CN112675142A - Large-scale preparation process of high-purity mesalazine enteric-coated sustained-release tablet preparation - Google Patents
Large-scale preparation process of high-purity mesalazine enteric-coated sustained-release tablet preparation Download PDFInfo
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- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 title claims abstract description 79
- 229960004963 mesalazine Drugs 0.000 title claims abstract description 79
- 238000002360 preparation method Methods 0.000 title claims abstract description 79
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 45
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims abstract description 12
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims abstract description 12
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 4
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- 229940005550 sodium alginate Drugs 0.000 claims description 4
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 3
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a large-scale preparation process of a high-purity mesalazine enteric-coated sustained-release tablet preparation, which comprises the following steps: dissolving polyglutamic acid in water, adding an N-hydroxysuccinimide NHS solution and a 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDC solution, and reacting at room temperature for 4-8 h to obtain an activated polyglutamic acid solution; and then adding the activated polyamino acid solution into a mixture with the mass ratio of 1: (0.1-0.5) uniformly mixing a cross-linking agent and an initiator, reacting for 0.5-1 h at 0-5 ℃, then mixing the product with a water-soluble polymer solution, and reacting for 1-3 h at 30-40 ℃ with stirring to obtain a water-soluble polymer-polyglutamic acid copolymer; slowly adding mesalazine and water-soluble polymer-polyglutamic acid copolymer into a granulator under stirring, adding a thickening agent, and stirring to form a proper soft material; and preparing the soft material into dry granules, and then tabletting and coating to obtain the high-purity mesalazine enteric-coated sustained-release tablet preparation. The preparation process is simple and suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of preparation of chemicals, and particularly relates to a large-scale preparation process of a high-purity mesalazine enteric-coated sustained-release tablet preparation.
Background
Ulcerative Colitis (UC) is a chronic nonspecific intestinal inflammation whose etiology is not well-defined, and the diseased region is mainly in the mucous membrane and submucosa of the colon and rectum, and can form macroscopic erosion and ulcer. The lesions range from the distal colon, with reversible progression to the proximal, even affecting the entire colon, and occasionally affecting the terminal ileum, in a continuous distribution. The incidence rate of the UC is high in European and American areas, the incidence rate of the UC is relatively low in non-national countries, the number of cases reported in China is gradually increased in recent years, and the incidence rate of the UC in China is on an increasing trend. As the etiology and pathogenesis of the disease are not clarified, the treatment lacks specificity, so that the disease condition is delayed and repeated, even the disease becomes cancerous, the physical and mental health of a patient is seriously influenced, and the disease is listed as difficult disease by the world health organization.
Mesalamine (mesalamine) is also called 5-aminosalicylic acid (5-ASA) and is a first-line medicament for clinically treating mild-moderate UC at present due to definite curative effect. It exerts an anti-inflammatory effect by inhibiting the formation of prostaglandin E and leukotrienes, its action is local, i.e. it exerts an effect when contacting and complexing with the intestinal mucosa, its therapeutic effect is related to the concentration and duration of the drugs contacting the inflammatory intestinal mucosa, and is not much related to the blood drug concentration. The mesalazine can be absorbed by stomach and small intestine quickly by direct oral administration, can not reach colon to play an anti-inflammatory role, and meanwhile, the medicine inhaled into the body is easy to generate toxicity, so the mesalazine oral preparation must be designed into an enteric preparation to reduce the absorption in the upper gastrointestinal tract, so that the mesalazine oral preparation is positioned to the terminal ileum or colon to release the medicine, and the effective medicine concentration in the pathological intestinal section can be maintained.
