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

Abstract

The present 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 present invention comprises the following steps: S1: uniformly mixing mesalazine, a pH regulator, modified hydroxypropyl methylcellulose, a filler, and a binder, wet granulating, drying, granulating, adding a lubricant and a glidant, mixing, and tableting to obtain a tablet core; S2: uniformly mixing hydroxypropyl methylcellulose and deionized water 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; and S3: uniformly mixing a methacrylic acid-ethyl acrylate copolymer dispersion, a modified polyacrylate emulsion, an ethanol aqueous solution, Tween 80, a plasticizer, and talc to obtain an enteric coating liquid; spraying the enteric coating liquid onto the isolation-coated tablet core to form an enteric coating layer to obtain a mesalazine enteric-coated sustained-release tablet.

Description

Technical Field

[0001] The present 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 primarily used to treat inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Mesalazine exerts its anti-inflammatory effects 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 pharmaceutical formulation designed to release the drug in specific areas 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, existing technologies have the following problems:

[0004] 1. Low bioavailability: After oral administration, mesalazine is partially destroyed in gastric acid, resulting in reduced bioavailability.

[0005] 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.

[0006] 3. Severe irritation to the gastrointestinal tract: Mesalazine has a certain irritation to the gastrointestinal tract, and traditional dosage forms may increase the incidence of adverse reactions.

[0007] Therefore, we propose a mesalazine enteric-coated sustained-release tablet and a preparation process thereof. Summary of the Invention

[0008] 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.

[0009] To achieve the above object, the present invention provides the following technical solutions:

[0010] A preparation process of mesalazine enteric-coated sustained-release tablets comprises the following steps:

[0011] Step S1: mixing mesalazine, a pH adjuster, modified hydroxypropyl methylcellulose, a filler, and a binder, wet granulating, drying, and granulating, then adding a lubricant and a glidant, mixing, and tableting to obtain a tablet core;

[0012] Step S2: mixing hydroxypropyl methylcellulose and deionized water to obtain an isolation coating solution; spraying the isolation coating solution onto the tablet core to form an isolation coating layer to obtain an isolation-coated tablet core;

[0013] Step S3: uniformly mixing a methacrylic acid-ethyl acrylate copolymer dispersion, a modified polyacrylate emulsion, an ethanol aqueous solution, Tween 80, a plasticizer, and talc to obtain an enteric coating solution; spraying the enteric coating solution onto the isolation-coated tablet core to form an enteric coating layer, thereby obtaining mesalazine enteric-coated sustained-release tablets.

[0014] Furthermore, 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.

[0015] Furthermore, the preparation method of the modified hydroxypropyl methylcellulose is as follows:

[0016] Step (1): uniformly mix the hydroxypropyl methylcellulose aqueous solution and sodium periodate, adjust the pH to 2-6, heat to 30-50°C, react under light-shielding conditions for 3-5 hours, dialyze, and dry to obtain dialdehyde hydroxypropyl methylcellulose;

[0017] Step (2): uniformly mix the ethylene glycol chitosan aqueous solution and the octenyl succinic anhydride ethanol aqueous solution, adjust the pH to 8.3-8.5, react at 30-40°C for 22-24h, dialyze and dry to obtain ethylene glycol chitosan containing double bonds;

[0018] 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 chitosan containing double bond glycol and continue to react for 22-24 hours, remove the organic solvent, dialyze and dry to obtain modified hydroxypropyl methylcellulose.

[0019] In the above technical scheme, hydroxypropyl methylcellulose (HPMC) is oxidized by sodium periodate (NaIO4), and the hydroxyl groups at the C2 and C3 positions of its molecular chain are oxidized to aldehyde groups to obtain dialdehyde hydroxypropyl methylcellulose; then, water-soluble glycol chitosan (GC) is partially hydrophobically modified by octenylsuccinic anhydride, and double bonds and hydrophobic groups are introduced to form a derivative with amphiphilic properties, namely, glycol chitosan containing double bonds; finally, the aldehyde groups in dialdehyde hydroxypropyl methylcellulose react with amino groups, and glycol chitosan containing double bonds and polylactic acid-polyethylene glycol-amino groups are respectively grafted to the two ends of dialdehyde hydroxypropyl methylcellulose to obtain modified hydroxypropyl methylcellulose.

[0020] Furthermore, in step (1), the concentration of the hydroxypropyl methylcellulose aqueous solution is 1-3 wt %.

