WO2011001954A1 - Therapeutic agent for abnormal defecation in inflammatory bowel disease patient who is in remission phase - Google Patents

Therapeutic agent for abnormal defecation in inflammatory bowel disease patient who is in remission phase Download PDF

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WO2011001954A1
WO2011001954A1 PCT/JP2010/061009 JP2010061009W WO2011001954A1 WO 2011001954 A1 WO2011001954 A1 WO 2011001954A1 JP 2010061009 W JP2010061009 W JP 2010061009W WO 2011001954 A1 WO2011001954 A1 WO 2011001954A1
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remission
inflammatory bowel
bowel disease
defecation
ramosetron
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PCT/JP2010/061009
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French (fr)
Japanese (ja)
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拓也 平田
明登 西田
竜一 武沢
仁 土居原
俊英 横山
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アステラス製薬株式会社
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Priority to JP2011520921A priority Critical patent/JP5741433B2/en
Publication of WO2011001954A1 publication Critical patent/WO2011001954A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals

Definitions

  • the present invention relates to a medicament, particularly a therapeutic agent for abnormal defecation in inflammatory bowel disease patients in remission phase.
  • IBD Inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn's disease
  • Non-Patent Document 1 it is known that stool abnormalities such as diarrhea continue to occur even during remission, and patients continue to suffer from digestive symptoms (see, for example, Non-Patent Document 2).
  • Antidiarrheal drugs such as loperamide are commonly used for general diarrheal symptoms, but loperamide is a contraindication in principle for IBD because it may cause a toxic large intestine.
  • new therapeutic agents having high efficacy and safety are desired. (For example, refer nonpatent literature 3).
  • IBS irritable bowel syndrome
  • Ramosetron hydrochloride and allosetron hydrochloride have been developed as therapeutic agents for IBS and have been reported to show high efficacy against various symptoms associated with diarrhea-type IBS (for example, Patent Documents 1 and 2). , 6).
  • restraint stress-induced defecation rats, fear-conditioned stress-induced defecation rats, 5-HT (5-hydroxytriptamine) -induced diarrhea rats, CRF (corticotropin-releasing factor) This is also supported by an improvement effect on animal models of diarrhea-type IBS such as rats with enhanced defecation (see, for example, Non-Patent Documents 7 and 8).
  • Patent Document 3 discloses that a series of tetrahydrobenzimidazole derivatives including ramosetron and a pharmaceutically acceptable salt thereof have a 5-HT 3 receptor antagonistic action, and based on this action, cisplatin is disclosed. This suggests the possibility of prevention and treatment of anti-emetics such as anticancer drugs and radiation, migraine, complex headache, trigeminal neuralgia, anxiety, gastrointestinal motility disorder, peptic ulcer, irritable bowel syndrome and the like.
  • Patent Document 4 discloses that a series of lactam derivatives including allosetron and a pharmaceutically acceptable salt thereof have a 5-HT 3 receptor antagonistic action, and based on this action, mental disorders are disclosed.
  • Anxiety symptoms such as nausea and vomiting, especially with cancer chemotherapy and radiation therapy; gastric stagnation; gastrointestinal dysfunction symptoms such as those caused by dyspepsia, reflux esophagitis, flatulence and irritable bowel syndrome; migraine; Suggestions for the treatment of symptoms such as obesity and morbidity; pain; abused drug and substance addiction, depression, dementia and other sensory disorders.
  • diarrhea associated with diseases other than diarrhea-type IBS particularly diarrhea observed in the remission phase of IBD as described above, can be treated with 5- such as ramosetron hydrochloride and allosetron hydrochloride.
  • HT 3 receptor antagonists There are no reports of attempts to use HT 3 receptor antagonists.
  • Non-Patent Document 9 reports that tropisetron showed an anti-inflammatory effect on a rat colitis model, suggesting the possibility of treatment of IBD. No effect on is described.
  • the present inventors have conducted intensive studies for the purpose of creating a better treatment method for defecation abnormalities in IBD patients in remission.
  • the present invention was completed by confirming an excellent effect of improving stool abnormalities by administration of ramosetron or alosetron.
  • ramosetron or alosetron When the effect of ramosetron or alosetron was examined using a defecation enhancement model using rats in which enteritis induced by intracolonic administration of acetic acid was ameliorated, all showed a significant inhibitory effect.
  • the present invention [1-1] A therapeutic agent for defecation abnormalities in patients with inflammatory bowel disease in remission phase, containing ramosetron, alosetron, or a pharmaceutically acceptable salt thereof as an active ingredient; [1-2] The agent according to [1-1], wherein the active ingredient is ramosetron or a pharmaceutically acceptable salt thereof; [1-3] The agent according to [1-1], wherein the active ingredient is allosetron or a pharmaceutically acceptable salt thereof; and [1-4] The agent according to any one of [1-1] to [1-3], wherein defecation abnormality in a patient with inflammatory bowel disease in remission is diarrhea.
  • the present invention also provides: [2-1] A pharmaceutical composition for treating defecation abnormalities in patients with inflammatory bowel disease in remission phase, containing ramosetron, alosetron, or a pharmaceutically acceptable salt thereof as an active ingredient; [2-2] The pharmaceutical composition of [2-1], wherein the active ingredient is ramosetron or a pharmaceutically acceptable salt thereof; [2-3] The pharmaceutical composition of [2-1], wherein the active ingredient is allosetron or a pharmaceutically acceptable salt thereof; and [2-4] The pharmaceutical composition according to any one of [2-1] to [2-3], wherein defecation abnormality in a patient with inflammatory bowel disease in remission is diarrhea.
  • the present invention also provides: [3-1] Use of ramosetron, alosetron, or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for abnormal bowel movement in patients with inflammatory bowel disease in remission phase; [3-2] Use of ramosetron or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for defecation in patients with inflammatory bowel disease in remission phase; [3-3] Use of allosetron or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for defecation in patients with inflammatory bowel disease in remission; and [3-4] Use of any one of [3-1] to [3-3], in which defecation abnormalities in inflammatory bowel disease patients in remission are diarrhea symptoms; The present invention also provides: [4-1] Ramosetron, alosetron, or a pharmaceutically acceptable salt thereof for the treatment of bowel abnormalities in patients with inflammatory bowel disease in remission; [4-2] Ramosetron or
  • the present invention also provides: [5-1] A method of treating defecation abnormality in a patient with inflammatory bowel disease in remission phase, comprising administering to the patient an effective amount of ramosetron, alosetron, or a pharmaceutically acceptable salt thereof ; [5-2] The method of [5-1], comprising administering to the patient an effective amount of ramosetron or a pharmaceutically acceptable salt thereof; [5-3] The method of [5-1], comprising administering to the patient an effective amount of allosetron or a pharmaceutically acceptable salt thereof; and [5-4] The method according to any one of [5-1] to [5-3], wherein defecation abnormality in a patient with inflammatory bowel disease in remission is diarrhea.