The prior art also discloses a preparation method of the mesalazine enteric sustained-release tablet preparation, for example, the application numbers are as follows: the Chinese patent of CN201611115822.X discloses a preparation method of a mesalazine enteric-coated sustained-release tablet, which takes povidone as an adhesive, adopts wet granulation and tabletting processes to prepare a mesalazine sustained-release tablet core, and then prepares the enteric-coated sustained-release tablet through enteric coating, wherein each tablet contains 1.2g of mesalazine. As another example, application numbers are: CN201210318122.6, a chinese patent invention, discloses a mesalazine enteric coated tablet and a preparation method thereof, which are prepared by adopting a nanotechnology, an enteric coating technology and a pellet tabletting technology. The enteric-coated sustained-release tablets are prepared by an enteric-coated technology and a tabletting technology, other substances are added, and the obtained enteric-coated sustained-release tablets are used for conventional administration and are not obvious in improvement of treatment effect. In addition, povidone (PVP), which is used as a binder, is a class 3 carcinogen and causes damage to health in long-term use.
Disclosure of Invention
The invention mainly aims to provide a large-scale preparation process of a high-purity mesalazine enteric-coated sustained-release tablet preparation aiming at the defects in the prior art. The preparation method is simple, the obtained mesalazine enteric-coated sustained-release tablet has good effect and no harm to human body, and no pollutant is generated in the preparation process, so that the mesalazine enteric-coated sustained-release tablet is an environment-friendly medicine.
The purpose of the invention and the technical problem to be solved are realized by adopting the following technical scheme.
The invention provides a large-scale preparation process of a high-purity mesalazine enteric-coated sustained-release tablet preparation, which comprises the following steps:
dissolving polyglutamic acid in water, adding an N-hydroxysuccinimide NHS solution and a 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDC solution, and reacting at room temperature for 4-8 h to obtain an activated polyglutamic acid solution; and then adding the activated polyamino acid solution into a mixture with the mass ratio of 1: (0.1-0.5) uniformly mixing a cross-linking agent and an initiator, reacting for 0.5-1 h at 0-5 ℃, then mixing the product with a water-soluble polymer solution, and reacting for 1-3 h at 30-40 ℃ with stirring to obtain a water-soluble polymer-polyglutamic acid copolymer;
slowly adding mesalazine and the water-soluble polymer-polyglutamic acid copolymer into a fast wet mixing granulator under stirring, immediately adding a thickening agent after the adding, and keeping stirring until a proper soft material is formed; the soft material is properly rounded after passing through an extruder, dried to obtain dry particles, and then the particles are tabletted through a double-layer tabletting machine to prepare tablets; finally, the tablet is placed in a film coating machine, and the coating liquid is sprayed for enteric coating, so that the high-purity mesalazine enteric sustained-release tablet preparation is obtained.
In the large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation, the volume ratio of the N-hydroxysuccinimide NHS solution to the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDC solution is 1: (1-2).
According to the large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation, the cross-linking agent is ethylene glycol dimethacrylate; the initiator is azobisisobutyronitrile.
According to the large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation, the water-soluble polymer is selected from any one of polyvinyl alcohol, polylactic acid and chitosan.
According to the large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation, the mass ratio of the polyglutamic acid to the water-soluble polymer is 1: (2-4).
According to the large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation, the thickening agent is selected from any one of sodium alginate, carboxymethyl cellulose, guar gum, agar and hydroxypropyl methyl cellulose.
According to the large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation, the mass ratio of the thickening agent to the mesalazine is (0.1-0.4): 1.
The large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation comprises the following steps: 6 parts of coating material, 2 parts of plasticizer, 2 parts of surfactant and 120 parts of solvent.
According to the large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation, the coating material is polyacrylic resin III; the plasticizer is polyethylene glycol; the surfactant is polysorbate 80; the solvent is ethanol.
According to the large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation, the weight of the coating solution to the tablet core is 1.0-2.5%.
