JP7396585B2 - Composition for suppressing TSLP gene expression, suppressing IL-33 gene expression, or promoting filaggrin production - Google Patents
Composition for suppressing TSLP gene expression, suppressing IL-33 gene expression, or promoting filaggrin production Download PDFInfo
- Publication number
- JP7396585B2 JP7396585B2 JP2019199175A JP2019199175A JP7396585B2 JP 7396585 B2 JP7396585 B2 JP 7396585B2 JP 2019199175 A JP2019199175 A JP 2019199175A JP 2019199175 A JP2019199175 A JP 2019199175A JP 7396585 B2 JP7396585 B2 JP 7396585B2
- Authority
- JP
- Japan
- Prior art keywords
- trehalose
- skin
- suppressing
- tslp
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000000203 mixture Substances 0.000 title claims description 51
- 230000014509 gene expression Effects 0.000 title claims description 43
- 101710088660 Filaggrin Proteins 0.000 title claims description 40
- 102100028314 Filaggrin Human genes 0.000 title claims description 36
- 238000004519 manufacturing process Methods 0.000 title claims description 26
- 230000001737 promoting effect Effects 0.000 title claims description 21
- 108010067003 Interleukin-33 Proteins 0.000 title description 40
- 102000017761 Interleukin-33 Human genes 0.000 title description 31
- 101150072278 Tslp gene Proteins 0.000 title description 10
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 91
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 88
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 82
- 239000004480 active ingredient Substances 0.000 claims description 15
- 230000003526 lymphopoietic effect Effects 0.000 claims description 10
- 230000002992 thymic effect Effects 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 description 50
- 210000003491 skin Anatomy 0.000 description 36
- 239000008194 pharmaceutical composition Substances 0.000 description 34
- 210000004027 cell Anatomy 0.000 description 26
- 201000004624 Dermatitis Diseases 0.000 description 25
- 239000000499 gel Substances 0.000 description 25
- 210000001519 tissue Anatomy 0.000 description 19
- 239000002609 medium Substances 0.000 description 17
- 239000002585 base Substances 0.000 description 16
- 239000006071 cream Substances 0.000 description 16
- 239000003814 drug Substances 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 231100000241 scar Toxicity 0.000 description 15
- 239000007788 liquid Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 230000008591 skin barrier function Effects 0.000 description 11
- 208000006673 asthma Diseases 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 206010040849 Skin fissures Diseases 0.000 description 9
- 230000037390 scarring Effects 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 150000003431 steroids Chemical class 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 206010061218 Inflammation Diseases 0.000 description 8
- 108020004999 messenger RNA Proteins 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 206010012438 Dermatitis atopic Diseases 0.000 description 7
- 201000008937 atopic dermatitis Diseases 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 230000003020 moisturizing effect Effects 0.000 description 7
- 239000002674 ointment Substances 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 208000032544 Cicatrix Diseases 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000004113 cell culture Methods 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 210000004920 epithelial cell of skin Anatomy 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 235000019271 petrolatum Nutrition 0.000 description 6
- 230000037387 scars Effects 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 238000012795 verification Methods 0.000 description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 238000005336 cracking Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 206010049153 Allergic sinusitis Diseases 0.000 description 4
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 4
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 4
- 208000011231 Crohn disease Diseases 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 4
- 206010039085 Rhinitis allergic Diseases 0.000 description 4
- 206010039580 Scar Diseases 0.000 description 4
- 208000002205 allergic conjunctivitis Diseases 0.000 description 4
- 201000010105 allergic rhinitis Diseases 0.000 description 4
- 208000024998 atopic conjunctivitis Diseases 0.000 description 4
- 208000019425 cirrhosis of liver Diseases 0.000 description 4
- 239000002537 cosmetic Substances 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 210000002615 epidermis Anatomy 0.000 description 4
- 210000002919 epithelial cell Anatomy 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 210000002950 fibroblast Anatomy 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 229960003511 macrogol Drugs 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 238000003753 real-time PCR Methods 0.000 description 4
- 150000003625 trehaloses Chemical class 0.000 description 4
- -1 urocanic acid sugars Chemical class 0.000 description 4
- 239000003871 white petrolatum Substances 0.000 description 4
- 150000008494 α-glucosides Chemical class 0.000 description 4
- 208000009304 Acute Kidney Injury Diseases 0.000 description 3
- 206010002199 Anaphylactic shock Diseases 0.000 description 3
- 206010009900 Colitis ulcerative Diseases 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000721454 Pemphigus Species 0.000 description 3
- 208000033626 Renal failure acute Diseases 0.000 description 3
- 206010039710 Scleroderma Diseases 0.000 description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 description 3
- 201000011040 acute kidney failure Diseases 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 208000003455 anaphylaxis Diseases 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 230000037365 barrier function of the epidermis Effects 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000000512 collagen gel Substances 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 210000004247 hand Anatomy 0.000 description 3
- 239000002628 heparin derivative Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000000865 liniment Substances 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 description 3
- 230000036620 skin dryness Effects 0.000 description 3