  • the present invention can provide an agent for improving defecation abnormalities during remission that contributes to the maintenance of remission of inflammatory bowel disease, which is an intractable chronic disease for which there is no effective treatment yet.
  • the vertical axis of the graph indicates the number of defecations during a 1 hour restraint stress load.
  • ## indicates a p-value ⁇ 0.01 for the stress group compared to the normal group
  • ### indicates a p-value ⁇ 0.001 for the stress group relative to the normal group
  • * indicates a remission IBD rat (4% relative to the control group (saline treatment)) Acetic acid treatment) p-value ⁇ 0.05 (Student's t test).
  • a patient with inflammatory bowel disease in remission is a patient who suffers from an inflammatory bowel disease such as ulcerative colitis or Crohn's disease, and once symptoms of enteritis have been cured by treatment.
  • defecation abnormalities in patients with inflammatory bowel disease in remission are mainly diarrhea symptoms.
  • the active ingredient of the present invention can be produced by a method known per se.
  • Ramosetron and a pharmaceutically acceptable salt thereof can be easily obtained by the production method described in Patent Document 3 or according thereto.
  • Arosetron and a pharmaceutically acceptable salt thereof can be easily obtained by the production method described in Patent Document 4 or according thereto.
  • Pharmaceutically acceptable salts are pharmaceutically acceptable acid and base addition salts with inorganic and organic acids or bases, such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like.
  • Mineral acid salts acetic acid, oxalic acid, succinic acid, citric acid, maleic acid, malic acid, fumaric acid, tartaric acid, salts with organic acids such as methanesulfonic acid, and salts with acidic amino acids such as glutamic acid and aspartic acid It is done.
  • commercially available ramosetron hydrochloride and alosetron hydrochloride are preferable.
  • the dosage of the active ingredient of the present invention is within the range of 0.0005 to 50 mg per day, and is appropriately determined according to each case, taking into consideration the administration route, disease symptoms, age of the administration subject, sex, etc. for each drug. It is determined. Moreover, from the correlation between the IBD animal experiment results shown in Example 2 described later, the IBS animal experiment results (see Non-Patent Documents 5 and 6), and the clinically effective dose (see Non-Patent Documents 3 and 4) for IBS, The following preferable range is converted as a clinically effective amount for.
  • Ramosetron hydrochloride is preferably about 0.001 to 0.05 mg per day, more preferably about 0.001 to 0.02 mg per day for an adult, and is orally administered once a day after meals.
  • alosetron hydrochloride is preferably about 0.1 mg to 10 mg per day, more preferably about 0.5 mg to 8 mg per day for an adult, divided into 1 or 2 doses after meals. Oral administration.
  • the drug of the present invention should be prepared as an oral solid preparation, oral liquid preparation, or injection according to a conventional method using an organic or inorganic carrier, excipient, or other additive suitable for oral or parenteral administration.
  • Can do Preference is given to oral solid preparations that can be easily taken by the patient and are convenient to store and carry. Specifically, tablets, powders, granules, fine granules, capsules, pills and the like are preferred.
  • the active substance is mixed with at least one inert diluent such as lactose, mannitol, glucose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate.
  • composition is prepared according to conventional methods with additives other than inert diluents, for example, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, starch, talc , Disintegrants such as calcium calcium glycolate, stabilizers such as lactose, solubilizers such as glutamic acid or aspartic acid, Tween 80, plasticizers such as triacetin, titanium oxide, ferric oxide It may contain a colorant.
  • additives other than inert diluents, for example, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, starch, talc , Disintegrants such as calcium calcium glycolate, stabilizers such as lactose, solubilizers such as glutamic acid or aspartic acid, Tween 80,
  • tablets or pills may be coated with a sugar coating such as sucrose, gelatin, agar, pectin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.
  • Orally disintegrating tablets may be used.
  • an orally disintegrating tablet can be prepared according to US 5,466,464, US 5,576,014, US 6,589,554, WO 03/009831, WO 02/092057, and the like.
  • a preparation subjected to a stabilization technique against temperature and humidity is particularly preferable because of its low dose.
  • stabilization of ramosetron against temperature and humidity can be achieved by adding a specific compound having a carbonyl group.
  • Specific examples of the specific compound having a carbonyl group include aliphatic carboxylic acids such as maleic acid, malonic acid, succinic acid and fumaric acid or esters thereof, hydroxycarboxylic acids such as tartaric acid, malic acid and citric acid, aspartic acid, Examples include acidic amino acids such as glutamic acid, enolic acids such as ascorbic acid and erythorbic acid, aromatic carboxyl compounds such as phthalic acid and propyl gallate, and polymer substances having a carboxyl group such as carboxymethylcellulose and alginic acid. One kind or a combination of two or more kinds can be used as appropriate.
  • ramosetron hydrochloride when ramosetron hydrochloride is used as an active ingredient, commercially available iribo tablets 2.5 ⁇ g and 5 ⁇ g can be used.
  • allosetron hydrochloride when allosetron hydrochloride is used as the active ingredient, commercially available LOTRONEX® Tablets 0.5 mg or 1 mg can be used.
  • the drug of the present invention is sufficiently effective when administered alone, but at the same time or at the same time as aminosalicylic acid (for example, brand name salazopyrine) and mesalazine (for example, brand name Pentasa) used for maintaining remission in IBD patients. Can be used together.
  • aminosalicylic acid for example, brand name salazopyrine
  • mesalazine for example, brand name Pentasa
  • Example 1 Preparation of remission stage IBD rat (acetic acid-induced enteritis healing model) Acetic acid-induced enteritis by the following method with reference to the method of Blandino II et al. (J. Gastroenterol. Hepatol, 2001, 16 (10), 1105-1111) A model was created. Male Sprague-Dawley (SD) rats or Wistar rats under overnight fasting were used. Under ether light anesthesia, a 10 cm long plastic sonde was inserted from the rat anus and adjusted so that the tip of the sonde was 8 cm from the anus.
  • SD Male Sprague-Dawley rats or Wistar rats under overnight fasting were used.
  • Example 2 1 mL of physiological saline containing 4% acetic acid was injected from a plastic sonde and allowed to stand for 30 seconds, and then the rectum was washed twice with 1 mL of physiological saline.
  • the test shown in Example 2 was conducted by setting the rats 7 days after the treatment as “remission-phase IBD rats”. A control group was injected with physiological saline by the same operation.
  • myeloperoxidase (MPO) activity which is an index of inflammation in the intestine, increases after 1-2 days after acetic acid treatment, MPO activity returns to the same level as in the control group after 7 days. was also observed.
  • MPO myeloperoxidase
  • Example 2 Restraint stress-induced defecation enhancement test
  • Ramosetron hydrochloride or allosetron hydrochloride was dissolved in 0.5% aqueous methylcellulose solution and used.
