WO2017111069A1 - Antipruritic - Google Patents
Antipruritic Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pruritus
- sulforaphane
- dermatitis
- precursor
- atopic dermatitis
- Prior art date
Links
- 239000003908 antipruritic agent Substances 0.000 title abstract description 17
- 230000001139 anti-pruritic effect Effects 0.000 title abstract description 14
- SUVMJBTUFCVSAD-UHFFFAOYSA-N sulforaphane Chemical compound CS(=O)CCCCN=C=S SUVMJBTUFCVSAD-UHFFFAOYSA-N 0.000 claims abstract description 103
- 208000003251 Pruritus Diseases 0.000 claims abstract description 69
- SUVMJBTUFCVSAD-JTQLQIEISA-N 4-Methylsulfinylbutyl isothiocyanate Natural products C[S@](=O)CCCCN=C=S SUVMJBTUFCVSAD-JTQLQIEISA-N 0.000 claims abstract description 42
- 229960005559 sulforaphane Drugs 0.000 claims abstract description 42
- 235000015487 sulforaphane Nutrition 0.000 claims abstract description 42
- 206010012438 Dermatitis atopic Diseases 0.000 claims abstract description 34
- 201000008937 atopic dermatitis Diseases 0.000 claims abstract description 34
- 239000002243 precursor Substances 0.000 claims abstract description 24
- 239000004480 active ingredient Substances 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims description 24
- 239000002537 cosmetic Substances 0.000 claims description 16
- 235000013305 food Nutrition 0.000 claims description 13
- 239000003793 antidiarrheal agent Substances 0.000 claims description 11
- 229940125714 antidiarrheal agent Drugs 0.000 claims description 9
- 230000003405 preventing effect Effects 0.000 claims description 8
- 208000024780 Urticaria Diseases 0.000 claims description 5
- 238000001631 haemodialysis Methods 0.000 claims description 5
- 230000000322 hemodialysis Effects 0.000 claims description 5
- 208000019838 Blood disease Diseases 0.000 claims description 4
- 206010012442 Dermatitis contact Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 4
- 230000001142 anti-diarrhea Effects 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 208000020832 chronic kidney disease Diseases 0.000 claims description 4
- 208000010247 contact dermatitis Diseases 0.000 claims description 4
- 230000007812 deficiency Effects 0.000 claims description 4
- 238000000502 dialysis Methods 0.000 claims description 4
- 208000014951 hematologic disease Diseases 0.000 claims description 4
- 208000018706 hematopoietic system disease Diseases 0.000 claims description 4
- 201000006370 kidney failure Diseases 0.000 claims description 4
- 208000019423 liver disease Diseases 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 210000002374 sebum Anatomy 0.000 claims description 4
- 201000004624 Dermatitis Diseases 0.000 description 37
- 230000002393 scratching effect Effects 0.000 description 23
- 238000006748 scratching Methods 0.000 description 19
- 230000006399 behavior Effects 0.000 description 18
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 12
- 210000003491 skin Anatomy 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 239000000739 antihistaminic agent Substances 0.000 description 7
- 229940125715 antihistaminic agent Drugs 0.000 description 7
- 230000007803 itching Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- GMMLNKINDDUDCF-JRWRFYLSSA-N [(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (1e)-5-[(r)-methylsulfinyl]-n-sulfooxypentanimidothioate Chemical compound C[S@@](=O)CCCC\C(=N/OS(O)(=O)=O)S[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O GMMLNKINDDUDCF-JRWRFYLSSA-N 0.000 description 6
- 229960001340 histamine Drugs 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000010172 mouse model Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 239000003246 corticosteroid Substances 0.000 description 4
- 229960001334 corticosteroids Drugs 0.000 description 4
- 210000004209 hair Anatomy 0.000 description 4
- 229960003444 immunosuppressant agent Drugs 0.000 description 4
- 239000003018 immunosuppressive agent Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 210000005036 nerve Anatomy 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 206010040882 skin lesion Diseases 0.000 description 4
- 231100000444 skin lesion Toxicity 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 235000011299 Brassica oleracea var botrytis Nutrition 0.000 description 3
- 240000003259 Brassica oleracea var. botrytis Species 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 206010070834 Sensitisation Diseases 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 239000000043 antiallergic agent Substances 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 208000037920 primary disease Diseases 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000008313 sensitization Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 2
- 235000017647 Brassica oleracea var italica Nutrition 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 102100024304 Protachykinin-1 Human genes 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 101800003906 Substance P Proteins 0.000 description 2
- 244000299461 Theobroma cacao Species 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229960003677 chloroquine Drugs 0.000 description 2
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- -1 etc. Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 210000003630 histaminocyte Anatomy 0.000 description 2
- 239000003906 humectant Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000003908 liver function Effects 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 238000001050 pharmacotherapy Methods 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 230000036620 skin dryness Effects 0.000 description 2
- 239000000344 soap Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- HJRJRUMKQCMYDL-UHFFFAOYSA-N 1-chloro-2,4,6-trinitrobenzene Chemical compound [O-][N+](=O)C1=CC([N+]([O-])=O)=C(Cl)C([N+]([O-])=O)=C1 HJRJRUMKQCMYDL-UHFFFAOYSA-N 0.000 description 1
- ARSRBNBHOADGJU-UHFFFAOYSA-N 7,12-dimethyltetraphene Chemical compound C1=CC2=CC=CC=C2C2=C1C(C)=C(C=CC=C1)C1=C2C ARSRBNBHOADGJU-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 206010063409 Acarodermatitis Diseases 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241001237961 Amanita rubescens Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000012657 Atopic disease Diseases 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 240000007124 Brassica oleracea Species 0.000 description 1
- 235000003899 Brassica oleracea var acephala Nutrition 0.000 description 1
- 235000004221 Brassica oleracea var gemmifera Nutrition 0.000 description 1
- 235000012905 Brassica oleracea var viridis Nutrition 0.000 description 1
- 244000308368 Brassica oleracea var. gemmifera Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- RUQCCAGSFPUGSZ-OBWQKADXSA-N Glucoraphanin Natural products C[S@](=O)CCCCC(=NS(=O)(=O)O)S[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O RUQCCAGSFPUGSZ-OBWQKADXSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 206010021531 Impetigo Diseases 0.000 description 1
- 208000006877 Insect Bites and Stings Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 201000009053 Neurodermatitis Diseases 0.000 description 1
- 229940100208 Opioid mu receptor antagonist Drugs 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000447727 Scabies Species 0.000 description 1
- 206010048908 Seasonal allergy Diseases 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 241000893966 Trichophyton verrucosum Species 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 238000003975 animal breeding Methods 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000005549 barrier dysfunction Effects 0.000 description 1
- 239000003788 bath preparation Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 231100000749 chronicity Toxicity 0.000 description 1
- 235000013353 coffee beverage Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000014510 cooky Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- 239000000551 dentifrice Substances 0.000 description 1
- 239000002781 deodorant agent Substances 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000004709 eyebrow Anatomy 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000000118 hair dye Substances 0.000 description 1
- 239000003676 hair preparation Substances 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- VNYSSYRCGWBHLG-AMOLWHMGSA-M leukotriene B4(1-) Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC([O-])=O VNYSSYRCGWBHLG-AMOLWHMGSA-M 0.000 description 1
- 235000021056 liquid food Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 235000020124 milk-based beverage Nutrition 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 229910001172 neodymium magnet Inorganic materials 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 235000012149 noodles Nutrition 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- 235000011962 puddings Nutrition 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 235000019685 rice crackers Nutrition 0.000 description 1
- 208000005687 scabies Diseases 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000002316 solid fats Nutrition 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 235000011496 sports drink Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 230000000475 sunscreen effect Effects 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 108010058651 thioglucosidase Proteins 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000006097 ultraviolet radiation absorber Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
- 108020001588 κ-opioid receptors Proteins 0.000 description 1
Images
Classifications
-
- 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.
