KR101239541B1 - Therapeutic agent for ulcerative colitis comprising mizoribine - Google Patents

Abstract

The present invention has a therapeutic effect against ulcerative colitis, and there is no need to worry about side effects in the maintenance of ulcerative colitis. do. The present invention is a ulcerative colitis treatment drug containing myzoribin, which is used for ulcerative colitis patients who have undergone leukocyte depletion therapy and do not administer an immunosuppressant other than myzoribin at least after the start of leukocyte depletion therapy. At least once per day so that the start of administration of the therapeutic drug is during leukocyte reduction therapy and after the improvement of clinical symptoms, and the peak blood concentration of myzoribin is not less than 0.6 µg / ml and less than 1.5 µg / ml. The present invention relates to a ulcerative colitis therapeutic drug containing myzoribin, which is administered.

Description

Ulcerative Colitis Therapeutics Containing Missouri Beans {THERAPEUTIC AGENT FOR ULCERATIVE COLITIS COMPRISING MIZORIBINE}

The present invention relates to an ulcerative colitis therapeutic drug containing misoribin. In particular, it relates to the treatment of ulcerative colitis containing myzoribin, which can be used in combination with leukopenia therapy.

Inflammatory bowel disease, especially ulcerative colitis and Crohn's disease, are chronic inflammatory diseases that form erosions or ulcers in the intestinal mucosa.They relieve the symptoms of subsidence and the active phase of frequent diarrhea or bleeding. It is symptomatic and the number of patients is increasing year by year. It is estimated that about 100,000 people in Japan and about 1 million people in the United States. As the causes of these diseases, bacterial and viral infections, genetic predisposition, blood vessels in the digestive tract and lymphatic disorders, etc. have been speculated, but the exact cause is not yet known. These diseases are designated as specific intractable diseases of the Ministry of Health, Labor and Welfare, and the treatment of ulcerative colitis is a steroid, salazulfopyridine, 5-aminosalicylic acid (hereinafter referred to as "5-ASA"), azathioprine, Cyclosporin and leukocyte removal therapy are used to increase or decrease the amount according to symptoms. (Non-Patent Document 4) In addition, the treatment of Crohn's disease includes ingredient nutrients, steroid hormones, salazulfopyridine, 5-ASA, and azathioprine. Infliximab or the like is used to increase or decrease the amount according to symptoms (Non-Patent Document 5).

As described above, as a drug for inflammatory bowel disease, steroid drugs have been mainly used in addition to salazulfapyridine and mesalazine, which have an inflammatory inhibitory action. However, there are not many refractory examples (steroid invalidation examples) in which steroid drugs do not sufficiently exhibit effects, and 6-mercaptopurine (hereinafter referred to as "6-MP") and azathioprine, which are immunosuppressive drugs, have been used before. . In addition, in steroid dependent Crohn's disease and ulcerative colitis, which respond to steroid drugs but lose their symptoms, 6-MP or azathioprine is often used together to avoid long-term high dose administration of steroid drugs.

However, 6-MP or azathioprine, when in use, suppresses bone marrow (reduces blood cells, decreases platelets, etc.), shock-like symptoms (chills, tremors, lowers blood pressure, etc.), infectious diseases, liver dysfunction, jaundice, and epilepsy. Care should be taken to develop serious side effects, such as pneumonia and severe diarrhea. Of these, bone marrow suppression requires monitoring of leukocyte count once every 1 to 2 weeks for 3 months after the start of administration to confirm the onset of side effects, and thereafter, once every 2 to 3 months (non-patent) Document 1). This requires a great deal of effort for securing the safety and control of the patient for the doctor who examines the outpatient.

Drugs for maintaining the relief of inflammatory bowel disease are easy to secure safety against serious side effects, and because they are administered for a long time, there is a need for a drug that has a laxative effect and has fewer side effects and can be safely administered for a long time. It is becoming.

In addition to the above treatment methods, there is also a report that myzoribin is effective for maintenance therapy of inflammatory bowel disease (Non-Patent Document 7). Here, mizoribin has a chemical name of 4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate, and is euphenicillium breppelidium belonging to the genus Eupenicillium. (Eupenicilliumebrfeldianum) A nucleic acid-related substance found in the culture solution of M-2166 strain (FERM P-1104), which is easily soluble in water, and is a weakly acidic substance which brownish-decomposes and decomposes at around 200 ° C, and various methods are known as the preparation method thereof. (Non-patent Documents 2-3, Patent Documents 1-4). In addition, mizoribin has an immunosuppressive effect and is effective in suppressing rejection in kidney transplantation, nephrotic syndrome caused by primary glomerular disease, lupus nephritis, and chronic joint rheumatism.

