WO2017104728A1 - Médicament destiné à traiter une allergie alimentaire - Google Patents

Médicament destiné à traiter une allergie alimentaire Download PDF

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Publication number
WO2017104728A1
WO2017104728A1 PCT/JP2016/087326 JP2016087326W WO2017104728A1 WO 2017104728 A1 WO2017104728 A1 WO 2017104728A1 JP 2016087326 W JP2016087326 W JP 2016087326W WO 2017104728 A1 WO2017104728 A1 WO 2017104728A1
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WIPO (PCT)
Prior art keywords
cells
allergen
food allergy
crth2 antagonist
specific ige
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PCT/JP2016/087326
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English (en)
Japanese (ja)
Inventor
幸久 村田
真吾 前田
達朗 中村
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国立大学法人東京大学
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Priority to JP2017556113A priority Critical patent/JPWO2017104728A1/ja
Publication of WO2017104728A1 publication Critical patent/WO2017104728A1/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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a food allergy allergen-specific IgE production inhibitor useful for the treatment of food allergies.
  • Food allergies are various allergic reactions that occur when allergens contained in food are taken into the body. Symptoms include diarrhea, vomiting, dermatitis, etc., and when severe, causes anaphylactic shock leading to death. The incidence of adults in Japan is as high as 2.6%, but it is a serious problem because it is 5.3% higher in newborns and there are many severe cases. In addition to eggs, milk and wheat that cause severe symptoms, there are many foods that can be allergens, and these are dangerous because even a very small amount can cause strong symptoms. The only way to prevent food allergies is to identify allergens and avoid eating, but this is difficult under the current food situation where processed foods are distributed globally, and the QOL of patients who cannot eat food with peace of mind is significantly impaired. It is. Changes in the living environment of modern people change the immune response balance in the body, further increasing the prevalence of allergic diseases and worsening symptoms, and the development of therapeutic drugs is urgently needed .
  • Dendritic cells take in antigens that have entered the body and migrate to secondary lymphoid tissues such as the spleen to transmit antigen information to T cells.
  • T cells transmit antigen information to B cells.
  • B cells Promotes proliferation and IgE production
  • IgE IgE production
  • mast cells recognize it via IgE and release pro-inflammatory substances, causing strong inflammation.
  • Prostaglandin D 2 (PGD 2 ) is a physiologically active substance that mast cells produce most.
  • CRTH2 which is a receptor for PGD 2 exists in eosinophils and the like, and it is known that the CRTH2 antagonist is effective for allergic rhinitis and the like (Patent Documents 1 to 4).
  • Non-patent Document 1 Non-patent Document 1
  • food allergies are treated by removing foods that do not consume the causative allergen, and some desensitization treatments (oral immunotherapy) that ingest the causative allergen in small quantities are also dangerous.
  • oral immunotherapy oral immunotherapy
  • bronchodilators ⁇ 2 agonists
  • an object of the present invention is to provide a drug capable of treating food allergy.
  • ovalbumin ovalbumin
  • a CRTH2 antagonist which is a representative food allergen
  • symptom such as diarrhea
  • inhibition of allergen-specific IgE production by a CRTH2 antagonist is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by the CRTH2 antagonist.
  • Allergic rhinitis also occurs in mast cell-deficient mice and is less dependent on mast cells.
  • the present invention provides the following [1] to [20].
  • a food allergy allergen-specific IgE production inhibitor comprising a CRTH2 antagonist as an active ingredient.
  • Food allergy allergen-specific IgE production according to [1] wherein the suppression of food allergen-specific IgE production is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by a CRTH2 antagonist. Inhibitor.
  • a food allergy remedy comprising the food allergy allergen-specific IgE production inhibitor of any one of [1] to [3].
  • a CRTH2 antagonist for producing a food allergy allergen-specific IgE production inhibitor.
  • a food allergy allergen-specific IgE production inhibitor containing a CRTH2 antagonist for the production of a food allergy therapeutic agent.
  • a CRTH2 antagonist for producing an inhibitor of increased mast cell number and / or mast cell activity in food allergy.
  • CRTH2 antagonist according to [11] or [12], wherein the CRTH2 antagonist is a component selected from ramatroban and CAY10471.
  • a method for inhibiting food allergy allergen-specific IgE production comprising administering an effective amount of a CRTH2 antagonist.
  • a CRTH2 antagonist is used, food allergy can be treated as a result by suppressing the production of food allergen allergen-specific IgE and further suppressing the increase of mast cells and / or the activity of mast cells.
  • the lipid dynamics of the secondary lymph nodes are shown. Serum OVA-specific IgE and IgA are shown. Showing food allergy symptoms. PGD 2 and IgE production are shown. Cell localization in the spleen is shown. FIG. 2 shows OVA-specific IgE of T cells, B cells, dendritic cell transplanted CRTH2 ⁇ / ⁇ mice. Cell localization in the spleen is shown. Shows food allergy treatment effect of ramatroban. Fig. 5 shows changes in mast cells by food allergy stimulation to CRHT2 knockout mice. The change of the mast cell of the food allergy mouse
  • the active ingredient of the food allergy allergen-specific IgE production inhibitor, mast cell increase and / or mast cell activity inhibitor and food allergy therapeutic agent of the present invention is a CRTH2 antagonist.
  • CRTH2 antagonists are effective for the treatment of allergic rhinitis and bronchial asthma as described in Patent Documents 1 to 3, but there are no examples of whether or not they are effective for the treatment of food allergies. There is no example of testing whether it is effective in suppressing specific IgE production. Allergic rhinitis also occurs in mast cell-deficient mice and is less dependent on mast cells.
  • CRTH2 antagonists include ramatroban and CAY10471, as well as, for example, Japanese Patent No. 4313819, Japanese Patent No. 5629403, Japanese Translation of PCT International Publication No. 2009-511591, Japanese Patent Publication No. 2009-533473, Japanese Patent Publication No. And compounds described in JP-A No. 544721 and JP-A No. 2014-507449.
  • ramatroban 4- (3- [3- [3- (diphenylmethyl) -6-oxopyridazin-1 (6H) -yl] propyl] phenoxy) butanoic acid, 1- ⁇ 6- [2- (2,4-dichloro-phenyl) -ethylamino] -2-methyl-pyrimidin-4-yl ⁇ -pyrrolidine-3-carboxylic acid, 2- (1- ⁇ 2-methoxy-6- [2- (4-trifluoromethoxy-phenyl) -ethylamino] -pyrimidin-4-yl ⁇ -piperidin-3-yl) -2-methyl-propionic acid, 2- [3- ⁇ 6- [2- (2,4-Dichloro-phenyl) -ethylamino] -2-methoxy-pyrimidin-4-yl ⁇ -5- (1-hydroxy-1-methyl-ethyl)- Phenyl] -propan-2-ol
  • the CRTH2 antagonist has the effect of remarkably suppressing food allergy allergen-specific IgE production and improving food allergy symptoms.
  • the IgE production inhibitory action is due to inhibition of association of dendritic cells, T cells and B cells in secondary lymphoid tissues by the CRTH2 antagonist.
  • CRTH2 antagonists suppress the increase in the number of mast cells and / or mast cell activity in food allergy.
  • Foods containing food allergens include chicken eggs, dairy products, wheat, crustaceans, fruits, buckwheat, fish, peanuts, fish eggs, soybeans, and the like. Since IgE whose production is suppressed by the medicament of the present invention is specific to these allergens, it can effectively improve food allergy symptoms.
  • Symptoms of food allergy improved by the medicament of the present invention include skin symptoms such as hives, itching and redness; respiratory symptoms such as cough and dyspnea; mucosal symptoms such as oral mucosa and throat mucosa; diarrhea, abdominal pain, Gastrointestinal symptoms such as nausea and vomiting; anaphylactic symptoms and the like.
  • the IgE production inhibitor and food allergy therapeutic agent of the present invention can be a pharmaceutical composition containing CRTH2 as an active ingredient.
  • the pharmaceutical composition can contain a pharmaceutically acceptable carrier.
  • This pharmaceutical composition can be administered orally or parenterally in the form of tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments or poultices. May be.
  • Tablets, powders, granules, etc. are used as solid compositions intended for oral administration.
  • These types of solid compositions are one mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc. Or more active substances.
  • the composition is in addition to the inert excipients described above, for example, a lubricant such as magnesium stearate, a disintegrant such as cellulose calcium glycolate, a stabilizer such as lactose, and glutamic acid or aspartic acid.
  • tablets and pills may be coated with a sugar or gastric or enteric film, such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or the like.
  • Liquid compositions intended for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like containing conventional inert diluents such as pure water or ethyl alcohol.
  • these compositions are further used for pharmaceuticals such as solubilizers, solubilizers, wetting promoters, suspension promoters, and sweeteners, flavoring agents, fragrances, and preservatives.
  • An adjuvant may be contained.
  • Injectables intended for parenteral administration include, for example, sterile, aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Diluents for aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