Landscapes
- 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
The purpose of the invention is to provide an antipruritic that exerts an antipruritic effect immediately against refractory pruritus typified by atopic dermatitis. The invention provides an antipruritic containing sulforaphane or a precursor thereof as an active ingredient.
Description
本発明は、止痒剤に関する。
The present invention relates to an antidiarrheal agent.
アトピー性皮膚炎は、表皮、なかでも角層の異常に起因する皮膚の乾燥とバリアー機能異常という皮膚の生理学的異常を伴い、多彩な非特異的刺激反応及び特異的アレルギー反応が関与して生じ、慢性に経過する炎症とそう痒をその病態とする湿疹皮膚炎群の一疾患である（非特許文献１）。
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).
アトピー性皮膚炎に伴うそう痒の発現メカニズムは未だ十分には解明されてはいないが、マスト細胞やケラチノサイト等の細胞から放出される、ヒスタミンやロイコトリエンＢ４等の痒み誘発物質が、皮膚の痒みを伝える神経上の受容体に結合することで神経が興奮し、この痒みシグナルが脊髄後角を介して大脳皮質まで伝達され、痒みとして認識されると考えられている。
Although the mechanism of pruritus associated with atopic dermatitis has not been fully elucidated, itching substances such as histamine and leukotriene B4 released from cells such as mast cells and keratinocytes can cause skin itching. It is thought that the nerve is excited by binding to a receptor on the nerve to be transmitted, and this itching signal is transmitted to the cerebral cortex through the dorsal horn of the spinal cord and recognized as itching.
アトピー性皮膚炎においては、神経成長因子の働きにより、表皮内への神経伸長や神経の活性化閾値の低下が起こり、痒みシグナルを受容又は伝達しやすい、痒み過敏状態が形成されていると考えられている。また、アトピー性皮膚炎に伴うそう痒は、そう痒に対する引っ掻き行動を起こすことで皮膚炎の悪化を招き、皮膚炎の悪化によりさらにそう痒が増強されるという、「そう痒－引っ掻き－皮膚炎悪化」サイクルの原因となっており、アトピー性皮膚炎の治療においては、アトピー性皮膚炎自体の治療のみならず、そう痒を抑制することが早期改善に重要であると考えられている（非特許文献２）。
In 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. In addition, 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. 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. Patent Document 2).
アトピー性皮膚炎に対する薬物療法では、外用では皮膚炎を抑えるために副腎皮質ステロイド剤又は免疫抑制剤が主に用いられ、皮膚の乾燥及びバリアー機能を補完し、皮膚炎の再燃を予防する目的で保湿剤等も用いられる。また、アトピー性皮膚炎に伴うそう痒に対しては、内服剤として抗ヒスタミン薬又は抗アレルギー薬が用いられている（非特許文献１）。
In pharmacotherapy for 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. For pruritus associated with atopic dermatitis, antihistamines or antiallergic agents are used as internal preparations (Non-patent Document 1).
一方、スルフォラファンは、ブロッコリー、ブロッコリースプラウト、カリフラワー、ケール及び芽キャベツ等のアブラナ科の植物に含まれる物質である。通常、植物中では、スルフォラファンは、その前駆物質であるスルフォラファングルコシノレートとして存在し、摂取後、体内で分解されることでスルフォラファンへと変化する（非特許文献３）。
On the other hand, sulforaphane is a substance contained in cruciferous plants such as broccoli, broccoli sprout, cauliflower, kale and brussels sprouts. Usually, in a plant, 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).
スルフォラファンの作用としては、以下の報告がある。スルフォラファン前駆物質であるスルフォラファングルコシノレートを含むサプリメントを２ヶ月間摂取することにより、肝機能マーカーの値が高いヒトの肝機能を改善する効果を示すことが報告されている（非特許文献３）。また、胃炎や胃がんの原因の一つと考えられているヘリコバクターピロリに対する、スルフォラファンの静菌作用及び殺菌作用も報告されている（非特許文献４）。さらに、９，１０－ジメチル－１，２－ベンズアントラセン誘発ラット乳がんモデルにおいて、スルフォラファンの抗がん作用も報告されている（非特許文献５）。
There are the following reports on the action of sulforaphane. It has been reported that by taking a supplement containing sulforaphane glucosinolate, which is a precursor of sulforaphane, for 2 months, it shows an effect of improving human liver function with a high liver function marker value (Non-patent Document 3). . In addition, 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).
また、イソチオシアネート類は、好中球や好酸球といった炎症性細胞の遊走抑制作用、マスト細胞の脱顆粒抑制作用を有し、これにより生体のＩ型アレルギー症状が改善され、結果として花粉症やアトピー性皮膚炎、気管支喘息といったアトピー性疾患が改善することが報告されているが（特許文献１）、スルフォラファンの抗炎症作用は開示されておらず、スルフォラファンの止痒作用については開示も示唆もされていない。
In addition, 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.
しかしながら、外用の副腎皮質ステロイド剤や免疫抑制剤は、アトピー性皮膚炎の治療のために長期間にわたる投与が必要であり、副作用が懸念される。また、これら既存薬は、皮膚炎を抑制することにより二次的にそう痒を抑制することはできても、アトピー性皮膚炎に伴うそう痒を即時的に抑制することは困難であるのが現状である。
However, 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. Although these existing drugs can suppress pruritus secondary by suppressing dermatitis, it is difficult to immediately suppress pruritus associated with atopic dermatitis. Currently.
さらに、アトピー性皮膚炎に伴うそう痒に対して、抗ヒスタミン薬や抗アレルギー薬が用いられてはいるが、そう痒を緩和することを示すエビデンスは少ないと報告されており（Ｋｌｅｉｎら、Ａｒｃｈｉｖｅｓ ｏｆ Ｄｅｒｍａｔｏｌｏｇｙ、１９９９年、第１３５巻、ｐ．１５２２）、アトピー性皮膚炎に伴うそう痒の治療に単調に用いることは推奨されていない（Ｂｅｒｋｅら、Ａｍｅｒｉｃａｎ Ｆａｍｉｌｙ Ｐｈｙｓｉｃｉａｎ、２０１２年、第８６巻、ｐ．３５）。
Furthermore, although antihistamines and antiallergic drugs have been used for pruritus associated with atopic dermatitis, it has been reported that there is little evidence to alleviate pruritus (Klein et al., Archives). of Dermatology, 1999, Vol. 135, p. 1522), it is not recommended for monotonic treatment of pruritus associated with atopic dermatitis (Berke et al., American Family Physician, 2012, Vol. 86, p.35).