According to the investigation and post-marketing investigation by the approval of Breizin (registered trademark) (Asahi Kasei Pharma Co., Ltd.), a myzoribin formulation, the frequency of occurrence of side effects of misoribin was 14.65% (719 cases / 4,909 cases), The main causes are 4.95% (243 cases) of digestive system disorders such as abdominal pain and anorexia, 2.46% (121 cases) of blood system disorders such as leukocyte reduction, and 2.42% (119 cases) of hypersensitivity such as rashes. 0.63% (31 cases) (nonpatent literature 6). In addition to these, as a clinical site of side effects, mizoribin tends to be strongly expressed in respect to bone marrow suppression compared to 6-MP or azathioprine.

In the case of pediatric ulcerative colitis patients and children with Crohn's disease who were able to maintain the maximum daily dose of Missouribin at 200 mg / 1 day and maintain blood levels of 1.5 μg / ml or more, the dose of steroid drug was reduced. Also, it could not be replayed, so the steroid drug's underwear could be stopped. However, in one case of pediatric ulcerative colitis, the administration of mizoribin was stopped because fever was complained after the start of mizoribin (Non-Patent Document 7). Compared with 6-MP and azathioprine described above, mizoribin can be regarded as a drug having fewer side effects, but it is required to establish a safer method of administration.

Patent Document 1: Japanese Patent Laid-Open No. 48-56894

Patent Document 2: Japanese Patent Laid-Open No. 51-1693

Patent Document 3: Japanese Patent Laid-Open No. 50-121275

Patent Document 4: Japanese Unexamined Patent Publication No. 50-121276

Non Patent Literature 1: Gastroenterology 130; 935-939 (2006)

Non Patent Literature 2: J. Antibiotics, 27 (10), 775 (1974)

[Non-Patent Document 3] Chem. Pharm. Bull., 23, 245 (1975)

Non-Patent Document 4: Munakata Akihiro. Amendment to the Ulcerative Colitis Treatment Guidelines 2005 (Ministry of Health, Labor and Welfare grant subsidy research project "Research on Refractory Inflammatory Bowel Disorders" 2005 p13-15, 2006

Non-Patent Document 5: Iida Mitsuo. Amendment to Crohn's Disease Treatment Guidelines (2006) (Ministry of Health, Labor and Welfare Research Grant Subsidy Research Project "Research on Intractable Inflammatory Bowel Disorders" 2005 Research Report) p26-28, 2006

[Non-Patent Document 6] Bredinin Tablet: Product Information Overview, Asahi Kasei Co., Ltd. (December 2001)

[Non-Patent Document 7] Otani Kiyotaka et al., Japan Pediatric Nutritional Digestive Liver Soy Society Magazine (p51, No. 20, Additional Issues, 2006)

DISCLOSURE OF INVENTION

Problems to be solved by the invention

The present invention has a therapeutic effect against ulcerative colitis in view of the problems of the prior art, and there is no need to worry about side effects in the maintenance of ulcerative colitis, and ulcerative colitis that contains long-term administration It aims to provide a therapeutic drug.

Means for solving the problem

MEANS TO SOLVE THE PROBLEM In order to solve the said subject, the present inventors earnestly researched about safer dosing protocol of a myzoribin. As a result, when administration of Missouribin to patients with ulcerative colitis during the period of leukocyte depletion therapy, Missouribin has a sufficient effect on the treatment and maintenance of ulcerative colitis and also suppresses the dosage of Missouribin low. As a result, it was found that the side effects were much lower than before, and the present invention was completed. That is, the present invention relates to the following.

(1) A drug for treating ulcerative colitis containing misoribin, which is used in patients with ulcerative colitis who have undergone leukocyte depletion therapy and have not been administered an immunosuppressant other than myzoribin, at least after the initiation of leukopenia therapy. The onset of administration of the drug is during leukocyte ablation therapy and after the improvement of clinical symptoms, and at least once / day so that the peak blood concentration of myzoribin is not less than 0.6 µg / ml and less than 1.5 µg / ml. An ulcerative colitis treatment drug containing miso bean, characterized by the above-mentioned.

