CN111700871A - Mesalazine composition and preparation method thereof - Google Patents
Mesalazine composition and preparation method thereof Download PDFInfo
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- CN111700871A CN111700871A CN202010586418.0A CN202010586418A CN111700871A CN 111700871 A CN111700871 A CN 111700871A CN 202010586418 A CN202010586418 A CN 202010586418A CN 111700871 A CN111700871 A CN 111700871A
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/606—Salicylic acid; Derivatives thereof having amino groups
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Abstract
The invention discloses a mesalazine composition and a preparation method thereof, wherein the mesalazine composition is prepared from the following raw materials in parts by weight: 100-120 parts of mesalazine bulk drug, 5.5-6 parts of dextrin, 8-10 parts of sodium sulfite, 10-12 parts of starch, 20-30 parts of mannitol, 10-15 parts of microcrystalline cellulose, 10-15 parts of calcium carbonate, 1.6-2 parts of magnesium stearate and 0.15-0.3 part of Chinese wax; the catalyst is prepared in the process of preparing the mesalazine bulk drug, has high catalytic activity, greatly improves the preparation rate of the mesalazine bulk drug, increases the yield of the mesalazine bulk drug, and prepares a coating solution, the coating solution replaces an organic solvent with deionized water, avoids the defects of high toxicity, volatility, flammability and explosiveness, high price and potential environmental pollution of the organic solvent, and can not disintegrate in the stomach and rapidly disintegrate in the intestinal tract, so that the mesalazine composition can effectively treat enteritis.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to a mesalazine composition and a preparation method thereof.
Background
Mesalazine is an active ingredient of SASP for treating ulcerative colitis, and has a remarkable inhibition effect on inflammation of intestinal wall; mesalazine can inhibit synthesis of prostaglandin causing inflammation and formation of inflammatory mediator leukotriene, so as to play a significant role in inhibiting inflammation of intestinal mucosa, and mesalazine can inhibit synthesis of prostaglandin in a dose-dependent manner and reduce release of PGE2 in human colon mucosa.
Most of the existing mesalazine compositions are enteric preparations, after a user takes the mesalazine composition, part of the mesalazine composition is disintegrated in the stomach in a small amount, and part of the mesalazine cannot treat enteritis, so that the treatment effect is poor.
Disclosure of Invention
The invention aims to provide a mesalazine composition and a preparation method thereof.
The technical problems to be solved by the invention are as follows:
most of the existing mesalazine compositions are enteric preparations, after a user takes the mesalazine composition, part of the mesalazine composition is disintegrated in the stomach in a small amount, and part of the mesalazine cannot treat enteritis, so that the treatment effect is poor.
The purpose of the invention can be realized by the following technical scheme:
the mesalazine composition is prepared from the following raw materials in parts by weight: 100-120 parts of mesalazine bulk drug, 5.5-6 parts of dextrin, 8-10 parts of sodium sulfite, 10-12 parts of starch, 20-30 parts of mannitol, 10-15 parts of microcrystalline cellulose, 10-15 parts of calcium carbonate, 1.6-2 parts of magnesium stearate and 0.15-0.3 part of Chinese wax.
Further, the mesalazine composition is prepared by the following steps:
step S1: adding dextrin and sodium sulfite into a reaction kettle, adding deionized water, stirring at the temperature of 25-30 ℃ until the dextrin and the sodium sulfite are completely dissolved to prepare a mixed solution, adding mesalazine bulk drug, starch, mannitol and microcrystalline cellulose into a mixer, mixing until the mixture is uniformly mixed to prepare a first mixed material, adding the first mixed material and the mixed solution into the reaction kettle, and stirring for 20-30min at the rotation speed of 200-300r/min to prepare a soft material;
step S2: granulating the soft material prepared in the step S1 through a 15-20-mesh screen, drying for 15-30min at the temperature of 75-80 ℃ to obtain solid particles, adding the solid particles, calcium carbonate and magnesium stearate into a mixer, mixing uniformly, tabletting, and preparing a tablet core;
step S3: and (4) adding the tablet core prepared in the step (S2) into a coating pan, heating to 40-45 ℃ of the surface temperature of the tablet core under the conditions of 5-10r/min and 60-70 ℃ of inlet air temperature, coating the tablet core with coating liquid under the conditions of 2.5-3bar of atomization pressure until the coating liquid is used up, blowing cold air until the air outlet temperature reaches 35-40 ℃, stopping blowing, adding Chinese wax into the coating pan, and polishing for 15-20min under the condition of 10-15r/min of rotation speed to obtain the mesalazine composition.