このため、アトピー性皮膚炎に伴うそう痒に対する既存の薬物療法では、即時的に止痒効果を得ることができずに、患者が自身の皮膚を引っ掻くことで皮膚炎を悪化させ、皮膚炎の慢性化を引き起こし、難治性に至るという悪循環に陥っている。したがって、アトピー性皮膚炎に伴うそう痒に対して、即時的に薬効を発揮する止痒剤の開発が切望されている。
For this reason, the existing pharmacotherapy for pruritus associated with atopic dermatitis cannot obtain an immediate antipruritic effect, exacerbates the dermatitis by scratching the patient's own skin, and It is in a vicious cycle of causing chronicity and intractability. Therefore, development of an antidiarrheal agent that immediately exhibits a medicinal effect against pruritus associated with atopic dermatitis is eagerly desired.
そこで本発明は、アトピー性皮膚炎に代表される難治性そう痒に対して即時的に止痒効果を発揮する、止痒剤を提供することを目的とする。
Therefore, 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.
本発明者らは、難治性そう痒に対して有効性を示す新たな化学構造を有する化合物について鋭意研究を重ねた結果、スルフォラファン又はその前駆物質が難治性そう痒に対して、即時的に止痒効果を発揮し得ることを見出し、本発明を完成するに至った。
As a result of intensive research on a compound having a new chemical structure that is effective against refractory pruritus, the present inventors have immediately stopped sulforaphane or its precursor against refractory pruritus. The inventors have found that the cocoon effect can be exhibited, and have completed the present invention.
すなわち、本発明は、スルフォラファン又はその前駆物質を有効成分として含有する止痒剤を提供する。
That is, the present invention provides an antidiarrheal agent containing sulforaphane or a precursor thereof as an active ingredient.
上記の止痒剤は、アトピー性皮膚炎、接触性皮膚炎、皮脂欠乏症、老人性皮膚そう痒、蕁麻疹、乾癬、悪性腫瘍、肝疾患、慢性腎疾患、腎不全、血液疾患、血液透析、腹膜透析又は多発性硬化症に伴う難治性そう痒に対する止痒剤であることが好ましく、アトピー性皮膚炎に伴う難治性そう痒に対する止痒剤であることが特に好ましい。
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.
上記の止痒剤は、難治性そう痒に対して即時的に薬効を発揮し、これまでに止痒効果が認められている薬剤（副腎皮質ステロイド剤、免疫抑制剤、抗ヒスタミン薬、抗アレルギー薬等）とは異なるメカニズムでそう痒を治療又は予防できる。
The above antidiarrheal drugs have immediate effects on intractable pruritus, and drugs that have been confirmed to have antipruritic effects (corticosteroids, immunosuppressants, antihistamines, antiallergic drugs) Pruritus can be treated or prevented by a mechanism different from that of drugs.
また、本発明は、上記の有効成分を含有する、そう痒の改善又は予防のための化粧品組成物を提供する。
The present invention also provides a cosmetic composition for improving or preventing pruritus, which contains the above active ingredient.
また、本発明は、上記の有効成分を含有する、そう痒の改善又は予防のための食品組成物を提供する。
The present invention also provides a food composition for improving or preventing pruritus, which contains the above active ingredient.
本発明の止痒剤は、アトピー性皮膚炎に代表される難治性そう痒に対して、即時的に止痒効果を発揮する。このため、本発明の止痒剤は、「そう痒－引っ掻き－皮膚炎悪化」サイクルの停止と患者のＱＯＬの改善に大きく貢献し、治療が困難とされるアトピー性皮膚炎に対しても、新たなメカニズムで治療効果を発揮できる。
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.
また、本発明の化粧品組成物や食品組成物は、皮膚のそう痒を早期に改善又は予防できる点で有用である。
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.
本発明の止痒剤は、スルフォラファンを有効成分として含有することを特徴とする。
The antidiarrheal agent of the present invention is characterized by containing sulforaphane as an active ingredient.
上記のスルフォラファンは、１－イソチオシアネート－４－メチルスルフィニルブタンとしても知られる、下記式（Ｉ）で示される物質である。
The sulforaphane is a substance represented by the following formula (I), also known as 1-isothiocyanate-4-methylsulfinylbutane.
上記式（Ｉ）で示されるスルフォラファンには、ラセミ体や光学異性体が存在するが、単一異性体のみならず、ラセミ体や光学異性体の混合物も包含する。なお、スルフォラファンのラセミ体は、例えば、Ｄ，Ｌ－スルフォラファン又はＲ，Ｓ－スルフォラファン等と表記される。
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.
上記式（Ｉ）で示されるスルフォラファンは、植物中から単離・精製した天然スルフォラファン、化学合成により製造された合成スルフォラファンのいずれでもよい。スルフォラファンの単離・精製方法（特表２０１５－５１９３５８号）及び合成方法（特表２０１５－５１８０４１号、Ｓｃｈｍｉｄら、Ｈｅｌｖｅｔｉｃａ Ｃｈｉｍｉｃａ Ａｃｔａ、１９４８年、第３１巻（６）、ｐ.１４９７―１５０５）は、当技術分野において公知である。また、上記式（Ｉ）で示されるスルフォラファンは市販されており、市販品を用いることもできる。
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.
さらに、上記の止痒剤は、スルフォラファン前駆物質を有効成分として含有することを特徴とする。上記のスルフォラファン前駆物質とは、酵素によってスルフォラファンに変換又は代謝される物質である。上記のスルフォラファン前駆物質としては、好ましくは、スルフォラファングルコシノレートである。なお、スルフォラファングルコシノレートはグルコラファニンとも呼ばれる。
Furthermore, 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. In addition, sulforaphane glucosinolate is also called glucoraphanin.
上記のスルフォラファン前駆物質には、ラセミ体や光学異性体が存在するが、単一異性体のみならず、ラセミ体や光学異性体の混合物も包含する。
The above-mentioned sulforaphane precursors include racemates and optical isomers, but include not only single isomers but also racemic and optical isomer mixtures.
上記のスルフォラファン前駆物質（好ましくは、スルフォラファングルコシノレート）は、植物中から単離・精製した天然スルフォラファン前駆物質、化学合成により製造された合成スルフォラファン前駆物質のいずれでもよい。スルフォラファン前駆物質の単離・精製方法及び合成方法は、当技術分野において公知である。また、スルフォラファン前駆物質は、市販されており、市販品を用いることもできる。
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.