(2) The ulcerative colitis therapeutic drug containing myzoribin is an ulcerative colitis therapeutic drug for oral administration, wherein the highest blood concentration of the myrizobin is (1), which is 2 to 4 hours after oral administration of the therapeutic drug. The ulcerative colitis therapeutic drug containing the above-mentioned missoribin.

(3) The ulcerative colitis treatment drug containing misoribin according to (1) or (2), wherein the clinical symptom is improved when the clinical activity index (CAI) of Lichtiger is improved.

(4) Said leukocyte removal therapy includes the process of taking blood from a patient, removing leukocytes in this blood by leukocyte removal means, and then half-blooding to this patient (1)-(3) The ulcerative colitis therapeutic drug containing miso bean as described in any one of them.

(5) The ulcerative colitis therapeutic drug according to (4), wherein the leukocyte removing means is any one of a centrifuge or a carrier having affinity for leukocytes.

(6) a group in which the carrier having affinity for leukocytes comprises a cellulose derivative, polyester, polyolefin, polyvinylidene fluoride, polyamide, polyimide, polyurethane, polysulfone or polyacrylonitrile containing cellulose acetate The ulcerative colitis therapeutic drug containing miso bean as described in (5) which is chosen from.

(7) A method for treating ulcerative colitis using a myzoribin-containing immunosuppressant, in which a leukocyte depletion therapy is performed, and at least after the start of the leukocyte depletion therapy, an ulcerative colitis patient not being administered with an immunosuppressant other than myzoribin Administering a myzoribin-containing immunosuppressant after the point at which clinical symptoms have improved as the leukocyte ablation regimen is being administered,

A method for treating ulcerative colitis, characterized in that administration is performed at least once per day so that the peak blood concentration of myzoribin is not less than 0.6 µg / ml and less than 1.5 µg / ml.

(8) A method of treating ulcerative colitis by orally administering a mirizobin-containing immunosuppressant, wherein the ulcerative colitis according to (7), wherein the maximum blood concentration of mirizobin is 2-4 hours after oral administration. Method of treatment.

(9) The method for treating ulcerative colitis according to (7) or (8), wherein the clinical symptom is improved when the clinical activity index of Lichtiger is improved.

(10) In any one of (7) to (9), the leukocyte removal therapy includes a step of collecting blood from a patient, removing leukocytes in the blood by means of leukocyte removal means, and then half-blooding the patient. A method of treating ulcerative colitis as described.

(11) The method for treating ulcerative colitis according to (10), wherein the leukocyte removing means is either a centrifuge or a carrier having affinity for leukocytes.

(12) a group in which the carrier having affinity for leukocytes comprises a cellulose derivative, polyester, polyolefin, polyvinylidene fluoride, polyamide, polyimide, polyurethane, polysulfone, or polyacrylonitrile containing cellulose acetate The method of treating ulcerative colitis according to (11), which is selected from

Effects of the Invention

The ulcerative colitis therapeutic drug containing the myzoribin according to the present invention has a therapeutic effect and a relaxation effect when used in a ulcerative colitis patient undergoing leukocyte removal therapy. In addition, compared to the case of the use of mirizobin alone, which is not used in combination with leukocyte removal therapy, the dosage of mizoribin can be suppressed to a low level. There is no worry of side effects and it is safe.

Best mode for carrying out the invention

EMBODIMENT OF THE INVENTION Hereinafter, although the embodiment of the ulcerative colitis therapeutic drug containing the mycoribin which concerns on this invention is described, this invention is not limited only to these aspects.

Inflammatory bowel disease is a generic term for a chronic disease that causes unknown inflammation in the digestive tract, and mainly consists of two diseases, ulcerative colitis and Crohn's disease. Ulcerative colitis is a disease characterized by colorectal and rectal ulcers accompanied by rectal bleeding, mucous abscesses, inflammatory gapolyps, abdominal pain, diarrhea, and often causes anemia, low protein plasma, and electrolyte abnormalities. . Crohn's disease is a disease that causes discontinuous inflammation and ulcers throughout the digestive tract, mainly from the oral cavity to the anus, and the lesion invades the entire layer from the mucous membrane of the digestive tract to the chorion and narrows the intestines as it progresses. It may cause intestinal obstruction, or perforations or fistulas in which the intestines are punctured, or pus abscesses may develop in these. Repeat the remission phase of any disease or symptoms and the active phase of frequent diarrhea or bleeding. The transition from relaxation to activity is called reenactment.