- 230000007480 spreading Effects 0.000 description 3
- 238000003892 spreading Methods 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 206010069748 Burkholderia pseudomallei infection Diseases 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 206010012442 Dermatitis contact Diseases 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 206010064212 Eosinophilic oesophagitis Diseases 0.000 description 2
- 108700041153 Filaggrin Proteins Proteins 0.000 description 2
- 208000002260 Keloid Diseases 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- SUHOOTKUPISOBE-UHFFFAOYSA-N O-phosphoethanolamine Chemical compound NCCOP(O)(O)=O SUHOOTKUPISOBE-UHFFFAOYSA-N 0.000 description 2
- 239000004264 Petrolatum Substances 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 206010038546 Renal vasculitis Diseases 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 150000001719 carbohydrate derivatives Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000007376 cm-medium Substances 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000006003 cornification Effects 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 2
- 201000000708 eosinophilic esophagitis Diseases 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 210000001117 keloid Anatomy 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 229940039717 lanolin Drugs 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229940040145 liniment Drugs 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 201000004015 melioidosis Diseases 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 230000037311 normal skin Effects 0.000 description 2
- 229940041672 oral gel Drugs 0.000 description 2
- 229940066842 petrolatum Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000004761 scalp Anatomy 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 101710175576 Aggregation substance Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010012455 Dermatitis exfoliative Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 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
- 239000007995 HEPES buffer Substances 0.000 description 1
- 229920001499 Heparinoid Polymers 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 206010023330 Keloid scar Diseases 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 201000009053 Neurodermatitis Diseases 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 101710093543 Probable non-specific lipid-transfer protein Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 206010037083 Prurigo Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 238000011530 RNeasy Mini Kit Methods 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 108060008646 TRPA Proteins 0.000 description 1
- 210000004241 Th2 cell Anatomy 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 208000002029 allergic contact dermatitis Diseases 0.000 description 1
- CAKGLMPBYAPFCR-UHFFFAOYSA-N alpha-maltosyl alpha-glucoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(OC2C(C(O)C(O)C(CO)O2)O)C(CO)O1 CAKGLMPBYAPFCR-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000010805 cDNA synthesis kit Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000000515 collagen sponge Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002327 eosinophilic effect Effects 0.000 description 1
- 210000001339 epidermal cell Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 208000004526 exfoliative dermatitis Diseases 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000004565 granule cell Anatomy 0.000 description 1
- 239000002554 heparinoid Substances 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 210000002570 interstitial cell Anatomy 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 208000001875 irritant dermatitis Diseases 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 210000004936 left thumb Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229940037525 nasal preparations Drugs 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 1
- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 210000002741 palatine tonsil Anatomy 0.000 description 1
- 229940056211 paraffin Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 229920006255 plastic film Polymers 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 210000004935 right thumb Anatomy 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 239000002884 skin cream Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- LOIYMIARKYCTBW-UHFFFAOYSA-N trans-urocanic acid Natural products OC(=O)C=CC1=CNC=N1 LOIYMIARKYCTBW-UHFFFAOYSA-N 0.000 description 1
- 125000000647 trehalose group Chemical group 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 239000000003 vaginal tablet Substances 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現抑制用組成物、ＩＬ－３３遺伝子発現抑制用組成物、又はフィラグリン産生促進用組成物に関する。 The present invention relates to a composition for suppressing thymic stromal lymphopoietic factor (TSLP) gene expression, a composition for suppressing IL-33 gene expression, or a composition for promoting filaggrin production.
胸腺間質性リンパ球新生因子（ＴＳＬＰ）は、胸腺、皮膚、腸、扁桃、肺の上皮細胞、肺線維芽細胞、間質性細胞等が発現するサイトカインである（非特許文献１）。これらの細胞では、炎症を惹起する刺激に応答して、ＴＳＬＰが産生されることが知られている。ＴＳＬＰは、樹状細胞、マスト細胞等の活性化を通じて、アレルギー性の炎症応答を引き起こすことが知られている。 Thymic stromal lymphopoietic factor (TSLP) is a cytokine expressed by epithelial cells, lung fibroblasts, interstitial cells, etc. of the thymus, skin, intestines, tonsils, and lungs (Non-Patent Document 1). It is known that these cells produce TSLP in response to stimuli that induce inflammation. TSLP is known to cause allergic inflammatory responses through activation of dendritic cells, mast cells, and the like.
例えば、アトピー性皮膚炎では、皮膚バリア機能異常や掻破によって、上皮細胞でＴＳＬＰが誘導される。そしてＴＳＬＰはＴｈ２リンパ球を介して炎症を誘導するだけでなく、ＴＲＰＡを介して掻痒を誘導し、バリア機能をさらに悪化させる要因となる。そのため、ＴＳＬＰは、アトピー性皮膚炎をはじめとする炎症性皮膚疾患において、薬剤ターゲットの一つとして注目されている（非特許文献２）。 For example, in atopic dermatitis, TSLP is induced in epithelial cells due to abnormal skin barrier function or scratching. TSLP not only induces inflammation via Th2 lymphocytes, but also induces itching via TRPA, which becomes a factor that further deteriorates the barrier function. Therefore, TSLP is attracting attention as one of the drug targets in inflammatory skin diseases including atopic dermatitis (Non-Patent Document 2).
その他にも、喘息等の慢性炎症にＴＳＬＰが関与することが知られている。 In addition, TSLP is known to be involved in chronic inflammation such as asthma.
インターロイキン－３３（ＩