KR102270073B1 - Composition for preventing or treating inflammatory bowel disease comprising sulglycotide as effective component - Google Patents

Abstract

The present invention relates to a composition for preventing or treating inflammatory bowel disease comprising sulfolglycotide as an active ingredient. The group administered with the active ingredient of the present invention, sulglycotide, had a relatively low colitis score compared to the control group that induced colitis, the degree of inflammation in the optical image was low, and the colon of the control group reduced by inflammation. Compared to the length, there is an effect that the colon length in the group administered with the sulfolglycotide of the present invention is longer. Therefore, the composition of the present invention can be usefully used as a pharmaceutical for inflammatory bowel disease.

Description

TECHNICAL FIELD [0001] Composition for preventing or treating inflammatory bowel disease comprising sulglycotide as effective component

The present invention relates to a composition for preventing or treating inflammatory bowel disease comprising sulfolglycotide as an active ingredient.

Inflammatory bowel disease (IBD) is a disease in which abnormal chronic inflammation in the intestinal tract repeats improvement and recurrence. It is known that genetic and immunological abnormalities and environmental factors such as stress or drugs are related, and it mainly occurs from young people, and is accompanied by symptoms such as abdominal pain, bleeding, diarrhea, and bleeding.

As described above, ulcerative colitis and Crohn's disease are difficult to treat because the cause and pathophysiology are not clearly known. As the living environment is westernized, ulcerative colitis and Crohn's disease are gradually increasing. It is a growing trend.

Ulcerative colitis is characterized by inflammation only in the mucous membrane and submucosal tissue, and no inflammation in the underlying tissues, the muscle layer and the serous layer. It usually occurs in the anus and rectum, and symptoms include squeezing abdominal pain, anal bleeding, and discharge of pus or strange mucus in the stool. If it persists for a long time, it may progress to colorectal cancer. Since the method of curing ulcerative colitis is not known yet, the current medical treatment method is to calm the inflammatory reaction, to allow tissue damage to heal, and to relieve symptoms such as diarrhea, bloody stool, and abdominal pain. For this, it is necessary to accurately evaluate the site and extent of ulcerative colitis and the degree of inflammation before starting treatment, and the effectiveness of treatment is determined based on the condition before treatment.

Although the cause of ulcerative colitis is not yet known, a certain amount of knowledge has been accumulated on the development process, and various drugs have been developed and used based on this. The commonly used therapeutic agents for ulcerative colitis can be classified into anti-inflammatory drugs, corticosteroids, immunosuppressants, and antibiotics. For example, sulfasalazine and mesalazine are known as anti-inflammatory agents, and prednisone, prednisolone, hydrocortisone, and entocort, budesonide are known as corticosteroids. Immuran, 6-MP, cyclosporine, and methotrexate are known as immunosuppressants, metronidazole and ciprobay are known as antibiotics, and short-chain luminal converters Fatty acids and glutamine are known, allopurinol and dimethyl sulfoxide are known as antioxidants, lidocaine is known as a local anesthetic, and other drugs include nicotine, heparin, ketotifen, thalidomide, Colony stimulating factors, epidermal growth factors are known.

On the other hand, Crohn's disease can occur in any part of the digestive system, but among them, it is an inflammatory bowel disease that occurs mainly at the distal end of the large intestine, which is connected to the large intestine. It causes intestinal symptoms such as diarrhea, weight loss, lower abdominal pain, fever and rectal bleeding. Symptoms include anemia, malnutrition, musculoskeletal and renal dysfunction, and complex symptoms such as ophthalmic symptoms. Complications such as intestinal stenosis, intestinal abscess, and fistula may occur, and rarely, intestinal cancer. It is characterized by chronic intestinal inflammation, high recurrence rate, and deep invasion of the colon wall to form granulomas. It occurs most often in young people in their 20s and 30s, and the exact cause is still unknown. Treatment should be differentiated from other infectious bowel diseases, ischemic bowel disease, ulcerative colitis, and tuberculous bowel disease. used together to treat In principle, drug treatment is administered. In severe cases, steroids are administered, and when symptoms are relieved, sulfasalazine or mesalazine is administered. To reduce the risk of complications and recurrence, the drug must be taken for almost a lifetime. If complications arise and are not controlled with drugs, surgery may be performed, but it is not completely cured and may recur after surgery.

Sulfasalazine, used as an anti-inflammatory agent for the treatment of ulcerative colitis and Crohn's disease, is a drug in which a sulfapyridine molecule, a sulfa antibiotic, and a 5-aminosalicylic acid (5-ASA) molecule similar to aspirin are combined. By breaking the bond between these two molecules, 5-ASA, which exhibits anti-inflammatory action, is liberated. Sulfasalazine is effective for ulcerative colitis and Crohn's disease and Behcet's disease that invade the large intestine. The effectiveness of prevention of relapse has not been conclusively proven in the disease. Side effects of sulfasalazine may include skin rash, nausea, abdominal pain, liver dysfunction, and, rarely, bone marrow dysfunction.

Since most of the side effects of sulfasalazine are caused by the sulfapyridine molecule, mesalazine (also called mesalamine) is a drug that has only the 5-ASA molecule without the sulfapyridine molecule. If you take 5-ASA as it is, all of it is absorbed in the disease-free small intestine and does not reach the area where the drug is needed, so 5-ASA was specially treated in various ways to reach the diseased area. Mesalazine is sulfasalazine The effect is similar to the above, but the side effects are slightly less. Mesalazine is also a drug for oral administration, and it can be administered as a suppository or enema. The suppository and enema, respectively, are effective when the rectum or left large intestine is inflamed, and can also be used for the purpose of maintaining remission. Oral mesalamine has recently been shown to be effective in active ulcerative colitis, Crohn's disease and Behcet's disease, as well as in maintaining remission of these diseases. To deliver 5-ASA to the end of the small intestine or colon, various forms of mesalazine preparations have been developed and marketed. Dipentum, olsalazine, which combines two 5-ASA molecules, and other nontoxic molecules instead of sulfapyridine Colazide and ipsalazide using pentasa and azalan adsorbed to cellulose or resin so that 5-ASA is gradually released, and when the intestinal acidity (pH) becomes alkaline Examples are asacol, rowasa, and salofalk (claversal, mesasal) packaged to be free of 5-ASA. While sulfasalazine and dipentum are effective against inflammation of the large intestine, asacol, salofalc and pentasa are also effective against inflammation of the small intestine.

Currently, mesalazine preparations are widely used for the treatment of inflammatory bowel diseases such as ulcerative colitis or Crohn's disease, but they still cause hypersensitivity reactions such as allergic skin rash, drug-induced hyperthermia, bronchospasm, and lupus erythematosus syndrome. There is a problem that it can cause side effects such as , nausea, vomiting, and headache. Therefore, research on a new composition having a preventive or ameliorating effect on inflammatory bowel disease and not accompanied by side effects is being actively conducted.

On the other hand, as a technology related to sulfolglycotide, Korean Patent No. 1820519 discloses the use of sulfolglycotide for promoting skin wound healing and an external composition containing the same, and Korean Patent No. 1819709 discloses sulfglycotide or a pharmaceutical thereof. Although a pharmaceutical composition for the prevention or treatment of dry eye disease containing an acceptable salt is disclosed, there is no disclosure of a composition for preventing or treating inflammatory bowel disease comprising the sulfolglycotide of the present invention as an active ingredient.

The present invention has been derived from the above needs, and the present invention provides a composition for preventing or treating inflammatory bowel disease comprising sulfolglycotide as an active ingredient, and administering the active ingredient sulfolglycotide of the present invention. In the group, the colitis score was relatively low compared to the control group that induced colitis, the degree of inflammation was low in the optical image, and the group administered with the sulfolglycotide of the present invention compared to the colon length of the control group reduced by inflammation. By confirming that the length of the large intestine is longer, the present invention was completed.