Further, the mesalazine bulk drug is prepared by the following steps:
step A1: adding salicylic acid and 1/4 amount of deionized water into a reaction kettle, stirring until the salicylic acid is completely dissolved under the conditions that the rotating speed is 300-500r/min and the temperature is 50-55 ℃, slowly adding first mixed acid, reacting for 2-3h under the condition that the temperature is 70-75 ℃, adding the rest deionized water, standing in an ice-water bath for 10-15min, and filtering to remove filtrate to obtain 5-nitro salicylic acid;
step A2: adding the carbon nanotubes into the second mixed acid, performing ultrasonic treatment for 10-15min under the condition of the frequency of 40-50kHz, heating and refluxing for 2-3h at the temperature of 120-130 ℃, adding deionized water until the pH value is 7, and drying to obtain modified carbon nanotubes;
step A3: adding the modified carbon nanotube prepared in the step A2, stannous chloride and hydrochloric acid solution into a reaction kettle, stirring for 1-2h at the rotation speed of 800-1000r/min and the temperature of 30-40 ℃, filtering to remove filtrate, adding the filtrate into saturated ferric chloride solution, performing ultrasonic treatment for 10-15min at the frequency of 60-80kHz, adding zinc powder, stirring for 4-5h at the rotation speed of 500-800r/min, filtering to remove filtrate, and drying to obtain a catalyst;
step A4: adding concentrated hydrochloric acid and deionized water into a reaction kettle, adding 1/4 amount of the catalyst prepared in the step A3 at the temperature of 60-65 ℃, refluxing for 3-5min, adding 1/3 amount of the 5-nitrosalicylic acid prepared in the step A1, stirring for 5-10min at the rotation speed of 300-500r/min, adding the rest of the catalyst and the 5-nitrosalicylic acid into the reaction kettle in batches at intervals of 5-8min, reacting for 30-50min at the temperature of 95-100 ℃, adding a sodium hydroxide solution, adjusting the pH value to 11-12, filtering to remove filtrate, and drying to obtain the mesalazine bulk drug.
Further, the first mixed acid in the step a1 is prepared by mixing 9 mL: 1g of nitric acid solution and glacial acetic acid, wherein the mass concentration of the nitric acid solution is 68-70%, and the mass ratio of the salicylic acid to the nitric acid solution is 1: 3, the dosage ratio of the salicylic acid to the water is 7 g: 100mL, wherein the dosage ratio of the carbon nanotube and the second mixed acid in the step A2 is 1 g: 20mL, and the volume ratio of the second mixed acid is 1: 3, mixing the nitric acid solution with the sulfuric acid solution, wherein the mass concentration of the nitric acid solution is 50-60%, the mass concentration of the sulfuric acid solution is 60-70%, and the dosage ratio of the modified carbon nanotube, the stannous chloride and the hydrochloric acid solution in the step A3 is 1 g: 1.2 g: 50mL, the volume concentration of hydrochloric acid in the hydrochloric acid solution is 1-1.5%, and the dosage ratio of the filtrate, the ferric chloride solution and the zinc powder is 1 g: 1mL of: 0.5g, wherein the mass fraction of ferric chloride in the ferric chloride solution is 2-4%, and the dosage ratio of concentrated hydrochloric acid, deionized water, the catalyst and 5-nitro salicylic acid in the step A4 is 3 mL: 50mL of: 4 g: 6 g.
Further, the coating liquid is prepared by the following steps:
step B1: adding azodiisobutyronitrile and ethanol into a reaction kettle, stirring until the azodiisobutyronitrile is completely dissolved, adding methyl methacrylate, hydroxyethyl acrylate, butyl acrylate and acrylic acid, stirring for 5-10min at the rotation speed of 300-500r/min, adding sodium bisulfite, performing reflux reaction for 5-8h at the temperature of 80-85 ℃, adding ammonia water to adjust the pH value to 7-7.5, and distilling at the temperature of 80-90 ℃ to remove ethanol to obtain an intermediate;
step B1: and D, adding the intermediate prepared in the step B1 and deionized water into a reaction kettle, stirring for 5-10min at the temperature of 30-40 ℃ and the rotating speed of 1000-1500r/min, adding triethyl citrate, and continuing stirring for 10-15min to prepare a coating solution.
Further, the amount ratio of the methyl methacrylate, the hydroxyethyl acrylate, the butyl acrylate and the acrylic acid in the step B1 is 1: 1: 1: 0.2, the dosage of the azodiisobutyronitrile is 3.5-4% of the total mass of the methyl methacrylate, the hydroxyethyl acrylate, the butyl acrylate and the acrylic acid, the dosage of the sodium bisulfite is 13-15% of the total mass of the methyl methacrylate, the hydroxyethyl acrylate, the butyl acrylate and the acrylic acid, and the dosage mass ratio of the intermediate in the step B2 to the deionized water is 1: 4, the amount of triethyl citrate is 8-10% of the mass of the intermediate.