By the technical scheme, the invention at least has the following advantages: the polyglutamic acid is activated and then copolymerized with the water-soluble high molecular substance to obtain the water-soluble high molecular-polyglutamic acid copolymer, the copolymer can be used as a binding agent in the process of preparing the mesalazine enteric-coated sustained-release tablet, the traditional binding agent povidone is replaced, the toxicity of the medicine is reduced, and the performance of the medicine is ensured. According to the invention, the N-hydroxysuccinimide NHS solution and the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDC solution are used as the activating agents, so that the activating efficiency is greatly improved, the reaction time is shortened, the influence of the used reagent on the structural change of the polyglutamic acid is small, the loss of the polyglutamic acid in the modification process is reduced, and the cost is reduced. The ethylene glycol dimethacrylate and the azobisisobutyronitrile are respectively used as a cross-linking agent and an initiator, so that the binding capacity between the polyglutamic acid and the water-soluble high molecular substance can be promoted, the copolymerization reaction between the polyglutamic acid and the water-soluble high molecular substance can be promoted, and the stability and the viscosity of the product can be improved. The preparation method is simple, the used raw materials are simple in components, and the preparation is non-toxic and harmless to human bodies, has no pollution to the environment, and is an environment-friendly preparation.
The foregoing is a summary of the present invention, and in order to provide a clear understanding of the technical means of the present invention and to be implemented in accordance with the present specification, the following is a detailed description of the preferred embodiments of the present invention.
Detailed Description
In order to make the technical means, the creation features, the achievement purposes and the effects of the invention easy to understand, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Dissolving 300 parts of 100 parts of polyglutamic acid in water according to parts by weight, adding an N-hydroxysuccinimide NHS solution and a 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDC solution (volume ratio is 1:1), and reacting at room temperature for 6 hours to obtain an activated polyglutamic acid solution. And then adding the activated polyamino acid solution into a mixture with the mass ratio of 1: 0.3 ethylene glycol dimethacrylate and azobisisobutyronitrile are evenly mixed and react for 0.5h at the temperature of 3 ℃, then the product is mixed with 300 parts of aqueous solution (the mass fraction is 25 wt%) of polyvinyl alcohol, and the mixture is stirred and reacts for 2h at the temperature of 30 ℃, so that the polyvinyl alcohol-polyglutamic acid copolymer is obtained. Slowly adding 50 parts of mesalazine and 200 parts of polyvinyl alcohol-polyglutamic acid copolymer into a fast wet mixing granulator under stirring, immediately adding 15 parts of sodium alginate, and keeping stirring until a proper soft material is formed; the soft material is properly rounded after passing through an extruder, dried to obtain dry particles, and then the particles are tabletted through a double-layer tabletting machine to prepare tablets; finally, putting the tablets into a film coating machine, spraying coating liquid (6 parts of polyacrylic resin III, 2 parts of polyethylene glycol, 802 parts of polysorbate and 120 parts of ethanol) for enteric coating, wherein the weight of the coating liquid to the tablet core is increased by 1.5%, and thus obtaining the high-purity mesalazine enteric sustained-release tablet preparation.
Example 2
Dissolving 100 parts of polyglutamic acid in 300 parts of water, adding an N-hydroxysuccinimide NHS solution and a 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDC solution (volume ratio is 1:2), and reacting for 4 hours at room temperature to obtain an activated polyglutamic acid solution. And then adding the activated polyamino acid solution into a mixture with the mass ratio of 1: 0.3 ethylene glycol dimethacrylate and azobisisobutyronitrile are evenly mixed and react for 1h at 0 ℃, then the product is mixed with 400 parts of aqueous solution (mass fraction is 30 wt%) of polyvinyl alcohol, and the mixture is stirred and reacts for 3h at 40 ℃ to obtain the polyvinyl alcohol-polyglutamic acid copolymer. Slowly adding 50 parts of mesalazine and 250 parts of polyvinyl alcohol-polyglutamic acid copolymer into a fast wet mixing granulator under stirring, immediately adding 5 parts of hydroxypropyl methyl cellulose, and keeping stirring until a proper soft material is formed; the soft material is properly rounded after passing through an extruder, dried to obtain dry particles, and then the particles are tabletted through a double-layer tabletting machine to prepare tablets; finally, putting the tablets into a film coating machine, spraying coating liquid (6 parts of polyacrylic resin III, 2 parts of polyethylene glycol, 802 parts of polysorbate and 120 parts of ethanol) for enteric coating, wherein the weight of the coating liquid to the tablet core is increased by 1.5%, and thus obtaining the high-purity mesalazine enteric sustained-release tablet preparation.