「そう痒」とは、引っ掻く欲求を伴う皮膚特有の感覚であり、例えば、アトピー性皮膚炎、神経性皮膚炎、接触性皮膚炎、脂漏性皮膚炎、自己感作性皮膚炎、毛虫皮膚炎、皮脂欠乏症、老人性皮膚そう痒、虫刺症、光線過敏症、蕁麻疹、痒疹、疱疹、膿痂疹、湿疹、白癬、苔癬、乾癬、疥癬若しくは尋常性座瘡等の皮膚疾患を原疾患とするそう痒、悪性腫瘍、糖尿病、肝疾患、慢性腎疾患、腎不全、血液疾患、血液透析、腹膜透析若しくは多発性硬化症を原疾患とするそう痒又は薬剤性若しくは心因性で起こるそう痒が挙げられる。また、そう痒は、ヒスタミンが介在するそう痒と、ヒスタミンが介在しないそう痒（難治性そう痒）とに大別されるが、本発明の止痒剤は、特に、ヒスタミンが介在しないそう痒（難治性そう痒）に対して有効である。ヒスタミンが介在しないそう痒（難治性そう痒）としては、例えば、アトピー性皮膚炎、接触性皮膚炎、皮脂欠乏症、老人性皮膚そう痒、蕁麻疹、乾癬、悪性腫瘍、肝疾患、慢性腎疾患、腎不全、血液疾患、血液透析、腹膜透析又は多発性硬化症等を原疾患とするそう痒が挙げられ、抗ヒスタミン薬に対して治療抵抗性を示す。
“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 For 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. Moreover, 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). Examples of pruritus without histamine (refractory pruritus) 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.
「止痒剤」とは、そう痒を軽減する目的で用いられる薬剤等であり、例えば、内服剤としては主に抗ヒスタミン薬が用いられ、血液透析患者に対してはオピオイドκ受容体作動薬が用いられることもある。また、外用剤としては、抗ヒスタミン薬、副腎皮質ステロイド剤、免疫抑制剤又は非ステロイド系抗炎症剤が用いられている。なお、これらの止痒剤は、そう痒が起こらないように制御する目的で、予防的に用いることもできる。
“Antidepressants” are drugs used for the purpose of reducing pruritus, for example, antihistamines are mainly used as internal medicines, and opioid κ 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.
「即時的」とは、単回の投与によって、投与後６時間以内、好ましくは投与後３時間以内、更に好ましくは投与後１時間以内に止痒効果が得られることを意味する。
“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.
上記の止痒剤の止痒効果は、そう痒モデル動物を用いたｉｎ ｖｉｖｏの実験系で評価でき、ヒスタミン、クロロキン又サブスタンスＰに代表される各種起痒物質によって惹起されるマウスの引っ掻き行動を指標とするそう痒モデルが一般的である。例えば、Ｔｏｇａｓｈｉらの文献（Ｅｕｒｏｐｅａｎ Ｊｏｕｒｎａｌ ｏｆ Ｐｈａｒｍａｃｏｌｏｇｙ、２００２年、第４３５巻、ｐ．２５９）やＡｎｄｏｈらの文献（Ｅｕｒｏｐｅａｎ Ｊｏｕｒｎａｌ ｏｆ Ｐｈａｒｍａｃｏｌｏｇｙ、２００２年、第４３６巻、ｐ．２３５）に記載されているマウスを用いたサブスタンスＰ誘発引っ掻き行動や、Ｍａｒｉｎｏらの文献（Ｊｏｕｒｎａｌ ｏｆ Ｎｅｕｒｏｓｃｉｅｎｃｅ Ｍｅｔｈｏｄｓ、２０１２年、第２１１巻、ｐ．１）に記載されているマウスを用いたクロロキン誘発引っ掻き行動は、抗ヒスタミン薬が無効の難治性そう痒モデルの一つとして利用できるものである。
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. For example, Togashi et al. (European Journal of Pharmacology, 2002, Vol. 435, p. 259) and 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. (Journal of Neuroscience Methods, 2012, Vol. 211, p. 1) are antihistamines. Can be used as one of the ineffective refractory pruritus models.
また、アトピー性皮膚炎に伴うそう痒に対する止痒剤の止痒効果は、例えば、アトピー性皮膚炎様の皮膚病変を有したそう痒モデル動物の引っ掻き行動を指標としたｉｎ ｖｉｖｏの実験系で評価できる。アトピー性皮膚炎様の皮膚病変を有したそう痒モデル動物としては、例えば、通常飼育環境下で皮膚炎を自然発症するＮＣ／Ｎｇａ系マウス（Ｔａｋａｎｏら、Ｅｕｒｏｐｅａｎ Ｊｏｕｒｎａｌ ｏｆ Ｐｈａｒｍａｃｏｌｏｇｙ、２００４年、第４９５巻、ｐ．１５９）、又は、ハプテンである２，４，６－トリニトロクロロベンゼン若しくは４－エトキシメチレン－２－フェニル－２－オキサゾリン－５－オン（以下、オキサゾロン）をマウスの皮膚へ反復塗布することにより皮膚炎を誘発したモデル（オキサゾロン誘発皮膚炎モデル）（Ｕｅｄａら、Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｍｍｕｎｏｐｈａｒｍａｃｏｌｏｇｙ、２００６年、第６巻、ｐ．１６０９又はＴｓｕｋｕｍｏら、Ｊｏｕｒｎａｌ ｏｆ Ｐｈａｒｍａｃｏｌｏｇｉｃａｌ Ｓｃｉｅｎｃｅｓ、２０１０年、第１１３巻、ｐ．２５５）等を用いることができる。これらアトピー性皮膚炎様の皮膚病変を有したそう痒モデル動物の引っ掻き行動は、オピオイドμ受容体拮抗薬で抑制されるため、疼痛関連反応ではなく、そう痒関連反応として認知されている。
In addition, 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. 159), or the hapten 2,4,6-trinitrochlorobenzene or 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (hereinafter referred to as oxazolone) was repeatedly applied to the skin of mice. 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 μ receptor antagonist, and thus is recognized as an itching-related reaction rather than a pain-related reaction.
上記の止痒剤は、哺乳動物（例えば、マウス、ラット、ハムスター、ウサギ、イヌ、サル、ウシ、ヒツジ又はヒト）、特にヒトに対して投与した場合に、有用な医薬等（特に、アトピー性皮膚炎に伴うそう痒に対する止痒剤）として用いることができる。あるいは、上記のスルフォラファン又はその前駆物質を化粧料組成物又は食品組成物の有効成分として使用するか、又はこれに含有させてもよい。
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.