Further, the preparation method of the mesalazine composition specifically comprises the following steps:
step S1: adding dextrin and sodium sulfite into a reaction kettle, adding deionized water, stirring at the temperature of 25-30 ℃ until the dextrin and the sodium sulfite are completely dissolved to prepare a mixed solution, adding mesalazine bulk drug, starch, mannitol and microcrystalline cellulose into a mixer, mixing until the mixture is uniformly mixed to prepare a first mixed material, adding the first mixed material and the mixed solution into the reaction kettle, and stirring for 20-30min at the rotation speed of 200-300r/min to prepare a soft material;
step S2: granulating the soft material prepared in the step S1 through a 15-20-mesh screen, drying for 15-30min at the temperature of 75-80 ℃ to obtain solid particles, adding the solid particles, calcium carbonate and magnesium stearate into a mixer, mixing uniformly, tabletting, and preparing a tablet core;
step S3: and (4) adding the tablet core prepared in the step (S2) into a coating pan, heating to 40-45 ℃ of the surface temperature of the tablet core under the conditions of 5-10r/min and 60-70 ℃ of inlet air temperature, coating the tablet core with coating liquid under the conditions of 2.5-3bar of atomization pressure until the coating liquid is used up, blowing cold air until the air outlet temperature reaches 35-40 ℃, stopping blowing, adding Chinese wax into the coating pan, and polishing for 15-20min under the condition of 10-15r/min of rotation speed to obtain the mesalazine composition.
The invention has the beneficial effects that: the invention prepares mesalamine bulk drug by taking salicylic acid as raw material and nitrating the salicylic acid under the action of first mixed acid, and simultaneously prepares catalyst in the process of preparing mesalamine bulk drug, the catalyst takes carbon nano-tube as carrier, the surface of the carbon nano-tube is treated by second mixed acid firstly, so that oxygen-containing functional group is introduced on the surface of the carbon nano-tube, further metal can be fixed on the surface of the carbon nano-tube, stannous chloride is used for soaking the modified carbon nano-tube, so that bivalent tin ions are adsorbed on the surface of the modified carbon nano-tube by the action of electric charge, ferric chloride solution is added, the modified carbon nano-tube adsorbs ferric ions, the ferric ions are contacted with the bivalent tin ions, and the bivalent tin ions have high reducibility and react with the ferric ions, the method comprises the steps of converting bivalent tin ions into tetravalent tin ions, converting trivalent iron ions into bivalent iron ions, hydrolyzing the tetravalent tin ions to generate tin dioxide, adding zinc powder to convert the bivalent iron ions into iron simple substances to further prepare a catalyst, reacting 5-nitro salicylic acid with the catalyst to prepare a mesalazine bulk drug, wherein the catalyst has high catalytic activity, greatly improves the preparation rate of the mesalazine bulk drug, increases the yield of the mesalazine bulk drug, and also prepares a coating solution, wherein the coating solution is prepared by copolymerizing methyl methacrylate, hydroxyethyl acrylate, butyl acrylate and acrylic acid under the action of an initiator azobisisobutyronitrile, removing a solvent ethanol to prepare an aqueous intermediate, dissolving the intermediate in deionized water, adding triethyl citrate, continuously stirring the coating solution, and is different from the traditional coating solution, the coating liquid replaces an organic solvent with deionized water, so that the defects of high toxicity, volatility, flammability, explosiveness, high price and potential environmental pollution of the organic solvent are overcome, the preparation cost of the mesalazine composition is reduced, the mesalazine composition is more beneficial to market popularization, and the mesalazine composition cannot disintegrate in the stomach and can disintegrate rapidly when entering the intestinal tract, so that the mesalazine composition can effectively treat enteritis.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all 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
The mesalazine composition is prepared from the following raw materials in parts by weight: 100 parts of mesalazine bulk drug, 5.5 parts of dextrin, 8 parts of sodium sulfite, 10 parts of starch, 20 parts of mannitol, 10 parts of microcrystalline cellulose, 10 parts of calcium carbonate, 1.6 parts of magnesium stearate and 0.15 part of Chinese wax;
the mesalazine composition is prepared by the following steps:
step S1: adding dextrin and sodium sulfite into a reaction kettle, adding deionized water, stirring at the temperature of 25 ℃ until the dextrin and the sodium sulfite are completely dissolved to prepare a mixed solution, adding mesalazine bulk drug, starch, mannitol and microcrystalline cellulose into a mixer, mixing until the mixture is uniformly mixed to prepare a first mixed material, adding the first mixed material and the mixed solution into the reaction kettle, and stirring for 20min at the rotation speed of 200r/min to prepare a soft material;
step S2: granulating the soft material prepared in the step S1 through a 15-mesh screen, drying for 15min at the temperature of 75 ℃ to obtain solid particles, adding the solid particles, calcium carbonate and magnesium stearate into a mixer, mixing uniformly, tabletting, and preparing a tablet core;
step S3: adding the tablet core prepared in the step S2 into a coating pan, heating to 40 ℃ of the surface temperature of the tablet core under the conditions of 5r/min and 60 ℃ of inlet air temperature, coating the tablet core with a coating liquid under the condition of 2.5bar of atomization pressure until the coating liquid is used up, blowing cold air until the air outlet temperature reaches 35 ℃, stopping blowing, adding Chinese wax into the coating pan, and polishing for 15min under the condition of 10r/min of rotation speed to obtain the mesalazine composition.
