阅读说明：本技术 一种美沙拉嗪口服缓释药物组合物及其制备方法 (Mesalazine oral sustained-release pharmaceutical composition and preparation method thereof ) 是由 刘加林 方朝杰 张渊源 霍萧勇 于 2020-07-08 设计创作，主要内容包括：本发明公开了一种美沙拉嗪口服缓释药物组合物及其制备方法,该美沙拉嗪口服缓释药物组合物,包括如下重量份原料：美沙拉嗪20-30份、红背叶根提取物10-15份、白芍提取物10-15份、药物载体50-60份、木糖醇5-10份、柠檬酸3-8份、羧甲基壳聚糖20-30份；在制备药物组合物的过程中制备了一种药物载体,该药物载体以醋酸纤维素为基体并对其进行氧化,使得醋酸纤维素表面插入羧基,当药物载体与羧甲基壳聚糖接触时,药物载体上的羧基与羧甲基壳聚糖的伯氨基通过正负电荷吸引形成聚电解质膜,使得药物载体的生物相容性提升,进而使得药物组合物肠道中能够持续释放,进而达到缓释效果,延长吸收,增加美沙拉嗪的治疗效果。(The invention discloses a mesalazine oral sustained-release pharmaceutical composition and a preparation method thereof, wherein the mesalazine oral sustained-release pharmaceutical composition comprises the following raw materials in parts by weight: 20-30 parts of mesalazine, 10-15 parts of Mallotus apelta extract, 10-15 parts of white peony root extract, 50-60 parts of drug carrier, 5-10 parts of xylitol, 3-8 parts of citric acid and 20-30 parts of carboxymethyl chitosan; the drug carrier is prepared in the process of preparing the drug composition, the drug carrier takes cellulose acetate as a matrix and oxidizes the cellulose acetate to insert carboxyl on the surface of the cellulose acetate, when the drug carrier is contacted with carboxymethyl chitosan, the carboxyl on the drug carrier and primary amino of the carboxymethyl chitosan are attracted through positive and negative charges to form a polyelectrolyte membrane, so that the biocompatibility of the drug carrier is improved, the drug composition can be continuously released in intestinal tracts, the slow release effect is further achieved, the absorption is prolonged, and the treatment effect of mesalazine is improved.)

1. A mesalazine oral sustained-release pharmaceutical composition is characterized in that: the feed comprises the following raw materials in parts by weight: 20-30 parts of mesalazine, 10-15 parts of Mallotus apelta extract, 10-15 parts of white peony root extract, 50-60 parts of drug carrier, 5-10 parts of xylitol, 3-8 parts of citric acid and 20-30 parts of carboxymethyl chitosan;

the mesalazine oral sustained-release pharmaceutical composition is prepared by the following steps:

step S1: adding mesalazine, the radix Malloti Apeltae extract, the radix Paeoniae alba extract and a drug carrier into dichloroethane, stirring at the rotation speed of 300-500r/min and the temperature of 30-40 ℃ for 5-15min, adding lecithin, and continuously stirring for 1-1.5h to prepare a first mixed solution;

step S2: adding xylitol, citric acid and deionized water into a reaction kettle, and stirring until the xylitol and the citric acid are completely dissolved to prepare a second mixed solution;

step S3: adding carboxymethyl chitosan and deionized water into a reaction kettle, stirring at the rotation speed of 300-500r/min until the carboxymethyl chitosan is completely dissolved, adding tween, and continuously stirring at the temperature of 80-85 ℃ for 40-60min to prepare a third mixed solution;

step S4: adding the first mixed solution prepared in the step S1 into a reaction kettle, stirring and adding the second mixed solution under the condition that the rotating speed is 3000-4000r/min, and continuously stirring for 5-8min to prepare a fourth mixed solution;

step S5: and adding the third mixed solution prepared in the step S3 into a reaction kettle, stirring at the rotation speed of 800-1000r/min, adding the fourth mixed solution prepared in the step S4, continuously stirring for 2-3h, filtering to remove filtrate, and drying at the temperature of 50-60 ℃ for 5-8h to prepare the mesalazine oral sustained-release pharmaceutical composition.

2. The mesalazine oral sustained release pharmaceutical composition according to claim 1, characterized in that: the amount of dichloroethane in step S1 is twice the sum of the masses of mesalazine, radix haleniae, radix paeoniae alba and drug carrier, the amount of deionized water in step S2 is fifty times the sum of the masses of xylitol and citric acid, and the ratio of the amounts of carboxymethyl chitosan and deionized water in step S3 is 1g: 5mL, wherein the dosage of the Tween is 8-15% of the mass of the carboxymethyl chitosan, and the dosage volume ratio of the first mixed solution to the second mixed solution in the step S4 is 1: 1, the volume ratio of the third mixed solution to the fourth mixed solution in the step S5 is 1: 2.