上記の止痒剤を臨床で使用する際には、スルフォラファン又はその前駆物質をそのまま用いてもよいし、賦形剤、安定化剤、保存剤、緩衝剤、溶解補助剤、乳化剤、希釈剤又は等張化剤等の添加剤が適宜混合されていてもよい。また、上記の止痒剤は、これらの薬剤用担体を適宜用いて、通常の方法によって製造することができる。上記の止痒剤の投与形態としては、例えば、錠剤、カプセル剤、顆粒剤、散剤若しくはシロップ剤等による経口剤、吸入剤、注射剤、座剤若しくは液剤等による非経口剤又は局所投与をするための軟膏剤、クリーム剤若しくは貼付剤等が挙げられる。また、公知の持続型製剤としても構わない。また、スルフォラファン前駆物質の場合は、スルフォラファンに変換させる酵素（例えば、ミロシナーゼ）を配合又は併用して使用しても構わない。
When the above antidiarrheal is used clinically, 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. Moreover, 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. In the case of a sulforaphane precursor, an enzyme (for example, myrosinase) that is converted to sulforaphane may be used in combination or in combination.
上記の止痒剤は、スルフォラファン又はその前駆物質を有効成分として０．００１～９０重量％含有することが好ましく、０．０１～７０重量％含有することがより好ましい。用量は、症状、年齢、体重、性別及び投与方法等に応じて適宜選択されるが、成人に対する有効成分量として、注射剤の場合１日０．００１ｍｇ～５ｇ、経口剤の場合０．０１ｍｇ～１０ｇであり、それぞれ１回又は数回に分けて投与することができる。
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.
上記の止痒剤の薬理学的に許容される担体又は希釈剤としては、例えば、結合剤（シロップ、ゼラチン、アラビアゴム、ソルビトール、ポリビニルクロリド又はトラガント等）、賦形剤（砂糖、乳糖、コーンスターチ、リン酸カルシウム、ソルビトール又はグリシン等）又は滑沢剤（ステアリン酸マグネシウム、ポリエチレングリコール、タルク又はシリカ等）を挙げることができる。
Examples of the pharmacologically acceptable carrier or diluent for the antidiarrheal 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.).
上記の止痒剤は、止痒の補完若しくは増強又は投与量の低減のために、他の薬剤と適量配合又は併用して使用しても構わない。
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.
また、本発明の化粧品組成物は、スルフォラファン又はその前駆物質を有効成分として含有することでそう痒を改善又は予防することを特徴とする。
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.
化粧料組成物の形態は適宜選択することができ、溶液、乳液、粉末、水－油二層系、水－油－粉末三層系、ゲル、タブレット等の固形、エアゾール、ミスト、カプセル、シート等任意の形態とすることができる。また、化粧料組成物の製品形態も任意であり、例えば、洗顔料、メーク落とし、化粧水、美容液、パック、乳液、クリーム、サンスクリーン等のスキンケア化粧料、ファンデーション、化粧下地、口紅、アイシャドー、アイライナー、マスカラ、アイブロー、頬紅、ネイルエナメル等のメイクアップ化粧料、ヘアシャンプー、ヘアリンス、整髪料、染毛料、育毛剤等の毛髪化粧料、石鹸、ボディソープ、デオドラント化粧料、浴用剤等のボディ洗浄料、歯磨剤及び洗口剤等の口腔化粧料、香水等の芳香化粧料等が挙げられる。
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. In addition, the product form of the cosmetic composition is also arbitrary. For example, 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.
化粧料組成物は、化粧品、医薬部外品及び医薬等に許容される担体、例えば、粉末成分、液体油脂、固体油脂、ロウ、炭化水素、高級脂肪酸、高級アルコール、エステル、シリコーン、アニオン界面活性剤、カチオン界面活性剤、両性界面活性剤、非イオン界面活性剤、保湿剤、水溶性高分子、増粘剤、皮膜剤、紫外線吸収剤、金属イオン封鎖剤、低級アルコール、多価アルコール、糖、アミノ酸、有機アミン、高分子エマルジョン、ｐＨ調整剤、皮膚栄養剤、ビタミン、酸化防止剤、酸化防止助剤、香料、水等を必要に応じて配合し、常法により製造することができる。
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. Agent, cationic surfactant, amphoteric surfactant, nonionic surfactant, humectant, water-soluble polymer, thickener, film agent, ultraviolet absorber, sequestering agent, lower alcohol, polyhydric alcohol, sugar , Amino acids, organic amines, polymer emulsions, pH adjusters, skin nutrients, vitamins, antioxidants, antioxidant aids, fragrances, water and the like can be blended as necessary and produced by conventional methods.
また、本発明の食品組成物は、スルフォラファン又はその前駆物質を有効成分として含有することでそう痒を改善又は予防することを特徴とする。
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.
上記の食品組成物は、食料、飲料、飼料、ペットフードに添加又は配合して使用することができる。あるいは、製剤形態の食品は、医薬製剤と同様に製造することができ、スルフォラファン又はその前駆物質と、食品として許容できる担体、例えば適当な賦形剤（例えば、でん粉、加工でん粉、乳糖、ブドウ糖、水等）等とを混合した後、慣用の手段を用いて製造することができる。さらに、スープ類、ジュース類、乳飲料、茶飲料、コーヒー飲料、ココア飲料、ゼリー状飲料、スポーツ飲料、ダイエット飲料などの液状食品組成物、プリン、ヨーグルトなどの半固形食品組成物、パン類、うどんなどの麺類、クッキー、チョコレート、キャンディ、ガム、せんべいなどの菓子類、ふりかけ、バター、ジャムなどのスプレッド類等に、上記の食品組成物を添加又は配合して、食品組成物を製造することができる。
The above food composition can be used by adding to or blending with food, beverages, feed, and pet food. Alternatively, 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. Furthermore, 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.
以下の実施例により本発明をさらに詳細に説明するが、本発明はこれらによって限定されるものではない。
The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
（実施例１） Ｄ，Ｌ－スルフォラファンのオキサゾロン誘発皮膚炎モデルマウスの引っ掻き行動に対する抑制効果：
オキサゾロンの反復塗布により皮膚病変を誘発したアトピー性皮膚炎モデルマウス（オキサゾロン誘発皮膚炎モデルマウス）は、公知文献（Ｔｓｕｋｕｍｏら、Ｊｏｕｒｎａｌ ｏｆ Ｐｈａｒｍａｃｏｌｏｇｉｃａｌ Ｓｃｉｅｎｃｅｓ、２０１０年、第１１３巻、ｐ．２５５等）記載の方法に基づき、作製した。また、引っ掻き行動の評価は、公知文献（Ｈａｓｈｉｍｏｔｏら、Ａｌｌｅｒｇｏｌｏｇｙ Ｉｎｔｅｒｎａｔｉｏｎａｌ、２００４年、第５３巻、ｐ．３４９）記載の方法に基づき、ＭｉｃｒｏＡｃｔ（ニューロサイエンス社）を用いて自動的に検出し、客観的に行った。 (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.
オキサゾロンの反復塗布により皮膚病変を誘発したアトピー性皮膚炎モデルマウス（オキサゾロン誘発皮膚炎モデルマウス）は、公知文献（Ｔｓｕｋｕｍｏら、Ｊｏｕｒｎａｌ ｏｆ Ｐｈａｒｍａｃｏｌｏｇｉｃａｌ Ｓｃｉｅｎｃｅｓ、２０１０年、第１１３巻、ｐ．２５５等）記載の方法に基づき、作製した。また、引っ掻き行動の評価は、公知文献（Ｈａｓｈｉｍｏｔｏら、Ａｌｌｅｒｇｏｌｏｇｙ Ｉｎｔｅｒｎａｔｉｏｎａｌ、２００４年、第５３巻、ｐ．３４９）記載の方法に基づき、ＭｉｃｒｏＡｃｔ（ニューロサイエンス社）を用いて自動的に検出し、客観的に行った。 (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.
１．実験方法
（１）オキサゾロン誘発皮膚炎モデルマウスの作製
オキサゾロンの濃度が３ｗ／ｖ％となるように、オキサゾロンをアセトン：オリーブオイル＝４：１（ｖ／ｖ）の混液に溶解した。３ｗ／ｖ％オキサゾロン溶液１００μＬを、イソフルラン麻酔下にて、７～８週齢の雌性ＨＲ－１マウス（星野試験動物飼育所）の背部全体に塗布することにより、感作を行った（感作日を「Ｄａｙ －７」とする）。感作１週間後（Ｄａｙ ０）から、イソフルラン麻酔下にて、３ｗ／ｖ％オキサゾロン溶液又はその溶媒（アセトン：オリーブオイル＝４：１（ｖ／ｖ）の混液）６０μＬを、１日につき１回、週３回（２又は３日間隔）の頻度で吻側背部へ塗布した。オキサゾロンを反復塗布したマウスを「皮膚炎惹起群」とし、溶媒を反復塗布したマウスを「皮膚炎非惹起群」とした。 1. Experimental Method (1) Preparation of Oxazolone-Induced Dermatitis Model Mice Oxazolone was dissolved in a mixture of acetone: olive oil = 4: 1 (v / v) so that the concentration of oxazolone was 3 w / v%. Sensitization was performed by applying 100 μL of 3 w / v% oxazolone solution to the entire back of 7-8 week old female HR-1 mice (Hoshino Test Animal Breeding) under isoflurane anesthesia (sensitization). Day as “Day -7”). One week after sensitization (Day 0), 60 μL of 3 w / v% oxazolone solution or its solvent (a mixture of acetone: olive oil = 4: 1 (v / v)) under isoflurane anesthesia 1 Was applied to the rostral dorsal region at a frequency of 3 times a week (2 or 3 day intervals). Mice repeatedly applied with oxazolone were designated as “dermatitis-inducing group”, and mice repeatedly applied with solvent were designated as “non-dermatitis-inducing group”.
（１）オキサゾロン誘発皮膚炎モデルマウスの作製
オキサゾロンの濃度が３ｗ／ｖ％となるように、オキサゾロンをアセトン：オリーブオイル＝４：１（ｖ／ｖ）の混液に溶解した。３ｗ／ｖ％オキサゾロン溶液１００μＬを、イソフルラン麻酔下にて、７～８週齢の雌性ＨＲ－１マウス（星野試験動物飼育所）の背部全体に塗布することにより、感作を行った（感作日を「Ｄａｙ －７」とする）。感作１週間後（Ｄａｙ ０）から、イソフルラン麻酔下にて、３ｗ／ｖ％オキサゾロン溶液又はその溶媒（アセトン：オリーブオイル＝４：１（ｖ／ｖ）の混液）６０μＬを、１日につき１回、週３回（２又は３日間隔）の頻度で吻側背部へ塗布した。オキサゾロンを反復塗布したマウスを「皮膚炎惹起群」とし、溶媒を反復塗布したマウスを「皮膚炎非惹起群」とした。 1. Experimental Method (1) Preparation of Oxazolone-Induced Dermatitis Model Mice Oxazolone was dissolved in a mixture of acetone: olive oil = 4: 1 (v / v) so that the concentration of oxazolone was 3 w / v%. Sensitization was performed by applying 100 μL of 3 w / v% oxazolone solution to the entire back of 7-8 week old female HR-1 mice (Hoshino Test Animal Breeding) under isoflurane anesthesia (sensitization). Day as “Day -7”). One week after sensitization (Day 0), 60 μL of 3 w / v% oxazolone solution or its solvent (a mixture of acetone: olive oil = 4: 1 (v / v)) under isoflurane anesthesia 1 Was applied to the rostral dorsal region at a frequency of 3 times a week (2 or 3 day intervals). Mice repeatedly applied with oxazolone were designated as “dermatitis-inducing group”, and mice repeatedly applied with solvent were designated as “non-dermatitis-inducing group”.
（２）Ｄ，Ｌ－スルフォラファンの投与
Ｄ，Ｌ－スルフォラファン投与液は、Ｄ，Ｌ－スルフォラファン（Ｓａｎｔａ Ｃｒｕｚ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ社）をジメチルスルホキシド及びＴｗｅｅｎ８０と混和した後、蒸留水を添加し、ジメチルスルホキシド及びＴｗｅｅｎ８０が、各々１ｖ／ｖ％の濃度となるように調製した。Ｄ，Ｌ－スルフォラファン投与液又はその溶媒を１０ｍＬ／ｋｇの容量で、引っ掻き行動回数の測定開始の６０分間前に、皮膚炎惹起群又は皮膚炎非惹起群のマウスに単回経口投与した。Ｄ，Ｌ－スルフォラファンは、１００ｍｇ／ｋｇの用量で投与した。皮膚炎非惹起群に溶媒を投与した群を「皮膚炎非惹起－溶媒投与群」、皮膚炎惹起群に溶媒を投与した群を「皮膚炎惹起－溶媒投与群」、皮膚炎惹起群にＤ，Ｌ－スルフォラファンを投与した群を「皮膚炎惹起－Ｄ，Ｌ－スルフォラファン（１００ｍｇ／ｋｇ）投与群」とした。 (2) Administration of D, L-sulforaphane 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”, and 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”.
Ｄ，Ｌ－スルフォラファン投与液は、Ｄ，Ｌ－スルフォラファン（Ｓａｎｔａ Ｃｒｕｚ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ社）をジメチルスルホキシド及びＴｗｅｅｎ８０と混和した後、蒸留水を添加し、ジメチルスルホキシド及びＴｗｅｅｎ８０が、各々１ｖ／ｖ％の濃度となるように調製した。Ｄ，Ｌ－スルフォラファン投与液又はその溶媒を１０ｍＬ／ｋｇの容量で、引っ掻き行動回数の測定開始の６０分間前に、皮膚炎惹起群又は皮膚炎非惹起群のマウスに単回経口投与した。Ｄ，Ｌ－スルフォラファンは、１００ｍｇ／ｋｇの用量で投与した。皮膚炎非惹起群に溶媒を投与した群を「皮膚炎非惹起－溶媒投与群」、皮膚炎惹起群に溶媒を投与した群を「皮膚炎惹起－溶媒投与群」、皮膚炎惹起群にＤ，Ｌ－スルフォラファンを投与した群を「皮膚炎惹起－Ｄ，Ｌ－スルフォラファン（１００ｍｇ／ｋｇ）投与群」とした。 (2) Administration of D, L-sulforaphane 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”, and 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”.