The mesalazine bulk drug is prepared by the following steps:
step A1: adding salicylic acid and deionized water into a reaction kettle, stirring until the salicylic acid is completely dissolved under the conditions that the rotating speed is 300r/min and the temperature is 50 ℃, slowly adding first mixed acid, reacting for 2 hours under the condition that the temperature is 70 ℃, standing for 10 minutes in an ice water bath, and filtering to remove filtrate to obtain 5-nitro salicylic acid;
step A2: adding the carbon nanotubes into a second mixed acid, performing ultrasonic treatment for 10min under the condition of the frequency of 40kHz, heating and refluxing for 2h at the temperature of 120 ℃, adding deionized water until the pH value is 7, and drying to obtain modified carbon nanotubes;
step A3: adding the modified carbon nanotube prepared in the step A2, stannous chloride and hydrochloric acid solution into a reaction kettle, stirring for 1h at the rotation speed of 800r/min and the temperature of 30 ℃, filtering to remove filtrate, adding the filtrate into saturated ferric chloride solution, performing ultrasonic treatment for 10min at the frequency of 60kHz, adding zinc powder, stirring for 4h at the rotation speed of 500r/min, filtering to remove filtrate, and drying to obtain a catalyst;
step A4: adding concentrated hydrochloric acid and deionized water into a reaction kettle, adding 1/4 amount of the catalyst prepared in the step A3 at the temperature of 60 ℃, refluxing for 3min, adding 1/3 amount of the 5-nitro salicylic acid prepared in the step A1, stirring for 5min at the rotation speed of 300r/min, adding the rest of the catalyst and the 5-nitro salicylic acid into the reaction kettle in batches at intervals of 5min, reacting for 30min at the temperature of 95 ℃, adding a sodium hydroxide solution, adjusting the pH value to 11, filtering to remove filtrate, and drying to obtain the mesalazine bulk drug.
The coating liquid is prepared by the following steps:
step B1: adding azodiisobutyronitrile and ethanol into a reaction kettle, stirring until the azodiisobutyronitrile is completely dissolved, adding methyl methacrylate, hydroxyethyl acrylate, butyl acrylate and acrylic acid, stirring for 5min at the rotation speed of 300r/min, adding sodium bisulfite, performing reflux reaction for 5h at the temperature of 80 ℃, adding ammonia water to adjust the pH value to be 7, and distilling at the temperature of 80 ℃ to remove ethanol to obtain an intermediate;
step B1: and D, adding the intermediate prepared in the step B1 and deionized water into a reaction kettle, stirring for 5min at the temperature of 30 ℃ and the rotating speed of 1000r/min, adding triethyl citrate, and continuing stirring for 10min to prepare the coating solution.
Example 2
The mesalazine composition is prepared from the following raw materials in parts by weight: 110 parts of mesalazine bulk drug, 5.8 parts of dextrin, 9 parts of sodium sulfite, 11 parts of starch, 25 parts of mannitol, 13 parts of microcrystalline cellulose, 13 parts of calcium carbonate, 1.8 parts of magnesium stearate and 0.2 part of Chinese wax;
the mesalazine composition is prepared by the following steps:
step S1: adding dextrin and sodium sulfite into a reaction kettle, adding deionized water, stirring at the temperature of 28 ℃ until the dextrin and the sodium sulfite are completely dissolved to prepare a mixed solution, adding mesalazine bulk drug, starch, mannitol and microcrystalline cellulose into a mixer, mixing until the mixture is uniformly mixed to prepare a first mixed material, adding the first mixed material and the mixed solution into the reaction kettle, and stirring for 25min at the rotation speed of 250r/min to prepare a soft material;
step S2: granulating the soft material prepared in the step S1 through an 18-mesh screen, drying for 20min at the temperature of 78 ℃ to obtain solid particles, adding the solid particles, calcium carbonate and magnesium stearate into a mixer, mixing uniformly, tabletting, and preparing a tablet core;
step S3: and (4) adding the tablet core prepared in the step (S2) into a coating pan, heating to 43 ℃ of the surface temperature of the tablet core under the conditions of 8r/min and 65 ℃ of inlet air temperature, coating the tablet core with a coating liquid under the condition of 2.8bar of atomization pressure until the coating liquid is used up, blowing cold air until the air outlet temperature reaches 38 ℃, stopping blowing, adding Chinese wax into the coating pan, and polishing for 18min under the condition of 13r/min to obtain the mesalazine composition.