3. the mesalazine oral sustained release pharmaceutical composition according to claim 2, wherein: the extract of the roots of the redback roots is prepared by the following steps:

step A1: adding the redback roots and deionized water into a reaction kettle, stirring for 5-10min at the rotation speed of 100-200r/min and the temperature of 30-35 ℃, filtering to remove the deionized water, and crushing the redback roots to obtain redback root powder;

step A2: adding the gynura bicolor root powder prepared in the step A1 and ethanol into a reaction kettle, heating and refluxing for 2-3 hours at the temperature of 80-90 ℃, filtering to remove filter substances, adding a hydrochloric acid solution into the filtrate until the pH value is 4-5, adding an ammonia water solution until the pH value is 9-10 to prepare a first mixed solution, extracting the first mixed solution for 2-3 times by using chloroform, combining chloroform extract solutions, adding deionized water, mixing uniformly, removing water by using phosphorus pentoxide, and distilling at the temperature of 65-70 ℃ to remove the chloroform to prepare the gynura bicolor root extract.

4. The mesalazine oral sustained release pharmaceutical composition according to claim 1, wherein: the white peony root extract is prepared by the following steps:

step B1: pulverizing radix Paeoniae alba, and soaking in ethanol solution at 40-50 deg.CFiltering after soaking, soaking for 3-4 times, each time for 1-2 hr, mixing the filtrates to obtain radix Paeoniae alba mixed solution, concentrating the radix Paeoniae alba mixed solution to relative density of 1.05-1.15g/cm³To obtain radix Paeoniae alba concentrated solution;

step B2: adding the white paeony root concentrated solution prepared in the step B1 and a hydrochloric acid solution into a reaction kettle, carrying out ultrasonic treatment for 30-40min under the condition of 30-40kHz frequency, filtering to remove filter substances, adding a sodium hydroxide solution into the filtrate until the pH value is 8-10, extracting with chloroform to obtain a chloroform extract, distilling the chloroform extract, extracting with isopropanol to obtain an isopropanol extract, and distilling the isopropanol extract to remove isopropanol to obtain a white paeony root extract.

5. The mesalazine oral sustained release pharmaceutical composition according to claim 4, wherein: the mass fraction of the hydrochloric acid solution in the step A2 is 20-30%, and the mass fraction of the ammonia water solution is 40-50%.

6. The mesalazine oral sustained release pharmaceutical composition according to claim 1, wherein: the white peony root extract is prepared by the following steps:

step B1: pulverizing radix Paeoniae alba, soaking in ethanol solution at 40-50 deg.C for 3-4 times (each for 1-2 hr), mixing the filtrates to obtain radix Paeoniae alba mixed solution, and concentrating to relative density of 1.05-1.15g/cm³To obtain radix Paeoniae alba concentrated solution;

step B2: adding the white paeony root concentrated solution prepared in the step B1 and a hydrochloric acid solution into a reaction kettle, carrying out ultrasonic treatment for 30-40min under the condition of 30-40kHz frequency, filtering to remove filter substances, adding a sodium hydroxide solution into the filtrate until the pH value is 8-10, extracting with chloroform to obtain a chloroform extract, distilling the chloroform extract, extracting with isopropanol to obtain an isopropanol extract, and distilling the isopropanol extract to remove isopropanol to obtain a white paeony root extract.

7. The mesalazine oral sustained release pharmaceutical composition according to claim 6, wherein: the mass fraction of the sodium hydroxide solution in the step B2 is 15-20%.

8. The mesalazine oral sustained release pharmaceutical composition according to claim 1, wherein: the drug carrier is prepared by the following steps:

step C1: adding cotton and glacial acetic acid into a reaction kettle, stirring for 30-40min at the rotation speed of 300-500r/min and the temperature of 70-75 ℃, dropwise adding a sulfuric acid solution and acetic anhydride, introducing nitrogen for protection, and continuously stirring for 1-1.5h at the temperature of 80-100 ℃ to obtain paste;

step C2: adding the paste prepared in the step C1 into a reaction kettle, stirring and slowly adding an acetic acid solution under the conditions that the rotation speed is 200-300r/min and the temperature is 60-70 ℃, continuously stirring for 15-20min, adding deionized water and filtering, removing filtrate, washing a filter cake with distilled water until the pH value is 7, and drying to obtain a first powder;

step C3: c2, adding the first powder and sodium hydroxide solution into a reaction kettle, soaking for 30-40min at the temperature of 30-50 ℃, washing with ethanol until the pH value is 7, filtering to remove filtrate, and drying at the temperature of 50-60 ℃ for 1-2h to obtain a second powder;

step C4: and D, adding the second powder prepared in the step C3 and mixed acid into a reaction kettle, stirring for 10-15min at the rotation speed of 300-50 ℃ and the temperature of 40-50 ℃, adding sodium nitrite, continuously stirring for 1-2h, centrifuging for 5-10min at the rotation speed of 3000-5000r/min, washing with deionized water until the pH value of the supernatant is 7, removing the supernatant, and drying to obtain the drug carrier.