[0021] Furthermore, in step (1), the mass ratio of hydroxypropyl methylcellulose to sodium periodate is 1:(0.04-0.20).

[0022] Furthermore, in step (2), the concentration of the ethylene glycol chitosan aqueous solution is 1-3 wt %,

[0023] Furthermore, in step (2), the concentration of the octenylsuccinic 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.

[0024] Furthermore, in step (3), the concentration of the dialdehyde hydroxypropyl methylcellulose aqueous solution is 10-20 wt%.

[0025] Furthermore, in step (3), the mass ratio of polylactic acid-polyethylene glycol-amino to tetrahydrofuran is 1:(2-4).

[0026] Furthermore, in step (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:(0.4-0.6).

[0027] Furthermore, in step (3), the mass of the double-bond ethylene glycol chitosan is 1-2 times the mass of the dialdehyde hydroxypropyl methylcellulose.

[0028] Furthermore, the pH regulator is one or more of calcium carbonate, sodium carbonate, glycine, and a glycine-sodium carbonate complex.

[0029] Furthermore, the glidant is colloidal silicon dioxide.

[0030] Furthermore, the adhesive is povidone.

[0031] Furthermore, the filler is one or more of starch, lactose, mannitol and microcrystalline cellulose.

[0032] Furthermore, the lubricant is magnesium stearate.

[0033] Furthermore, in the isolation coating liquid, the mass ratio of hydroxypropyl methylcellulose to deionized water is 1:(9-10).

[0034] Furthermore, the enteric coating solution 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.

[0035] Furthermore, the preparation of the modified polyacrylate emulsion comprises the following steps:

[0036] Ammonium persulfate, sodium lauryl 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.

[0037] 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.

[0038] Furthermore, the plasticizer is one or more of triethyl citrate, polyethylene glycol 6000, tributyl citrate, and dibutyl sebacate.

[0039] Furthermore, the concentration of the ethanol aqueous solution is 80-90wt%.

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] 1. A mesalazine enteric-coated sustained-release tablet and a preparation process thereof are disclosed. The invention comprises the following steps: dialdehyde hydroxypropyl methylcellulose and double-bond ethylene glycol chitosan are respectively grafted onto both ends of the dialdehyde hydroxypropyl methylcellulose to obtain an amphiphilic modified hydroxypropyl methylcellulose. The modified hydroxypropyl methylcellulose can not only be well dispersed in an aqueous phase, but also has a hydrophobic property that ensures that the drug is not easily dissolved in the stomach but is released in the intestine, effectively protecting the gastric mucosa from irritation. The modified hydroxypropyl methylcellulose can also be mixed with other film-forming materials to effectively regulate the release rate of the drug and achieve a sustained-release effect. The compounding of double-bond ethylene glycol chitosan and polylactic acid-polyethylene glycol-amino groups can exert a synergistic effect between the materials, effectively improve the sustained-release performance of the material, and enhance the drug loading capacity and biocompatibility of the drug. In addition, the introduction of double bonds also provides the possibility for subsequent cross-linking reactions, thereby enhancing the mechanical properties and structural stability of the material.

[0042] 2. The present invention relates to an enteric-coated sustained-release mesalazine tablet and a preparation process thereof. Modified hydroxypropyl methylcellulose is introduced into a modified polyacrylate emulsion, thereby significantly improving affinity with a methacrylic acid-ethyl acrylate copolymer dispersion, promoting uniform dispersion of emulsion particles, and thereby improving the stability and film-forming properties of the coating solution. The enteric coating solution is prepared by using the methacrylic acid-ethyl acrylate copolymer dispersion and the modified polyacrylate emulsion as the main components of the coating solution, in combination with an ethanol aqueous solution, Tween 80, and a plasticizer. The enteric coating solution can effectively prevent drug degradation in a gastric acid environment, slow down the drug release rate in the intestine, help prolong the drug release time in the body, and improve bioavailability. DETAILED DESCRIPTION