  • the test compound or solvent was orally administered to the “control rat” treated with physiological saline instead of the 4% acetic acid of Example 1 or the “remission phase IBD rat”, and the animal was restrained by a restraint stress cage (product) Name: KN-468 (B), Natsume Seisakusho).
  • KN-468 (B), Natsume Seisakusho The total number of feces excreted from the beginning of restraint stress load and the total wet weight were measured 1 hour later.
  • Example 3 Clinical trial for patients with inflammatory bowel disease in remission phase
  • 5 ⁇ g of iribo tablet is orally administered once daily after breakfast To do.
  • iribo tablet ramosetron hydrochloride
  • patients will be inquired about defecation symptoms before the start of administration and 2 weeks after the start of administration.
  • the dose of the drug is adjusted as appropriate within a range of 2.5 ⁇ g to 10 ⁇ g as a once-daily dose.
  • the present invention can provide an agent for improving defecation abnormalities during remission that contributes to maintaining remission in IBD patients who are intractable chronic diseases for which there is still no effective treatment.

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Abstract

A therapeutic agent for abnormal defecation in an inflammatory bowel disease patient who is in the remission phase, which comprises ramosetron, alosetron or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

緩解期の炎症性腸疾患患者における排便異常治療剤A therapeutic agent for abnormal defecation in patients with inflammatory bowel disease in remission
　本発明は、医薬、とりわけ緩解期の炎症性腸疾患患者における排便異常治療剤に係るものである。 The present invention relates to a medicament, particularly a therapeutic agent for abnormal defecation in inflammatory bowel disease patients in remission phase.
　潰瘍性大腸炎(ulcerative colitis, UC)及びクローン病(Crohn's disease, CD)に代表される炎症性腸疾患(inflammatory bowel disease, IBD)は、若年者に好発し、緩解と増悪を繰り返すことを特徴とする難治性の非特異的な器質性疾患である。IBDには、免疫的な異常に加え、遺伝的素因及び環境因子が深く関与していると考えられているが、正確な原因や病態生理は未だ完全には解明されていない。また、IBDに対して根治が期待できる治療法も確立されておらず、再燃、緩解を繰り返しながら慢性の経過をとるが、原則的には薬物による内科的治療が行われ、重症の場合や薬物療法が有効でない場合には手術が必要となる。このため、本疾患の内科的治療の目標は、腸炎の活動期を速やかに治め（緩解導入）、症状のない状態を維持する（緩解維持）とともに、再燃要因を回避することとされている。ただし、IBDが緩解期に移行した場合でも、内視鏡的及び病理学的な病変は完全に消失していないことがある（例えば、非特許文献１参照）。
　また、緩解期においても、下痢などの便通異常は継続して発生することが知られており、患者においては消化器症状に苦慮する状態が続いてしまう（例えば、非特許文献２参照）。一般的な下痢症状には、ロペラミドのような止瀉薬が汎用されるが、ロペラミドは中毒性巨大大腸を起こす恐れがあることから、IBDには原則禁忌とされており、IBD緩解後の下痢に対して高い有効性と安全性を有する新たな治療薬が望まれている。（例えば、非特許文献３参照）。 Inflammatory bowel disease (IBD), typified by ulcerative colitis (UC) and Crohn's disease (CD), is common among young people and is characterized by repeated remissions and exacerbations. It is an intractable non-specific organic disease. In addition to immune abnormalities, genetic predisposition and environmental factors are thought to be deeply involved in IBD, but the exact cause and pathophysiology have not yet been fully elucidated. In addition, there is no established treatment that can be expected to cure IBD, and it will take a chronic course with repeated relapses and remissions. Surgery is required if therapy is not effective. For this reason, the goal of medical treatment of this disease is to quickly control the active phase of enteritis (introduction of remission), maintain an asymptomatic state (maintenance of remission), and avoid relapse factors. However, even when the IBD transitions to the remission phase, the endoscopic and pathological lesions may not completely disappear (for example, see Non-Patent Document 1).
In addition, it is known that stool abnormalities such as diarrhea continue to occur even during remission, and patients continue to suffer from digestive symptoms (see, for example, Non-Patent Document 2). Antidiarrheal drugs such as loperamide are commonly used for general diarrheal symptoms, but loperamide is a contraindication in principle for IBD because it may cause a toxic large intestine. On the other hand, new therapeutic agents having high efficacy and safety are desired. (For example, refer nonpatent literature 3).
　一方、過敏性腸症候群(irritable bowel syndrome, IBS)は、IBDと異なり、大腸組織に器質的な病変が認められないにもかかわらず、慢性的な便通異常（便秘あるいは下痢）、腹痛及び腹部不快感を生じる機能性疾患である。2006年に発表されたIBSの診断基準（Rome III基準）によると、排便回数や便性状などの違いから、IBSは下痢型、便秘型、混合型及び分類不能型に分類されている（例えば、非特許文献４参照）。
　IBSの薬物治療には、抗コリン薬などの鎮痙薬、オピオイド受容体作動薬などの止瀉薬若しくは腸内環境を整えるための高分子製剤や乳酸菌製剤が汎用されてきたが、近年、新しいタイプのIBS治療薬として、ラモセトロン塩酸塩やアロセトロン塩酸塩が開発され、下痢型IBSに伴う諸症状に対して高い有効性を示すことが報告されている（例えば、特許文献１，２，非特許文献５，６参照）。これは，下痢型IBS患者を対象とした臨床試験の他、拘束ストレス誘発排便亢進ラット、恐怖条件付けストレス誘発排便亢進ラット、5-HT(5-hydroxytriptamine)誘発下痢ラット、CRF(corticotropin-releasing factor)誘発排便亢進ラット等，下痢型IBSの病態動物モデルに対する改善効果でも裏付けられている（例えば、非特許文献７，８参照）。 On the other hand, irritable bowel syndrome (IBS) differs from IBD in that it has chronic bowel movements (constipation or diarrhea), abdominal pain, and abdominal insufficiency despite no organic lesions in the colon tissue. It is a functional disease that produces pleasure. According to the diagnostic criteria for IBS (Rome III criteria) published in 2006, IBS is classified into diarrhea, constipation, mixed, and non-classifiable types due to differences in the number of bowel movements and stool characteristics (for example, Non-patent document 4).
In IBS drug treatment, antispasmodic drugs such as anticholinergic drugs, antipruritic drugs such as opioid receptor agonists, and polymer preparations and lactic acid bacteria preparations for preparing the intestinal environment have been widely used. Ramosetron hydrochloride and allosetron hydrochloride have been developed as therapeutic agents for IBS and have been reported to show high efficacy against various symptoms associated with diarrhea-type IBS (for example, Patent Documents 1 and 2). , 6). In addition to clinical trials in patients with diarrhea-type IBS, restraint stress-induced defecation rats, fear-conditioned stress-induced defecation rats, 5-HT (5-hydroxytriptamine) -induced diarrhea rats, CRF (corticotropin-releasing factor) This is also supported by an improvement effect on animal models of diarrhea-type IBS such as rats with enhanced defecation (see, for example, Non-Patent Documents 7 and 8).
　また、特許文献３には、ラモセトロンおよびその製薬学的に許容される塩を含む一連のテトラヒドロベンズイミダゾール誘導体が5-HT3受容体拮抗作用を有することが開示されており、当該作用に基づきシスプラチンなどの制癌剤及び放射線による嘔吐の抑制、偏頭痛、複合頭痛、三叉神経痛、不安症状、胃腸運動障害、消化性潰瘍、過敏性腸症候群等の予防・治療の可能性が示唆されている。
　同様に、特許文献４には、アロセトロンおよびその製薬学的に許容される塩を含む一連のラクタム誘導体が5-HT3受容体拮抗作用を有することが開示されており、当該作用に基づき精神障害；不安；特に癌化学療法及び放射線療法に伴う悪心及び嘔吐のような症状；胃内容停滞；消化不良、逆流性食道炎、鼓腸及び過敏性腸症候群で生じるような胃腸機能不全症状；片頭痛；肥満及び病的飢餓のような症状；痛み；乱用薬物及び物質依存症、うつ病、痴呆及び他の知覚障害の治療の可能性が示唆されている。
　しかし、非臨床及び臨床のいずれにおいても、下痢型IBS以外の疾患に伴う下痢、特に、上述したようなIBDの緩解期に認められる下痢に対して、ラモセトロン塩酸塩やアロセトロン塩酸塩等の5-HT3受容体拮抗薬の使用を試みたとの報告はない。
　非特許文献９には、トロピセトロンが、ラットの大腸炎モデルに対して抗炎症効果を示したことが報告され、IBDの治療可能性が示唆されているが、炎症が治まった緩解期のIBDに対する効果は何ら記載されていない。 Patent Document 3 discloses that a series of tetrahydrobenzimidazole derivatives including ramosetron and a pharmaceutically acceptable salt thereof have a 5-HT 3 receptor antagonistic action, and based on this action, cisplatin is disclosed. This suggests the possibility of prevention and treatment of anti-emetics such as anticancer drugs and radiation, migraine, complex headache, trigeminal neuralgia, anxiety, gastrointestinal motility disorder, peptic ulcer, irritable bowel syndrome and the like.
Similarly, Patent Document 4 discloses that a series of lactam derivatives including allosetron and a pharmaceutically acceptable salt thereof have a 5-HT 3 receptor antagonistic action, and based on this action, mental disorders are disclosed. Anxiety; symptoms such as nausea and vomiting, especially with cancer chemotherapy and radiation therapy; gastric stagnation; gastrointestinal dysfunction symptoms such as those caused by dyspepsia, reflux esophagitis, flatulence and irritable bowel syndrome; migraine; Suggestions for the treatment of symptoms such as obesity and morbidity; pain; abused drug and substance addiction, depression, dementia and other sensory disorders.
However, in both non-clinical and clinical cases, diarrhea associated with diseases other than diarrhea-type IBS, particularly diarrhea observed in the remission phase of IBD as described above, can be treated with 5- such as ramosetron hydrochloride and allosetron hydrochloride. There are no reports of attempts to use HT 3 receptor antagonists.
Non-Patent Document 9 reports that tropisetron showed an anti-inflammatory effect on a rat colitis model, suggesting the possibility of treatment of IBD. No effect on is described.
米国特許第7,358,270号明細書U.S. Patent No. 7,358,270 国際公開第99/17755号パンフレットWO99 / 17755 pamphlet 米国特許第5,344,927号明細書U.S. Pat.No. 5,344,927 米国特許第5,360,800号明細書U.S. Pat.No. 5,360,800
　本発明者らは緩解期のIBD患者における排便異常に対する更に優れた治療方法の創製を目的として鋭意検討を行った。 The present inventors have conducted intensive studies for the purpose of creating a better treatment method for defecation abnormalities in IBD patients in remission.
　その結果、ラモセトロン又はアロセトロンの投与により優れた排便異常改善効果を確認して発明を完成させた。
　酢酸の大腸内投与により誘発された腸炎が緩解したラットを用いた排便亢進モデルを用いて、ラモセトロンもしくはアロセトロンの効果を検討したところ、いずれも有意な抑制効果を示した。
　すなわち、本発明は、
[1-1]ラモセトロン、アロセトロン又はこれらの製薬学的に許容される塩を有効成分として含有する緩解期の炎症性腸疾患患者における排便異常治療剤；
[1-2]有効成分がラモセトロン又はその製薬学的に許容される塩である[1-1]の剤；
[1-3]有効成分がアロセトロン又はその製薬学的に許容される塩である[1-1]の剤；及び
[1-4]緩解期の炎症性腸疾患患者における排便異常が下痢症状である[1-1]乃至[1-3]のいずれかの剤；に関する。
　また、本発明は、
[2-1]ラモセトロン、アロセトロン又はこれらの製薬学的に許容される塩を有効成分として含有する緩解期の炎症性腸疾患患者における排便異常治療用医薬組成物；
[2-2]有効成分がラモセトロン又はその製薬学的に許容される塩である[2-1]の医薬組成物；
[2-3]有効成分がアロセトロン又はその製薬学的に許容される塩である[2-1]の医薬組成物；及び
[2-4]緩解期の炎症性腸疾患患者における排便異常が下痢症状である[2-1]乃至[2-3]のいずれかの医薬組成物；に関する。
　また、本発明は、
[3-1]緩解期の炎症性腸疾患患者における排便異常治療剤の製造のための、ラモセトロン、アロセトロン又はこれらの製薬学的に許容される塩の使用；
[3-2]緩解期の炎症性腸疾患患者における排便異常治療剤の製造のための、ラモセトロン又はその製薬学的に許容される塩の使用；
[3-3]緩解期の炎症性腸疾患患者における排便異常治療剤の製造のための、アロセトロン又はその製薬学的に許容される塩の使用；及び
[3-4]緩解期の炎症性腸疾患患者における排便異常が下痢症状である[3-1]乃至[3-3]のいずれかの使用；に関する。
　また、本発明は、
[4-1]緩解期の炎症性腸疾患患者における排便異常の治療用のラモセトロン、アロセトロン又はこれらの製薬学的に許容される塩；
[4-2]緩解期の炎症性腸疾患患者における排便異常の治療用のラモセトロン又はその製薬学的に許容される塩；
[4-3]緩解期の炎症性腸疾患患者における排便異常の治療用のアロセトロン又はその製薬学的に許容される塩；及び
[4-4]緩解期の炎症性腸疾患患者における排便異常が下痢症状である[4-1]乃至[4-3]のいずれかの化合物又はその塩；に関する。
　また、本発明は、
[5-1]緩解期の炎症性腸疾患患者における排便異常の治療方法であって、ラモセトロン、アロセトロン又はこれらの製薬学的に許容される塩の有効量を当該患者に投与することを含む方法；
[5-2]ラモセトロン又はその製薬学的に許容される塩の有効量を患者に投与することを含む[5-1]の方法；
[5-3]アロセトロン又はその製薬学的に許容される塩の有効量を患者に投与することを含む[5-1]の方法；及び
[5-4]緩解期の炎症性腸疾患患者における排便異常が下痢症状である[5-1]乃至[5-3]のいずれかの方法；に関する。 As a result, the present invention was completed by confirming an excellent effect of improving stool abnormalities by administration of ramosetron or alosetron.
When the effect of ramosetron or alosetron was examined using a defecation enhancement model using rats in which enteritis induced by intracolonic administration of acetic acid was ameliorated, all showed a significant inhibitory effect.
That is, the present invention
[1-1] A therapeutic agent for defecation abnormalities in patients with inflammatory bowel disease in remission phase, containing ramosetron, alosetron, or a pharmaceutically acceptable salt thereof as an active ingredient;
[1-2] The agent according to [1-1], wherein the active ingredient is ramosetron or a pharmaceutically acceptable salt thereof;
[1-3] The agent according to [1-1], wherein the active ingredient is allosetron or a pharmaceutically acceptable salt thereof; and
[1-4] The agent according to any one of [1-1] to [1-3], wherein defecation abnormality in a patient with inflammatory bowel disease in remission is diarrhea.
The present invention also provides:
[2-1] A pharmaceutical composition for treating defecation abnormalities in patients with inflammatory bowel disease in remission phase, containing ramosetron, alosetron, or a pharmaceutically acceptable salt thereof as an active ingredient;
[2-2] The pharmaceutical composition of [2-1], wherein the active ingredient is ramosetron or a pharmaceutically acceptable salt thereof;
[2-3] The pharmaceutical composition of [2-1], wherein the active ingredient is allosetron or a pharmaceutically acceptable salt thereof; and
[2-4] The pharmaceutical composition according to any one of [2-1] to [2-3], wherein defecation abnormality in a patient with inflammatory bowel disease in remission is diarrhea.
The present invention also provides:
[3-1] Use of ramosetron, alosetron, or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for abnormal bowel movement in patients with inflammatory bowel disease in remission phase;
[3-2] Use of ramosetron or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for defecation in patients with inflammatory bowel disease in remission phase;
[3-3] Use of allosetron or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for defecation in patients with inflammatory bowel disease in remission; and
[3-4] Use of any one of [3-1] to [3-3], in which defecation abnormalities in inflammatory bowel disease patients in remission are diarrhea symptoms;
The present invention also provides:
[4-1] Ramosetron, alosetron, or a pharmaceutically acceptable salt thereof for the treatment of bowel abnormalities in patients with inflammatory bowel disease in remission;
[4-2] Ramosetron or a pharmaceutically acceptable salt thereof for the treatment of bowel abnormalities in patients with inflammatory bowel disease in remission;
[4-3] Alosetron or a pharmaceutically acceptable salt thereof for the treatment of bowel abnormalities in patients with inflammatory bowel disease in remission; and
[4-4] A compound or a salt thereof according to any one of [4-1] to [4-3], wherein defecation abnormality in a patient with inflammatory bowel disease in remission is diarrhea.
The present invention also provides:
[5-1] A method of treating defecation abnormality in a patient with inflammatory bowel disease in remission phase, comprising administering to the patient an effective amount of ramosetron, alosetron, or a pharmaceutically acceptable salt thereof ;
[5-2] The method of [5-1], comprising administering to the patient an effective amount of ramosetron or a pharmaceutically acceptable salt thereof;
[5-3] The method of [5-1], comprising administering to the patient an effective amount of allosetron or a pharmaceutically acceptable salt thereof; and
[5-4] The method according to any one of [5-1] to [5-3], wherein defecation abnormality in a patient with inflammatory bowel disease in remission is diarrhea.
　本発明により、未だ有効な治療法のない難治性慢性疾患である炎症性腸疾患の緩解維持に寄与する、緩解期の排便異常改善剤を提供できる。 The present invention can provide an agent for improving defecation abnormalities during remission that contributes to the maintenance of remission of inflammatory bowel disease, which is an intractable chronic disease for which there is no effective treatment yet.
対照群ラット（生理食塩水処置）及び緩解期IBDラット（4%酢酸処置）における拘束ストレス誘発排便亢進を示す図である(N=5-10)。グラフの縦軸は１時間の拘束ストレス負荷中の排便個数を示す。##は正常群に対するストレス群のp値＜0.01を、###は正常群に対するストレス群のp値＜0.001を、*は対照群ラット（生理食塩水処置）に対する緩解期IBDラット（4%酢酸処置）のp値＜0.05を示す（Student's t検定）。FIG. 4 is a graph showing restraint stress-induced defecation enhancement in control group rats (saline treatment) and remission IBD rats (4% acetic acid treatment) (N = 5-10). The vertical axis of the graph indicates the number of defecations during a 1 hour restraint stress load. ## indicates a p-value <0.01 for the stress group compared to the normal group, ### indicates a p-value <0.001 for the stress group relative to the normal group, and * indicates a remission IBD rat (4% relative to the control group (saline treatment)) Acetic acid treatment) p-value <0.05 (Student's t test). 緩解期IBDラット（4%酢酸処置）における拘束ストレス誘発排便亢進に対するラモセトロンの効果を示す図である（N=10）。グラフの縦軸は１時間の拘束ストレス負荷中の排便個数を示す。横軸の投与量単位はすべてmg/kgである。###は正常群に対するストレス群のp値＜0.001を（Student's t検定）、*は非薬剤投与群に対する薬剤投与群のp値＜0.05をを示す（Dunnettの多重比較）。It is a figure which shows the effect of ramosetron with respect to restraint stress induction | stimulation defecation enhancement in a remission stage IBD rat (4% acetic acid treatment) (N = 10). The vertical axis of the graph indicates the number of defecations during a 1 hour restraint stress load. All dose units on the horizontal axis are mg / kg. ### indicates p value <0.001 of the stress group with respect to the normal group (Student's t test), and * indicates the p value <0.05 of the drug administration group with respect to the non-drug administration group (Dunnett's multiple comparison). 緩解期IBDラット（4%酢酸処置）における拘束ストレス誘発排便亢進に対するアロセトロン塩酸塩の効果を示す図である（N=12）。グラフの縦軸は１時間の拘束ストレス負荷中の排便個数を示す。横軸の投与量単位はすべてmg/kgである。###は正常群に対するストレス群のp値＜0.001を（Student's t検定）、**は非薬剤投与群に対する薬剤投与群のp値＜0.01を示す（Dunnettの多重比較）。It is a figure which shows the effect of allosetron hydrochloride with respect to the restraint stress-induced defecation enhancement in the remission IBD rat (4% acetic acid treatment) (N = 12). The vertical axis of the graph indicates the number of defecations during a 1 hour restraint stress load. All dose units on the horizontal axis are mg / kg. ### indicates p value <0.001 of the stress group relative to the normal group (Student's t test), and ** indicates the p value <0.01 of the drug administration group relative to the non-drug administration group (Dunnett's multiple comparison).
　以下、本発明を更に詳細に説明する。
　本発明において、緩解期の炎症性腸疾患患者とは、潰瘍性大腸炎、クローン病などの炎症性腸疾患に罹患し、治療により一旦腸炎の症状が治まった患者である。
　本発明において、緩解期の炎症性腸疾患患者における排便異常とは、主として下痢症状である。
　本発明の有効成分は、自体周知の方法により製造できる。ラモセトロン及びその製薬学的に許容される塩は特許文献３に記載された製法により、或いはそれに準じて容易に入手可能である。アロセトロン及びその製薬学的に許容される塩は特許文献４に記載された製法により、或いはそれに準じて容易に入手可能である。
　製薬的に許容される塩とは、無機及び有機の酸あるいは塩基との製薬学的に許容しうる酸及び塩基付加塩であり、例えば、塩酸、硫酸、リン酸、臭化水素酸などとの鉱酸塩、酢酸、シュウ酸、コハク酸、クエン酸、マレイン酸、リンゴ酸、フマール酸、酒石酸、メタンスルホン酸などの有機酸との塩、グルタミン酸、アスパラギン酸などの酸性アミノとの塩が挙げられる。中でも、市販されているラモセトロン塩酸塩、アロセトロン塩酸塩が好ましい。 Hereinafter, the present invention will be described in more detail.
In the present invention, a patient with inflammatory bowel disease in remission is a patient who suffers from an inflammatory bowel disease such as ulcerative colitis or Crohn's disease, and once symptoms of enteritis have been cured by treatment.
In the present invention, defecation abnormalities in patients with inflammatory bowel disease in remission are mainly diarrhea symptoms.
The active ingredient of the present invention can be produced by a method known per se. Ramosetron and a pharmaceutically acceptable salt thereof can be easily obtained by the production method described in Patent Document 3 or according thereto. Arosetron and a pharmaceutically acceptable salt thereof can be easily obtained by the production method described in Patent Document 4 or according thereto.
Pharmaceutically acceptable salts are pharmaceutically acceptable acid and base addition salts with inorganic and organic acids or bases, such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like. Mineral acid salts, acetic acid, oxalic acid, succinic acid, citric acid, maleic acid, malic acid, fumaric acid, tartaric acid, salts with organic acids such as methanesulfonic acid, and salts with acidic amino acids such as glutamic acid and aspartic acid It is done. Of these, commercially available ramosetron hydrochloride and alosetron hydrochloride are preferable.
　本発明の有効成分の投与量は、１日量0.0005～50mgの範囲内で、薬剤毎に、投与ルート、疾患の症状、投与対象の年齢、性別等を考慮して個々の場合に応じて適宜決定される。
　また、後述の実施例２に示すIBDの動物実験結果と、IBSに対する動物実験結果（非特許文献５，６参照）とIBSに対する臨床有効量（非特許文献３、４参照）の相関から、IBDに対する臨床有効量として以下の好ましい範囲が換算される。ラモセトロン塩酸塩は、経口投与の場合、好ましくは成人１人当たり１日量約0.001～0.05mg、より好ましくは１日量約0.001～0.02mgであり、これを１日１回食後に経口投与する。アロセトロン塩酸塩は、経口投与の場合、好ましくは成人１人当たり１日量約0.1mg～10mg、より好ましくは１日量約0.5mg～8mgであり、これを1回あるいは２回に分けて食後に経口投与する。 The dosage of the active ingredient of the present invention is within the range of 0.0005 to 50 mg per day, and is appropriately determined according to each case, taking into consideration the administration route, disease symptoms, age of the administration subject, sex, etc. for each drug. It is determined.
Moreover, from the correlation between the IBD animal experiment results shown in Example 2 described later, the IBS animal experiment results (see Non-Patent Documents 5 and 6), and the clinically effective dose (see Non-Patent Documents 3 and 4) for IBS, The following preferable range is converted as a clinically effective amount for. Ramosetron hydrochloride is preferably about 0.001 to 0.05 mg per day, more preferably about 0.001 to 0.02 mg per day for an adult, and is orally administered once a day after meals. In the case of oral administration, alosetron hydrochloride is preferably about 0.1 mg to 10 mg per day, more preferably about 0.5 mg to 8 mg per day for an adult, divided into 1 or 2 doses after meals. Oral administration.
　本発明の薬剤は、経口または非経口投与に適した有機又は無機の担体、賦形剤、その他の添加剤を用いて、常法に従って、経口固形製剤、経口液状製剤または注射剤として調製することができる。好ましいのは患者が自ら容易に服用でき且つ保存、持ち運びに便利な経口固形製剤であり、具体的には錠剤、散剤、顆粒剤、細粒剤、カプセル剤、丸剤等である。
　このような固形製剤においては、活性物質が、少なくとも一つの不活性な希釈剤、例えば乳糖、マンニトール、ブドウ糖、微結晶セルロース、デンプン、ポリビニルピロリドン、メタケイ酸アルミン酸マグネシウムと混合される。組成物は常法に従って、不活性な希釈剤以外の添加剤、例えばヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースのような結合剤、ステアリン酸マグネシウム、ステアリン酸カルシウム、ポリエチレングリコール、スターチ、タルクのような滑沢剤、繊維素グリコール酸カルシウムのような崩壊剤、ラクトースのような安定化剤、グルタミン酸又はアスパラギン酸のような溶解補助剤、ツイーン８０、トリアセチンのような可塑剤、酸化チタン、三二酸化鉄のような着色剤を含有していてもよい。錠剤又は丸剤は必要によりショ糖、ゼラチン、寒天、ペクチン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースフタレートなどの糖衣又は胃溶性若しくは腸溶性物質のフィルムで被膜してもよい。
　また、口腔内崩壊錠にしてもよい。例えば、US 5,466,464、US 5,576,014、US 6,589,554、WO 03/009831、WO 02/092057などに従い、口腔内崩壊錠とすることができる。 The drug of the present invention should be prepared as an oral solid preparation, oral liquid preparation, or injection according to a conventional method using an organic or inorganic carrier, excipient, or other additive suitable for oral or parenteral administration. Can do. Preference is given to oral solid preparations that can be easily taken by the patient and are convenient to store and carry. Specifically, tablets, powders, granules, fine granules, capsules, pills and the like are preferred.
In such solid preparations, the active substance is mixed with at least one inert diluent such as lactose, mannitol, glucose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate. The composition is prepared according to conventional methods with additives other than inert diluents, for example, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, starch, talc , Disintegrants such as calcium calcium glycolate, stabilizers such as lactose, solubilizers such as glutamic acid or aspartic acid, Tween 80, plasticizers such as triacetin, titanium oxide, ferric oxide It may contain a colorant. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, agar, pectin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.
Orally disintegrating tablets may be used. For example, an orally disintegrating tablet can be prepared according to US 5,466,464, US 5,576,014, US 6,589,554, WO 03/009831, WO 02/092057, and the like.
　有効成分としてラモセトロン又はその塩を用いる場合には、低用量であることから温湿度に対する安定化技術を施した製剤が特に好ましい。
　例えば、WO 04/066998に従い、カルボニル基を有する特定の化合物を添加することにより、温湿度に対するラモセトロンの安定化を達成することができる。カルボニル基を有する特定の化合物として具体的には、マレイン酸、マロン酸、コハク酸、フマル酸等の脂肪族カルボン酸またはそのエステル、酒石酸、リンゴ酸、クエン酸等のヒドロキシカルボン酸、アスパラギン酸、グルタミン酸等の酸性アミノ酸、アスコルビン酸、エリソルビン酸等のエノール酸、フタル酸、没食子酸プロピル等の芳香族カルボキシル化合物、カルボキシメチルセルロース、アルギン酸等のカルボキシル基を有する高分子物質が挙げられ、これらの化合物は1種または2種以上組合せて適宜使用することができる。 When ramosetron or a salt thereof is used as an active ingredient, a preparation subjected to a stabilization technique against temperature and humidity is particularly preferable because of its low dose.
For example, according to WO 04/066998, stabilization of ramosetron against temperature and humidity can be achieved by adding a specific compound having a carbonyl group. Specific examples of the specific compound having a carbonyl group include aliphatic carboxylic acids such as maleic acid, malonic acid, succinic acid and fumaric acid or esters thereof, hydroxycarboxylic acids such as tartaric acid, malic acid and citric acid, aspartic acid, Examples include acidic amino acids such as glutamic acid, enolic acids such as ascorbic acid and erythorbic acid, aromatic carboxyl compounds such as phthalic acid and propyl gallate, and polymer substances having a carboxyl group such as carboxymethylcellulose and alginic acid. One kind or a combination of two or more kinds can be used as appropriate.
　また、有効成分としてラモセトロン塩酸塩を用いる場合には、市販のイリボー錠2.5μgや同5μgを使用することができる。有効成分として、アロセトロン塩酸塩を用いる場合には、市販のLOTRONEX Tablet 0.5mgや同1mgを使用することができる。 In addition, when ramosetron hydrochloride is used as an active ingredient, commercially available iribo tablets 2.5 μg and 5 μg can be used. When allosetron hydrochloride is used as the active ingredient, commercially available LOTRONEX® Tablets 0.5 mg or 1 mg can be used.
　尚、本発明の薬剤は単独での投与において充分有効であるが、IBD患者の緩解維持に用いられるアミノサリチル酸（例えば、商品名サラゾピリン）やメサラジン（例えば、商品名ペンタサ）などと同時にまたは時間をおいて併用することができる。 The drug of the present invention is sufficiently effective when administered alone, but at the same time or at the same time as aminosalicylic acid (for example, brand name salazopyrine) and mesalazine (for example, brand name Pentasa) used for maintaining remission in IBD patients. Can be used together.
　以下に実施例に基づいて本発明をより詳細に説明するが、本発明はこれらの実施例等に限定されるものではない。
実施例１：緩解期IBDラット（酢酸誘発腸炎治癒モデル）の作成
　Blandino IIらの方法（J. Gastroenterol. Hepatol, 2001, 16 (10), 1105-1111）を参考に以下の方法で酢酸誘発腸炎モデルの作成を行った。一晩絶食下の雄性スプラグ・ダウレー (Sprague-Dawley:SD) 系ラット又はウィスター (Wistar) 系ラットを用いた。エーテル軽麻酔下で10 cm長のプラスチックゾンデをラット肛門より挿入し、ゾンデ先端が肛門から8 cmの位置になるように調節した。4%酢酸を含む生理食塩水1 mLをプラスチックゾンデより注入後30秒間静置し、その後1 mLの生理食塩水にて2回直腸内を洗浄した。本処置7日後のラットを「緩解期IBDラット」として、実施例２に示す試験を行った。また、同様の操作により生理食塩水の注入を行ったものを対照群とした。
　なお、酢酸処置１～２日後は腸内の炎症の指標であるミエロパーオキシダーゼ（MPO）活性が上昇するものの、７日後にはMPO活性は対照群と同等にまで戻り、肉眼的には炎症像も観察されないことを確認した。 Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.
Example 1: Preparation of remission stage IBD rat (acetic acid-induced enteritis healing model) Acetic acid-induced enteritis by the following method with reference to the method of Blandino II et al. (J. Gastroenterol. Hepatol, 2001, 16 (10), 1105-1111) A model was created. Male Sprague-Dawley (SD) rats or Wistar rats under overnight fasting were used. Under ether light anesthesia, a 10 cm long plastic sonde was inserted from the rat anus and adjusted so that the tip of the sonde was 8 cm from the anus. 1 mL of physiological saline containing 4% acetic acid was injected from a plastic sonde and allowed to stand for 30 seconds, and then the rectum was washed twice with 1 mL of physiological saline. The test shown in Example 2 was conducted by setting the rats 7 days after the treatment as “remission-phase IBD rats”. A control group was injected with physiological saline by the same operation.
Although myeloperoxidase (MPO) activity, which is an index of inflammation in the intestine, increases after 1-2 days after acetic acid treatment, MPO activity returns to the same level as in the control group after 7 days. Was also observed.
実施例２：拘束ストレス誘発排便亢進試験
　ラモセトロン塩酸塩もしくはアロセトロン塩酸塩を0.5%メチルセルロース水溶液にそれぞれ溶解して使用した。「緩解期IBDラット」又は実施例１の4%酢酸の代わりに生理食塩水を処置した「対照群ラット」に、被験化合物又は溶媒を経口投与し、その30分後に動物を拘束ストレスケージ（商品名：KN-468(B)、夏目製作所）内に挿入した。拘束ストレス負荷開始から1時間後までに排泄した便の総個数及び総湿重量を測定した。一方、正常群として「緩解期IBDラット」を個別ケージに入れ、同様に1時間で排泄した便の個数を測定した。
　図１のとおり、「緩解期IBDラット」（4%酢酸処置）では「対照群ラット」（生理食塩水処置）に比べて、拘束ストレスによる排便亢進反応が有意に増大していることが明らかとなった。
　図２及び３のとおり、ラモセトロン塩酸塩及びアロセトロン塩酸塩は、「緩解期IBDラット」（4%酢酸処置）における拘束ストレス誘発排便亢進に対して、有意な抑制作用を示した。 Example 2: Restraint stress-induced defecation enhancement test Ramosetron hydrochloride or allosetron hydrochloride was dissolved in 0.5% aqueous methylcellulose solution and used. The test compound or solvent was orally administered to the “control rat” treated with physiological saline instead of the 4% acetic acid of Example 1 or the “remission phase IBD rat”, and the animal was restrained by a restraint stress cage (product) Name: KN-468 (B), Natsume Seisakusho). The total number of feces excreted from the beginning of restraint stress load and the total wet weight were measured 1 hour later. On the other hand, “remission phase IBD rats” as normal groups were placed in individual cages, and the number of feces excreted in 1 hour was measured in the same manner.