  • Diluents for non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, polysorbate 80 (registered trademark)).
  • compositions may further contain additives such as isotonicity adjusting agents, preservatives, wetting accelerators, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizers, and dissolution accelerators. They are sterilized by filtration through a bacteria capture filter or by adding a bactericidal agent to them or by irradiating them with radiation. Sterile solid compositions may be prepared in advance and may be dissolved in sterile water or solvent for injection before use.
  • additives such as isotonicity adjusting agents, preservatives, wetting accelerators, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizers, and dissolution accelerators. They are sterilized by filtration through a bacteria capture filter or by adding a bactericidal agent to them or by irradiating them with radiation. Sterile solid compositions may be prepared in advance and may be dissolved in sterile water or solvent for injection before use.
  • the dose of the medicament of the present invention may be appropriately determined according to the disease state, body weight, age, and sex of the patient to be administered.
  • the amount of the active ingredient is 0.1 to 500 mg /
  • parenteral administration 0.01 to 100 mg / adult / day is preferred. This may be administered to the patient in full doses at once, or divided into several doses for multiple doses.
  • Example 1 (Method) Using C57BL / 6 mice (wild; CRTH2 + / + ) and the same type of CRTH2 ⁇ / ⁇ (CRTH2 knockout mice), allergic symptoms, secondary lymph node lipid dynamics, dendritic cells in secondary lymphoid tissues, T cells and B cells: OVA-specific IgE was examined. Ovalbumin (OVA) was used as an antigen. Sensitization was performed by intraperitoneally administering 50 ⁇ g of OVA twice from Day 0 to Day 14. OVA 10 mg was orally administered once every two days from Day 28 to Day 46.
  • OVA Ovalbumin
  • FIG. 1 shows that arachidonic acid (AA), PGE 2, PGD 2 and the like in the spleen are significantly increased in food allergy.
  • T cells, B cells, and dendritic cells were isolated from the spleen of wild-type mice, and each cell was transferred to CRTH2 knockout mice. Thereafter, sensitization with OVA was performed, and OVA-specific IgE of Day 28 was measured. As shown in FIG. 6, the production of OVA-specific IgE was suppressed in CRTH2 knockout mice compared to the wild type, whereas the production of OVA-specific IgE was increased in CRTH2 knockout mice transfected with wild type dendritic cells. . Transplantation of wild-type T cells and B cells did not change the production of OVA-specific IgE.
  • H-PGDS prostaglandin D synthase
  • Example 2 In the food allergy model mouse (wild type) by OVA administration used in Example 1, 30 mg / kg of ramatroban was orally administered once a day to Day 28 to Day 46. Allergic symptoms, diarrhea and serum OVA-specific IgE concentrations were measured. As a result, as shown in FIG. 8, administration of ramatroban, which is a CRTH2 antagonist, improved allergic symptoms and diarrhea symptoms, and significantly reduced the production of serum OVA-specific IgE.
  • Example 3 Changes in the number of mast cells in food allergy and the effect of ramatroban administration on the number of mast cells were investigated.
  • CRVA2-deficient mice were administered OVA in the same manner as in Example 1, and the number of mast cells in food allergy was measured.
  • the change of the number of mast cells by ramatroban administration was also examined.
  • the number of mast cells in the colon and ileum was increased by food allergy, but the number of mast cells in the colon and ileum was suppressed in CRTH2 knockout mice.
  • the number of mast cells in the skin (ear) does not increase.
  • Example 4 An antihistamine (diphenhydramine) used as a therapeutic agent for allergic rhinitis was administered to OVA-induced food allergies, and changes in the number of mast cells in the colon and ileum and changes in urinary PGDM were examined.
  • the antihistamine H 1 -blocker
  • FIG. 11A the antihistamine
  • FIG. 11B the number of mast cells
  • FIG. 11D the antihistamine (H 1 -blocker) does not suppress food allergy symptoms
  • FIG. 11B the number of mast cells
  • It does not affect urinary PGDM (FIG. 11C) and does not significantly change PGDM as an index of inflammation (FIG. 11D).
  • Example 5 Bala / c mice (wild; CRTH2 + / + ) and the same kind of CRTH2 ⁇ / ⁇ (CRTH2 knockout mice) were used to examine OVA-specific IgE.
  • Ovalbumin (OVA) was used as an antigen. Sensitization was performed by subcutaneously administering 300 ⁇ g of OVA twice every other week.
  • OVA-specific IgE concentration of OVA-specific IgE in the serum was measured. As a result, as shown in FIG. 12, OVA-specific IgE increased in the wild type, whereas suppression of OVA-specific IgE production was observed in the CRTH2 knockout mouse.