[0043] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0044] In this example, hydroxypropyl methylcellulose: K100M, sourced from Xi'an Jinxiang Pharmaceutical Excipients Co., Ltd.; ethylene glycol chitosan: model S41671, sourced from Shanghai Yuanye Biotechnology Co., Ltd.; polylactic acid-polyethylene glycol-amino: PLA-PEG-NH2, sourced from Xi'an Qiyue Biotechnology Co., Ltd.; methacrylic acid-ethyl acrylate copolymer dispersion: 30%, model L30D-55, sourced from Xi'an Jinxiang Pharmaceutical Excipients Co., Ltd.; pH adjuster: glycine, pharmaceutical grade, sourced from Wuxi Bikang Bioengineering Co., Ltd.; filler Filler: microcrystalline cellulose, model 101, sourced from JRS; binder: povidone, model PVP-K15; lubricant: magnesium stearate, model 767514, sourced from Shanghai McLean Biochemical Technology Co., Ltd.; glidant: colloidal silicon dioxide, model A200, sourced from Evonik; mesalazine: model A823148, sourced from Shanghai McLean Biochemical Technology Co., Ltd.; plasticizer: polyethylene glycol 6000, sourced from Nanjing Well; talc: product number tz0078, sourced from Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.

[0045] Unless otherwise specified, the following parts are by mass and percentage.

[0046] Example 1: A preparation process of mesalazine enteric-coated sustained-release tablets, comprising the following steps:

[0047] Step S1: 450 parts of mesalazine, 50 parts of a pH adjuster, 10 parts of modified hydroxypropyl methylcellulose, 30 parts of a filler, and 10 parts of a binder are mixed uniformly, and 110 parts of a 90% ethanol aqueous solution are added for wet granulation (stirring speed 500 rpm, cutter speed 1500 rpm, granulation time 60 s), drying (drying temperature 60°C, moisture controlled at 2%), granulation, and passing through a 1.2 mm sieve. 5 parts of a lubricant and 3 parts of a glidant are then added, mixed uniformly, and tabletted to obtain tablet cores;

[0048] Step S2: Hydroxypropyl methylcellulose and deionized water are mixed in a mass ratio of 1:9 to obtain an isolation coating solution; the isolation coating solution is sprayed 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 5 rpm, coating weight gain 3%), to obtain isolation coated tablet cores;

[0049] Step S3: 50 parts of methacrylic acid-ethyl acrylate copolymer dispersion, 20 parts of modified polyacrylate emulsion, 800 parts of 80 wt% ethanol aqueous solution, 20 parts of Tween 80, 5 parts of plasticizer and 5 parts of talc were mixed to obtain an enteric coating solution; the enteric coating solution was sprayed onto the isolation coated tablet core to form an enteric coating layer (the parameters of the fluidized bed coating were as follows: inlet air temperature 35°C, air volume 110m 3 / h, material temperature 30°C, peristaltic pump speed 20 rpm, coating weight gain 5%), to obtain mesalazine enteric-coated sustained-release tablets;

[0050] The preparation method of modified hydroxypropyl methylcellulose is as follows:

[0051] Step (1): uniformly mix a 1 wt% hydroxypropyl methylcellulose aqueous solution and sodium periodate, adjust the pH to 2, heat to 30°C, react under light-shielding conditions for 3 hours, dialyze, and dry to obtain dialdehyde hydroxypropyl methylcellulose; the mass ratio of hydroxypropyl methylcellulose to sodium periodate is 1:0.04;

[0052] Step (2): 1 wt% ethylene glycol chitosan aqueous solution and 10 wt% octenyl succinic anhydride ethanol aqueous solution were mixed uniformly in a mass ratio of 1:0.2, the pH was adjusted to 8.3, and the mixture was reacted at 30°C for 22 hours. After dialyzing and drying, ethylene glycol chitosan containing double bonds was obtained;

[0053] Step (3): prepare 200 parts of a 10 wt% aqueous solution of dialdehyde hydroxypropyl methylcellulose, add a mixed solution of polylactic acid-polyethylene glycol-amino and tetrahydrofuran in a mass ratio of 1:2, mix, adjust the pH to 3, react at 25°C for 12 hours, then add 20 parts of chitosan containing double-bond ethylene glycol, mix, continue to react for 22 hours, remove the organic solvent, dialyze, and dry to obtain modified hydroxypropyl methylcellulose; the molar ratio of aldehyde groups in the dialdehyde hydroxypropyl methylcellulose aqueous solution to amino groups in polylactic acid-polyethylene glycol-amino is 1:0.4;

[0054] The preparation of modified polyacrylate emulsion comprises the following steps:

[0055] Ammonium persulfate, sodium lauryl 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 hours, the pH was adjusted to 7, and the product was filtered and purified to obtain a modified polyacrylate emulsion;

[0056] 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.