As shown in FIG. 1, it is clear that the defecation enhancement response due to restraint stress is significantly increased in the “remission phase IBD rat” (4% acetic acid treatment) compared to the “control group rat” (saline treatment). became.
As shown in FIGS. 2 and 3, ramosetron hydrochloride and alosetron hydrochloride showed a significant inhibitory effect on restraint stress-induced defecation enhancement in “remission phase IBD rats” (4% acetic acid treatment).
実施例３：緩解期の炎症性腸疾患患者に対する臨床試験
　排便異常を訴える緩解期の炎症性腸疾患患者に対して、イリボー錠5μg（ラモセトロン塩酸塩）１日１回１錠を朝食後に経口投与する。原則として、投与開始前と投与開始後２週に患者の排便症状を問診する。投与開始後２週の患者の排便状態によって、薬剤の投与量を１日１回投与量として2.5μg～10μgの範囲で適宜増減する。 Example 3: Clinical trial for patients with inflammatory bowel disease in remission phase For patients with inflammatory bowel disease in remission phase complaining of defecation, 5 μg of iribo tablet (ramosetron hydrochloride) is orally administered once daily after breakfast To do. As a general rule, patients will be inquired about defecation symptoms before the start of administration and 2 weeks after the start of administration. Depending on the defecation status of the patient 2 weeks after the start of administration, the dose of the drug is adjusted as appropriate within a range of 2.5 μg to 10 μg as a once-daily dose.
　本発明により、未だ有効な治療法のない難治性慢性疾患であるIBD患者の緩解維持に寄与する、緩解期の排便異常改善剤を提供できる。 The present invention can provide an agent for improving defecation abnormalities during remission that contributes to maintaining remission in IBD patients who are intractable chronic diseases for which there is still no effective treatment.

Claims (15)

  1. ラモセトロン、アロセトロン又はこれらの製薬学的に許容される塩を有効成分として含有する緩解期の炎症性腸疾患患者における排便異常治療剤。 A therapeutic agent for defecation abnormalities in patients with inflammatory bowel disease in remission containing ramosetron, alosetron or a pharmaceutically acceptable salt thereof as an active ingredient.
  2. 有効成分がラモセトロン又はその製薬学的に許容される塩である請求項１の剤。 The agent of claim 1, wherein the active ingredient is ramosetron or a pharmaceutically acceptable salt thereof.
  3. 緩解期の炎症性腸疾患患者における排便異常が下痢症状である請求項１又は２の剤。 3. The agent according to claim 1 or 2, wherein the defecation abnormality in a patient with inflammatory bowel disease in remission is diarrhea.
  4. ラモセトロン、アロセトロン又はこれらの製薬学的に許容される塩を有効成分として含有する緩解期の炎症性腸疾患患者における排便異常治療用医薬組成物。 A pharmaceutical composition for treating defecation abnormalities in patients with inflammatory bowel disease in remission, comprising ramosetron, alosetron, or a pharmaceutically acceptable salt thereof as an active ingredient.
  5. 有効成分がラモセトロン又はその製薬学的に許容される塩である請求項４の医薬組成物。 The pharmaceutical composition according to claim 4, wherein the active ingredient is ramosetron or a pharmaceutically acceptable salt thereof.
  6. 緩解期の炎症性腸疾患患者における排便異常が下痢症状である請求項４又は５の医薬組成物。 6. The pharmaceutical composition according to claim 4 or 5, wherein the defecation abnormality in a patient with inflammatory bowel disease in remission is diarrhea.
  7. 緩解期の炎症性腸疾患患者における排便異常治療剤の製造のための、ラモセトロン、アロセトロン又はこれらの製薬学的に許容される塩の使用。 Use of ramosetron, alosetron or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for abnormal defecation in patients with inflammatory bowel disease in remission phase.
  8. 緩解期の炎症性腸疾患患者における排便異常治療剤の製造のための、ラモセトロン又はその製薬学的に許容される塩の使用。 Use of ramosetron or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for abnormal defecation in patients with inflammatory bowel disease in remission phase.
  9. 緩解期の炎症性腸疾患患者における排便異常が下痢症状である請求項７又は８の使用。 The use according to claim 7 or 8, wherein the defecation abnormality in a patient with inflammatory bowel disease in remission is diarrhea.
  10. 緩解期の炎症性腸疾患患者における排便異常の治療用のラモセトロン、アロセトロン又はこれらの製薬学的に許容される塩。 Ramosetron, alosetron or a pharmaceutically acceptable salt thereof for the treatment of defecation abnormalities in patients with inflammatory bowel disease in remission.
  11. 緩解期の炎症性腸疾患患者における排便異常の治療用のラモセトロン又はその製薬学的に許容される塩。 Ramosetron or a pharmaceutically acceptable salt thereof for the treatment of defecation abnormalities in patients with inflammatory bowel disease in remission phase.
  12. 緩解期の炎症性腸疾患患者における排便異常が下痢症状である請求項１０または１１の化合物又はその塩。 The compound or salt thereof according to claim 10 or 11, wherein the defecation abnormality in a patient with inflammatory bowel disease in remission is diarrhea.
  13. 緩解期の炎症性腸疾患患者における排便異常の治療方法であって、ラモセトロン、アロセトロン又はこれらの製薬学的に許容される塩の有効量を当該患者に投与することを含む方法。 A method for treating defecation abnormalities in a patient with inflammatory bowel disease in remission, comprising administering to the patient an effective amount of ramosetron, alosetron, or a pharmaceutically acceptable salt thereof.
  14. ラモセトロン又はその製薬学的に許容される塩の有効量を患者に投与することを含む請求項１３の方法。 14. The method of claim 13, comprising administering to the patient an effective amount of ramosetron or a pharmaceutically acceptable salt thereof.
  15. 緩解期の炎症性腸疾患患者における排便異常が下痢症状である請求項１３又は１４の方法。 The method according to claim 13 or 14, wherein the defecation abnormality in a patient with inflammatory bowel disease in remission is diarrhea.
PCT/JP2010/061009 2009-06-30 2010-06-29 Therapeutic agent for abnormal defecation in inflammatory bowel disease patient who is in remission phase WO2011001954A1 (en)

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JP2001518495A (en) * 1997-10-07 2001-10-16 グラクソ グループ リミテッド Medicine

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