WO2017111069A1 - Agent antiprurigineux - Google Patents

Agent antiprurigineux Download PDF

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Publication number
WO2017111069A1
WO2017111069A1 PCT/JP2016/088465 JP2016088465W WO2017111069A1 WO 2017111069 A1 WO2017111069 A1 WO 2017111069A1 JP 2016088465 W JP2016088465 W JP 2016088465W WO 2017111069 A1 WO2017111069 A1 WO 2017111069A1
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WO
WIPO (PCT)
Prior art keywords
pruritus
sulforaphane
dermatitis
precursor
atopic dermatitis
Prior art date
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PCT/JP2016/088465
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English (en)
Japanese (ja)
Inventor
幾雄 林
光洋 今野
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東レ株式会社
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Publication date
Application filed by 東レ株式会社 filed Critical 東レ株式会社
Priority to JP2017501045A priority Critical patent/JPWO2017111069A1/ja
Publication of WO2017111069A1 publication Critical patent/WO2017111069A1/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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/26—Cyanate or isocyanate esters; Thiocyanate or isothiocyanate esters

Definitions

  • the present invention relates to an antidiarrheal agent.
  • Atopic dermatitis is caused by various nonspecific irritation reactions and specific allergic reactions, accompanied by skin physiological abnormalities such as skin dryness and barrier dysfunction caused by abnormalities in the epidermis, especially stratum corneum. It is a disease in the eczema dermatitis group whose chronic pathology is inflammation and pruritus (Non-patent Document 1).
  • atopic dermatitis nerve growth factor causes nerve extension into the epidermis and a decrease in nerve activation threshold, and it is considered that a state of hypersensitivity that is easy to accept or transmit itching signals is formed. It has been.
  • pruritus associated with atopic dermatitis leads to worsening dermatitis by causing scratching action against pruritus, and itching is further enhanced by worsening dermatitis, “pruritus-scratching-dermatitis.
  • Patent Document 2 In the treatment of atopic dermatitis, it is considered that not only treatment of atopic dermatitis itself but also suppression of pruritus is important for early improvement in the treatment of atopic dermatitis.
  • corticosteroids or immunosuppressants are mainly used to suppress dermatitis when applied externally for the purpose of supplementing skin dryness and barrier function and preventing relapse of dermatitis.
  • a humectant is also used.
  • antihistamines or antiallergic agents are used as internal preparations (Non-patent Document 1).
  • sulforaphane is a substance contained in cruciferous plants such as broccoli, broccoli sprout, cauliflower, kale and brussels sprouts.
  • sulforaphane exists as sulforaphane glucosinolate which is a precursor thereof, and is converted into sulforaphane by being decomposed in the body after ingestion (Non-patent Document 3).
  • Non-patent Document 3 the bacteriostatic action and bactericidal action of sulforaphane against Helicobacter pylori, which is considered to be one of the causes of gastritis and gastric cancer, has been reported (Non-patent Document 4). Furthermore, in the 9,10-dimethyl-1,2-benzanthracene-induced rat breast cancer model, the anticancer effect of sulforaphane has also been reported (Non-patent Document 5).
  • isothiocyanates have an inhibitory effect on migration of inflammatory cells such as neutrophils and eosinophils, and an inhibitory effect on mast cell degranulation, which improves type I allergic symptoms in the body, resulting in pollinosis. It has been reported that atopic diseases such as atopic dermatitis and bronchial asthma improve (Patent Document 1), but the anti-inflammatory action of sulforaphane is not disclosed, and the antipruritic action of sulforaphane is also disclosed It has not been done.
  • topical corticosteroids and immunosuppressants for external use need to be administered over a long period of time for the treatment of atopic dermatitis, and there are concerns about side effects.
  • these existing drugs can suppress pruritus secondary by suppressing dermatitis, it is difficult to immediately suppress pruritus associated with atopic dermatitis.
  • an object of the present invention is to provide an antipruritic agent that immediately exerts an antipruritic effect against intractable pruritus typified by atopic dermatitis.
  • the present invention provides an antidiarrheal agent containing sulforaphane or a precursor thereof as an active ingredient.
  • the above antidiarrheal drugs are atopic dermatitis, contact dermatitis, sebum deficiency, senile skin pruritus, hives, psoriasis, malignant tumor, liver disease, chronic kidney disease, renal failure, blood disease, hemodialysis, It is preferably an antidiarrheal agent for intractable pruritus associated with peritoneal dialysis or multiple sclerosis, and particularly preferably an antidiarrheal agent for intractable pruritus associated with atopic dermatitis.
  • Pruritus can be treated or prevented by a mechanism different from that of drugs.
  • the present invention also provides a cosmetic composition for improving or preventing pruritus, which contains the above active ingredient.
  • the present invention also provides a food composition for improving or preventing pruritus, which contains the above active ingredient.
  • the antipruritic agent of the present invention immediately exerts an antipruritic effect against intractable pruritus typified by atopic dermatitis. For this reason, the antipruritic agent of the present invention greatly contributes to the cessation of the “pruritus-scratch-dermatitis worsening” cycle and improvement of the patient's QOL, and even for atopic dermatitis, which is difficult to treat, The therapeutic effect can be demonstrated by a new mechanism.
  • the cosmetic composition or food composition of the present invention is useful in that it can improve or prevent pruritus of the skin at an early stage.
  • the antidiarrheal agent of the present invention is characterized by containing sulforaphane as an active ingredient.
  • the sulforaphane is a substance represented by the following formula (I), also known as 1-isothiocyanate-4-methylsulfinylbutane.
  • the sulforaphane represented by the above formula (I) includes racemates and optical isomers, but includes not only single isomers but also mixtures of racemates and optical isomers.
  • the racemic form of sulforaphane is expressed as, for example, D, L-sulforaphane or R, S-sulforaphane.
  • the sulforaphane represented by the above formula (I) may be either a natural sulforaphane isolated and purified from a plant or a synthetic sulforaphane produced by chemical synthesis.
  • a method for isolating and purifying sulforaphane (special table 2015-519358) and a synthesis method (special table 2015-518041, Schmid et al., Helvetica Chimica Acta, 1948, Vol. 31 (6), pp. 1497-1505) are known in the art.
  • the sulforaphane represented by the above formula (I) is commercially available, and a commercially available product can also be used.
  • the antipruritic agent described above is characterized by containing a sulforaphane precursor as an active ingredient.
  • the aforementioned sulforaphane precursor is a substance that is converted or metabolized into sulforaphane by an enzyme.
  • the sulforaphane precursor is preferably sulforaphane glucosinolate.
  • sulforaphane glucosinolate is also called glucoraphanin.
  • sulforaphane precursors include racemates and optical isomers, but include not only single isomers but also racemic and optical isomer mixtures.
  • the above-mentioned sulforaphane precursor (preferably sulforaphane glucosinolate) may be either a natural sulforaphane precursor isolated and purified from a plant, or a synthetic sulforaphane precursor produced by chemical synthesis. Methods for isolating and purifying sulforaphane precursors and synthesis methods are known in the art. Moreover, the sulforaphane precursor is commercially available, and a commercially available product can also be used.
  • “Pruritus” is a skin-specific sensation accompanied by the desire to scratch, such as atopic dermatitis, neurodermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar skin
  • skin diseases such as inflammation, sebum deficiency, senile skin pruritus, insect bites, photosensitivity, hives, urticaria, blisters, impetigo, eczema, ringworm, lichen, psoriasis, scabies or acne vulgaris Pruritus as primary disease, malignant tumor, diabetes, liver disease, chronic kidney disease, renal failure, blood disease, hemodialysis, peritoneal dialysis or multiple sclerosis as primary disease, or drug or psychogenic The itch that happens is mentioned.
  • pruritus is roughly divided into pruritus mediated by histamine and pruritus not mediated by histamine (refractory pruritus).
  • the antipruritic agent of the present invention is particularly pruritus that is not mediated by histamine. It is effective against (refractory pruritus).
  • pruritus without histamine examples include, for example, atopic dermatitis, contact dermatitis, sebum deficiency, senile cutaneous pruritus, urticaria, psoriasis, malignant tumor, liver disease, chronic kidney disease And pruritus with primary diseases such as renal failure, blood disease, hemodialysis, peritoneal dialysis, or multiple sclerosis, and exhibits therapeutic resistance to antihistamines.
  • Antidepressants are drugs used for the purpose of reducing pruritus, for example, antihistamines are mainly used as internal medicines, and opioid ⁇ receptor agonists for hemodialysis patients May be used. As external preparations, antihistamines, corticosteroids, immunosuppressants or nonsteroidal anti-inflammatory agents are used. In addition, these antipruritic agents can also be used preventively for the purpose of controlling so as not to cause pruritus.