[0057] Example 2: A process for preparing mesalazine enteric-coated sustained-release tablets, comprising the following steps:

[0058] Step S1: 500 parts of mesalazine, 100 parts of a pH adjuster, 30 parts of modified hydroxypropyl methylcellulose, 50 parts of a filler, and 20 parts of a binder are mixed uniformly, 150 parts of a 90% ethanol aqueous solution are added, wet granulation is performed (stirring speed 500 rpm, cutter speed 1500 rpm, granulation time 60 s), drying (drying temperature 65°C, moisture content controlled at 2.5%), granulation is performed, and the granules are passed through a 1.2 mm sieve. 10 parts of a lubricant and 5 parts of a glidant are then added, mixed uniformly, and tableting is performed to obtain tablet cores;

[0059] Step S2: Hydroxypropyl methylcellulose and deionized water are mixed in a mass ratio of 1:9.5 to obtain an isolation coating solution; the isolation coating solution is sprayed 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 10 rpm, coating weight gain 5%), to obtain isolation coated tablet cores;

[0060] Step S3: 60 parts of methacrylic acid-ethyl acrylate copolymer dispersion, 25 parts of modified polyacrylate emulsion, 900 parts of 85 wt% ethanol aqueous solution, 30 parts of Tween 80, 10 parts of plasticizer and 8 parts of talc were mixed to obtain an enteric coating solution; the enteric coating solution was sprayed onto the isolation-coated tablet core to form an enteric coating layer (the parameters of the fluidized bed coating were as follows: inlet air temperature 40°C, air volume 120 m 3 / h, material temperature 35°C, peristaltic pump speed 30 rpm, coating weight gain 8%), to obtain mesalazine enteric-coated sustained-release tablets;

[0061] The preparation method of modified hydroxypropyl methylcellulose is as follows:

[0062] Step (1): uniformly mix a 2 wt % hydroxypropyl methylcellulose aqueous solution and sodium periodate, adjust the pH to 4, heat to 40° C., react for 4 h under light-shielding conditions, dialyze, and dry to obtain dialdehyde hydroxypropyl methylcellulose; the mass ratio of hydroxypropyl methylcellulose to sodium periodate is 1:0.1;

[0063] 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, and the mixture was reacted at 35°C for 23 h. After dialyzing and drying, ethylene glycol chitosan containing double bonds was obtained;

[0064] 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 chitosan containing double-bond ethylene glycol, mixing, continuing the reaction for 23 hours, removing the organic solvent, dialyzing, and drying to obtain modified hydroxypropyl methylcellulose; 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 is 1:0.5;

[0065] The preparation of modified polyacrylate emulsion comprises the following steps:

[0066] Ammonium persulfate, sodium lauryl 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 hours, the pH was adjusted to 7.5, and the product was filtered and purified to obtain a modified polyacrylate emulsion;

[0067] 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.

[0068] Example 3: A process for preparing mesalazine enteric-coated sustained-release tablets, comprising the following steps:

[0069] Step S1: 550 parts of mesalazine, 170 parts of a pH adjuster, 40 parts of modified hydroxypropyl methylcellulose, 80 parts of a filler, and 30 parts of a binder are mixed uniformly, and 217.5 parts of a 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 a lubricant and 10 parts of a glidant are added, mixed uniformly, and tableted to obtain tablet cores;

[0070] 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 20 rpm, coating weight gain 8%), to obtain isolation coated tablet cores;

[0071] Step S3: 70 parts of methacrylic acid-ethyl acrylate copolymer dispersion, 30 parts of modified polyacrylate emulsion, 1000 parts of 90 wt% ethanol aqueous solution, 40 parts of Tween 80, 15 parts of plasticizer and 10 parts of talc were mixed to obtain an enteric coating solution; the enteric coating solution was sprayed onto the isolation-coated tablet core to form an enteric coating layer (the parameters of the fluidized bed coating were as follows: inlet air temperature 45°C, air volume 130 m 3 / h, material temperature 40°C, peristaltic pump speed 40 rpm, coating weight gain 10%), to obtain mesalazine enteric-coated sustained-release tablets;

[0072] The preparation method of modified hydroxypropyl methylcellulose is as follows:

[0073] Step (1): uniformly mix a 3 wt % hydroxypropyl methylcellulose aqueous solution and sodium periodate, adjust the pH to 6, heat to 50° C., react for 5 h under light-shielding conditions, dialyze, and dry to obtain dialdehyde hydroxypropyl methylcellulose; the mass ratio of hydroxypropyl methylcellulose to sodium periodate is 1:0.2;