9. The mesalazine oral sustained release pharmaceutical composition according to claim 8, wherein: the dosage ratio of the cotton, the glacial acetic acid, the sulfuric acid solution and the acetic anhydride glacial acetic acid in the step C1 is 5 g: 35mL of: 0.08 mL: 25mL, the mass fraction of the sulfuric acid solution is 80-85%, and the volume ratio of the paste and the acetic acid solution in the step C2 is 2.4: 1, the mass fraction of the acetic acid solution is 80-85%, the dosage ratio of the first powder and the sodium hydroxide solution in the step C3 is 1g:1mL, the mass fraction of the sodium hydroxide solution is 18-20%, the dosage ratio of the second powder, the mixed acid and the sodium nitrite in the step C4 is 1g: 10mL of: 0.5g of mixed acid, wherein the mixed acid is prepared by mixing 65-70% of nitric acid and 85-90% of phosphoric acid in percentage by mass.

10. The preparation method of mesalazine oral sustained release pharmaceutical composition according to claim 1, characterized in that: the method specifically comprises the following steps:

step S1: adding mesalazine, the radix Malloti Apeltae extract, the radix Paeoniae alba extract and a drug carrier into dichloroethane, stirring at the rotation speed of 300-500r/min and the temperature of 30-40 ℃ for 5-15min, adding lecithin, and continuously stirring for 1-1.5h to prepare a first mixed solution;

step S2: adding xylitol, citric acid and deionized water into a reaction kettle, and stirring until the xylitol and the citric acid are completely dissolved to prepare a second mixed solution;

step S3: adding carboxymethyl chitosan and deionized water into a reaction kettle, stirring at the rotation speed of 300-500r/min until the carboxymethyl chitosan is completely dissolved, adding tween, and continuously stirring at the temperature of 80-85 ℃ for 40-60min to prepare a third mixed solution;

step S4: adding the first mixed solution prepared in the step S1 into a reaction kettle, stirring and adding the second mixed solution under the condition that the rotating speed is 3000-4000r/min, and continuously stirring for 5-8min to prepare a fourth mixed solution;

step S5: and adding the third mixed solution prepared in the step S3 into a reaction kettle, stirring at the rotation speed of 800-1000r/min, adding the fourth mixed solution prepared in the step S4, continuously stirring for 2-3h, filtering to remove filtrate, and drying at the temperature of 50-60 ℃ for 5-8h to prepare the mesalazine oral sustained-release pharmaceutical composition.

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a mesalazine oral sustained-release pharmaceutical 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.

The conventional mesalazine oral sustained-release pharmaceutical composition can cause rapid diffusion of mesalazine after being taken, so that the mesalazine cannot be completely absorbed by intestinal tracts, and further a large amount of mesalazine is wasted, so that a patient needs to take the composition for many times within one day, and the mesalazine can cause the content of glutamic pyruvic transaminase of a human body to be increased, so that the liver is damaged.

Disclosure of Invention

The invention aims to provide a mesalazine oral sustained-release pharmaceutical composition and a preparation method thereof.

The conventional mesalazine oral sustained-release pharmaceutical composition can cause rapid diffusion of mesalazine after being taken, so that the mesalazine cannot be completely absorbed by intestinal tracts, and further a large amount of mesalazine is wasted, so that a patient needs to take the composition for many times within one day, and the mesalazine can cause the content of glutamic pyruvic transaminase of a human body to be increased, so that the liver is damaged.

The technical problems to be solved by the invention are as follows:

the purpose of the invention can be realized by the following technical scheme:

the mesalazine oral sustained-release pharmaceutical composition comprises the following raw materials in parts by weight: 20-30 parts of mesalazine, 10-15 parts of Mallotus apelta extract, 10-15 parts of white peony root extract, 50-60 parts of drug carrier, 5-10 parts of xylitol, 3-8 parts of citric acid and 20-30 parts of carboxymethyl chitosan;

the mesalazine oral sustained-release pharmaceutical composition is prepared by the following steps:

step S1: adding mesalazine, the radix Malloti Apeltae extract, the radix Paeoniae alba extract and a drug carrier into dichloroethane, stirring at the rotation speed of 300-500r/min and the temperature of 30-40 ℃ for 5-15min, adding lecithin, and continuously stirring for 1-1.5h to prepare a first mixed solution;

step S2: adding xylitol, citric acid and deionized water into a reaction kettle, and stirring until the xylitol and the citric acid are completely dissolved to prepare a second mixed solution;

step S3: adding carboxymethyl chitosan and deionized water into a reaction kettle, stirring at the rotation speed of 300-500r/min until the carboxymethyl chitosan is completely dissolved, adding tween, and continuously stirring at the temperature of 80-85 ℃ for 40-60min to prepare a third mixed solution;

step S4: adding the first mixed solution prepared in the step S1 into a reaction kettle, stirring and adding the second mixed solution under the condition that the rotating speed is 3000-4000r/min, and continuously stirring for 5-8min to prepare a fourth mixed solution;

step S5: and adding the third mixed solution prepared in the step S3 into a reaction kettle, stirring at the rotation speed of 800-1000r/min, adding the fourth mixed solution prepared in the step S4, continuously stirring for 2-3h, filtering to remove filtrate, and drying at the temperature of 50-60 ℃ for 5-8h to prepare the mesalazine oral sustained-release pharmaceutical composition.

Further, the amount of dichloroethane in step S1 is twice the sum of the masses of mesalazine, radix rosae rubra extract, radix paeoniae alba extract and drug carrier, the amount of deionized water in step S2 is fifty times the sum of the masses of xylitol and citric acid, and the amount ratio of carboxymethyl chitosan to deionized water in step S3 is 1g: 5mL, wherein the dosage of the Tween is 8-15% of the mass of the carboxymethyl chitosan, and the dosage volume ratio of the first mixed solution to the second mixed solution in the step S4 is 1: 1, the volume ratio of the third mixed solution to the fourth mixed solution in the step S5 is 1: 2.

further, the extract of the roots of the Mallotus apelta is prepared by the following steps:

step A1: adding the redback roots and deionized water into a reaction kettle, stirring for 5-10min at the rotation speed of 100-200r/min and the temperature of 30-35 ℃, filtering to remove the deionized water, and crushing the redback roots to obtain redback root powder;

step A2: adding the gynura bicolor root powder prepared in the step A1 and ethanol into a reaction kettle, heating and refluxing for 2-3 hours at the temperature of 80-90 ℃, filtering to remove filter substances, adding a hydrochloric acid solution into the filtrate until the pH value is 4-5, adding an ammonia water solution until the pH value is 9-10 to prepare a first mixed solution, extracting the first mixed solution for 2-3 times by using chloroform, combining chloroform extract solutions, adding deionized water, mixing uniformly, removing water by using phosphorus pentoxide, and distilling at the temperature of 65-70 ℃ to remove the chloroform to prepare the gynura bicolor root extract.

Further, the mass fraction of the hydrochloric acid solution in the step A2 is 20-30%, and the mass fraction of the ammonia water solution is 40-50%.

Further, the white paeony root extract is prepared by the following steps:

step B1: pulverizing radix Paeoniae alba, soaking in ethanol solution at 40-50 deg.C for 3-4 times (each for 1-2 hr), mixing the filtrates to obtain radix Paeoniae alba mixed solution, and concentrating to relative density of 1.05-1.15g/cm³To obtain radix Paeoniae alba concentrated solution;

step B2: adding the white paeony root concentrated solution prepared in the step B1 and a hydrochloric acid solution into a reaction kettle, carrying out ultrasonic treatment for 30-40min under the condition of 30-40kHz frequency, filtering to remove filter substances, adding a sodium hydroxide solution into the filtrate until the pH value is 8-10, extracting with chloroform to obtain a chloroform extract, distilling the chloroform extract, extracting with isopropanol to obtain an isopropanol extract, and distilling the isopropanol extract to remove isopropanol to obtain a white paeony root extract.

Further, the mass fraction of the sodium hydroxide solution in the step B2 is 15-20%.

Further, the drug carrier is prepared by the following steps:

step C1: adding cotton and glacial acetic acid into a reaction kettle, stirring for 30-40min at the rotation speed of 300-500r/min and the temperature of 70-75 ℃, dropwise adding a sulfuric acid solution and acetic anhydride, introducing nitrogen for protection, and continuously stirring for 1-1.5h at the temperature of 80-100 ℃ to obtain paste;

step C2: adding the paste prepared in the step C1 into a reaction kettle, stirring and slowly adding an acetic acid solution under the conditions that the rotation speed is 200-300r/min and the temperature is 60-70 ℃, continuously stirring for 15-20min, adding deionized water and filtering, removing filtrate, washing a filter cake with distilled water until the pH value is 7, and drying to obtain a first powder;

step C3: c2, adding the first powder and sodium hydroxide solution into a reaction kettle, soaking for 30-40min at the temperature of 30-50 ℃, washing with ethanol until the pH value is 7, filtering to remove filtrate, and drying at the temperature of 50-60 ℃ for 1-2h to obtain a second powder;

step C4: and D, adding the second powder prepared in the step C3 and mixed acid into a reaction kettle, stirring for 10-15min at the rotation speed of 300-50 ℃ and the temperature of 40-50 ℃, adding sodium nitrite, continuously stirring for 1-2h, centrifuging for 5-10min at the rotation speed of 3000-5000r/min, washing with deionized water until the pH value of the supernatant is 7, removing the supernatant, and drying to obtain the drug carrier.

Further, the dosage ratio of the cotton, the glacial acetic acid, the sulfuric acid solution and the acetic anhydride glacial acetic acid in the step C1 is 5 g: 35mL of: 0.08 mL: 25mL, the mass fraction of the sulfuric acid solution is 80-85%, and the volume ratio of the paste and the acetic acid solution in the step C2 is 2.4: 1, the mass fraction of the acetic acid solution is 80-85%, the dosage ratio of the first powder and the sodium hydroxide solution in the step C3 is 1g:1mL, the mass fraction of the sodium hydroxide solution is 18-20%, the dosage ratio of the second powder, the mixed acid and the sodium nitrite in the step C4 is 1g: 10mL of: 0.5g of mixed acid, wherein the mixed acid is prepared by mixing 65-70% of nitric acid and 85-90% of phosphoric acid in percentage by mass.

Further, the preparation method of the mesalazine oral sustained-release pharmaceutical composition specifically comprises the following steps:

step S1: adding mesalazine, the radix Malloti Apeltae extract, the radix Paeoniae alba extract and a drug carrier into dichloroethane, stirring at the rotation speed of 300-500r/min and the temperature of 30-40 ℃ for 5-15min, adding lecithin, and continuously stirring for 1-1.5h to prepare a first mixed solution;

step S2: adding xylitol, citric acid and deionized water into a reaction kettle, and stirring until the xylitol and the citric acid are completely dissolved to prepare a second mixed solution;

step S3: adding carboxymethyl chitosan and deionized water into a reaction kettle, stirring at the rotation speed of 300-500r/min until the carboxymethyl chitosan is completely dissolved, adding tween, and continuously stirring at the temperature of 80-85 ℃ for 40-60min to prepare a third mixed solution;

step S4: adding the first mixed solution prepared in the step S1 into a reaction kettle, stirring and adding the second mixed solution under the condition that the rotating speed is 3000-4000r/min, and continuously stirring for 5-8min to prepare a fourth mixed solution;

step S5: and adding the third mixed solution prepared in the step S3 into a reaction kettle, stirring at the rotation speed of 800-1000r/min, adding the fourth mixed solution prepared in the step S4, continuously stirring for 2-3h, filtering to remove filtrate, and drying at the temperature of 50-60 ℃ for 5-8h to prepare the mesalazine oral sustained-release pharmaceutical composition.

The invention has the beneficial effects that: the invention adds the red-backed radix paeoniae alba extract and the red-backed radix paeoniae alba extract in the process of preparing the mesalazine oral sustained-release pharmaceutical composition, the red-backed radix paeoniae alba extract and the white peony root extract have good liver protection effect, the red-backed radix paeoniae alba can obviously reduce the MDA content of the liver and can also obviously improve the SOD activity of the liver, the white peony root contains a large amount of galactosamine, the galactosamine can reduce the glutamic-pyruvic transaminase content in the serum of a human body, so as to achieve the liver protection effect, the effects of the increase of the glutamic-pyruvic transaminase content caused by taking the mesalazine are mutually counteracted, so that the ulcerative colitis of a patient is ensured to be treated, the liver is not damaged, the xylitol and the citric acid are added so that the mouth feel of the pharmaceutical composition is better, the pharmaceutical composition is suitable for being taken by the diabetes patient without using cane sugar, the drug carrier takes the cellulose acetate as a matrix and oxidizes the cellulose acetate to insert carboxyl into the surface of the cellulose acetate, when the drug carrier is contacted with the carboxymethyl chitosan, the carboxyl on the drug carrier and the primary amino group of the carboxymethyl chitosan are attracted through positive and negative charges to form a polyelectrolyte membrane, so that the biocompatibility of the drug carrier is improved, the drug composition can be continuously released in intestinal tracts, the slow release effect is further achieved, the absorption is prolonged, and the treatment effect of the mesalazine is improved.

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 oral sustained-release pharmaceutical composition comprises the following raw materials in parts by weight: 20 parts of mesalazine, 10 parts of an extract of Mallotus apelta, 10 parts of an extract of white peony root, 50 parts of a drug carrier, 5 parts of xylitol, 3 parts of citric acid and 20 parts of carboxymethyl chitosan;

the mesalazine oral sustained-release pharmaceutical composition is prepared by the following steps:

step S1: adding mesalazine, the radix Malloti Apeltae extract, the radix Paeoniae alba extract and the drug carrier into dichloroethane, stirring at the rotation speed of 300r/min and the temperature of 30 ℃ for 5min, adding lecithin, and continuously stirring for 1h to obtain a first mixed solution;

step S2: adding xylitol, citric acid and deionized water into a reaction kettle, and stirring until the xylitol and the citric acid are completely dissolved to prepare a second mixed solution;

step S3: adding carboxymethyl chitosan and deionized water into a reaction kettle, stirring at the rotating speed of 300r/min until the carboxymethyl chitosan is completely dissolved, adding tween, and continuously stirring at the temperature of 80 ℃ for 40min to prepare a third mixed solution;

step S4: adding the first mixed solution prepared in the step S1 into a reaction kettle, stirring and adding the second mixed solution under the condition that the rotating speed is 3000r/min, and continuously stirring for 5min to prepare a fourth mixed solution;

step S5: and (3) adding the third mixed solution prepared in the step (S3) into a reaction kettle, stirring at the rotation speed of 800r/min, adding the fourth mixed solution prepared in the step (S4), continuously stirring for 2 hours, filtering to remove filtrate, and drying at the temperature of 50 ℃ for 5 hours to prepare the mesalazine oral sustained-release pharmaceutical composition.

The extract of the roots of the redback roots is prepared by the following steps:

step A1: adding redback root and deionized water into a reaction kettle, stirring for 5min at the rotation speed of 100r/min and the temperature of 30 ℃, filtering to remove the deionized water, and crushing the redback root to prepare redback root powder;

step A2: adding the gynura bicolor root powder prepared in the step A1 and ethanol into a reaction kettle, heating and refluxing for 2 hours at the temperature of 80 ℃, filtering to remove filter substances, adding a hydrochloric acid solution into the filtrate until the pH value is 4, adding ammonia water until the pH value is 9 to prepare a first mixed solution, extracting the first mixed solution for 2 times by using chloroform, combining chloroform extract, adding deionized water, mixing uniformly, removing water by using phosphorus pentoxide, and distilling at the temperature of 65 ℃ to remove the chloroform to prepare the gynura bicolor root extract.

The white peony root extract is prepared by the following steps:

step B1: pulverizing radix Paeoniae alba, soaking in ethanol solution at 40 deg.C, filtering, soaking for 3 times (each time for 1 hr), mixing the filtrates to obtain radix Paeoniae alba mixed solution, and concentrating to relative density of 1.05g/cm³To obtain radix Paeoniae alba concentrated solution;

step B2: and B1, adding the white paeony root concentrated solution and the hydrochloric acid solution prepared in the step B into a reaction kettle, carrying out ultrasonic treatment for 30min under the condition of 30kHz frequency, filtering to remove filter substances, adding a sodium hydroxide solution into the filtrate until the pH value is 8, extracting with chloroform to obtain a chloroform extract, distilling the chloroform extract to remove the chloroform, extracting with isopropanol to obtain an isopropanol extract, and distilling the isopropanol extract to remove the isopropanol to obtain the white paeony root extract.

The drug carrier is prepared by the following steps:

step C1: adding cotton and glacial acetic acid into a reaction kettle, stirring for 30min at the rotation speed of 300r/min and the temperature of 70 ℃, dropwise adding a sulfuric acid solution and acetic anhydride, introducing nitrogen for protection, and continuously stirring for 1h at the temperature of 80 ℃ to obtain paste;

step C2: c1, adding the paste prepared in the step C1 into a reaction kettle, stirring and slowly adding an acetic acid solution under the conditions that the rotating speed is 200r/min and the temperature is 60 ℃, continuously stirring for 15min, adding deionized water and filtering, removing filtrate, washing a filter cake with distilled water until the pH value is 7, and drying to prepare a first powder;

step C3: adding the first powder prepared in the step C2 and a sodium hydroxide solution into a reaction kettle, soaking for 30min at the temperature of 30 ℃, washing with ethanol until the pH value is 7, filtering to remove filtrate, and drying for 1h at the temperature of 50 ℃ to prepare a second powder;

step C4: and D, adding the second powder prepared in the step C3 and mixed acid into a reaction kettle, stirring for 10min at the rotation speed of 300r/min and the temperature of 40 ℃, adding sodium nitrite, continuously stirring for 1h, centrifuging for 5min at the rotation speed of 3000r/min, washing with deionized water until the pH value of the supernatant is 7, removing the supernatant, and drying to obtain the drug carrier.

Example 2

The mesalazine oral sustained-release pharmaceutical composition comprises the following raw materials in parts by weight: 25 parts of mesalazine, 13 parts of an extract of Mallotus apelta, 13 parts of an extract of white paeony root, 55 parts of a drug carrier, 8 parts of xylitol, 5 parts of citric acid and 25 parts of carboxymethyl chitosan;

the mesalazine oral sustained-release pharmaceutical composition is prepared by the following steps:

step S1: adding mesalazine, the radix Malloti Apeltae extract, the radix Paeoniae alba extract and the drug carrier into dichloroethane, stirring at the rotation speed of 400r/min and the temperature of 35 ℃ for 10min, adding lecithin, and continuously stirring for 1.3h to obtain a first mixed solution;

step S2: adding xylitol, citric acid and deionized water into a reaction kettle, and stirring until the xylitol and the citric acid are completely dissolved to prepare a second mixed solution;

step S3: adding carboxymethyl chitosan and deionized water into a reaction kettle, stirring at the rotation speed of 400r/min until the carboxymethyl chitosan is completely dissolved, adding tween, and continuously stirring at 83 ℃ for 50min to obtain a third mixed solution;

step S4: adding the first mixed solution prepared in the step S1 into a reaction kettle, stirring and adding the second mixed solution under the condition that the rotating speed is 3500r/min, and continuously stirring for 6min to prepare a fourth mixed solution;

step S5: and (4) adding the third mixed solution prepared in the step (S3) into a reaction kettle, stirring at the rotation speed of 900r/min, adding the fourth mixed solution prepared in the step (S4), continuously stirring for 2.5 hours, filtering to remove filtrate, and drying at the temperature of 55 ℃ for 6 hours to prepare the mesalazine oral sustained-release pharmaceutical composition.