  • “Immediately” means that a single effect can provide a stopping effect within 6 hours after administration, preferably within 3 hours after administration, and more preferably within 1 hour after administration.
  • the antipruritic effect of the above antipruritic agent can be evaluated in an in vivo experimental system using pruritus model animals, and the scratching behavior of mice induced by various nuisance substances typified by histamine, chloroquine or substance P
  • the pruritus model as an index is common.
  • Togashi et al. European Journal of Pharmacology, 2002, Vol. 435, p. 259
  • Andoh et al. European Journal of Pharmacology, 2002, Vol. 436, p. 436.
  • Substance P-induced scratching behavior using mice and chloroquine-induced scratching behavior using mice described in the literature of Marino et al. are antihistamines. Can be used as one of the ineffective refractory pruritus models.
  • the antipruritic effect of antipruritic agents against pruritus associated with atopic dermatitis is, for example, an in vivo experimental system using the scratching behavior of pruritus model animals having an atopic dermatitis-like skin lesion as an index. Can be evaluated.
  • Examples of pruritus model animals having atopic dermatitis-like skin lesions include, for example, NC / Nga mice that spontaneously develop dermatitis in a normal rearing environment (Takano et al., European Journal of Pharmacology, 2004, No. 495). Volume, p.
  • oxazolone the hapten 2,4,6-trinitrochlorobenzene or 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one
  • oxazolone-induced dermatitis model Model in which dermatitis was induced (Oxazolone-induced dermatitis model) (Ueda et al., International Immunopharmacology, 2006, Vol. 6, p. 1609, or Tsukumo et al., Journal of Pharmacolog cal Sciences, 2010 years, vol. 113, p.255) or the like can be used.
  • the scratching behavior of pruritus model animals having such atopic dermatitis-like skin lesions is suppressed by an opioid ⁇ receptor antagonist, and thus is recognized as an itching-related reaction rather than a pain-related reaction.
  • the antipruritic agent described above is a useful drug (especially atopic) when administered to mammals (eg, mice, rats, hamsters, rabbits, dogs, monkeys, cows, sheep or humans), particularly humans. It can be used as an antipruritic agent for pruritus associated with dermatitis). Or you may use said sulforaphane or its precursor as an active ingredient of cosmetics composition or a food composition, or make it contain in this.
  • sulforaphane or a precursor thereof may be used as it is, or an excipient, stabilizer, preservative, buffer, solubilizer, emulsifier, diluent or Additives such as tonicity agents may be appropriately mixed.
  • said antipruritic agent can be manufactured by a normal method using these pharmaceutical carriers as appropriate.
  • the dosage form of the above antipruritic agent is, for example, an oral preparation such as a tablet, capsule, granule, powder or syrup, a parenteral preparation such as an inhalant, an injection, a suppository or a liquid, or a topical administration. Ointments, creams or patches for the purpose. Further, it may be a known continuous preparation.
  • an enzyme for example, myrosinase
  • sulforaphane an enzyme that is converted to sulforaphane may be used in combination or in combination.
  • the above-mentioned antidiarrheal agent preferably contains 0.001 to 90% by weight, more preferably 0.01 to 70% by weight, of sulforaphane or its precursor as an active ingredient.
  • the dose is appropriately selected according to symptoms, age, body weight, sex, administration method, etc.
  • As the amount of active ingredient for adults 0.001 mg to 5 g per day for injections, 0.01 mg for oral preparations It is 10 g, and can be administered once or several times.
  • binders examples include binders (syrup, gelatin, gum arabic, sorbitol, polyvinyl chloride, tragacanth, etc.), excipients (sugar, lactose, corn starch, etc.) , Calcium phosphate, sorbitol, glycine, etc.) or lubricants (magnesium stearate, polyethylene glycol, talc, silica, etc.).
  • the above antipruritic agent may be used in combination with or in combination with other drugs in order to supplement or enhance antipruritic or reduce the dose.
  • the cosmetic composition of the present invention is characterized by improving or preventing pruritus by containing sulforaphane or a precursor thereof as an active ingredient.
  • the form of the cosmetic composition can be appropriately selected and is a solution, emulsion, powder, water-oil two-layer system, water-oil-powder three-layer system, gel, tablet, etc., aerosol, mist, capsule, sheet Any form can be adopted.
  • the product form of the cosmetic composition is also arbitrary.