The mesalazine bulk drug is prepared by the following steps:
step A1: adding salicylic acid and deionized water into a reaction kettle, stirring until the salicylic acid is completely dissolved under the conditions of the rotating speed of 400r/min and the temperature of 53 ℃, slowly adding first mixed acid, reacting for 2.5 hours under the condition of the temperature of 72 ℃, standing for 13min in an ice water bath, and filtering to remove filtrate to obtain 5-nitro salicylic acid;
step A2: adding the carbon nanotubes into a second mixed acid, performing ultrasonic treatment for 13min under the condition of the frequency of 45kHz, heating and refluxing for 2.5h under the condition of the temperature of 125 ℃, adding deionized water until the pH value is 7, and drying to obtain modified carbon nanotubes;
step A3: adding the modified carbon nanotube prepared in the step A2, stannous chloride and hydrochloric acid solution into a reaction kettle, stirring for 1.5h at the rotation speed of 900r/min and the temperature of 35 ℃, filtering to remove filtrate, adding the filtrate into saturated ferric chloride solution, performing ultrasonic treatment for 13min at the frequency of 70kHz, adding zinc powder, stirring for 4.5h at the rotation speed of 650r/min, filtering to remove filtrate, and drying to obtain a catalyst;
step A4: adding concentrated hydrochloric acid and deionized water into a reaction kettle, adding 1/4 amount of the catalyst prepared in the step A3 at the temperature of 63 ℃, refluxing for 4min, adding 1/3 amount of the 5-nitrosalicylic acid prepared in the step A1, stirring for 8min at the rotation speed of 400r/min, adding the rest of the catalyst and the 5-nitrosalicylic acid into the reaction kettle in batches at intervals of 6min, reacting for 40min at the temperature of 98 ℃, adding a sodium hydroxide solution, adjusting the pH value to 11.5, filtering to remove filtrate, and drying to obtain the mesalazine.
The coating liquid is prepared by the following steps:
step B1: adding azodiisobutyronitrile and ethanol into a reaction kettle, stirring until the azodiisobutyronitrile is completely dissolved, adding methyl methacrylate, hydroxyethyl acrylate, butyl acrylate and acrylic acid, stirring for 8min at the rotation speed of 400r/min, adding sodium bisulfite, performing reflux reaction for 6h at the temperature of 83 ℃, adding ammonia water to adjust the pH value to 7, and distilling at the temperature of 85 ℃ to remove ethanol to obtain an intermediate;
step B1: and D, adding the intermediate prepared in the step B1 and deionized water into a reaction kettle, stirring for 8min at the temperature of 35 ℃ and the rotating speed of 1300r/min, adding triethyl citrate, and continuing stirring for 13min to prepare the coating solution.
Example 3
The mesalazine composition is prepared from the following raw materials in parts by weight: 120 parts of mesalazine bulk drug, 6 parts of dextrin, 10 parts of sodium sulfite, 12 parts of starch, 30 parts of mannitol, 15 parts of microcrystalline cellulose, 15 parts of calcium carbonate, 2 parts of magnesium stearate and 0.3 part of Chinese wax;
the mesalazine composition is prepared by the following steps:
step S1: adding dextrin and sodium sulfite into a reaction kettle, adding deionized water, stirring at the temperature of 30 ℃ until the dextrin and the sodium sulfite are completely dissolved to prepare a mixed solution, adding mesalazine bulk drug, starch, mannitol and microcrystalline cellulose into a mixer, mixing until the mixture is uniformly mixed to prepare a first mixed material, adding the first mixed material and the mixed solution into the reaction kettle, and stirring for 30min at the rotation speed of 300r/min to prepare a soft material;
step S2: granulating the soft material prepared in the step S1 through a 20-mesh screen, drying for 30min at the temperature of 80 ℃ to obtain solid particles, adding the solid particles, calcium carbonate and magnesium stearate into a mixer, mixing uniformly, tabletting, and preparing a tablet core;
step S3: and (4) adding the tablet core prepared in the step (S2) into a coating pan, heating to 45 ℃ of the surface temperature of the tablet core under the conditions of 10r/min and 70 ℃ of inlet air temperature, coating the tablet core with a coating liquid under the condition of 3bar of atomization pressure until the coating liquid is used up, blowing cold air until the air outlet temperature reaches 40 ℃, stopping blowing, adding Chinese wax into the coating pan, and polishing for 20min under the condition of 15r/min of rotation speed to obtain the mesalazine composition.