Example 3
Dissolving 100 parts of polyglutamic acid in 200 parts of water, adding an N-hydroxysuccinimide NHS solution and a 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDC solution (volume ratio is 1:2), and reacting at room temperature for 8 hours to obtain an activated polyglutamic acid solution. And then adding the activated polyamino acid solution into a mixture with the mass ratio of 1: 0.5 ethylene glycol dimethacrylate and azobisisobutyronitrile are evenly mixed and then react for 0.5h at the temperature of 5 ℃, and then the product is mixed with 400 parts of polylactic acid aqueous solution (the mass fraction is 20wt percent), and the mixture is stirred and reacts for 2h at the temperature of 35 ℃ to obtain the polylactic acid-polyglutamic acid copolymer. Slowly adding 50 parts of mesalazine and 400 parts of polylactic acid-polyglutamic acid copolymer into a quick wet mixing granulator under stirring, immediately adding 20 parts of agar, and keeping stirring until a proper soft material is formed; the soft material is properly rounded after passing through an extruder, dried to obtain dry particles, and then the particles are tabletted through a double-layer tabletting machine to prepare tablets; finally, putting the tablets into a film coating machine, spraying coating liquid (6 parts of polyacrylic resin III, 2 parts of polyethylene glycol, 802 parts of polysorbate and 120 parts of ethanol) for enteric coating, wherein the weight of the coating liquid to the tablet core is increased by 1.5%, and thus obtaining the high-purity mesalazine enteric sustained-release tablet preparation.
Example 4
Dissolving 100 parts of polyglutamic acid in 250 parts of water, adding an N-hydroxysuccinimide NHS solution and a 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDC solution (volume ratio is 1:1), and reacting at room temperature for 5 hours to obtain an activated polyglutamic acid solution. And then adding the activated polyamino acid solution into a mixture with the mass ratio of 1: 0.4 ethylene glycol dimethacrylate and azobisisobutyronitrile are evenly mixed and then react for 0.7h at the temperature of 2 ℃, and then the product is mixed with 350 parts of polylactic acid aqueous solution (the mass fraction is 30wt percent), and the mixture is stirred and reacts for 1h at the temperature of 40 ℃ to obtain the polylactic acid-polyglutamic acid copolymer. Slowly adding 50 parts of mesalazine and polylactic acid-polyglutamic acid copolymer into a fast wet mixing granulator under stirring, immediately adding 15 parts of guar gum, and keeping stirring until a proper soft material is formed; the soft material is properly rounded after passing through an extruder, dried to obtain dry particles, and then the particles are tabletted through a double-layer tabletting machine to prepare tablets; finally, putting the tablets into a film coating machine, spraying coating liquid (6 parts of polyacrylic resin III, 2 parts of polyethylene glycol, 802 parts of polysorbate and 120 parts of ethanol) for enteric coating, wherein the weight of the coating liquid to the tablet core is increased by 1.0%, and thus obtaining the high-purity mesalazine enteric sustained-release tablet preparation.
Example 5
Dissolving 100 parts of polyglutamic acid in 200 parts of water, adding an N-hydroxysuccinimide NHS solution and a 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDC solution (volume ratio is 1:2), and reacting at room temperature for 7 hours to obtain an activated polyglutamic acid solution. And then adding the activated polyamino acid solution into a mixture with the mass ratio of 1: 0.3 ethylene glycol dimethacrylate and azobisisobutyronitrile are evenly mixed and reacted for 0.8h at 4 ℃, then the product is mixed with 250 parts of chitosan aqueous solution (mass fraction is 20 wt%), and the mixture is stirred and reacted for 1h at 35 ℃ to obtain the chitosan-polyglutamic acid copolymer. Slowly adding 50 parts of mesalazine and 300 parts of chitosan-polyglutamic acid copolymer into a rapid wet mixing granulator under stirring, immediately adding 15 parts of carboxymethyl cellulose, and keeping stirring until a proper soft material is formed; the soft material is properly rounded after passing through an extruder, dried to obtain dry particles, and then the particles are tabletted through a double-layer tabletting machine to prepare tablets; finally, putting the tablets into a film coating machine, spraying coating liquid (6 parts of polyacrylic resin III, 2 parts of polyethylene glycol, 802 parts of polysorbate and 120 parts of ethanol) for enteric coating, wherein the weight of the coating liquid to the tablet core is increased by 1.0%, and thus obtaining the high-purity mesalazine enteric sustained-release tablet preparation.