  • skin care cosmetics such as face wash, makeup remover, lotion, cosmetic liquid, pack, milky lotion, cream, sunscreen, foundation, makeup base, lipstick, eye Makeup cosmetics such as shadow, eyeliner, mascara, eyebrow, blusher, nail enamel, hair shampoo, hair rinse, hair styling, hair dye, hair cosmetics such as hair restorer, soap, body soap, deodorant cosmetic, bath preparation And other body cleansing agents, oral cosmetics such as dentifrices and mouthwashes, and aromatic cosmetics such as perfumes.
  • the cosmetic composition is a carrier acceptable for cosmetics, quasi-drugs, pharmaceuticals, etc., for example, powder components, liquid fats and oils, solid fats and oils, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, silicones, anionic surfactants.
  • the food composition of the present invention is characterized by improving or preventing pruritus by containing sulforaphane or a precursor thereof as an active ingredient.
  • the above food composition can be used by adding to or blending with food, beverages, feed, and pet food.
  • a food product in a pharmaceutical form can be produced in the same manner as a pharmaceutical preparation, and sulforaphane or a precursor thereof and a food-acceptable carrier such as a suitable excipient (eg, starch, processed starch, lactose, glucose, It can be produced using conventional means after mixing with water or the like.
  • a suitable excipient eg, starch, processed starch, lactose, glucose, It can be produced using conventional means after mixing with water or the like.
  • liquid food compositions such as soups, juices, milk drinks, tea drinks, coffee drinks, cocoa drinks, jelly drinks, sports drinks and diet drinks, semi-solid food compositions such as pudding and yogurt, breads, Adding or blending the above food composition into udon, noodles, cookies, chocolate, candy, gum, confectionery such as rice crackers, spreads such as sprinkles, butter, jam, etc. to produce a food composition Can do.
  • Example 1 The inhibitory effect of D, L-sulforaphan on the scratching behavior of oxazolone-induced dermatitis model mice: Atopic dermatitis model mice (oxazolone-induced dermatitis model mice) in which skin lesions are induced by repeated application of oxazolone are described in known literature (Tsukumo et al., Journal of Pharmaceutical Sciences, 2010, Vol. 113, p. 255, etc.). It produced based on the method of. In addition, the evaluation of the scratching behavior is automatically detected using MicroAct (Neuroscience) based on the method described in a publicly known document (Hashimoto et al., Allergy International, 2004, Vol. 53, p.349). I went there.
  • D, L-sulforaphane administration solution was prepared by mixing D, L-sulforaphane (Santa Cruz Biotechnology) with dimethyl sulfoxide and Tween 80, adding distilled water, and adding dimethyl sulfoxide and Tween 80. Were adjusted to a concentration of 1 v / v% each.
  • the D, L-sulforaphan administration solution or its solvent was orally administered to a mouse in the dermatitis-induced group or non-dermatitis-induced group 60 minutes before the start of measurement of the number of scratching behaviors at a volume of 10 mL / kg.
  • D, L-sulforaphane was administered at a dose of 100 mg / kg.
  • the group in which the solvent was administered to the dermatitis non-induced group was the “dermatitis non-induced-solvent administration group”
  • the group in which the solvent was administered to the dermatitis-induced group was the “dermatitis-induced solvent administration group”
  • the dermatitis-induced group was D
  • the group to which L-sulforaphan was administered was designated as “dermatitis-inducing group D, L-sulforaphan (100 mg / kg) administration group”.
  • t-test was performed as a test for the dermatitis induction-dermatosis induction-solvent administration group-D, L-sulforaphane (100 mg / kg) administration group.
  • the significance level was 5% (both sides).
  • FIG. 1 shows the effect of D, L-sulforaphane on the number of scratching behaviors of oxazolone-induced dermatitis model mice.
  • the horizontal axis shows the dermatitis non-induced-solvent administration group, dermatitis-induced solvent administration group, and dermatitis-induced D, L-sulforaphan (100 mg / kg) administration group.
  • the * mark in the figure indicates that the comparison with the dermatitis induction-solvent administration group is statistically significant (*: p ⁇ 0.05, t test).
  • D L-sulforaphan significantly suppresses the scratching behavior of an oxazolone-induced dermatitis model mouse known as an atopic dermatitis model and has an excellent antipruritic effect.
  • D L-sulforaphane was administered orally once 60 minutes before the start of the measurement of the number of scratching behaviors, and the result that the scratching behavior was suppressed was the result of pruritus associated with atopic dermatitis. It suggests that it has an immediate antipruritic effect.
  • the present invention can be used as an antidiarrheal agent for intractable pruritus typified by atopic dermatitis or a cosmetic composition or food composition for improving or preventing pruritus.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Cosmetics (AREA)