（３）引っ掻き行動の評価
Ｄａｙ ７に、イソフルラン麻酔下にて、マウスの両後肢甲部皮下にパラフィルムでコーティングしたネオジム磁石（直径１ｍｍ、長さ３ｍｍ）を挿入した。Ｄａｙ ７９に、引っ掻き行動回数を測定し、各群の引っ掻き行動回数の平均値がほぼ均等になるように群分けを行った。Ｄａｙ ８１に、引っ掻き行動に対するＤ，Ｌ－スルフォラファンの抑制効果を評価した。なお、引っ掻き行動回数の測定開始の少なくとも３０分間前から、測定用チャンバー（直径１１ｃｍ、高さ１８ｃｍ）内へマウスを１匹ずつ収容し、試験環境へ馴化させた。Ｄ，Ｌ－スルフォラファン投与液又はその溶媒の単回経口投与の６０分間後に、引っ掻き行動回数の測定を開始し６０分間測定した。引っ掻き行動回数は、測定用チャンバー周囲のラウンドコイル内で、後肢に挿入された磁石の動きによって誘導された電流を増幅して記録した。 (3) Evaluation of scratching behavior Under Day 7 anisoflurane anesthesia, a neodymium magnet (diameter: 1 mm, length: 3 mm) coated with parafilm was inserted under both hind limbs of mice. On Day 79, the number of scratching actions was measured, and grouping was performed so that the average value of the number of scratching actions in each group was almost equal. On Day 81, the inhibitory effect of D, L-sulforaphane on the scratching behavior was evaluated. In addition, from at least 30 minutes before the start of measurement of the number of scratching behaviors, one mouse was housed in the measurement chamber (diameter 11 cm, height 18 cm) and acclimated to the test environment. After 60 minutes of single oral administration of the D, L-sulforaphan administration solution or its solvent, measurement of the number of scratching behaviors was started and measured for 60 minutes. The number of scratching behaviors was recorded by amplifying the current induced by the movement of the magnet inserted into the hind limb in a round coil around the measurement chamber.
Ｄａｙ ７に、イソフルラン麻酔下にて、マウスの両後肢甲部皮下にパラフィルムでコーティングしたネオジム磁石（直径１ｍｍ、長さ３ｍｍ）を挿入した。Ｄａｙ ７９に、引っ掻き行動回数を測定し、各群の引っ掻き行動回数の平均値がほぼ均等になるように群分けを行った。Ｄａｙ ８１に、引っ掻き行動に対するＤ，Ｌ－スルフォラファンの抑制効果を評価した。なお、引っ掻き行動回数の測定開始の少なくとも３０分間前から、測定用チャンバー（直径１１ｃｍ、高さ１８ｃｍ）内へマウスを１匹ずつ収容し、試験環境へ馴化させた。Ｄ，Ｌ－スルフォラファン投与液又はその溶媒の単回経口投与の６０分間後に、引っ掻き行動回数の測定を開始し６０分間測定した。引っ掻き行動回数は、測定用チャンバー周囲のラウンドコイル内で、後肢に挿入された磁石の動きによって誘導された電流を増幅して記録した。 (3) Evaluation of scratching behavior Under Day 7 anisoflurane anesthesia, a neodymium magnet (diameter: 1 mm, length: 3 mm) coated with parafilm was inserted under both hind limbs of mice. On Day 79, the number of scratching actions was measured, and grouping was performed so that the average value of the number of scratching actions in each group was almost equal. On Day 81, the inhibitory effect of D, L-sulforaphane on the scratching behavior was evaluated. In addition, from at least 30 minutes before the start of measurement of the number of scratching behaviors, one mouse was housed in the measurement chamber (diameter 11 cm, height 18 cm) and acclimated to the test environment. After 60 minutes of single oral administration of the D, L-sulforaphan administration solution or its solvent, measurement of the number of scratching behaviors was started and measured for 60 minutes. The number of scratching behaviors was recorded by amplifying the current induced by the movement of the magnet inserted into the hind limb in a round coil around the measurement chamber.
統計学的処理としては、皮膚炎惹起－溶媒投与群に対する皮膚炎惹起－Ｄ，Ｌ－スルフォラファン（１００ｍｇ／ｋｇ）投与群の検定としてｔ検定を行った。有意水準は５％（両側）とした。
As a statistical treatment, 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).
２．結果
図１に、オキサゾロン誘発皮膚炎モデルマウスの引っ掻き行動回数に対する、Ｄ，Ｌ－スルフォラファンの効果を示す。縦軸は、６０分間の引っ掻き行動回数（平均値±標準誤差、ｎ＝８～１８）を示す。横軸は、皮膚炎非惹起－溶媒投与群、皮膚炎惹起－溶媒投与群及び皮膚炎惹起－Ｄ，Ｌ－スルフォラファン（１００ｍｇ／ｋｇ）投与群を示す。図中の＊印は、皮膚炎惹起－溶媒投与群との比較で統計学的に有意であることを示す（＊：ｐ＜０．０５、ｔ検定）。 2. Results FIG. 1 shows the effect of D, L-sulforaphane on the number of scratching behaviors of oxazolone-induced dermatitis model mice. The vertical axis represents the number of scratching actions for 60 minutes (average value ± standard error, n = 8 to 18). 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).
図１に、オキサゾロン誘発皮膚炎モデルマウスの引っ掻き行動回数に対する、Ｄ，Ｌ－スルフォラファンの効果を示す。縦軸は、６０分間の引っ掻き行動回数（平均値±標準誤差、ｎ＝８～１８）を示す。横軸は、皮膚炎非惹起－溶媒投与群、皮膚炎惹起－溶媒投与群及び皮膚炎惹起－Ｄ，Ｌ－スルフォラファン（１００ｍｇ／ｋｇ）投与群を示す。図中の＊印は、皮膚炎惹起－溶媒投与群との比較で統計学的に有意であることを示す（＊：ｐ＜０．０５、ｔ検定）。 2. Results FIG. 1 shows the effect of D, L-sulforaphane on the number of scratching behaviors of oxazolone-induced dermatitis model mice. The vertical axis represents the number of scratching actions for 60 minutes (average value ± standard error, n = 8 to 18). 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).
この結果から、Ｄ，Ｌ－スルフォラファンは、アトピー性皮膚炎モデルとして知られるオキサゾロン誘発皮膚炎モデルマウスの引っ掻き行動を顕著に抑制し、優れた止痒効果を有することが明らかとなった。
From these results, it was revealed that 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.
さらに、Ｄ，Ｌ－スルフォラファンを、引っ掻き行動回数の測定開始の６０分前に単回経口投与することにより、引っ掻き行動が抑制されたという結果は、アトピー性皮膚炎に伴うそう痒に対して、即時的に止痒効果を有することを示唆するものである。
Furthermore, 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.
本発明は、アトピー性皮膚炎に代表される難治性そう痒に対する止痒剤やそう痒の改善又は予防のための化粧品組成物又は食品組成物として利用できる。
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.