Example 6
Dissolving 100 parts of polyglutamic acid in 300 parts of water, adding an N-hydroxysuccinimide NHS solution and a 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDC solution (volume ratio is 1:1), and reacting at room temperature for 6 hours to obtain an activated polyglutamic acid solution. And then adding the activated polyamino acid solution into a mixture with the mass ratio of 1: 0.2 ethylene glycol dimethacrylate and azobisisobutyronitrile are evenly mixed and react for 1h at the temperature of 2 ℃, then the product is mixed with 200 parts of chitosan aqueous solution (the mass fraction is 25wt percent), and the mixture is stirred and reacts for 3h at the temperature of 40 ℃, so that the chitosan-polyglutamic acid copolymer is obtained. Slowly adding 50 parts of mesalazine and 200 parts of chitosan-polyglutamic acid copolymer into a fast wet mixing granulator under stirring, immediately adding 5 parts of sodium alginate, and keeping stirring until a proper soft material is formed; the soft material is properly rounded after passing through an extruder, dried to obtain dry particles, and then the particles are tabletted through a double-layer tabletting machine to prepare tablets; finally, putting the tablets into a film coating machine, spraying coating liquid (6 parts of polyacrylic resin III, 2 parts of polyethylene glycol, 802 parts of polysorbate and 120 parts of ethanol) for enteric coating, wherein the weight of the coating liquid to the tablet core is increased by 2.0%, and thus obtaining the high-purity mesalazine enteric sustained-release tablet preparation.
Comparative example 1
The mesalazine enteric-coated tablet is sold on the market.
Comparative example 2
The mesalazine enteric-coated tablet prepared by Chinese invention patent CN 201210318122.6.
Test example 1 comparison of Release amounts in acid-neutralizing buffer solution for Mesalazine enteric-coated tablets
Sample preparation: the mesalamine enteric coated tablets obtained in example 1 and the mesalamine enteric coated tablets of comparative example 1.
The method comprises the following steps: the results are shown in table 1 and table 2, measured according to the release degree measurement method of the chinese pharmacopoeia 2015 edition.
TABLE 1 comparison of the amount of acid released
| Sample (I) | Amount released in acid (% by weight) |
| Example 1 | 0.03～0.15 |
| Comparative example 1 | 1.2～3.5 |
TABLE 2 comparison of the amount released in the buffer
| Sample (I) | Release amount in buffer (% indicated) |
| Example 1 | Over 99.8 |
| Comparative example 1 | 94.2～98.3 |
As can be seen from the results in tables 1 and 2, the release amount of the mesalamine enteric sustained-release tablet preparation obtained by the method of the present invention is significantly reduced compared with the acid release amount of the commercially available mesalamine enteric sustained-release tablet; but the release amount is obviously higher than that of the buffer solution of the commercially available mesalazine enteric-coated tablet.
Test example 2 comparison of stability of Mesalazine enteric-coated tablets
Samples of the mesalamine enteric coated tablets prepared in example 1 of the present invention and the mesalamine preparation prepared in comparative example 2 were placed at 25 ℃ ± 2 ℃ and RH 60% ± 10% in an environment, and were sampled at the end of 0, 12, 24, 36, 48, and 60 months, and the release amount in acid, the release amount in buffer, the limit of impurities, and the content were measured, and the results are shown in table 3.
TABLE 3 comparison of stability
The above results indicate that the mesalamine enteric coated tablet prepared in example 1 of the present invention has a significantly longer shelf life and increased stability than the mesalamine preparation of comparative example 2.