In order to achieve the above object, the present invention provides a pharmaceutical composition for the prevention or treatment of inflammatory bowel disease comprising sulfolglycotide or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention relates to a composition for preventing or treating inflammatory bowel disease comprising sulfolglycotide as an active ingredient. The group administered with the active ingredient of the present invention, sulglycotide, had a relatively low colitis score compared to the control group that induced colitis, the degree of inflammation in the optical image was low, and the colon of the control group reduced by inflammation. Compared to the length, there is an effect that the colon length in the group administered with the sulfolglycotide of the present invention is longer. Therefore, the composition of the present invention can be usefully used as a pharmaceutical for inflammatory bowel disease.

1 is a graph showing the colitis scores confirmed through fecal and anal examination of the sterile drinking water administration group (G1) and the sulfolglycotide administration group (G2) by date.
2 is a result of measuring in vivo optical images to confirm the degree of inflammation in the sterile drinking water administration group (G1) and the sulfolglycotide administration group (G2) according to an embodiment of the present invention.
3 is a result of measuring the length of the sterile drinking water administration group (G1) and sulfolglycotide administration group (G2) according to an embodiment of the present invention.

The present invention relates to a pharmaceutical composition for the prevention or treatment of inflammatory bowel disease comprising sulfolglycotide or a pharmaceutically acceptable salt thereof as an active ingredient.

The sulfolglycotide may be used in the form of a non-salt or a pharmaceutically acceptable salt of sulfolglycotide, which may be appropriately prepared by those skilled in the art.

Based on the total weight of the composition, it is preferable to include 0.01 to 80% by weight of sulfolglycotide or a pharmaceutically acceptable salt thereof, and more preferably 20 to 60% by weight, but is not limited thereto. .

The pharmaceutically acceptable salt is any one organic acid selected from oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid; Or it is preferably in the form of an acid addition salt formed by any one inorganic acid selected from hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, but is not limited thereto.

The term 'prevention' in the present invention refers to any action that inhibits or delays the onset of inflammatory bowel disease by administration of the pharmaceutical composition according to the present invention, and 'treatment' refers to any act of inhibiting or delaying the onset of inflammatory bowel disease by administration of the pharmaceutical composition according to the present invention. It means any action that improves or beneficially changes the symptoms of the suspected and affected individual.

The administration route for effective administration of the pharmaceutical composition according to the present invention is not particularly limited, and may be used in a patient by appropriately adopting the administration route. For example, oral, rectal, transdermal, parenteral (subcutaneous, intramuscular, vascular), transdermal, topical, inhalation and other administration methods can be used.

The dosage form of the pharmaceutical composition according to the present invention may be administered through various formulations according to conventional methods known in the pharmaceutical field, and preferred examples include powders, granules, tablets, troches, dispersions, suspensions, and solutions. , capsules, emulsions, syrups, oral dosage forms such as aerosols, external preparations, suppositories, injections, patches, and other suitable dosage forms can be used.

The pharmaceutical composition of the present invention may further include suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions. Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, and the like.

In the case of formulation, it is prepared using diluents or excipients, such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one or more excipients in the strain or the vesicles derived from the strain, for example, starch, calcium carbonate , sucrose or lactose, gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.

The pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount, and the term 'pharmaceutically effective amount' of the present invention is sufficient to prevent or treat a disease at a reasonable benefit/risk ratio applicable to medical prevention or treatment. means the amount, and the effective dose level is the severity of the disease, the activity of the drug, the patient's age, weight, health, sex, the patient's sensitivity to the drug, the time of administration of the composition of the present invention used, the route of administration and the rate of excretion, the treatment The duration may be determined according to factors including drugs used in combination with or concurrently with the composition of the present invention and other factors well known in the medical arts. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. and may be administered single or multiple. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects.

