Application of ethyl sulfate in preparation of medicine for preventing and / or treating inflammatory bowel disease

Abstract

The invention discloses application of ethyl sulfate in preparation of a medicine for preventing and / or treating inflammatory bowel diseases, and belongs to the technical field of medicines. The invention finds that ethyl sulfate has the effect of preventing and / or treating inflammatory bowel disease for the first time: the ethyl sulfate can obviously improve the survival index of an inflammatory bowel disease model mouse and reduce the disease activity index; the symptoms of weight loss, stool character, inflammation-related diarrhea and bloody stool are relieved; the length of colon tissue is improved, and the size and number of tumors in colorectum are reduced; the pharmaceutical composition has the effects of inhibiting the level of proinflammatory cytokines (TNF-alpha, IL-8, IL-1beta and IL-6), recovering the level of anti-inflammatory cytokines (IL-10 and INF-gamma), inhibiting the enzymatic activity of MPO and MDA and improving the enzymatic activity of SOD and GSH-Px, so that the inflammatory reaction and oxidative stress reaction in the inflammatory bowel disease microenvironment are improved, and the pharmaceutical composition has the pharmacological action of preventing and / or treating the inflammatory bowel disease.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to the application of ethyl sulfate in the preparation of a drug for preventing and / or treating inflammatory bowel disease. BACKGROUND

[0002] Inflammatory bowel disease (IBD), mainly including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic and recurrent intestinal inflammatory disease. It is believed that in individuals with genetic predisposition, a variety of environmental factors (such as diet, smoking, antibiotic use, and changes in microbial exposure related to the hygiene hypothesis, etc.) trigger an abnormal and persistent immune response of the intestinal mucosal immune system to the intestinal flora (microbiome), ultimately causing damage to the intestinal tissue and chronic inflammation. Epidemiological analysis found that IBD showed obvious regional differences worldwide, with the highest incidence and prevalence in North America and Europe, but in recent years, the incidence in emerging industrialized countries such as Asia and South America has increased significantly.

[0003] The clinical manifestations of inflammatory bowel disease are diverse, including 1) diarrhea, which is a common symptom of Crohn's disease, with most patients having 2-6 bowel movements per day; bloody diarrhea is the most common symptom of ulcerative colitis, with blood, pus and mucus in the stool, with 2-4 times per day in mild cases, and up to 10-30 times in severe cases, appearing as blood water.

[0004] 2) Abdominal pain, abdominal mass, and anal internal pain, IBD is often limited to the left lower abdomen or lower abdomen, paroxysmal spastic colic, followed by periumbilical or abdominal pain, and a few cases of intestinal obstruction or intestinal perforation. Some Crohn's disease may have abdominal mass, occasional anal internal pain, and anal canal formation.

[0005] 3) Complications, including weight loss, nausea, vomiting, anorexia, anemia, hypoproteinemia, fever, peripheral arthritis, nodular erythema, gangrenous pyoderma, scleritis, uveitis, recurrent oral ulcers, etc.

[0006] 4) In addition, the colorectal epithelial cells of IBD patients are in a constant process of damage and repair, and the continuous damage to the epithelial cells causes DNA mutations and activates the anti-apoptotic mechanism of colorectal epithelial cells. Inflammatory colorectal tissue is in such an environment for a long time, significantly increasing the risk of tumorigenesis and carcinogenesis. SUMMARY

[0007] The purpose of the present application is to provide the application of ethyl sulfate in the preparation of a drug for preventing and / or treating inflammatory bowel disease, so as to provide a new use of ethyl sulfate.

[0008] To achieve the above-mentioned purpose, the present application provides the application of ethyl sulfate in the preparation of a drug for preventing and / or treating inflammatory bowel disease.

[0009] Preferably, the structural formula of the ethyl sulfate is: , where R is one of sodium ions, potassium ions, calcium ions or magnesium ions.

[0010] Preferably, the drug uses ethyl sulfate as the active ingredient, and the dosage of ethyl sulfate is 10 mg / kg / d to 150 mg / kg / d.

[0011] Preferably, the drug further includes one or more pharmaceutically acceptable carriers or excipients.

[0012] Preferably, the carrier or excipient includes a diluent, filler, disintegrant, skeleton material, lubricant, plasticizer, anti-sticking agent, and preservative.

[0013] Preferably, the drug form includes oral medication, topical medication, and injectable medication.

[0014] Therefore, the specific technical effects of the application of the ethyl sulfate provided by this invention in the preparation of drugs for the prevention and / or treatment of inflammatory bowel disease are as follows: (1) Ethyl sulfate (EtS) is often used as a surfactant, wetting agent and emulsifier. It can also be used as an ethylating agent in organic synthesis. This invention is the first to discover that ethyl sulfate has the effect of preventing and / or treating inflammatory bowel disease. (2) Ethyl sulfate can significantly improve the survival index and reduce the disease activity index in mice with inflammatory bowel disease; alleviate symptoms of weight loss, stool characteristics, inflammation-related diarrhea and bloody stool; improve the length of colon tissue and reduce the size and number of tumors in the middle and distal colon and rectum. (3) Sodium ethyl sulfate has the effects of inhibiting the levels of pro-inflammatory cytokines (TNF-α, IL-8, IL-1β and IL-6), restoring the levels of anti-inflammatory cytokines (IL-10, INF-γ), inhibiting the enzyme activity of MPO and MDA, and enhancing the enzyme activity of SOD and GSH-Px, thereby improving the inflammatory response and oxidative stress response in the microenvironment of inflammatory bowel disease, thus having the pharmacological effects of preventing and / or treating inflammatory bowel disease.

[0015] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0016] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments of the present invention will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1This is the survival curve of the mice in Example 6 of the present invention; Figure 2 This is the mouse weight change curve in Example 6 of the present invention; Figure 3 It is the mouse disease activity index in Example 6 of the present invention; Figure 4 These are images of rectal prolapsed mice from the model group in Example 6 of this invention; where A is a frontal photograph of the mouse with rectal prolapse; and B is a side photograph of the mouse. Figure 5 This is a photograph of the mouse colon and rectum in Example 6 of the present invention; Figure 6 This is the statistical result of the distribution of colorectal tumors in mice in Example 6 of the present invention; Figure 7 This refers to the HE staining results of colorectal tissue in Example 6 of this invention; Figure 8 This refers to the colorectal tissue scoring results in Example 6 of the present invention; Figure 9 These are the detection results of cytokines in Example 6 of the present invention; wherein A is IL-1β; B is IL-6; C is IL-8; D is TNF-α; E is IL-10; and F is INF-γ. Figure 10 These are the detection results of oxidative stress indicators in Example 6 of the present invention; where A is MPO; B is MDA; C is SOD; and D is GSH-Px. Detailed Implementation

[0018] The technical solution of the present invention will be further described below with reference to the accompanying drawings and embodiments.

[0019] To make the objectives, technical solutions, and advantages of this application clearer, more thorough, and more complete, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings and embodiments. The following detailed descriptions are all illustrations of embodiments, intended to provide further detailed explanation of the present invention. Unless otherwise specified, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0020] The instruments, equipment, reagents and materials used in the embodiments were all obtained through commercial means; the methods and steps not described in detail in the embodiments are all conventional techniques in the art.

[0021] Example 1 The preparation of sodium ethyl sulfate tablets, with information on each component and its dosage shown in Table 1, and the specific steps are as follows: Table 1. Component Dosage and Function Information

[0022] (1) Core preparation.

[0023] 200.0g sodium ethyl sulfate, 80.0g microcrystalline cellulose, 60.0g lactose monohydrate, 10.0g crospovidone, and 40.0g hydroxypropyl methylcellulose (HPMC K4M) were placed in a high-efficiency wet granulator and mixed thoroughly. 10.0-20.0g purified water was added as a binder, and the mixture was granulated using high-speed shearing. The wet granules were placed in a fluidized bed and dried at 60°C until the moisture content was below 2.0%. The dried granules were then granulated through a 20-mesh vibrating sieve. The granulated granules were mixed with 5.0g magnesium stearate in a three-dimensional mixer for 15 minutes to ensure homogeneity. The final mixture was then compressed into tablet cores using a rotary tablet press.

[0024] (2) Preparation of coating solution.

[0025] Disperse 2.0 g of polyethylene glycol 6000 in 10.0 g of purified water. Slowly add 130.0 g of acrylic resin (Eudragit® FS 30D) dispersion to the polyethylene glycol 6000 aqueous solution. Add 20.0 g of talc powder and stir continuously for at least 45 minutes to form a homogeneous suspension. Pass the suspension through a 100-mesh sieve to remove particles and continue stirring at 10-20 rpm until the coating process begins to prevent sedimentation.

[0026] (3) Coating.

[0027] The tablet cores prepared in step (1) were placed in a high-efficiency coating pan (pan speed: 10-12 rpm, air inlet temperature: 38-40℃) and coated continuously until the coating weight gain reached 10% of the tablet core weight. After coating, the tablets were cured at 40℃ for 2 hours to form a complete and stable colonic dissolution coating film.

[0028] Example 2 The preparation of sodium ethyl sulfate capsules, with information on each component and its dosage shown in Table 2, and the specific steps are as follows: Table 2. Component Dosage and Function Information

[0029] (1) Preparation of drug-loaded pellet cores.

[0030] 5.0 g of hydroxypropyl methylcellulose (HPMC E5) was dispersed in 40.0 g of purified water and stirred until completely dissolved to prepare a clear binder solution (hydroxypropyl methylcellulose solution). Sodium ethyl sulfate powder was dispersed in 10.0 g of purified water and subjected to high-speed shearing to form a homogeneous suspension. This suspension was then mixed evenly with the hydroxypropyl methylcellulose solution to obtain a drug liquid. Sucrose pellet cores were placed in a fluidized bed coating machine, and the prepared drug was sprayed onto the fluidized sucrose pellet cores at a rate of 5-10 mL / min using a bottom spray method (Wurster method), while hot air was simultaneously introduced to dry the material. Process parameters: inlet air temperature 50-60℃, material temperature 35-40℃, spray rate 5-10 mL / min.

[0031] (2) Isolation layer coating.

[0032] 5.0 g of hydroxypropyl methylcellulose and polyethylene glycol 6000 were dissolved in purified water to prepare an isolation layer coating solution. The isolation layer coating solution was then sprayed onto the drug-loaded pellet core prepared in (1) in a fluidized bed. This isolation layer serves to prevent the drug from interacting with the subsequent acidic coating and provides a smooth surface for colonic coating.

[0033] (3) Colonic dissolution coating.

[0034] Dissolve 50.0 g of acrylic resin (Eudragit® S100) in 800 mL of anhydrous ethanol. Add triethyl citrate while stirring magnetically at 10-20 rpm, and continue stirring until completely dissolved. Finally, add talc and homogenize at 12000 rpm to form a uniform suspension. In a fluidized bed, spray the colonic dissolving coating solution onto the microspheres with the isolation layer prepared in (2) until the coating weight gain reaches 20%.

[0035] (4) Drying and filling.

[0036] The coated microspheres obtained in (3) were solidified and dried in a fluidized bed at 40°C for 2 hours to form a stable coating. The final microspheres were sampled and tested according to the Chinese Pharmacopoeia Dissolution and Release Determination Method. After passing the test, a quantitative amount of microspheres (e.g., containing 100 mg of sodium ethyl sulfate) was filled into No. 2 empty capsules using a capsule filling machine.

[0037] Example 3 The preparation of sodium ethyl sulfate enema, with information on each component and its dosage shown in Table 3, and the specific steps are as follows: Table 3. Component Dosage and Function Information

[0038] (1) Weigh 18.0g of poloxamer 407 and 2.0g of poloxamer 188, and slowly add them to purified water in an ice bath at 5℃±3℃, which accounts for about 1 / 3 of the total water volume, while stirring. Continue stirring at 100-200rpm until the powder is completely dispersed and a clear solution is formed. Place the solution in a refrigerator at 5℃±3℃ and let it stand overnight.

[0039] (2) In another container, 5.0g sodium ethyl sulfate, 2.5g glycerol and 0.02g ethyl p-hydroxybenzoate are dissolved in the remaining purified water and stirred until completely dissolved to obtain solution I. 0.2g carbomer 974P powder is slowly dispersed in solution I under high-speed shear at 12000rpm and stirred to allow carbomer 974P to fully swell to obtain carbomer dispersion.

[0040] (3) Slowly add the carbomer dispersion to (1) while stirring at 100-200 rpm. Keep the solution at 5℃±3℃ and stir continuously at 100-200 rpm for at least 1 hour to form a uniform and clear mixed solution II.

[0041] Fill Mixture II into single-dose pharmaceutical plastic bottles or soft bags at 100-200 rpm, 50 mL per bottle (containing 2.5 g of sodium ethyl sulfate). Seal, label, and store at room temperature or under refrigeration.

[0042] Example 4 The sodium ethyl sulfate bioadhesive suppository was prepared. Information on each component and its dosage is shown in Table 4. The specific steps are as follows: Table 4. Component Dosage and Function Information

[0043] (1) Weigh 70.0g of polyethylene glycol 1500 and 30.0g of polyethylene glycol 6000, place them in a water bath and heat to 70-75℃, stirring until completely melted to form a uniform molten matrix. Keep warm for later use.

[0044] (2) Mix 25.0g sodium ethyl sulfate, 5.0g carbomer 974P and 5.0g hydroxypropyl methylcellulose K100M in a container beforehand. Slowly add the resulting solution to the molten matrix obtained in (1) while stirring at 10-20 rpm, and continue mechanical stirring until a solution is formed.

[0045] Stop heating and lower the temperature to approximately 65°C (close to the freezing point). While the solution is still flowing, quickly inject it into a rectal suppository mold (2g size) pre-coated with a small amount of magnesium stearate as a lubricant.

[0046] Cool at room temperature for at least 30 minutes to allow it to fully solidify and set. Use a blade to scrape off any excess material from the mold opening, open the mold, and remove the molding plug.

[0047] Example 5 The preparation of sodium ethyl sulfate injection, with information on each component and its dosage, is shown in Table 5. The specific steps are as follows:

[0048] Table 5. Component Dosage and Function Information (1) Take 160 mL of water for injection, add 5.0 g of sodium ethyl sulfate, 1.0 g of mannitol and 40.0 mg of disodium edetate in sequence, stir until completely dissolved, and control the pH of the solution to 4.5~6.5 using a pH adjuster. Filter aseptically using a 0.22 μm polyethersulfone filter membrane, and fill the filtered solution into vials.

[0049] (2) Transfer the partially stoppered vials to a freeze dryer shelf pre-cooled at 5℃±3℃, freeze the product to -45℃, and maintain this temperature for 2-3 hours. Raise the shelf temperature to -25℃, and simultaneously turn on the vacuum to below 100mbar, sublimating for approximately 20 hours to remove most of the free water. Raise the shelf temperature to 30℃ at a rate of 0.5℃ / min, maintaining the vacuum to further remove bound water until the residual moisture content of the product is below 2.0%. After freeze drying, perform full stoppering under vacuum or nitrogen purging conditions. After removal from the freezer, perform aluminum cap crimping.

[0050] Example 6 The efficacy study of sodium ethyl sulfate in treating ulcerative colitis is detailed below: SPF-grade male C57BL / 6J mice (6-8 weeks old, 20±2g) were randomly divided into 6 groups (n=10): control group, model group, positive control drug mesalazine group (5-ASA), low-dose sodium ethyl sulfate group (EtS-L, 37.5mg / kg), medium-dose sodium ethyl sulfate group (EtS-M, 75mg / kg), and high-dose sodium ethyl sulfate group (EtS-H, 150mg / kg).

[0051] Mice were acclimatized (25℃, 60% humidity, 12h light cycle) for one week before enteritis modeling and prophylactic drug administration. Before modeling, mice in each group were weighed. Except for the control group, mice in each experimental group were intraperitoneally injected with 1 mg / mL AOM solution at a dose of 10 mg / kg. The control group received an equal volume of physiological saline. Seven days after intraperitoneal injection, mice were fed a 2% sodium dextran sulfate (DSS) solution for 7 days, followed by purified water for 14 days, for a total of three cycles of 2% DSS solution administration.

[0052] The following parameters were used to evaluate the efficacy of the sodium ethyl sulfate tablets prepared in Example 1. SPSS 22 software was used for statistical processing, and the results are expressed as mean ± standard deviation (Mean ± SD). Origin 2025 software was used for image plotting, and the data were analyzed using one-way ANOVA. p A value <0.05 is considered statistically significant. Specific evaluation indicators are as follows: (1) Survival status of mice.

[0053] Observe and record the mental state, diet, coat color, and activity of C57BL / 6 mice during the modeling process and before and after drug administration. Also observe the characteristics of stool, inflammation-related diarrhea and bloody stool, and record the survival status and weight of the mice.

[0054] The results are as follows Figure 1 As shown, four mice in the model group died within three cycles of feeding with 2% DSS solution. Three mice died in each of the three cycles in the EtS-L group, and two mice died in each of the 5-ASA, EtS-M, and EtS-H groups. Compared with the model group (four deaths), the 5-ASA and EtS treatment groups (EtS-L, EtS-M, and EtS-H groups) improved the survival index of mice with inflammatory bowel disease to some extent.

[0055] (2) Assessment of weight change and disease activity index.

[0056] The degree of inflammation in the enteritis of C57BL / 6J mice was evaluated using the Disease Activity Index (DAI). The evaluation criteria for the Disease Activity Index are shown in Table 6.

[0057] Table 6 Evaluation criteria for disease activity index

[0058] The results are as follows Figure 2 As shown, in the azomethane / sodium dextran sulfate model of inflammation-related colorectal disease and during drug administration, the control group mice showed a significant trend of increasing body weight. The model group, 5-ASA group, and EtS-treated groups (EtS-L, EtS-M, and EtS-H groups) all showed varying degrees of decreasing body weight during the three cycles of DSS solution feeding. During the cycle of feeding purified water, the body weight of all groups showed a steady increasing trend; compared with the model group, the 5-ASA group, EtS-M, and EtS-H group showed significant body weight recovery.

[0059] Disease activity index assessment results as follows Figure 3As shown in Table 7, the mice were in good spirits, had smooth fur, and normal activity and food intake at the beginning of the experiment. After being fed a 2% DSS solution, the mice in each group modeled with azomethane / sodium dextran sulfate showed weight loss, diarrhea, and bloody stools. Figure 4 It can be seen that rectal prolapse occurred in the model group during the modeling process. The DAI score of mice in the model group treated with azomethane / sodium dextran sulfate was significantly increased compared to the blank group. p <0.01), while the DAI scores of the 5-ASA and EtS administration groups were significantly lower than those of the model group ( p <0.01). There was no significant difference in DAI results between the EtS-M group and the EtS-L group. p >0.05), while the DAI score of the EtS-H group was significantly lower ( p <0.05), indicating that EtS-H can effectively alleviate symptoms of weight loss, stool characteristics, enteritis-related diarrhea, and bloody stool in mice with azomethane / dextran sulfate-induced inflammation-related colorectal disease model.

[0060] Table 7 Results of Disease Activity Index in Mice (n=10)

[0061] Note: ## This indicates a highly significant difference compared to the control group. p< 0.01 p <0.01).

[0062] (3) Assessment of colorectal tumors.

[0063] After three feedings with 2% DSS solution, mice in each group were dissected, and intestinal tissue from the colon to the rectum was collected. The length of the colorectal segment was measured using a ruler. The colorectum was opened along the longitudinal axis of the intestinal segment, and the intestine was cleansed with 0.9% sodium chloride injection solution. The distribution of tumors was photographed and recorded. The number of tumors in the colorectum of each mouse was counted, and the size of the tumors was measured using calipers.

[0064] The results are as follows Figure 5 As shown, no tumors were observed in the colon and rectum of mice in the control group, while tumors were visible to the naked eye in the model group with a tumor formation rate of 100%, indicating that the inflammation-related colorectal disease model induced by azomethane / dextran sulfate sodium was successfully established. Compared with the control group, fleshy, round tumors were clearly visible in the middle and distal colon and rectum of mice in the model group, and the colon length was significantly shortened. p <0.01). Compared with the model group, both the 5-ASA group and the EtS administration group significantly improved the length of colonic tissue ( p <0.05), and at the same time, it reduced the size and number of tumors in the middle and distal parts of the colorectal region to varying degrees.

[0065] The statistical results of tumor distribution are as follows: Figure 6 As shown in Table 8.

[0066] Table 8. Distribution of colorectal tumors (n=10)

[0067] Note: ## This indicates a highly significant difference compared to the control group. p< 0.01 p <0.01).

[0068] Compared with the model group, the 5-ASA and EtS administration groups significantly reduced the number of large tumors (greater than 2.5 mm). p <0.01). There was no significant difference between the EtS-L group and the EtS-M group ( p >0.05). Compared with the EtS-L group, the EtS-H group showed a highly significant reduction in the number of tumors (>2.5 mm and <1.0 mm). p <0.01).

[0069] (4) HE staining and tissue scoring of rectal tissue.

[0070] Intestinal tissue samples were collected after tumor assessment and fixed in 4% paraformaldehyde fixative for 36 hours. The samples were first soaked in 75% ethanol for 5 minutes, then dehydrated in anhydrous ethanol for 5 minutes. The tissue was then defatted and cleared twice with xylene, 20 minutes each time. The defatted intestinal tissue was then dehydrated using a gradient of ethanol (75%, 100%), embedded in paraffin, and cut into 4 μm thick sections. After hematoxylin and eosin (HE) staining, the sections were mounted with neutral resin. Pathological changes in the tissue sections were observed under an inverted fluorescence microscope. A semi-quantitative scoring system was used to evaluate the histological sections of the intestinal tissue, with the histological disease score calculated as the sum of each individual score. The scoring criteria for intestinal tissue sections are shown in Table 7.

[0071] Table 7 Scoring Criteria for Intestinal Tissue Sections

[0072] HE staining results of rectal tissue are as follows Figure 7 As shown, in the control group, the upper layer of the colonic mucosa was intact, and the intestinal glands, composed of the epithelium, lamina propria, and muscularis mucosae, were neatly arranged with no destruction of the crypt structures, and there was no congestion, edema, or inflammatory cell infiltration. In the model group, the colonic mucosa was absent, with extensive destruction or disappearance of glands, a reduction in goblet cells, thickening of the mucosa and submucosa, distortion or disappearance of the crypt structures, and extensive infiltration of lymphocytes and neutrophils into the muscularis propria, resulting in tubular adenomas. Colorectal tissue scoring results. Figure 8As shown, compared with the model group, the crypt epithelium in the 5-ASA and EtS treatment groups showed extremely significant recovery and reduced histological inflammatory response. p <0.01. There was no significant difference between the EtS-L group and the EtS-M group ( p >0.05), indicating that the two groups had similar repair effects on crypt structures and mucosal tissues. Compared with the EtS-L group, the EtS-H group showed extremely significant ( p <0.01) reduced intestinal inflammation and damage to colorectal tissue.

[0073] (5) Detection of cytokines.

[0074] The colon and rectum of each group of mice were weighed and added to an appropriate amount of PBS buffer. The mixture was homogenized at 5℃±3℃ (15000rpm). The wavelengths of the enzyme-linked immunosorbent assay (ELISA) kits for IL-1β, IL-6, IL-8, IL-10, TNF-α, and INF-γ were measured according to the instructions of the kits. The relevant indicators were measured using an ELISA reader.

[0075] The results are as follows Figure 9 As shown, compared with the blank group, the levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α) in the model group were significantly increased. p <0.01), anti-inflammatory cytokines (IL-10, INF-γ) were significantly reduced ( p <0.01 indicates that it induces an inflammatory response in the gut microenvironment of inflammation-related colorectal diseases. Compared with the model group, both 5-ASA and EtS administration groups significantly inhibited the levels of pro-inflammatory cytokines and significantly restored the levels of anti-inflammatory factors. p <0.01).

[0076] (6) Detection of oxidative stress indicators.

