto the isolation coating core to form an enteric coating layer (the parameters of the fluidized bed coating are as follows: the inlet air temperature is 45°C, the air volume is 130 m 3 / h, material temperature 40°C, peristaltic pump speed 40rpm, coating weight gain 10%), to obtain mesalazine enteric-coated sustained-release tablets; The preparation method of modified hydroxypropyl methylcellulose is as follows: Step (1): uniformly mixing a 3 wt % hydroxypropyl methylcellulose aqueous solution and sodium periodate, adjusting the pH to 6, heating to 50° C., reacting for 5 h under light-shielding conditions, dialyzing, and drying to obtain dialdehyde hydroxypropyl methylcellulose; the mass ratio of hydroxypropyl methylcellulose to sodium periodate is 1:0.2; Step (2): 3 wt% ethylene glycol chitosan aqueous solution and 12 wt% octenyl succinic anhydride ethanol aqueous solution are mixed uniformly in a mass ratio of 1:0.2, the pH is adjusted to 8.5, reacted at 40°C for 24 hours, dialyzed and dried to obtain ethylene glycol chitosan containing double bonds; Step (3): preparing 250 parts of a 20 wt% aqueous solution of dialdehyde hydroxypropyl methylcellulose, adding a mixed solution of polylactic acid-polyethylene glycol-amino and tetrahydrofuran in a mass ratio of 1:4, mixing, adjusting the pH to 5, reacting at 35°C for 18 hours, then adding 100 parts of double bond glycol chitosan, mixing, continuing the reaction for 24 hours, removing the organic solvent, dialyzing, and drying to obtain modified hydroxypropyl methylcellulose; the molar ratio of aldehyde groups in the aqueous solution of dialdehyde hydroxypropyl methylcellulose to amino groups in polylactic acid-polyethylene glycol-amino is 1:0.6; The preparation of modified polyacrylate emulsion comprises the following steps: Ammonium persulfate, sodium dodecyl sulfate, Tween 80, dodecyl mercaptan and deionized water were mixed and uniformly mixed, nitrogen was introduced, methacrylic acid, hydroxyethyl methacrylate, ethyl acrylate, methyl methacrylate and modified hydroxypropyl methylcellulose were added, stirred uniformly, reacted at 80° C. for 6 h, the pH was adjusted to 8, and the material was filtered and purified to obtain a modified polyacrylate emulsion; The modified polyacrylate emulsion is composed of the following components in parts by weight: 0.5 parts of sodium lauryl sulfate, 1.5 parts of Tween 80, 0.3 parts of dodecyl mercaptan, 70 parts of deionized water, 15 parts of methacrylic acid, 6 parts of hydroxyethyl methacrylate, 15 parts of ethyl acrylate, 4 parts of methyl methacrylate, 10 parts of modified hydroxypropyl methylcellulose, and 0.3 parts of ammonium persulfate.

[0037] Comparative Example 1: A preparation process of mesalazine enteric-coated sustained-release tablets, comprising the following processes: A preparation process of mesalazine enteric-coated sustained-release tablets, comprising the following processes: Step S1: 500 parts of mesalazine, 100 parts of pH regulator, 30 parts of modified hydroxypropyl methylcellulose, 50 parts of filler, and 20 parts of binder are mixed evenly, 150 parts of 90% ethanol aqueous solution are added for wet granulation (stirring speed 500 rpm, cutter speed 1500 rpm, granulation time 60 s), drying (drying temperature 65°C, moisture controlled at 2.5%), granulation, passing through a 1.2 mm sieve, and then adding 10 parts of lubricant and 5 parts of flow aid, mixing evenly, and tableting to obtain tablet cores; Step S2: Mix hydroxypropyl methylcellulose and deionized water in a mass ratio of 1:9.5 to obtain an isolation coating solution; spray the isolation coating solution onto the tablet core to form an isolation coating layer (the parameters of the fluidized bed coating are as follows: inlet air temperature 55°C, air volume 110m 3 / h, material temperature 35°C, peristaltic pump speed 10rpm, coating weight gain 5%), to obtain isolation coated tablet cores; Step S3: 60 parts of methacrylic acid-ethyl acrylate copolymer dispersion, 10 parts of modified polyacrylate emulsion, 900 parts of 85wt% ethanol aqueous solution, 30 parts of Tween 80, 10 parts of plasticizer and 8 parts of talc are mixed evenly to obtain an enteric coating liquid; the enteric coating liquid is sprayed onto the isolation coating tablet core to form an enteric coating layer (the parameters of the fluidized bed coating are as follows: the inlet air temperature is 40°C, the air volume is 120 m 3 / h, material temperature 35°C, peristaltic pump speed 30rpm, coating weight gain 8%), to obtain mesalazine enteric-coated sustained-release tablets; Compared with Example 2, only 10 parts of modified polyacrylate emulsion were added in step S3 of Comparative Example 1, and the other steps were the same as those of Example 2.