Test example 3 comparison of the drug efficacy of mesalazine enteric coated tablets
6 mice were selected and randomly divided into 2 groups, fasted for 12 hours, and the mesalamine enteric coated tablets prepared in inventive example 1 and the mesalamine preparation of comparative example 2 were administered with the same dose, each group of mice was sacrificed after 60 minutes, colon tissues were separated, cut into small pieces, homogenized in ice bath for 5 minutes, propionic anhydride was added, shaken for 10 minutes, methanol was added, shaken for 2 minutes, centrifuged, and the supernatant was taken, and the mesalamine concentration was measured with a high performance liquid chromatograph. The results are shown in Table 4.
TABLE 4 comparison of drug concentrations in colon tissue fluid of mice
| Sample (I) | Drug concentration (ug/mL) |
| Example 1 | 10.02±0.25 |
| Comparative example 2 | 7.28±0.26 |
The results show that the concentration of the drug in the colon tissue fluid of the mesalamine enteric-coated tablet prepared by the invention is obviously increased compared with the colon tissue fluid of the mesalamine enteric-coated preparation prepared by the prior art, so that the product prepared by the invention has better curative effect than the product prepared by the prior art.
Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. A large-scale preparation process of a high-purity mesalazine enteric-coated sustained-release tablet preparation is characterized by comprising the following steps:
dissolving polyglutamic acid in water, adding an N-hydroxysuccinimide NHS solution and a 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDC solution, and reacting at room temperature for 4-8 h to obtain an activated polyglutamic acid solution; and then adding the activated polyamino acid solution into a mixture with the mass ratio of 1: (0.1-0.5) uniformly mixing a cross-linking agent and an initiator, reacting for 0.5-1 h at 0-5 ℃, then mixing the product with a water-soluble polymer solution, and reacting for 1-3 h at 30-40 ℃ with stirring to obtain a water-soluble polymer-polyglutamic acid copolymer;
slowly adding mesalazine and the water-soluble polymer-polyglutamic acid copolymer into a fast wet mixing granulator under stirring, immediately adding a thickening agent after the adding, and keeping stirring until a proper soft material is formed; the soft material is properly rounded after passing through an extruder, dried to obtain dry particles, and then the particles are tabletted through a double-layer tabletting machine to prepare tablets; finally, the tablet is placed in a film coating machine, and the coating liquid is sprayed for enteric coating, so that the high-purity mesalazine enteric sustained-release tablet preparation is obtained.
2. The large-scale preparation process of the high-purity mesalamine enteric-coated sustained-release tablet preparation according to claim 1, wherein the volume ratio of the N-hydroxysuccinimide NHS solution to the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDC solution is 1: (1-2).
3. The large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation according to claim 1, wherein the cross-linking agent is ethylene glycol dimethacrylate; the initiator is azobisisobutyronitrile.
4. The large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation according to claim 1, wherein the water-soluble polymer is any one of polyvinyl alcohol, polylactic acid and chitosan.
5. The large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation according to claim 1, wherein the mass ratio of the polyglutamic acid to the water-soluble polymer is 1: (2-4).
6. The large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation according to claim 1, wherein the thickener is any one selected from sodium alginate, carboxymethyl cellulose, guar gum, agar and hydroxypropyl methyl cellulose.
7. The large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation according to claim 1, wherein the mass ratio of the thickening agent to the mesalazine is (0.1-0.4): 1.
8. The large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation according to claim 1, wherein the coating solution comprises the following components: 6 parts of coating material, 2 parts of plasticizer, 2 parts of surfactant and 120 parts of solvent.
9. The large-scale preparation process of the high-purity mesalazine enteric sustained-release tablet preparation according to claim 8, wherein the coating material is polyacrylic resin III; the plasticizer is polyethylene glycol; the surfactant is polysorbate 80; the solvent is ethanol.
10. The large-scale preparation process of the high-purity mesalazine enteric-coated sustained-release tablet preparation according to claim 8, wherein the weight of the coating solution to the tablet core is increased by 1.0-2.5%.
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