Claims (5)
- スルフォラファン又はその前駆物質を有効成分として含有する、止痒剤。 An antidiarrheal agent containing sulforaphane or its precursor as an active ingredient.
- アトピー性皮膚炎、接触性皮膚炎、皮脂欠乏症、老人性皮膚そう痒、蕁麻疹、乾癬、悪性腫瘍、肝疾患、慢性腎疾患、腎不全、血液疾患、血液透析、腹膜透析又は多発性硬化症に伴う難治性そう痒に対する、請求項１記載の止痒剤。 Atopic dermatitis, contact dermatitis, sebum deficiency, senile cutaneous pruritus, urticaria, psoriasis, malignant tumor, liver disease, chronic kidney disease, renal failure, blood disease, hemodialysis, peritoneal dialysis or multiple sclerosis The antidiarrheal according to claim 1 for intractable pruritus associated with.
- アトピー性皮膚炎に伴う難治性そう痒に対する、請求項２記載の止痒剤。 The antidiarrheal according to claim 2 for intractable pruritus associated with atopic dermatitis.
- スルフォラファン又はその前駆物質を有効成分として含有する、そう痒の改善又は予防のための化粧品組成物。 A cosmetic composition for improving or preventing pruritus containing sulforaphane or its precursor as an active ingredient.
- スルフォラファン又はその前駆物質を有効成分として含有する、そう痒の改善又は予防のための食品組成物。 A food composition for improving or preventing pruritus that contains sulforaphane or its precursor as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2017501045A JPWO2017111069A1 (en) | 2015-12-25 | 2016-12-22 | Antidiarrheal |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2015252817 | 2015-12-25 | ||
| JP2015-252817 | 2015-12-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2017111069A1 true WO2017111069A1 (en) | 2017-06-29 |
Family
ID=59090485
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2016/088465 WO2017111069A1 (en) | 2015-12-25 | 2016-12-22 | Antipruritic |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPWO2017111069A1 (en) |
| WO (1) | WO2017111069A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019202987A (en) * | 2018-05-22 | 2019-11-28 | 花王株式会社 | Sensory stimulation reducing agent |
| CN111406113A (en) * | 2017-11-30 | 2020-07-10 | 花王株式会社 | Methods of evaluating or selecting sensory irritation reducing agents |
| JP7478895B1 (en) | 2022-11-30 | 2024-05-07 | 花王株式会社 | Agent for preventing or improving itching |
| JP7478894B1 (en) | 2022-11-30 | 2024-05-07 | 花王株式会社 | Agent for preventing or improving itching |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014178427A1 (en) * | 2013-05-02 | 2014-11-06 | 学校法人順天堂 | Method for controlling expression of semaphorin 3a |
-
2016
- 2016-12-22 JP JP2017501045A patent/JPWO2017111069A1/en active Pending
- 2016-12-22 WO PCT/JP2016/088465 patent/WO2017111069A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014178427A1 (en) * | 2013-05-02 | 2014-11-06 | 学校法人順天堂 | Method for controlling expression of semaphorin 3a |
Non-Patent Citations (2)
| 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 (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111406113A (en) * | 2017-11-30 | 2020-07-10 | 花王株式会社 | Methods of evaluating or selecting sensory irritation reducing agents |
| CN111406113B (en) * | 2017-11-30 | 2024-04-16 | 花王株式会社 | Methods for evaluating or selecting sensory irritation reducers |
| US11969436B2 (en) | 2017-11-30 | 2024-04-30 | Kao Corporation | Method for treating skin irritation caused by parabens |
| JP2019202987A (en) * | 2018-05-22 | 2019-11-28 | 花王株式会社 | Sensory stimulation reducing agent |
| JP7182440B2 (en) | 2018-05-22 | 2022-12-02 | 花王株式会社 | sensory irritation reducing agent |
| JP7478895B1 (en) | 2022-11-30 | 2024-05-07 | 花王株式会社 | Agent for preventing or improving itching |
| JP7478894B1 (en) | 2022-11-30 | 2024-05-07 | 花王株式会社 | Agent for preventing or improving itching |
| WO2024117172A1 (en) * | 2022-11-30 | 2024-06-06 | 花王株式会社 | Agent for preventing or ameliorating itch |
| WO2024117173A1 (en) * | 2022-11-30 | 2024-06-06 | 花王株式会社 | Agent for preventing or ameliorating pruritus |
Also Published As
| Publication number | Publication date |
|---|---|
| JPWO2017111069A1 (en) | 2018-10-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20230277477A1 (en) | Compositions for treating dermatological diseases | |
| US20220257482A1 (en) | Anti-aging and skin tone lightening compositions and methods for same | |
| JP2003526595A (en) | Treatment of cell-mediated immune disease | |
| WO2017111069A1 (en) | Antipruritic | |
| EP0717997B1 (en) | Use of substance P antagonist in pharmaceutical composition | |
| JP6343000B2 (en) | Composition for preventing or treating atopic dermatitis containing eugenol as an active ingredient | |
| JP4298204B2 (en) | Atopic dermatitis treatment | |
| JP2009062316A (en) | Skin care preparation for external application containing furan fatty acid or derivative thereof | |
| FR2911507A1 (en) | USE OF LIGNANS AND / OR FOR OBTAINING A PHARMACEUTICAL, COSMETIC, DERMATOLOGICAL AND / OR NEUTRACEUTICAL COMPOSITION | |
| JP4325908B2 (en) | Lipolysis accelerator, skin external preparation and food and drink using the same | |
| US20240197803A1 (en) | Use of mangosteen fruit shell extract in the preparation of a medicament for treating psoriasis | |
| JPH10120558A (en) | Skin preparation for improving sputum for external use | |
| CN110547975B (en) | Cosmetic material composition containing epipinoresinol | |
| JP6249598B2 (en) | Topical skin preparation | |
| US9408877B1 (en) | Compositions and process for skin restoration | |
| JP5956916B2 (en) | Anti-inflammatory agent | |
| KR102282246B1 (en) | Composition for preventing, alleviating, or treating atopic dermatitis | |
| KR102496723B1 (en) | A composition for prevention, improvement or treatment of skin diseases containing a Ophiopogonin-D | |
| KR20070000675A (en) | Compositions comprising mung bean extracts, platinum extracts and equestrian extracts and uses thereof | |
| JP2000119126A (en) | Effective composition for vital environment | |
| JP2016037453A (en) | Skin moisturizing agent | |
| JP2020164460A (en) | Preventing and improving agent of vitiligo or canities | |
| KR20240003499A (en) | A Composition for improving, preventing and treating of atopic dermatitis comprising Cornus Walter Stem Extracts | |
| KR20240104500A (en) | Peptide having activites for antimicrobial and uses thereof | |
| JP2014129268A (en) | Lipase inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| ENP | Entry into the national phase |
Ref document number: 2017501045 Country of ref document: JP Kind code of ref document: A |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 16878955 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 16878955 Country of ref document: EP Kind code of ref document: A1 |