[0074] Step (2): 3 wt% ethylene glycol chitosan aqueous solution and 12 wt% octenyl succinic anhydride ethanol aqueous solution were mixed uniformly in a mass ratio of 1:0.2, the pH was adjusted to 8.5, and the mixture was reacted at 40°C for 24 h. After dialyzing and drying, ethylene glycol chitosan containing double bonds was obtained;

[0075] Step (3): prepare 250 parts of a 20 wt% aqueous solution of dialdehyde hydroxypropyl methylcellulose, add a mixed solution of polylactic acid-polyethylene glycol-amino and tetrahydrofuran in a mass ratio of 1:4, mix, adjust the pH to 5, react at 35°C for 18 hours, then add 100 parts of chitosan containing double-bond ethylene glycol, mix, continue to react for 24 hours, remove the organic solvent, dialyze, and dry to obtain modified hydroxypropyl methylcellulose; the molar ratio of aldehyde groups in the dialdehyde hydroxypropyl methylcellulose aqueous solution to amino groups in polylactic acid-polyethylene glycol-amino is 1:0.6;

[0076] The preparation of modified polyacrylate emulsion comprises the following steps:

[0077] Ammonium persulfate, sodium lauryl 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 hours, the pH was adjusted to 8, and the product was filtered and purified to obtain a modified polyacrylate emulsion;

[0078] 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.

[0079] Comparative Example 1: A preparation process for mesalazine enteric-coated sustained-release tablets, comprising the following processes:

[0080] A preparation process for mesalazine enteric-coated sustained-release tablets comprises the following steps:

[0081] Step S1: 500 parts of mesalazine, 100 parts of a pH adjuster, 30 parts of modified hydroxypropyl methylcellulose, 50 parts of a filler, and 20 parts of a binder are mixed uniformly, 150 parts of a 90% ethanol aqueous solution are added, wet granulation is performed (stirring speed 500 rpm, cutter speed 1500 rpm, granulation time 60 s), drying (drying temperature 65°C, moisture content controlled at 2.5%), granulation is performed, and the granules are passed through a 1.2 mm sieve. 10 parts of a lubricant and 5 parts of a glidant are then added, mixed uniformly, and tableting is performed to obtain tablet cores;

[0082] Step S2: Hydroxypropyl methylcellulose and deionized water are mixed in a mass ratio of 1:9.5 to obtain an isolation coating solution; the isolation coating solution is sprayed 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 10 rpm, coating weight gain 5%), to obtain isolation coated tablet cores;

[0083] Step S3: 60 parts of methacrylic acid-ethyl acrylate copolymer dispersion, 10 parts of modified polyacrylate emulsion, 900 parts of 85 wt% ethanol aqueous solution, 30 parts of Tween 80, 10 parts of plasticizer and 8 parts of talc were mixed to obtain an enteric coating solution; the enteric coating solution was sprayed onto the isolation-coated tablet core to form an enteric coating layer (the parameters of the fluidized bed coating were as follows: inlet air temperature 40°C, air volume 120 m 3 / h, material temperature 35°C, peristaltic pump speed 30 rpm, coating weight gain 8%), to obtain mesalazine enteric-coated sustained-release tablets;

[0084] 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 in Example 2.

[0085] Comparative Example 2: A preparation process for mesalazine enteric-coated sustained-release tablets, comprising the following processes:

[0086] 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. The other steps are the same as in Example 2.

[0087] Comparative Example 3: A preparation process for mesalazine enteric-coated sustained-release tablets, comprising the following processes:

[0088] The preparation method of modified hydroxypropyl methylcellulose is as follows:

[0089] Step (1): uniformly mix a 2 wt % hydroxypropyl methylcellulose aqueous solution and sodium periodate, adjust the pH to 4, heat to 40° C., react for 4 h under light-shielding conditions, dialyze, and dry to obtain dialdehyde hydroxypropyl methylcellulose; the mass ratio of hydroxypropyl methylcellulose to sodium periodate is 1:0.1;

[0090] 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, and the mixture was reacted at 35°C for 23 h. After dialyzing and drying, ethylene glycol chitosan containing double bonds was obtained;

[0091] Step (3): prepare 280 parts of a 15 wt% aqueous solution of dialdehyde hydroxypropyl methylcellulose, add a mixed solution of polylactic acid-polyethylene glycol-amino and tetrahydrofuran in a mass ratio of 1:3, mix, adjust the pH to 4, react at 30°C for 16 hours, then add 63 parts of chitosan containing double bond glycol, mix, continue to react for 23 hours, remove the organic solvent, dialyze, and dry to obtain modified hydroxypropyl methylcellulose;

[0092] 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.

[0093] Experiment: Release test: The mesalazine enteric-coated sustained-release tablets obtained in Examples 1-3 and Comparative Examples 1-3 were measured according to the second method of General Rules 0931 of the 2020 edition of the Chinese Pharmacopoeia. The paddle method was used at a speed of 100 r / min and a temperature of (37±0.5) ° C. The tablets were soaked in 750 mL of 0.1 mol / L hydrochloric acid solution for 2 h, then transferred to 950 mL of pH 6.8 phosphate buffer, and the speed was kept constant. Samples were taken after 1, 2, 4, and 7 h. The results are as follows:

[0094]

[0095] According to the data in the above table, we can clearly draw the following conclusions:

[0096] 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 resulting in an excessively fast release rate of the drug in the intestine. It can be seen that the performance of the enteric coating liquid prepared by the present invention is affected by the composition ratio thereof. By selecting the composition ratio within the above 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, thereby slowing down the release rate of the drug.

[0097] Compared with Examples 1-3, the release rate 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 a double bond, and then preparing a modified polyacrylic acid emulsion with better effect.

[0098] 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 invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations that come within the meaning and range of equivalents of the claims be embraced therein.

Claims

1. A preparation process for mesalazine enteric-coated sustained-release tablets, characterized in that: The steps include: Step S1: mixing mesalazine, a pH adjuster, modified hydroxypropyl methylcellulose, a filler, and a binder, wet granulating, drying, and granulating, then adding a lubricant and a glidant, mixing, and tableting to obtain a tablet core; Step S2: mixing hydroxypropyl methylcellulose and deionized water to obtain an isolation coating solution; spraying the isolation coating solution onto the tablet core to form an isolation coating layer to obtain an isolation-coated tablet core; Step S3: uniformly mixing a methacrylic acid-ethyl acrylate copolymer dispersion, a modified polyacrylate emulsion, an ethanol aqueous solution, Tween 80, a plasticizer, and talc to obtain an enteric coating solution; spraying the enteric coating solution onto the isolation-coated tablet core to form an enteric coating layer, thereby obtaining mesalazine enteric-coated sustained-release tablets; The preparation method of the modified hydroxypropyl methylcellulose is as follows: Step (1): uniformly mix the hydroxypropyl methylcellulose aqueous solution and sodium periodate, adjust the pH to 2-6, heat to 30-50°C, react under light-shielding conditions for 3-5 hours, dialyze, and dry to obtain dialdehyde hydroxypropyl methylcellulose; Step (2): uniformly mix the ethylene glycol chitosan aqueous solution and the octenyl succinic anhydride ethanol aqueous solution, adjust the pH to 8.3-8.5, react at 30-40°C for 22-24h, dialyze and dry 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 chitosan containing double bond glycol, continue to react for 22-24 hours, remove the organic solvent, dialyze, and dry to obtain modified hydroxypropyl methylcellulose; In the step (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:(0.4-0.6); The enteric coating solution 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; The preparation of the modified polyacrylate emulsion comprises the following steps: Ammonium persulfate, sodium lauryl 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 70-80°C for 4-6 hours, the pH was adjusted to 7-8, and the product was filtered and purified to obtain a modified polyacrylate emulsion; The modified polyacrylate emulsion is composed of the following components in parts by weight: 0.4-0.5 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, 5-8 parts of modified hydroxypropyl methylcellulose, and 0.1-0.3 parts of ammonium persulfate.

2. A process for preparing 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 1, characterized in that: In the isolation coating liquid, the mass ratio of hydroxypropyl methylcellulose to deionized water is 1:(9-10).

4. The preparation process of a mesalazine enteric-coated sustained-release tablet according to claim 1, wherein: The filler is one or more of starch, lactose, mannitol and microcrystalline cellulose.

5. A process for preparing a mesalazine enteric-coated sustained-release tablet according to claim 1, characterized in that: The lubricant is magnesium stearate.

6. A mesalazine enteric-coated sustained-release tablet prepared according to the preparation process according to any one of claims 1 to 5.

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