The ulcerative colitis therapeutic drug containing myzoribin as used in the present invention refers to a formulation containing at least myzoribin as one of the active ingredients, and used in combination with leukocyte removal therapy to be used for the treatment and maintenance of inflammatory bowel disease. Can be. Until now, it has been thought that the combination of mizoribin with leukocyte depletion therapy may cause adsorption of mizoribin to the substrate used for leukocyte depletion therapy and lower its blood concentration. According to the ulcerative colitis therapeutic drug of the present invention, As a result of being able to suppress the use concentration lower than conventionally, it was effectively used for the treatment of ulcerative colitis and the maintenance of relaxation.

Here, the treatment of ulcerative colitis means the transition of the symptoms of ulcerative colitis from the active phase to the laxative, and the maintenance of ulcerative colitis means that the waning phase is continued without repeating the active phase.

Mizoribin can be suitably formulated as a formulation technique of a conventional method as preparations for oral administration, suppositories, transdermal absorption preparations, or injections, such as a capsule and granules. As the therapeutic drug for ulcerative colitis containing the myzoribin of the present invention, a commercially available formulation for oral administration of myzoribin (trademark) (Asahi Kasei Pharma Co., Ltd.) can be suitably used.

The ulcerative colitis therapeutic drug containing the myzoribin according to the present invention needs to be administered so that the highest blood concentration of the myzoribin is not less than 0.6 µg / ml and less than 1.5 µg / ml. Since there is no clear judgment as to when to take mijoribin for the maintenance of ulcerative colitis, and there is a possibility of long-term administration of mijoribin, the maximum blood concentration of mijoribin is less than 1.5 μg / ml. It was. When the maximum blood concentration of myzoribin is 0.6 µg / ml or more and less than 1.5 µg / ml, the laxative maintenance effect of ulcerative colitis is sufficiently exhibited in any patient, and the possibility of side effects is minimized. More preferably, the maximum blood concentration of myzoribin is 0.8 µg / ml or more and 1.3 µg / ml or less. If the maximum blood concentration of myzoribin is less than 0.6 µg / ml, the therapeutic effect and / or relaxation effect of ulcerative colitis may not be sufficient, so there is a possibility that symptoms may reappear even when entering the period of remission. In addition, when the maximum blood concentration of myzoribin is 1.5 µg / ml or more, the disadvantage of the possibility of developing side effects is higher than the advantage of the therapeutic effect and / or relaxation effect of ulcerative colitis. However, it is not necessary to measure the highest blood concentration every time administration of the myzoribin, and the oral dose may be set so that the maximum blood concentration of the myzoribin falls within the above range before the start of treatment or at the start of treatment.

In order to properly set the oral dosage, it is desirable to measure the blood concentration of myrizobin at an early time after the start of administration, and as a result, the dosage is increased when the blood concentration is low, and when it is high, Allow the highest blood concentration to fall within this range. Specifically, it can be set by increasing the amount of the formulation of a certain unit containing the myzoribin by one tablet to check the blood concentration.

Myzoribin may be any dosage form as long as its peak blood concentration is 0.6 µg / ml or more and less than 1.5 µg / ml. In the case of oral administration, since the highest blood concentration is reached 2 to 4 hours after administration, blood is collected at this time and the blood concentration is measured. Any method of measuring blood concentration of myzoribin may be used, for example, J Chromatogr. 1988 Nov 18; 432: 340-345 can be suitably used.

The oral dosage of the myzoribin according to the present invention varies from patient to patient, but in adults, the dosage is 3 mg / kg or more once less than 6 mg / kg once a day or 150 mg or more or less than 300 mg once a day.

