WO2011001954A1 - Agent thérapeutique pour la défécation anormale chez un patient atteint d'une maladie intestinale inflammatoire en phase de rémission - Google Patents

Agent thérapeutique pour la défécation anormale chez un patient atteint d'une maladie intestinale inflammatoire en phase de rémission Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
remission
inflammatory bowel
bowel disease
defecation
ramosetron
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PCT/JP2010/061009
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English (en)
Japanese (ja)
Inventor
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/ja
Publication of WO2011001954A1 publication Critical patent/WO2011001954A1/fr

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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.

Abstract

L'agent thérapeutique pour la défécation anormale chez un patient atteint d'une maladie intestinale inflammatoire en phase de rémission ci-décrit comprend du ramosétron, de l'alosétron, ou un sel pharmaceutiquement acceptable de ceux-ci à titre de principe actif.
PCT/JP2010/061009 2009-06-30 2010-06-29 Agent thérapeutique pour la défécation anormale chez un patient atteint d'une maladie intestinale inflammatoire en phase de rémission WO2011001954A1 (fr)

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JP2011520921A JP5741433B2 (ja) 2009-06-30 2010-06-29 緩解期の炎症性腸疾患患者における排便異常治療剤

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JP2009-154486 2009-06-30
JP2009154486 2009-06-30

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001518495A (ja) * 1997-10-07 2001-10-16 グラクソ グループ リミテッド 薬 剤

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3763360B2 (ja) * 2004-01-30 2006-04-05 アステラス製薬株式会社 下痢型過敏性腸症候群治療剤
TW200838534A (en) * 2007-02-07 2008-10-01 Astellas Pharma Inc Treatment for irritable bowel syndrome

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001518495A (ja) * 1997-10-07 2001-10-16 グラクソ グループ リミテッド 薬 剤

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHOI, Y. ET AL.: "Increased 5-Hydroxytryptamine Mediates Post-Inflammatory Visceral Hypersensitivity via the 5-Hydroxytryptamine 3 Receptor in Rats", DIGESTIVE DISEASES AND SCIENCES, vol. 53, no. 11, 2008, pages 2909 - 2916, XP019641042, DOI: doi:10.1007/s10620-008-0244-8 *
K. MOUSAVIZADEH ET AL.: "Anti-inflammatory effects of 5-HT3 receptor antagonist, tropisetron on experimental colitis in rats", EUR J CLIN INVEST, vol. 39, no. 5, May 2009 (2009-05-01), pages 375 - 383 *
MAGNUS SIMREN ET AL.: "Quality of life in inflammatory bowel disease in remission: the impact of IBS-like symptoms and associated psychological factors", THE AMERICAN JOURNAL OF GASTROENTEROLOGY, vol. 97, no. 2, February 2009 (2009-02-01), pages 389 - 396 *

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KR20120111954A (ko) 2012-10-11
JP5741433B2 (ja) 2015-07-01
JPWO2011001954A1 (ja) 2012-12-13

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