JP5697070B2 - Anti-ulcerative colitis drug containing mizoribine - Google Patents

Description

  The present invention relates to a therapeutic agent for ulcerative colitis containing mizoribine. In particular, the present invention relates to a therapeutic agent for ulcerative colitis containing mizoribine, which is used in combination with leukocyte removal therapy.

  Inflammatory bowel disease, especially ulcerative colitis and Crohn's disease, is a chronic inflammatory disease that forms erosions and ulcers in the intestinal mucosa, and it has a remission phase in which symptoms subside and an active phase in which diarrhea and diarrhea frequently occur. It is a disease with repeated symptoms and an increasing number of patients. It is estimated that about 100,000 people are affected in Japan and about one million people in the United States. The causes of these diseases are presumed to be bacterial and viral infections, genetic predispositions, and gastrointestinal vascular and lymphatic disorders, but the true cause has not yet been clarified. These diseases are designated as specific intractable diseases by the Ministry of Health, Labor and Welfare in Japan, and steroids, salazosulfapyridine, 5-aminosalicylic acid (hereinafter referred to as “5-ASA”) are used for the treatment of ulcerative colitis. , Azathioprine, cyclosporine and leukocyte depletion therapy, etc., should be used according to symptoms, (Non-patent Document 4) In addition, for the treatment of Crohn's disease, component nutrients, steroid hormones, salazosulfapyridine , 5-ASA, azathioprine, infliximab, and the like are used by increasing or decreasing the amount used according to symptoms (Non-patent Document 5).

  Thus, as drugs for inflammatory bowel disease, steroid drugs have been mainly used in addition to salazosulfapyridine and mesalazine which have anti-inflammatory effects. However, there are not a few intractable cases (steroid ineffective cases) in which steroid drugs do not sufficiently respond, and 6-mercaptopurine (hereinafter referred to as “6-MP”) and azathioprine, which are immunosuppressive drugs, have been used for some time. In addition, 6-MP and azathioprine are often used together to avoid long-term administration of steroids in steroid-dependent Crohn's disease and ulcerative colitis, which responds to steroids but worsens when the dose is reduced. Has been.

  However, when using 6-MP or azathioprine, myelosuppression (pancytopenia, thrombocytopenia, etc.), shock-like symptoms (chills, warfare, hypotension, etc.), infection, liver dysfunction, jaundice, interstitial pneumonia Care must be taken to develop serious side effects such as severe diarrhea. Among these, for myelosuppression, it is necessary to monitor the number of leukocytes once every 1-2 weeks for 3 months after the start of administration in order to confirm the occurrence of side effects, and then once every 2-3 months thereafter. Yes (Non-Patent Document 1). This requires a great deal of effort for doctors who examine outpatients to ensure and control the patient's safety.

  Drugs for maintaining remission of inflammatory bowel disease are easily administered for a long period of time as well as ensuring safety against serious side effects. Drugs that can be safely administered are desired.

  In addition to the above treatment methods, there is a report that mizoribine is effective for maintenance therapy of inflammatory bowel disease (Non-patent Document 7). Here, mizoribine has a chemical name of 4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate, and Eupenicillium brefeldianum M-2166 belonging to the genus Eupenicillium. It is a nucleic acid-related substance discovered from the culture solution of the strain (FERM P-1104). It is a weakly acidic substance that dissolves easily in water and decomposes brown at around 200 ° C. Various methods are known for its production. (Non-patent documents 2 to 3, Patent documents 1 to 4). In addition, mizoribine has an immunosuppressive effect and is effective in suppressing rejection in renal transplantation, nephrotic syndrome caused by primary glomerular disease, lupus nephritis, and rheumatoid arthritis.

  According to the investigation up to the approval of Bredinin (registered trademark) (Asahi Kasei Pharma Co., Ltd.), a mizoribine preparation, and the post-marketing investigation, the incidence of side effects of mizoribine was 14.65% (719 / 4,909) The main ones are 4.95% (243 cases) of digestive system disorders such as abdominal pain and loss of appetite, 2.46% (121 cases) of blood system disorders such as leukopenia, and hypersensitivity such as rash. 42% (119 cases), of which anemia is 0.63% (31 cases) (Non-patent Document 6). In addition to these, as an actual condition of side effects in clinical practice, mizoribine tends to be strongly expressed in terms of bone marrow suppression compared to 6-MP and azathioprine.

In patients with pediatric ulcerative colitis and pediatric Crohn's disease who were able to maintain the maximum daily dose of mizoribine at 200 mg / day and maintain the blood concentration at 1.5 μg / mL or higher, the dose of steroids was reduced. I could stop taking steroids without relapse. However, in one pediatric patient with ulcerative colitis, mizoribine was discontinued after complaining of fever after the start of mizoribine (Non-patent Document 7). Compared to the aforementioned 6-MP and azathioprine, mizoribine can be said to be a drug with fewer side effects, but establishment of a safer administration method has been desired.
Japanese Unexamined Patent Publication No. 48-56894 Japanese Unexamined Patent Publication No. 51-1693 Japanese Laid-Open Patent Publication No. 50-121275 Japanese Unexamined Patent Publication No. Sho 50-122276 Gastroenterology 130; 935-939 (2006) J. Antibiotics, 27 (10), 775 (1974) Chem. Pharm. Bull. , 23, 245 (1975) Akihiro Munakata. Proposed revision of guidelines for treatment of ulcerative colitis in 2005 (Research Project on Refractory Inflammatory Intestinal Disorders, 2005 Research Report) pp. 13-15, 2006 Iida Mitsuo. Revision plan for treatment of Crohn's disease (2006) (Research Project on Refractory Inflammatory Intestinal Disorders in 2005) (Research Project on Refractory Inflammatory Intestinal Disorders), p26-28, 2006 Bredinin Tablets: Product Information Summary, Asahi Kasei Corporation (created in December 2001) Kiyotaka Otani et al., Japanese Journal of Pediatric Nutrition and Gastroenterology (p51, Volume 20 Special Issue, 2006)

  In view of the above-mentioned problems of the prior art, the present invention has a therapeutic effect on ulcerative colitis, and does not need to worry about side effects in maintaining remission of ulcerative colitis, and contains ulcerative containing mizoribine that can be administered for a long period of time. The object is to provide a therapeutic agent for colitis.

In order to solve the above-mentioned problems, the present inventors have conducted intensive studies on a safer administration protocol for mizoribine. As a result, if mizoribine was administered to patients with ulcerative colitis during leukocyte removal therapy, mizoribine showed sufficient effects for the treatment and maintenance of remission of ulcerative colitis, and administration of mizoribine Since the amount can be kept low, it has been found that side effects are extremely lower than in the past, and the present invention has been completed. That is, the present invention relates to the following.
(1) Ulcerative colitis therapeutic agent containing mizoribine, wherein the therapeutic agent has been subjected to leukocyte removal therapy and has not been administered an immunosuppressive agent other than mizoribine at least since the start of leukocyte removal therapy Is used for patients with ulcerative colitis, and the administration start time of the therapeutic agent is after the time when leukocyte removal therapy is being performed and clinical symptoms are improved, and the maximum blood concentration of mizoribine is 0.6 μg / ml A therapeutic agent for ulcerative colitis containing mizoribine, which is administered at least once / day so as to be less than 1.5 μg / ml.
(2) The therapeutic agent for ulcerative colitis containing mizoribine is a therapeutic agent for ulcerative colitis for oral administration, and the highest blood concentration of mizoribine is 2 to 4 hours after oral administration of the therapeutic agent The therapeutic agent for ulcerative colitis containing mizoribine according to (1), which is a blood concentration.
(3) The therapeutic agent for ulcerative colitis containing mizoribine according to (1) or (2), wherein the clinical symptoms are improved when the clinical activity index of Lichtiger is improved.
(4) The leukocyte removal therapy includes a step of collecting blood from a patient, removing leukocytes in the blood by the leukocyte removal means, and then returning the blood to the patient. A therapeutic agent for ulcerative colitis comprising mizoribine according to claim 1.
(5) The ulcerative colitis therapeutic agent containing mizoribine according to (4), wherein the leukocyte removing means is either a centrifuge or a carrier having affinity for leukocytes.
(6) The carrier having affinity for leukocytes is selected from the group consisting of cellulose derivatives containing cellulose acetate, polyester, polyolefin, polyvinylidene fluoride, polyamide, polyimide, polyurethane, polysulfone, or polyacrylonitrile. ) Ulcerative colitis therapeutic agent containing mizoribine according to the above.
(7) A method for treating ulcerative colitis using a mizoribine-containing immunosuppressive agent,
For patients with ulcerative colitis who have undergone leukoreduction therapy and have not been administered any immunosuppressive agent other than mizoribine since at least the start of leukocyte depletion therapy
Administration of mizoribine-containing immunosuppressive agent was started after the time when clinical symptoms improved while the leukocyte removal therapy was being performed,
A method for treating ulcerative colitis, comprising administering at least once a day so that the maximum blood concentration of mizoribine is 0.6 μg / ml or more and less than 1.5 μg / ml.
(8) A method for treating ulcerative colitis by orally administering a mizoribine-containing immunosuppressive agent,
The method for treating ulcerative colitis according to (7), wherein the maximum blood concentration of mizoribine is the blood concentration of mizoribine for 2 to 4 hours after oral administration.
(9) The method for treating ulcerative colitis according to (7) or (8), wherein the clinical symptoms are improved when the clinical activity index of Lichtiger is improved.
(10) The method according to any one of (7) to (9), wherein the leukocyte removal therapy includes a step of collecting blood from a patient, removing leukocytes in the blood by a leukocyte removal means, and returning the blood to the patient. A method for treating ulcerative colitis according to claim 1.
(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) The carrier having affinity for leukocytes is selected from the group consisting of cellulose derivatives including cellulose acetate, polyester, polyolefin, polyvinylidene fluoride, polyamide, polyimide, polyurethane, polysulfone, or polyacrylonitrile. ) For treating ulcerative colitis.

  The therapeutic agent for ulcerative colitis containing mizoribine according to the present invention has a therapeutic effect and a remission maintenance effect when used for patients with ulcerative colitis undergoing leukocyte removal therapy. In addition, compared with the case of using only mizoribine, which is not used in combination with leukocyte removal therapy, the dose of mizoribine can be kept low. Therefore, even if the therapeutic agent for ulcerative colitis containing mizoribine according to the present invention is administered for a long time, there are concerns about side effects. There is no safety.

  Hereinafter, embodiments of the therapeutic agent for ulcerative colitis containing mizoribine according to the present invention will be described, but the present invention is not limited only to these embodiments.

  Inflammatory bowel disease is a general term for chronic diseases that cause unexplained inflammation mainly in the gastrointestinal tract, and mainly consists of two diseases, ulcerative colitis and Crohn's disease. Ulcerative colitis is a disease characterized by colon and rectal ulcers with rectal bleeding, mucous crypt abscess, inflammatory pseudopolyps, abdominal pain, and diarrhea, often resulting in anemia, low protein plasma, and electrolyte abnormalities. Crohn's disease is a disease that causes discontinuous inflammation and ulceration mainly in the entire digestive tract from the oral cavity to the anus. The lesion affects the entire layer from the mucosa to the serosa of the digestive tract, and when it progresses, the intestinal tract narrows. May cause bowel obstruction, perforations or fistulas that perforate the intestinal tract, and abscesses that contain pus. Each disease has a remission phase in which symptoms are resolved and an active phase in which diarrhea and diarrhea frequently occur. The transition from the remission period to the active period is called relapse.

  The therapeutic agent for ulcerative colitis containing mizoribine as used in the present invention means a preparation containing at least mizoribine as one of active ingredients, and is used in combination with leukocyte removal therapy to treat and maintain remission of inflammatory bowel disease. Can be suitably used. Until now, it was thought that when mizoribine was combined with leukocyte ablation therapy, the mizoribine was adsorbed on the base material used for leukocyte ablation therapy, and its blood concentration might be reduced. According to the anti-inflammatory agent, the use concentration of mizoribine could be kept lower than before, and it could be used effectively for the treatment and maintenance of ulcerative colitis.

  Here, treatment of ulcerative colitis means shifting the symptoms of ulcerative colitis from active phase to remission phase, and maintaining remission of ulcerative colitis continues remission phase without repeating the active phase It means that

  Mizoribine can be appropriately formulated by conventional formulation techniques as a preparation for oral administration such as capsules and granules, a suppository, a transdermal absorption preparation, and an injection. As a therapeutic agent for ulcerative colitis containing mizoribine of the present invention, a commercially available formulation for oral administration of mizoribine, Bredinin (registered trademark) (Asahi Kasei Pharma Co., Ltd.) can be preferably used.

  The therapeutic agent for ulcerative colitis containing mizoribine in the present invention needs to be administered so that the maximum blood concentration of mizoribine is 0.6 μg / ml or more and less than 1.5 μg / ml. Since there is no clear criterion for how long to take mizoribine to maintain remission of ulcerative colitis, and the possibility of prolonged administration of mizoribine is long, the maximum blood concentration of mizoribine is 1. The amount was less than 5 μg / ml. If the maximum blood concentration of mizoribine is 0.6 μg / ml or more and less than 1.5 μg / ml, the remission maintenance effect of ulcerative colitis is sufficiently exerted in any patient, and the possibility of occurrence of side effects is minimized. Become. More preferably, the maximum blood concentration of mizoribine is 0.8 μg / ml or more and 1.3 μg / ml or less. When the maximum blood concentration of mizoribine is less than 0.6 μg / ml, the therapeutic effect and / or the remission maintenance effect of ulcerative colitis are not sufficient, and there is a fear that the symptoms may relapse even once the remission phase is entered. In addition, when the maximum blood concentration of mizoribine is 1.5 μg / ml or higher, the demilit of the possibility of developing side effects is higher than the merit of the therapeutic effect or / and the remission maintenance effect of ulcerative colitis. However, it is not necessary to measure the maximum blood concentration every time mizoribine is administered, and the oral dose may be set so that the maximum blood concentration of mizoribine falls within the above range before or at the start of treatment.

  In order to set the oral dose appropriately, it is desirable to measure the blood concentration of mizoribine early in the beginning of administration, and as a result, if the blood concentration is low, the dosage is increased, and if it is high, To reduce the maximum blood concentration of mizoribine within the above range. Specifically, it can be set by increasing a unit amount of a preparation containing mizoribine for each tablet and checking the blood concentration.

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

  The oral dose of mizoribine according to the present invention varies from patient to patient, but in the case of an adult, it is 3 mg / kg to less than 6 mg / kg once a day or 150 mg to less than 300 mg once a day.

  The start of administration of mizoribine in the present invention must be after the time when clinical symptoms are improved during leukocyte removal therapy. The start of mizoribine administration can be any time as long as it is after the improvement of clinical symptoms and is in the middle of leukocyte removal therapy, but is preferably earlier. The time when clinical symptoms improved is the time when the number of bloody stools, the number of diarrhea, the number of bloody stools, the abdominal pain, the general condition, the colonoscopy findings, etc. representing the pathology of ulcerative colitis improved. Any index may be used as a comprehensive index for improving the pathological condition, but preferably Rachmilewitz's Clinical Activity Index (hereinafter abbreviated as CAI), DAI (Disease Activity Index), Lichtiger's CAI (Lichtiger S et al. N EnglJ Med. 1994; 330 (26): 1841-1845), most preferably Lichtiger CAI. al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. More specifically, the point of improvement of 3 points or more in Lichtiger CAI can be set as the point of improvement of clinical symptoms. Thereafter, it is desirable to continue administration for the purpose of maintaining remission even after the disease state has entered the remission phase. The dose of mizoribine during the remission maintenance period may be the same as that during the start period.

  Leukocyte removal therapy is insured against ulcerative colitis in Japan, and is usually conducted 1 or 2 courses, with a protocol of conducting treatment once a week for 5 consecutive weeks as 1 course. . In the present invention, during the execution of leukocyte removal therapy is the period during which one or two courses of leukocyte removal therapy are being performed.

  For leukocyte removal therapy, a leukocyte is removed using a centrifuge to separate the red blood cells and leukocytes using the difference in specific gravity, and a blood circulation column packed with a carrier having affinity for leukocytes. There are two types of methods. Any of the methods described above can be used in the present invention. While it is possible to remove leukocytes using a blood circulation column packed with a carrier having affinity for leukocytes, a carrier having affinity for leukocytes used here has been used for leukocyte removal therapy so far. For example, cellulose, cellulose derivatives including cellulose acetate, polyesters such as polyethylene terephthalate and polybutylene terephthalate, polyolefins such as polyethylene and polypropylene, polyvinylidene fluoride, polyamide, polyimide, polyurethane, polysulfone Examples thereof include polymer materials such as polyacrylonitrile. Among these, polyester nonwoven fabrics and cellulose beads are preferably used. The shape of these carriers may be in the form of fibers (nonwoven fabric, woven fabric), porous materials, particles (granular or beaded), film, flat membrane, hollow fiber, and the like. Specific examples of such columns include columns that have already been used clinically for various leukocyte depletion therapies. For example, Celsova E (registered trademark) sold by Asahi Kasei Medical Co., Ltd. And a granulocyte removal column commercially available under the trade name Adacolumn (registered trademark) from JIMRO.

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

[Example 1]
(1) Target patients Four patients with ulcerative colitis (UC, ulcerative colitis) at a hospital to which the present inventor belongs (Oita Red Cross Hospital, hereinafter the same) were examined. Cases 1 to 4 were patients with a history of adverse drug reactions that occurred in the past due to oral administration of 6-MP or azathioprine with ulcerative colitis of moderate or higher severity classification by the Ministry of Health, Labor and Welfare. Hereinafter, patients with ulcerative colitis targeted in Comparative Example 1 and Comparative Example 2 also have a similar medical history.
(2) Method of measuring the maximum blood concentration of mizoribine The measurement of the maximum blood concentration of mizoribine was carried out according to the usual method (J Chromatogr. 1988 Nov 18; 432: 340-5). After oral administration of mizoribine to the patient, 2 ml of patient blood is collected after 2 to 4 hours when the maximum blood concentration is obtained, stored in a cold place for 30 to 60 minutes, and then separated into blood cells and serum using a centrifuge Then, 1 ml of the serum was frozen at −20 ° C. and used as a sample for measuring the maximum blood concentration.
(3) Judgment method of side effect expression The side effect expression during the period of mizoribine administration was determined based on general clinical laboratory values and clinical symptoms.
In other words, the side effects of myelosuppression were as follows: white blood cell count (reference value 4000 to 8000 / μl), hemoglobin concentration (reference value male 13.5 to 17.6 g / dl, female 11.3 to 15.2 g / dl), platelets The number (reference value 15-35 × 10 ⁴ / μl) was judged by comparing with the reference value. If the leukocyte count is 3000 / μl or less, serious infection, bleeding tendency, etc. may occur, which is contraindicated.
(4) Treatment details and results For the above patients, leukocyte removal therapy (Celsorber E (registered trademark), using polyester as a carrier) is performed once a week for 5 consecutive weeks. It was. None of the patients took any immunosuppressive agents other than mizoribine since the start of leukapheresis. A tablet containing 50 mg of mizoribine in one tablet (Bredinin (Registered) when a tendency to improve clinical symptoms such as bloody stool was observed during leukocyte removal therapy, specifically when the CAI of Lichtiger improved by 3 points or more (Trademark)) was started once a day at 3 tablets, ie 150 mg / day, and continued thereafter. In cases Nos. 1 to 4, the maximum blood concentration of mizoribine was 0.6 μg / ml or more and less than 1.5 μg / ml.
This treatment allowed all four patients to be introduced during remission. During the remission maintenance period, mizoribine was taken at the starting dose. The type and severity of ulcerative colitis depends on the ulcerative colitis classification of the Ministry of Health, Labor and Welfare.
The above results are shown in Table 1. The remission maintenance period of the patients with case numbers 1 to 4 reached 33 months or more. Furthermore, no serious side effects such as myelosuppression were observed during the period of mizoribine administration in any of the four cases, and no other side effects such as fever were observed.

[Comparative Example 1]
(1) Target patient One patient with ulcerative colitis in the hospital to which the present inventor belongs was studied as case number 5.
(2) Treatment details and results Leukocyte removal therapy and mizoribine administration were performed in the same manner as in Example 1 except that the dose of mizoribine was reduced so that the maximum blood concentration of mizoribine was 0.11 μg / ml. The results are shown in Table 1. The patient's symptoms resolved once but relapsed two months later.

[Comparative Example 2]
(1) Target patient Five patients with ulcerative colitis in the hospital to which the present inventor belongs were examined as case numbers 6 to 10.
(2) Treatment details and results Leukocyte removal therapy was performed in the same manner as in Example 1 except that 6-MP was administered at 30 mg / day or more instead of mizoribine. The blood count was monitored once every 1 to 2 weeks for 3 months after the start of administration, and then once a month thereafter.
The above results are shown in Table 2. The white blood cell count, hemoglobin concentration, and platelet count in Table 2 are measured values after administering 30 mg / day or more of 6-MP for the period shown in Table 2. All patients developed myelosuppressive side effects, and the 6-MP dose was reduced to 30 mg / day or less, or 6-MP administration had to be discontinued. It should be noted that the dose of 6-MP, which has been shown to have a remission-maintaining effect in Japan, is 30 mg / day. In addition, about 30% of refractory cases caused by bone marrow suppression by 6-MP or azathioprine in patients with ulcerative colitis in the hospital to which the present inventor belongs.

  The therapeutic agent for ulcerative colitis containing mizoribine according to the present invention can be suitably used as a therapeutic agent for ulcerative colitis patients and a drug for maintaining remission.

Claims (6)

A drug for treating ulcerative colitis containing mizoribine,
The therapeutic agent is a patient with ulcerative colitis who has been treated with leukoreduction therapy and has not been administered an immunosuppressive agent other than mizoribine at least since the start of leukocyte depletion therapy, and with 6-mercaptopurine or azathioprine Used for patients who had bone marrow suppression in the past, and the administration start time of the therapeutic agent is during the execution of leukocyte removal therapy and after the time when Lichtiger's Clinical Activity Index (CAI) has improved ,
A therapeutic agent for ulcerative colitis containing mizoribine, which is administered at least once / day so that the maximum blood concentration of mizoribine is 0.6 μg / ml or more and less than 1.5 μg / ml. The therapeutic agent for ulcerative colitis containing mizoribine is a therapeutic agent for ulcerative colitis for oral administration, and the highest blood concentration of mizoribine is 2 to 4 hours after oral administration of the therapeutic agent. A therapeutic agent for ulcerative colitis comprising mizoribine according to claim 1. The therapeutic agent for ulcerative colitis containing mizoribine according to claim 1 or 2, wherein the time point at which the clinical activity index (CAI) of Lichtiger has improved is a point at which CAI has improved by 3 points or more. The mizoribine according to any one of claims 1 to 3, wherein the leukocyte removal therapy comprises a step of collecting blood from a patient, removing leukocytes in the blood by a leukocyte removal means, and then returning the blood to the patient. Containing ulcerative colitis. The ulcerative colitis therapeutic drug containing mizoribine according to claim 4, wherein the leukocyte removing means is either a centrifuge or a carrier having affinity for leukocytes. 6. The carrier having affinity for leukocytes is selected from the group consisting of cellulose derivatives including cellulose acetate, polyester, polyolefin, polyvinylidene fluoride, polyamide, polyimide, polyurethane, polysulfone or polyacrylonitrile. A drug for treating ulcerative colitis containing mizoribine.