The initiation of the administration of myzoribin in the present invention should be after the time point at which clinical symptoms were improved during the leukocyte depletion therapy. The start time of the administration of myzoribin may be any time after the improvement of clinical symptoms and during the course of leukocyte depletion therapy, but the earlier is preferable. The clinical symptom was improved when the number of bloody stools indicating the condition of ulcerative colitis, the number of diarrhea, the number of bloody stools, abdominal pain, general condition, and colonoscopy findings were improved. Any indicator may be used as a comprehensive indicator of improving the condition, but preferably, Rachmilewitz's Clinical Activity Index (CAI), Disease Activity Index (DAI), and Lichtiger's CAI. (Lichtiger S et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy.N Engl J Med. 1994; 330 (26): 1841-1845), most preferably Lichtiger's CAI. More specifically, the point of improvement of at least 3 points in Lichtiger's CAI can be regarded as the point of improvement of clinical symptoms. After that, it is preferable to continue the administration for the purpose of laxative maintenance even after the condition has shifted to laxative condition. In addition, the dosage of mirizobin in a laxative phase is the same as that of the initiator.

Leukocyte depletion therapy is insured against ulcerative colitis in Japan, and is usually carried out with one cooler and one cooldown to two cooldowns. In the present invention, the implementation of leukocyte removal therapy is a period during which the 1st to 2nd cooldown leukocyte removal therapy is performed.

There are two types of leukocyte removal therapy: a method of separating using a centrifuge using a difference in specific gravity between red blood cells and white blood cells, and a method of removing white blood cells using a blood circulation column filled with a carrier having affinity for white blood cells. There is a way. In the present invention, all of the above methods can be used. Although leukocytes may be removed using a blood circulation column filled with a carrier having affinity for leukocytes, as carriers having affinity for leukocytes used herein, various carriers which have been used for leukocyte removal therapy Examples thereof include cellulose, cellulose derivatives containing cellulose acetate, polyesters such as polyethylene terephthalate and polybutylene terephthalate, polyolefins such as polyethylene and polypropylene, polyvinylidene fluoride, polyamide, polyimide, poly Polymeric materials, such as a urethane, polysulfone, and polyacrylonitrile, etc. are mentioned. Especially, polyester nonwoven fabric, cellulose beads, etc. can be used suitably. The shape of these carriers may be in the form of fibers (nonwoven fabrics, woven fabrics), porous bodies, particles (particles or beads), films, flat membranes, hollow fibers and the like. As such a column, the column currently already clinically used by various leukocyte removal therapy is mentioned, for example, the white blood cell marketed under the brand name of Cellsoba E (trademark) by Asahi Kasei Medical Co., Ltd. A removal column and the like, and a granulocyte removal column sold by JIMRO under the trade name of Ada Column (registered trademark), and the like.

The present invention will be described in detail by the following examples. These are preferred embodiments of the present invention, and the present invention is not limited to these examples.

Example 1

(1) target patient

Four patients with ulcerative colitis (UC) at the hospital to which the inventors belong (Oita Red Cross Hospital, hereinafter identical) were examined. Case numbers 1 to 4 were given to patients with severe classification of moderate to severe ulcerative colitis of the Ministry of Health, Labor and Welfare who had side effects in the past due to 6-MP or azathioprine undergarments. Hereinafter, the ulcerative colitis patient targeted in Comparative Example 1 and Comparative Example 2 also has the same medical history.

(2) Measurement method of the highest level of myrizobin blood

Determination of the maximum myzoribin blood concentration was performed according to conventional methods (J Chromatogr. 1988 Nov 18; 432: 340-5). After oral administration of mizoribin to the patient, after 2-4 hours of obtaining the highest blood concentration, 2 ml of the patient's blood was collected, and after 30-60 minutes cold preservation, a centrifuge was used with blood cells and serum. 1 mL of the serum was frozen at −20 ° C. to obtain a sample for peak blood concentration measurement.

(3) Judgment method of side effect expression

The onset of adverse events during the duration of the administration of myrizobin was determined based on general clinical test values and clinical symptoms.

In other words, the side effects of bone marrow suppression were leukocyte count (reference value 4000-8000 / μl), hemoglobin concentration (reference value male 13.5-17.6 g / dl, female 11.3-15.2 g / dl), platelet count (reference value 15-35 × 10 ^4). / Μl) was determined by comparison with a reference value. In addition, when the number of leukocytes is 3000 / μl or less, there is a fear that serious infectious diseases, bleeding tendencies, etc. may be expressed, which is contraindicated.