The mesalazine bulk drug is prepared by the following steps:
step A1: adding salicylic acid and deionized water into a reaction kettle, stirring until the salicylic acid is completely dissolved under the conditions of the rotating speed of 500r/min and the temperature of 55 ℃, slowly adding first mixed acid, reacting for 3 hours under the condition of the temperature of 75 ℃, standing for 15min in an ice water bath, and filtering to remove filtrate to obtain 5-nitro salicylic acid;
step A2: adding the carbon nanotubes into a second mixed acid, carrying out ultrasonic treatment for 15min under the condition of frequency of 50kHz, heating and refluxing for 3h under the condition of temperature of 130 ℃, adding deionized water until the pH value is 7, and drying to obtain modified carbon nanotubes;
step A3: adding the modified carbon nanotube prepared in the step A2, stannous chloride and hydrochloric acid solution into a reaction kettle, stirring for 2 hours at the rotation speed of 1000r/min and the temperature of 40 ℃, filtering to remove filtrate, adding the filtrate into saturated ferric chloride solution, performing ultrasonic treatment for 15 minutes at the frequency of 80kHz, adding zinc powder, stirring for 5 hours at the rotation speed of 800r/min, filtering to remove filtrate, and drying to obtain a catalyst;
step A4: adding concentrated hydrochloric acid and deionized water into a reaction kettle, adding 1/4 amount of the catalyst prepared in the step A3 at the temperature of 65 ℃, refluxing for 5min, adding 1/3 amount of the 5-nitrosalicylic acid prepared in the step A1, stirring for 10min at the rotation speed of 500r/min, adding the rest of the catalyst and the 5-nitrosalicylic acid into the reaction kettle in batches at intervals of 8min, reacting for 50min at the temperature of 100 ℃, adding a sodium hydroxide solution, adjusting the pH value to 12, filtering to remove filtrate, and drying to obtain the mesalazine bulk drug.
The coating liquid is prepared by the following steps:
step B1: adding azodiisobutyronitrile and ethanol into a reaction kettle, stirring until the azodiisobutyronitrile is completely dissolved, adding methyl methacrylate, hydroxyethyl acrylate, butyl acrylate and acrylic acid, stirring for 10min at the rotation speed of 500r/min, adding sodium bisulfite, performing reflux reaction for 8h at the temperature of 85 ℃, adding ammonia water to adjust the pH value to be 7.5, and distilling at the temperature of 90 ℃ to remove ethanol to obtain an intermediate;
step B1: and D, adding the intermediate prepared in the step B1 and deionized water into a reaction kettle, stirring for 10min at the temperature of 40 ℃ and the rotating speed of 1500r/min, adding triethyl citrate, and continuing stirring for 15min to prepare the coating solution.
Comparative example 1
Compared with the example 1, the preparation method of the mesalazine bulk drug comprises the following steps of:
step A1: adding salicylic acid and deionized water into a reaction kettle, stirring until the salicylic acid is completely dissolved under the conditions that the rotating speed is 300r/min and the temperature is 50 ℃, slowly adding first mixed acid, reacting for 2 hours under the condition that the temperature is 70 ℃, standing for 10 minutes in an ice water bath, and filtering to remove filtrate to obtain 5-nitro salicylic acid;
step A2: adding concentrated hydrochloric acid and deionized water into a reaction kettle, adding 1/4 amount of iron powder at the temperature of 60 ℃, refluxing for 3min, adding 1/3 amount of 5-nitro salicylic acid prepared in the step A1, stirring for 5min at the rotation speed of 300r/min, adding the rest iron powder and the 5-nitro salicylic acid into the reaction kettle in batches at intervals of 5min, reacting for 1.5h at the temperature of 95 ℃, adding a sodium hydroxide solution, adjusting the pH value to 11, filtering to remove filtrate, and drying to obtain the mesalazine bulk drug.
Comparative example 2
The comparative example is a mesalazine composition which is common in the market.
The mesalamine compositions prepared in examples 1 to 3 and comparative examples 1 to 2 were subjected to a performance test, and the test results are shown in table 1 below;
dissolution rate: first, 900mL of a 0.1mol/L hydrochloric acid solution (pH1.0) was added to a dissolution cup to measure the release amount of the mesalazine compositions prepared in examples 1 to 3 and comparative examples 1 to 2 within 2 hours; the acid solution was then discarded and immediately added to acetate buffer (pH4.5) at a temperature of 37 ℃. + -. 0.5 ℃ to measure the release amount in the buffer of the mesalamine compositions prepared in examples 1-3 and comparative examples 1-2.
TABLE 1
As can be seen from table 1 above, the mesalamine compositions prepared in examples 1-3 and comparative example 1 do not disintegrate under the hydrochloric acid solution condition of ph1.0, while the mesalamine composition prepared in comparative example 2 does disintegrate under the hydrochloric acid solution condition of ph1.0, the time for preparing the mesalamine bulk drug in the examples is 30-50min, and the yield is 72.85-73.21%, while the time for preparing comparative example 1 is 1.5h, and the yield is 56.35%, which indicates that the mesalamine composition prepared by the present invention does not disintegrate in the stomach, but rapidly disintegrates in the intestinal tract, so that the mesalamine composition can effectively treat enteritis, and the preparation efficiency is higher and the yield is higher.
The foregoing is merely exemplary and illustrative of the principles of the present invention and various modifications, additions and substitutions of the specific embodiments described herein may be made by those skilled in the art without departing from the principles of the present invention or exceeding the scope of the claims set forth herein.