The frequency of administration of the composition of the present invention is not particularly limited thereto, but it can be administered once a day or administered several times by dividing the dose, and the dosage is the patient's age, weight, sex, dosage form, health status, and disease degree. As a preferred example, based on an adult patient weighing 70 kg, the dosage is 0.1 to 300 mg/day, more preferably 0.5 to 100 mg/day, even more preferably 1 -60 mg/day, but does not limit the scope of the present invention in any way.

Hereinafter, the present invention will be described in more detail using examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited thereto.

Example One. DSS( Dextran Induction of inflammatory bowel disease by sodium sulfate and sulglycotide ( sulglycotide) Confirmation of the effect of colitis treatment by

In order to confirm the therapeutic effect on inflammatory bowel disease, the animal models were divided into two groups of 5 animals each, and drug (sulglycotide) was fed to one group (G1) for 3 weeks, and sterile drinking water was fed to the other group (G2). did.

Experimental conditions to confirm the therapeutic effect of colitis by sulfolglycotide test group disease-causing substances test substance Dosage number of animals G1 4% DSS sterile drinking water - 5 G2 4% DSS sulglycotide 125mg/kg 5

Thereafter, inflammatory bowel disease was induced with 4% dextran sodium sulfate (4% DSS). No death or moribund animals were observed on the day of induction of inflammation, and drinking water mixed with 4% DSS was induced for 7 days. It was provided for autonomous ingestion.

From the first day of feeding drinking water mixed with 4% DSS, the occurrence of inflammatory bowel disease was confirmed by checking the anus and feces of the mice every day.

As a result, as shown in FIG. 1 , it was confirmed that the colitis score for each day was significantly lower in the sulglycotide administration group (G2) compared to the sterile drinking water administration group (G1).

The colitis score is obtained by checking the condition of stool and intestinal bleeding through fecal and anal examination of the sterile drinking water administration group (G1) and the sulfolglycotide administration group (G2). After giving a relative reference value to each animal model, the value of each animal The sum was obtained by adding them, and the value was divided by the number of animals in each group (n=5).

Colitis score={(baseline value of feces 1 + reference value of feces 2 + ... + reference value of feces n) + (baseline value of anal examination 1 + reference value of anal examination 2 + ... + reference value of anus examination n)}/ (Number of animals)

On the other hand, on the 7th day of 4% DSS treatment, 2 animals in the sterile drinking water group and 2 animals in the drug treatment group were randomly injected with NpFlamma ^® MMP-2, MMP-9 675 probes, which are inflammation-specific probes, by tail vein injection, and for 12 hours. Afterwards, in vivo optical images were confirmed.

As a result, it was confirmed that inflammation was reduced in the drug treatment group than in the sterile drinking water group (FIG. 2).

In addition, after optical image evaluation, all 10 animal models were sacrificed, and intestines were removed. The excised intestines were washed with saline for about 3 seconds, dried, and then the length of the intestines was measured.

As a result, as shown in FIG. 3 , it was confirmed that the intestinal length of the glycotide administration group increased statistically significantly compared to the sterile drinking water administration group.

Claims (5)

A pharmaceutical composition for the treatment of ulcerative colitis, comprising sulfolglycotide or a pharmaceutically acceptable salt thereof as an active ingredient, and administered in an amount of 125 mg/kg based on the mouse body weight. delete The pharmaceutical composition for the treatment of ulcerative colitis according to claim 1, comprising 0.01 to 80% by weight of sulfglycotide or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. The method of claim 1, wherein the pharmaceutically acceptable salt is any one organic acid selected from oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid; Or hydrochloric acid, sulfuric acid, phosphoric acid, and a pharmaceutical composition for the treatment of ulcerative colitis, characterized in that in the form of an acid addition salt formed by any one inorganic acid selected from hydrobromic acid. The pharmaceutical composition for the treatment of ulcerative colitis according to claim 1, further comprising a pharmaceutically acceptable carrier, excipient or diluent in addition to the active ingredient.

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