[0038] Comparative Example 2: A preparation process of mesalazine enteric-coated sustained-release tablets, comprising the following processes: Compared with Example 2, Comparative Example 2 replaces the modified hydroxypropyl methylcellulose in the modified polyacrylate emulsion with hydroxypropyl methylcellulose of the same mass, and is composed of the following components in parts by weight: 0.45 parts of sodium lauryl sulfate, 1.4 parts of Tween 80, 0.25 parts of dodecyl mercaptan, 65 parts of deionized water, 12 parts of methacrylic acid, 5 parts of hydroxyethyl methacrylate, 12 parts of ethyl acrylate, 3 parts of methyl methacrylate, 8 parts of hydroxypropyl methylcellulose, and 0.2 parts of ammonium persulfate, and the other steps are the same as those in Example 2.

[0039] Comparative Example 3: A preparation process of mesalazine enteric-coated sustained-release tablets, comprising the following processes: The preparation method of modified hydroxypropyl methylcellulose is as follows: Step (1): uniformly mixing a 2 wt % hydroxypropyl methylcellulose aqueous solution and sodium periodate, adjusting the pH to 4, heating to 40° C., reacting for 4 hours under light-shielding conditions, dialyzing, and drying to obtain dialdehyde hydroxypropyl methylcellulose; the mass ratio of hydroxypropyl methylcellulose to sodium periodate is 1:0.1; Step (2): 2 wt% ethylene glycol chitosan aqueous solution and 11 wt% octenyl succinic anhydride ethanol aqueous solution were mixed uniformly in a mass ratio of 1:0.15, the pH was adjusted to 8.4, the mixture was reacted at 35°C for 23 hours, and after dialyzing and drying, ethylene glycol chitosan containing double bonds was obtained; Step (3): preparing 280 parts of a 15 wt% aqueous solution of dialdehyde hydroxypropyl methylcellulose, adding a mixed solution of polylactic acid-polyethylene glycol-amino and tetrahydrofuran in a mass ratio of 1:3, mixing, adjusting the pH to 4, reacting at 30°C for 16 hours, then adding 63 parts of double bond glycol chitosan, mixing, continuing the reaction for 23 hours, removing the organic solvent, dialyzing, and drying to obtain modified hydroxypropyl methylcellulose; Compared with Example 2, in step (3) of Comparative Example 3, the molar ratio of the aldehyde group in the dialdehyde hydroxypropyl methylcellulose aqueous solution to the amino group in the polylactic acid-polyethylene glycol-amino group is 1:1; the other steps are the same as those in Example 2.

[0040] Experiment: Release test: Take the mesalazine enteric-coated sustained-release tablets obtained in Example 1-3 and Comparative Example 1-3, and refer to the second method of General Rules 0931 of the 2020 edition of the Chinese Pharmacopoeia. The paddle method speed is 100r / min, the temperature is (37±0.5)°C, and it is soaked in 750mL of 0.1mol / L hydrochloric acid solution for 2h, and then transferred to 950mL of pH6.8 phosphate buffer. The speed remains unchanged, and samples are taken after 1, 2h, 4h, and 7h. The results are as follows:

[0041] According to the data in the above table, we can clearly draw the following conclusions: Compared with Examples 1-3, the release rates of Comparative Examples 1 and 2 are both increased. Reducing the modified polyacrylate emulsion will increase the hydrophilicity of the coating layer, thereby causing the drug to be released too quickly in the intestine. It can be seen that the performance of the enteric coating liquid prepared by the present invention is affected by its component ratio. By selecting the component ratio within the range, an enteric coating layer with better sustained-release effect can be prepared; at the same time, the present invention has good film-forming properties by introducing amphiphilic modified hydroxypropyl methylcellulose, which slows down the release rate of the drug.

[0042] Compared with Examples 1-3, the release degree of Comparative Example 3 is increased, which shows that the present invention controls the molar ratio of the aldehyde group in the dialdehyde hydroxypropyl methylcellulose aqueous solution to the amino group in the polylactic acid-polyethylene glycol-amino group to ensure that the double-bond ethylene glycol chitosan can be effectively grafted, thereby introducing double bonds and preparing a modified polyacrylic acid emulsion with better effect.