Claims (6)
1. A mesalazine composition characterized by: the feed is prepared from the following raw materials in parts by weight: 100-120 parts of mesalazine bulk drug, 5.5-6 parts of dextrin, 8-10 parts of sodium sulfite, 10-12 parts of starch, 20-30 parts of mannitol, 10-15 parts of microcrystalline cellulose, 10-15 parts of calcium carbonate, 1.6-2 parts of magnesium stearate and 0.15-0.3 part of Chinese wax;
the mesalazine composition is prepared by the following steps:
step S1: adding dextrin and sodium sulfite into a reaction kettle, adding deionized water, stirring at the temperature of 25-30 ℃ until the dextrin and the sodium sulfite are completely dissolved to prepare a mixed solution, adding mesalazine bulk drug, starch, mannitol and microcrystalline cellulose into a mixer, mixing until the mixture is uniformly mixed to prepare a first mixed material, adding the first mixed material and the mixed solution into the reaction kettle, and stirring for 20-30min at the rotation speed of 200-300r/min to prepare a soft material;
step S2: granulating the soft material prepared in the step S1 through a 15-20-mesh screen, drying for 15-30min at the temperature of 75-80 ℃ to obtain solid particles, adding the solid particles, calcium carbonate and magnesium stearate into a mixer, mixing uniformly, tabletting, and preparing a tablet core;
step S3: and (4) adding the tablet core prepared in the step (S2) into a coating pan, heating to 40-45 ℃ of the surface temperature of the tablet core under the conditions of 5-10r/min and 60-70 ℃ of inlet air temperature, coating the tablet core with coating liquid under the conditions of 2.5-3bar of atomization pressure until the coating liquid is used up, blowing cold air until the air outlet temperature reaches 35-40 ℃, stopping blowing, adding Chinese wax into the coating pan, and polishing for 15-20min under the condition of 10-15r/min of rotation speed to obtain the mesalazine composition.
2. A mesalamine composition according to claim 1, characterized in that: the mesalazine bulk drug is prepared by the following steps:
step A1: adding salicylic acid and 1/4 amount of deionized water into a reaction kettle, stirring until the salicylic acid is completely dissolved under the conditions that the rotating speed is 300-500r/min and the temperature is 50-55 ℃, slowly adding first mixed acid, reacting for 2-3h under the condition that the temperature is 70-75 ℃, adding the rest deionized water, standing in an ice-water bath for 10-15min, and filtering to remove filtrate to obtain 5-nitro salicylic acid;
step A2: adding the carbon nanotubes into the second mixed acid, performing ultrasonic treatment for 10-15min under the condition of the frequency of 40-50kHz, heating and refluxing for 2-3h at the temperature of 120-130 ℃, adding deionized water until the pH value is 7, and drying to obtain modified carbon nanotubes;
step A3: adding the modified carbon nanotube prepared in the step A2, stannous chloride and hydrochloric acid solution into a reaction kettle, stirring for 1-2h at the rotation speed of 800-1000r/min and the temperature of 30-40 ℃, filtering to remove filtrate, adding the filtrate into saturated ferric chloride solution, performing ultrasonic treatment for 10-15min at the frequency of 60-80kHz, adding zinc powder, stirring for 4-5h at the rotation speed of 500-800r/min, filtering to remove filtrate, and drying to obtain a catalyst;
step A4: adding concentrated hydrochloric acid and deionized water into a reaction kettle, adding 1/4 amount of the catalyst prepared in the step A3 at the temperature of 60-65 ℃, refluxing for 3-5min, adding 1/3 amount of the 5-nitrosalicylic acid prepared in the step A1, stirring for 5-10min at the rotation speed of 300-500r/min, adding the rest of the catalyst and the 5-nitrosalicylic acid into the reaction kettle in batches at intervals of 5-8min, reacting for 30-50min at the temperature of 95-100 ℃, adding a sodium hydroxide solution, adjusting the pH value to 11-12, filtering to remove filtrate, and drying to obtain the mesalazine bulk drug.
3. A mesalamine composition according to claim 2, characterized in that: the mesalazine bulk drug is prepared by the following steps: the first mixed acid in the step A1 is prepared by mixing 9 mL: 1g of nitric acid solution and glacial acetic acid, wherein the mass concentration of the nitric acid solution is 68-70%, and the mass ratio of the salicylic acid to the nitric acid solution is 1: 3, the dosage ratio of the salicylic acid to the water is 7 g: 100mL, wherein the dosage ratio of the carbon nanotube and the second mixed acid in the step A2 is 1 g: 20mL, and the volume ratio of the second mixed acid is 1: 3, mixing the nitric acid solution with the sulfuric acid solution, wherein the mass concentration of the nitric acid solution is 50-60%, the mass concentration of the sulfuric acid solution is 60-70%, and the dosage ratio of the modified carbon nanotube, the stannous chloride and the hydrochloric acid solution in the step A3 is 1 g: 1.2 g: 50mL, the volume concentration of hydrochloric acid in the hydrochloric acid solution is 1-1.5%, and the dosage ratio of the filtrate, the ferric chloride solution and the zinc powder is 1 g: 1mL of: 0.5g, wherein the mass fraction of ferric chloride in the ferric chloride solution is 2-4%, and the dosage ratio of concentrated hydrochloric acid, deionized water, the catalyst and 5-nitro salicylic acid in the step A4 is 3 mL: 50mL of: 8 g: 6 g.