(4) Treatment contents and results

The patient was subjected to leukocyte depletion therapy (Cellsova E® and polyester as a carrier) once a week for 5 weeks in a row, with 1 cool and 2 cool. Neither patient was dosed with an immunosuppressant other than myzoribin after initiation of leukocyte depletion therapy. When leukocyte depletion therapy showed improvement in clinical symptoms such as bloody stools, specifically, when Lichtiger's CAI improved by 3 points or more, tablets containing 50 mg of mirizobin in one tablet (Bredinine (registered trademark) The administration of)) started 3 tablets once daily, ie 150 mg / 1 day and then continued. In the cases of Case Nos. 1 to 4, the highest blood concentrations of misoribin were 0.6 µg / ml or more and less than 1.5 µg / ml.

By this treatment, all four patients were able to introduce a remission. During the laxative maintenance period, the starting dose was maintained to take the myzoribin. The type and severity of ulcerative colitis depend on the classification of ulcerative colitis in the Ministry of Health, Labor and Welfare.

The above results are shown in Table 1. The duration of relaxation of the patients of case numbers 1-4 reached more than 33 months. In addition, no serious side effects such as bone marrow suppression were observed in the four cases of the myzoribin administration, and no adverse effects such as fever were observed in any of the four cases.

Comparative Example 1

(1) target patient

One case of ulcerative colitis patients in the hospital to which the present inventor belongs was examined as case number 5.

(2) Treatment contents and result

The leukocyte removal therapy and the administration of missorivin were performed in the same manner as in Example 1 except that the dose of missorivin was reduced so that the maximum blood concentration of the myolivine was 0.11 µg / ml. The results are shown in Table 1. The patient's symptoms once relieved but reappeared two months later.

Comparative Example 2

(1) target patient

Five patients with ulcerative colitis in the hospital to which the present inventor belonged were examined as case numbers 6-10.

(2) Treatment contents and result

Leukocyte removal therapy was performed in the same manner as in Example 1 except that 6-MP was administered at least 30 mg / 1 day instead of mizoribin. Blood cell count monitoring was performed once every 1 to 2 weeks for 3 months after the start of administration, and once a month thereafter.

The above result is shown in Table 2. The leukocyte count, hemoglobin concentration, and platelet count in Table 2 are measured values after administration of 6-MP of 30 mg / day or more in the period shown in Table 2. Side effects of bone marrow suppression appeared in all patients, resulting in a reduction in the dose of 6-MP to 30 mg / day or less or the discontinuation of 6-MP. In addition, the dose of 6-MP whose laxative maintenance effect is confirmed in Japan is 30 mg / day, and it is said that if it is less than this, it is likely to be replayed. In addition, about 30% of the total non-compliance was caused by bone marrow suppression by 6-MP or azathioprine in ulcerative colitis patients in the hospital to which the inventor belongs.

The ulcerative colitis therapeutic drug containing the myzoribin according to the present invention can be suitably used as a therapeutic drug for ulcerative colitis patients and a laxative maintenance drug.

Claims (6)

As an ulcerative colitis treatment drug containing myzoribin, This therapeutic drug is undergoing leukopenia therapy, and has medicinal ulcerative colitis in which adverse reactions have appeared in the past by immunosuppressants other than missouribin, at least after the start of leukopenia therapy, in which no immunosuppressant other than missouribin was administered. For patients, The onset of administration of the drug is during the course of leukocyte depletion therapy after the improvement of any one or more of Rachmilewitz's Clinical Activity Index, Disease Activity Index, or Lichtiger's Clinical Activity Index. The ulcerative colitis therapeutic drug containing miso bean which has the use which is administered at least once / day so that the highest blood concentration of miso bean may be more than 0.6 microgram / ml less than 1.5 microgram / ml. The method for treating ulcerative colitis containing oral administration of claim 1, wherein The ulcerative colitis therapeutic drug containing the myzoribin whose maximum blood concentration is the myrizobin blood concentration of 2 to 4 hours after oral administration of the said therapeutic agent. The method according to claim 1 or 2, wherein the leukocyte removal therapy comprises the step of taking blood from a patient, removing leukocytes in the blood by means of leukocyte removal means, and then half-blooding the patient. Ulcerative colitis medicine. The ulcerative colitis therapeutic drug according to claim 3, wherein the leukocyte removal means contains one or more of a centrifuge or a carrier having affinity for leukocytes. The method of claim 4, wherein the carrier having affinity for leukocytes is a cellulose derivative, polyester, polyolefin, polyvinylidene fluoride, polyamide, polyimide, polyurethane, polysulfone or polyacrylonitrile comprising cellulose acetate. An ulcerative colitis treatment drug containing miso bean, which is selected from the group consisting of: delete