The extract of the roots of the redback roots is prepared by the following steps:

step A1: adding redback root and deionized water into a reaction kettle, stirring for 8min at the rotating speed of 150r/min and the temperature of 32 ℃, filtering to remove the deionized water, and crushing the redback root to prepare redback root powder;

step A2: adding the gynura bicolor root powder prepared in the step A1 and ethanol into a reaction kettle, heating and refluxing for 2.5 hours at the temperature of 85 ℃, filtering to remove filter substances, adding a hydrochloric acid solution into the filtrate until the pH value is 4.5, adding ammonia water until the pH value is 9.5 to prepare a first mixed solution, extracting the first mixed solution for 2 times by using chloroform, combining chloroform extract liquor, adding deionized water, mixing uniformly, removing water by using phosphorus pentoxide, and distilling at the temperature of 68 ℃ to remove the chloroform to prepare the gynura bicolor root extract.

The white peony root extract is prepared by the following steps:

step B1: pulverizing radix Paeoniae alba, soaking in ethanol solution at 45 deg.C, filtering, soaking for 3 times (each time for 1.5 hr), mixing the filtrates to obtain radix Paeoniae alba mixed solution, and concentrating to relative density of 1.10g/cm³To obtain radix Paeoniae alba concentrated solution;

step B2: adding the white paeony root concentrated solution prepared in the step B1 and a hydrochloric acid solution into a reaction kettle, carrying out ultrasonic treatment for 35min under the condition of the frequency of 35kHz, filtering to remove filter substances, adding a sodium hydroxide solution into the filtrate until the pH value is 9, extracting with chloroform to obtain a chloroform extract, distilling the chloroform extract to remove the chloroform, extracting with isopropanol to obtain an isopropanol extract, and distilling the isopropanol extract to remove the isopropanol to obtain the white paeony root extract.

The drug carrier is prepared by the following steps:

step C1: adding cotton and glacial acetic acid into a reaction kettle, stirring for 35min at the rotation speed of 400r/min and the temperature of 73 ℃, dropwise adding a sulfuric acid solution and acetic anhydride, introducing nitrogen for protection, and continuously stirring for 1.3h at the temperature of 80-100 ℃ to obtain paste;

step C2: c1, adding the paste prepared in the step C1 into a reaction kettle, stirring and slowly adding an acetic acid solution under the conditions that the rotating speed is 250r/min and the temperature is 65 ℃, continuously stirring for 18min, adding deionized water and filtering, removing filtrate, washing a filter cake with distilled water until the pH value is 7, and drying to prepare a first powder;

step C3: adding the first powder prepared in the step C2 and a sodium hydroxide solution into a reaction kettle, soaking for 35min at the temperature of 40 ℃, washing with ethanol until the pH value is 7, filtering to remove filtrate, and drying for 1.5h at the temperature of 55 ℃ to prepare a second powder;

step C4: and D, adding the second powder prepared in the step C3 and mixed acid into a reaction kettle, stirring for 13min at the rotation speed of 400r/min and the temperature of 45 ℃, adding sodium nitrite, continuously stirring for 1.5h, centrifuging for 8min at the rotation speed of 4000r/min, washing with deionized water until the pH value of the supernatant is 7, removing the supernatant, and drying to obtain the drug carrier.

Example 3

The mesalazine oral sustained-release pharmaceutical composition comprises the following raw materials in parts by weight: 30 parts of mesalazine, 15 parts of radix Malloti Apeltae extract, 15 parts of radix paeoniae alba extract, 60 parts of a drug carrier, 10 parts of xylitol, 8 parts of citric acid and 30 parts of carboxymethyl chitosan;

the mesalazine oral sustained-release pharmaceutical composition is prepared by the following steps:

step S1: adding mesalazine, the radix Malloti Apeltae extract, the radix Paeoniae alba extract and the drug carrier into dichloroethane, stirring at the rotation speed of 500r/min and the temperature of 40 ℃ for 15min, adding lecithin, and continuously stirring for 1.5h to obtain a first mixed solution;

step S2: adding xylitol, citric acid and deionized water into a reaction kettle, and stirring until the xylitol and the citric acid are completely dissolved to prepare a second mixed solution;

step S3: adding carboxymethyl chitosan and deionized water into a reaction kettle, stirring at the rotation speed of 500r/min until the carboxymethyl chitosan is completely dissolved, adding tween, and continuously stirring at the temperature of 85 ℃ for 60min to prepare a third mixed solution;

step S4: adding the first mixed solution prepared in the step S1 into a reaction kettle, stirring and adding the second mixed solution under the condition that the rotating speed is 4000r/min, and continuously stirring for 8min to prepare a fourth mixed solution;

step S5: adding the third mixed solution prepared in the step S3 into a reaction kettle, stirring at the rotation speed of 1000r/min, adding the fourth mixed solution prepared in the step S4, continuously stirring for 3 hours, filtering to remove filtrate, and drying at the temperature of 60 ℃ for 8 hours to prepare the mesalazine oral sustained-release pharmaceutical composition.