[0077] Weigh out the colon and rectum of each experimental group, add an appropriate amount of PBS buffer, homogenize at low temperature (15000 rpm), and measure the relevant indicators using an enzyme-linked immunosorbent assay (ELISA) reader according to the instructions and measurement wavelengths of the BCA, SOD, MDA, MPO, and GSH-PX kits.

[0078] The results are as follows Figure 10 As shown, compared with the blank group, the enzyme activity levels of MPO and MDA in the model group were significantly increased ( p <0.01), while the activities of SOD and GSH-Px enzymes decreased significantly ( p <0.01 indicates a persistent oxidative stress state in the intestinal microenvironment of inflammation-related colorectal diseases. Both 5-ASA and EtS administration groups significantly restored MPO and MDA enzyme activity levels (…). p<0.01), significantly reduced the activity levels of SOD and GSH-Px enzymes.

[0079] The results above show that before feeding with 2% DSS solution, the mice in each group were in good mental condition, had smooth fur, and normal activity and food intake. Mice with inflammation-related colorectal disease induced by azomethane / dextrose sulfate showed weight loss, diarrhea and bloody stools, and a significantly increased DAI index. Among them, 4 mice died during the three feeding cycles of 2% DSS solution. After the experiment, the model group showed obvious, fleshy, round tumors in the middle and distal segments of the colon and rectum, with 100% tumor formation. HE staining results showed the absence of colonic mucosa, destruction or disappearance of a large number of glands, reduction of goblet cells, thickening of the mucosa and submucosa, distortion or disappearance of crypt structures, and infiltration of a large number of lymphocytes and neutrophils, even reaching the muscle layer. Compared with the model group, the 5-ASA and EtS administration groups (EtS-L, EtS-M, EtS-H) improved the survival index of mice. During the period of feeding purified water, the body weight of mice in each group showed a steady increase trend, significantly reduced the DAI index, alleviated the weight loss, stool characteristics, inflammation-related diarrhea and bloody stool in mice with inflammation-related colorectal disease induced by azomethane / dextran sulfate sodium model, improved the length of colonic tissue, and reduced the size and number of tumors in the middle and distal segments of the colon and rectum. The EtS-treated groups (EtS-L, EtS-M, and EtS-H) significantly inhibited the levels of pro-inflammatory cytokines, restored the levels of anti-inflammatory factors, inhibited the enzyme activities of MPO and MDA, and increased the activities of SOD and GSH-Px enzymes, thereby significantly improving the inflammatory response and oxidative stress response in the intestinal microenvironment of inflammatory bowel disease. These pharmacodynamic results suggest that EtS-L, EtS-M, and EtS-H have a relatively direct and significant effect on the prevention and treatment of inflammatory bowel disease induced by azomethane / dextran sulfate sodium modeling.

[0080] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. The use of ethyl sulfate in the preparation of drugs for the prevention and / or treatment of inflammatory bowel disease.

2. The use of the ethyl sulfate according to claim 1 in the preparation of drugs for the prevention and / or treatment of inflammatory bowel disease, characterized in that, The structural formula of the ethyl sulfate is: , where R is one of sodium ions, potassium ions, calcium ions or magnesium ions.

3. The use of the ethyl sulfate according to claim 1 in the preparation of drugs for the prevention and / or treatment of inflammatory bowel disease, characterized in that: The drug uses ethyl sulfate as the active ingredient, and the dosage of ethyl sulfate is 10 mg / kg / d to 150 mg / kg / d.

4. The use of the ethyl sulfate according to claim 3 in the preparation of drugs for the prevention and / or treatment of inflammatory bowel disease, characterized in that: The drug also includes one or more pharmaceutically acceptable carriers or excipients.

5. The use of the ethyl sulfate according to claim 4 in the preparation of drugs for the prevention and / or treatment of inflammatory bowel disease, characterized in that: The carrier or excipients include diluents, fillers, disintegrants, skeleton materials, lubricants, plasticizers, anti-adhesion agents, and preservatives.

6. The use of the ethyl sulfate according to claim 1 in the preparation of drugs for the prevention and / or treatment of inflammatory bowel disease, characterized in that: The drug forms include oral medications, topical medications, and injectable medications.

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