4. A mesalamine composition according to claim 1, characterized in that: the coating liquid is prepared by the following steps:
step B1: adding azodiisobutyronitrile and ethanol into a reaction kettle, stirring until the azodiisobutyronitrile is completely dissolved, adding methyl methacrylate, hydroxyethyl acrylate, butyl acrylate and acrylic acid, stirring for 5-10min at the rotation speed of 300-500r/min, adding sodium bisulfite, performing reflux reaction for 5-8h at the temperature of 80-85 ℃, adding ammonia water to adjust the pH value to 7-7.5, and distilling at the temperature of 80-90 ℃ to remove ethanol to obtain an intermediate;
step B1: and D, adding the intermediate prepared in the step B1 and deionized water into a reaction kettle, stirring for 5-10min at the temperature of 30-40 ℃ and the rotating speed of 1000-1500r/min, adding triethyl citrate, and continuing stirring for 10-15min to prepare a coating solution.
5. The mesalamine composition according to claim 4, wherein: the mass ratio of the methyl methacrylate, the hydroxyethyl acrylate, the butyl acrylate and the acrylic acid in the step B1 is 1: 1: 1: 0.2, the dosage of the azodiisobutyronitrile is 3.5-4% of the total mass of the methyl methacrylate, the hydroxyethyl acrylate, the butyl acrylate and the acrylic acid, the dosage of the sodium bisulfite is 13-15% of the total mass of the methyl methacrylate, the hydroxyethyl acrylate, the butyl acrylate and the acrylic acid, and the dosage mass ratio of the intermediate in the step B2 to the deionized water is 1: 4, the amount of triethyl citrate is 8-10% of the mass of the intermediate.
6. The process for preparing a mesalamine composition according to claim 1, wherein: the method specifically comprises the following steps:
step S1: adding dextrin and sodium sulfite into a reaction kettle, adding deionized water, stirring at the temperature of 25-30 ℃ until the dextrin and the sodium sulfite are completely dissolved to prepare a mixed solution, adding mesalazine bulk drug, starch, mannitol and microcrystalline cellulose into a mixer, mixing until the mixture is uniformly mixed to prepare a first mixed material, adding the first mixed material and the mixed solution into the reaction kettle, and stirring for 20-30min at the rotation speed of 200-300r/min to prepare a soft material;
step S2: granulating the soft material prepared in the step S1 through a 15-20-mesh screen, drying for 15-30min at the temperature of 75-80 ℃ to obtain solid particles, adding the solid particles, calcium carbonate and magnesium stearate into a mixer, mixing uniformly, tabletting, and preparing a tablet core;
step S3: and (4) adding the tablet core prepared in the step (S2) into a coating pan, heating to 40-45 ℃ of the surface temperature of the tablet core under the conditions of 5-10r/min and 60-70 ℃ of inlet air temperature, coating the tablet core with coating liquid under the conditions of 2.5-3bar of atomization pressure until the coating liquid is used up, blowing cold air until the air outlet temperature reaches 35-40 ℃, stopping blowing, adding Chinese wax into the coating pan, and polishing for 15-20min under the condition of 10-15r/min of rotation speed to obtain the mesalazine composition.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101137354A (en) * | 2005-05-25 | 2008-03-05 | 罗姆有限公司 | Use of polymer mixtures for the production of coated pharmaceutical formulations and pharmaceutical formulation with mixed polymeric coating |
| CN102784154A (en) * | 2012-09-01 | 2012-11-21 | 朱文军 | Mesalazine enteric coatel tablet and preparation method thereof |
| CN106083623A (en) * | 2016-06-08 | 2016-11-09 | 黑龙江鑫创生物科技开发有限公司 | A kind of preparation method of 5 aminosallcylic acids |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101137354A (en) * | 2005-05-25 | 2008-03-05 | 罗姆有限公司 | Use of polymer mixtures for the production of coated pharmaceutical formulations and pharmaceutical formulation with mixed polymeric coating |
| CN102784154A (en) * | 2012-09-01 | 2012-11-21 | 朱文军 | Mesalazine enteric coatel tablet and preparation method thereof |
| CN106083623A (en) * | 2016-06-08 | 2016-11-09 | 黑龙江鑫创生物科技开发有限公司 | A kind of preparation method of 5 aminosallcylic acids |
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