The extract of the roots of the redback roots is prepared by the following steps:

step A1: adding redback root and deionized water into a reaction kettle, stirring for 10min at the rotating speed of 200r/min and the temperature of 35 ℃, filtering to remove the deionized water, and crushing the redback root to prepare redback root powder;

step A2: adding the gynura bicolor root powder prepared in the step A1 and ethanol into a reaction kettle, heating and refluxing for 3 hours at the temperature of 90 ℃, filtering to remove filter substances, adding a hydrochloric acid solution into the filtrate until the pH value is 5, adding ammonia water until the pH value is 10 to prepare a first mixed solution, extracting the first mixed solution for 3 times by using chloroform, combining chloroform extract, adding deionized water, mixing uniformly, removing water by using phosphorus pentoxide, and distilling at the temperature of 70 ℃ to remove the chloroform to prepare the gynura bicolor root extract.

The white peony root extract is prepared by the following steps:

step B1: pulverizing radix Paeoniae alba, soaking in ethanol solution at 50 deg.C, filtering, soaking for 4 times (each for 2 hr), mixing the filtrates to obtain radix Paeoniae alba mixed solution, and concentrating to relative density of 1.15g/cm³To obtain radix Paeoniae alba concentrated solution;

step B2: and D, adding the white paeony root concentrated solution prepared in the step B1 and a hydrochloric acid solution into a reaction kettle, carrying out ultrasonic treatment for 40min under the condition of 40kHz frequency, filtering to remove filter substances, adding a sodium hydroxide solution into the filtrate until the pH value is 10, extracting with chloroform to obtain a chloroform extract, distilling the chloroform extract to remove the chloroform, extracting with isopropanol to obtain an isopropanol extract, and distilling the isopropanol extract to remove the isopropanol to obtain the white paeony root extract.

The drug carrier is prepared by the following steps:

step C1: adding cotton and glacial acetic acid into a reaction kettle, stirring for 40min at the rotation speed of 500r/min and the temperature of 75 ℃, dropwise adding a sulfuric acid solution and acetic anhydride, introducing nitrogen for protection, and continuously stirring for 1.5h at the temperature of 100 ℃ to obtain paste;

step C2: c1, adding the paste prepared in the step C1 into a reaction kettle, stirring and slowly adding an acetic acid solution under the conditions that the rotating speed is 300r/min and the temperature is 70 ℃, continuously stirring for 20min, adding deionized water and filtering, removing filtrate, washing a filter cake with distilled water until the pH value is 7, and drying to prepare a first powder;

step C3: adding the first powder prepared in the step C2 and a sodium hydroxide solution into a reaction kettle, soaking for 40min at the temperature of 50 ℃, washing with ethanol until the pH value is 7, filtering to remove filtrate, and drying for 2h at the temperature of 60 ℃ to prepare a second powder;

step C4: and D, adding the second powder prepared in the step C3 and mixed acid into a reaction kettle, stirring for 15min at the rotation speed of 300-500r/min and the temperature of 50 ℃, adding sodium nitrite, continuously stirring for 2h, centrifuging for 10min at the rotation speed of 5000r/min, washing with deionized water until the pH value of the supernatant is 7, removing the supernatant, and drying to obtain the drug carrier.

Comparative example 1

The comparative example is a common mesalazine pharmaceutical composition on the market.

The mesalamine pharmaceutical compositions prepared in examples 1 to 3 and comparative example 1 were tested, and the test results are shown in table 1 below;

and (3) testing the curative effect: 200 volunteers with ulcerative colitis were evenly divided into four groups, wherein three groups of volunteers respectively took the mesalamine pharmaceutical composition prepared in examples 1-3 once a day, the rest group of volunteers took the mesalamine pharmaceutical composition prepared in comparative example 1 once a day, the rest eating and living conditions were the same and suitable, and after taking the mesalamine pharmaceutical composition every day, the mesalamine pharmaceutical composition was continuously used until the ulcerative colitis was completely eliminated.

Liver effects: 200 volunteers suffering from ulcerative colitis were evenly divided into four groups, wherein three groups of volunteers respectively took the mesalamine pharmaceutical composition prepared in examples 1-3 once a day, the remaining group of volunteers took the mesalamine pharmaceutical composition prepared in comparative example 1 once a day, the rest eating and living conditions were the same and suitable, and after taking for 10, 20, 30 and 40 days continuously, the volunteers were tested whether glutamate pyruvate transaminase exceeded.

TABLE 1

As can be seen from table 1 above, the treatment time of the mesalamine pharmaceutical compositions prepared in examples 1-3 is 13-16 days, the treatment time of comparative example 1 is 22 days, the content of glutamic-pyruvic transaminase of the mesalamine pharmaceutical compositions prepared in examples 1-3 is stabilized at 28-30U/L after 30 days of administration, and the content of glutamic-pyruvic transaminase of comparative example 1 exceeds the normal index of 40U/L after 30 days of administration, which indicates that the mesalamine pharmaceutical compositions prepared by the present invention can be released in the intestinal tract continuously, so as to achieve the sustained release effect, prolong absorption, and increase the treatment effect of mesalamine.

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.