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  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne un nouveau médicament destiné à traiter une allergie alimentaire. Un inhibiteur de la production des IgE spécifiques d'un allergène provoquant une allergie alimentaire est décrit, ledit inhibiteur comprenant un antagoniste de CRTH2 à titre de principe actif.
PCT/JP2016/087326 2015-12-16 2016-12-15 Médicament destiné à traiter une allergie alimentaire WO2017104728A1 (fr)

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JP2017556113A JPWO2017104728A1 (ja) 2015-12-16 2016-12-15 食物アレルギー治療薬

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021066136A1 (fr) * 2019-10-03 2021-04-08 国立大学法人東京大学 Agent thérapeutique pour dystrophies musculaires

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009063215A2 (fr) * 2007-11-13 2009-05-22 Oxagen Limited Utilisation de composés antagonistes de crth2
JP2010513224A (ja) * 2006-12-14 2010-04-30 アステラス製薬株式会社 Ｃｒｔｈ２拮抗剤および抗アレルギー剤として有用な多環酸化合物
JP2011503045A (ja) * 2007-11-13 2011-01-27 オキサジェン リミテッド Ｃｒｔｈ２拮抗化合物の使用
US20110311483A1 (en) * 2010-03-30 2011-12-22 Ironwood Pharmaceuticals, Inc. Crth2 modulators
WO2012137885A1 (fr) * 2011-04-05 2012-10-11 学校法人 慶應義塾 Agent pour inhiber ou prévenir la fibrose interstitielle rénale
JP2013515726A (ja) * 2009-12-23 2013-05-09 アイロンウッド ファーマシューティカルズ， インコーポレイテッド Ｃｒｔｈ２モジュレーター

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010513224A (ja) * 2006-12-14 2010-04-30 アステラス製薬株式会社 Ｃｒｔｈ２拮抗剤および抗アレルギー剤として有用な多環酸化合物
WO2009063215A2 (fr) * 2007-11-13 2009-05-22 Oxagen Limited Utilisation de composés antagonistes de crth2
JP2011503045A (ja) * 2007-11-13 2011-01-27 オキサジェン リミテッド Ｃｒｔｈ２拮抗化合物の使用
JP2013515726A (ja) * 2009-12-23 2013-05-09 アイロンウッド ファーマシューティカルズ， インコーポレイテッド Ｃｒｔｈ２モジュレーター
US20110311483A1 (en) * 2010-03-30 2011-12-22 Ironwood Pharmaceuticals, Inc. Crth2 modulators
WO2012137885A1 (fr) * 2011-04-05 2012-10-11 学校法人 慶應義塾 Agent pour inhiber ou prévenir la fibrose interstitielle rénale

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021066136A1 (fr) * 2019-10-03 2021-04-08 国立大学法人東京大学 Agent thérapeutique pour dystrophies musculaires

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