[0043] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

Claims

1. A preparation process of mesalazine enteric-coated sustained-release tablets, characterized in that: The steps include: Step S1: mixing mesalazine, pH adjuster, modified hydroxypropyl methylcellulose, filler and binder uniformly, wet granulating, drying, granulating, adding lubricant and glidant, mixing uniformly, tableting to obtain tablet cores; Step S2: mixing hydroxypropyl methylcellulose and deionized water evenly to obtain an isolation coating liquid; spraying the isolation coating liquid onto the tablet core to form an isolation coating layer to obtain an isolation coated tablet core; Step S3: uniformly mixing the methacrylic acid-ethyl acrylate copolymer dispersion, the modified polyacrylate emulsion, the ethanol aqueous solution, Tween 80, the plasticizer and the talcum powder to obtain an enteric coating solution; spraying the enteric coating solution onto the isolation coating tablet core to form an enteric coating layer to obtain mesalazine enteric sustained-release tablets.

2. The preparation process of a mesalazine enteric-coated sustained-release tablet according to claim 1, characterized in that: The tablet core is composed of the following components in parts by weight: 450-550 parts of mesalazine, 50-170 parts of pH regulator, 30-80 parts of filler, 10-40 parts of modified hydroxypropyl methylcellulose, 10-30 parts of binder, 3-10 parts of glidant and 5-20 parts of lubricant.

3. A process for preparing a mesalazine enteric-coated sustained-release tablet according to claim 2, characterized in that: The preparation method of modified hydroxypropyl methylcellulose is as follows: Step (1): uniformly mixing a hydroxypropyl methylcellulose aqueous solution and sodium periodate, adjusting the pH to 2-6, heating to 30-50° C., reacting for 3-5 hours under light-shielding conditions, dialyzing, and drying to obtain dialdehyde hydroxypropyl methylcellulose; Step (2): uniformly mixing the ethylene glycol chitosan aqueous solution and the octenyl succinic anhydride ethanol aqueous solution, adjusting the pH to 8.3-8.5, reacting at 30-40° C. for 22-24 hours, dialyzing and drying to obtain ethylene glycol chitosan containing double bonds; Step (3): prepare a dialdehyde hydroxypropyl methylcellulose aqueous solution, add a mixed solution of polylactic acid-polyethylene glycol-amino and tetrahydrofuran, adjust the pH to 3-5, react at 25-35°C for 12-18 hours, then add double bond ethylene glycol chitosan and continue to react for 22-24 hours, remove the organic solvent, dialyze and dry to obtain modified hydroxypropyl methylcellulose.

4. A process for preparing a mesalazine enteric-coated sustained-release tablet according to claim 1, characterized in that: In the isolation coating liquid, the mass ratio of hydroxypropyl methylcellulose to deionized water is 1:(9-10).

5. The preparation process of a mesalazine enteric-coated sustained-release tablet according to claim 1, characterized in that: The enteric coating liquid is composed of the following components in parts by weight: 50-70 parts of methacrylic acid-ethyl acrylate copolymer dispersion, 800-1000 parts of ethanol aqueous solution, 20-40 parts of Tween 80, 20-30 parts of modified polyacrylate emulsion, 5-15 parts of plasticizer, and 5-10 parts of talc.

6. A process for preparing a mesalazine enteric-coated sustained-release tablet according to claim 5, characterized in that: The preparation of the modified polyacrylate emulsion comprises the following steps: Ammonium persulfate, sodium dodecyl sulfate, Tween 80, dodecyl mercaptan and deionized water are mixed and uniformly mixed, nitrogen is introduced, methacrylic acid, hydroxyethyl methacrylate, ethyl acrylate, methyl methacrylate and modified hydroxypropyl methylcellulose are added, stirred uniformly, reacted at 70-80° C. for 4-6 hours, the pH is adjusted to 7-8, and the material is filtered and purified to obtain a modified polyacrylate emulsion.

7. A process for preparing a mesalazine enteric-coated sustained-release tablet according to claim 6, characterized in that: The modified polyacrylate emulsion is composed of the following components in parts by weight: 0.4-0.5 parts of sodium lauryl sulfate, 1.2-1.5 parts of Tween 80, 0.2-0.3 parts of dodecyl mercaptan, 60-70 parts of deionized water, 10-15 parts of methacrylic acid, 4-6 parts of hydroxyethyl methacrylate, 10-15 parts of ethyl acrylate, 2-4 parts of methyl methacrylate, 5-10 parts of modified hydroxypropyl methylcellulose, and 0.1-0.3 parts of ammonium persulfate.

8. The preparation process of a mesalazine enteric-coated sustained-release tablet according to claim 2, characterized in that: The filler is one or more of starch, lactose, mannitol and microcrystalline cellulose.

9. The process for preparing a mesalazine enteric-coated sustained-release tablet according to claim 2, characterized in that: The lubricant is magnesium stearate.

10. A mesalazine enteric-coated sustained-release tablet prepared according to the preparation process according to any one of claims 1 to 9.

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