Abstract

L'objet de la présente invention est de fournir un agent antiprurigineux qui exerce un effet antiprurigineux immédiatement contre un prurit réfractaire caractérisé par une dermatite atopique. L'invention concerne un agent antiprurigineux contenant du sulforaphane ou un précurseur de celui-ci utilisé comme principe actif.
PCT/JP2016/088465 2015-12-25 2016-12-22 Agent antiprurigineux WO2017111069A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019202987A (ja) * 2018-05-22 2019-11-28 花王株式会社 感覚刺激低減剤
CN111406113A (zh) * 2017-11-30 2020-07-10 花王株式会社 评价或选择感觉刺激降低剂的方法
JP7478894B1 (ja) 2022-11-30 2024-05-07 花王株式会社 痒みの予防又は改善剤
JP7478895B1 (ja) 2022-11-30 2024-05-07 花王株式会社 痒みの予防又は改善剤

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014178427A1 (fr) * 2013-05-02 2014-11-06 学校法人順天堂 Procede pour controler l'expression de la semaphorine 3a

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014178427A1 (fr) * 2013-05-02 2014-11-06 学校法人順天堂 Procede pour controler l'expression de la semaphorine 3a

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SHIBATA,A. ET AL.: "Sulforaphane suppresses ultraviolet B induced inflammation in HaCaT keratinocytes and HR-1 hairless mice", J. NUTR. BIOCHEM., vol. 21, no. 8, August 2010 (2010-08-01), pages 702 - 709, XP027139885, ISSN: 0955-2863 *
THIMMULAPPA,R.K. ET AL.: "Identification of Nrf2-regulated Genes Induced by the Chemopreventive Agent Sulforaphane by Oligonucleotide Microarray", CANCER RES., vol. 62, no. 18, 15 September 2002 (2002-09-15), pages 5196 - 5203, XP002471401, ISSN: 1538-7445 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111406113A (zh) * 2017-11-30 2020-07-10 花王株式会社 评价或选择感觉刺激降低剂的方法
CN111406113B (zh) * 2017-11-30 2024-04-16 花王株式会社 评价或选择感觉刺激降低剂的方法
US11969436B2 (en) 2017-11-30 2024-04-30 Kao Corporation Method for treating skin irritation caused by parabens
JP2019202987A (ja) * 2018-05-22 2019-11-28 花王株式会社 感覚刺激低減剤
JP7182440B2 (ja) 2018-05-22 2022-12-02 花王株式会社 感覚刺激低減剤
JP7478894B1 (ja) 2022-11-30 2024-05-07 花王株式会社 痒みの予防又は改善剤
JP7478895B1 (ja) 2022-11-30 2024-05-07 花王株式会社 痒みの予防又は改善剤

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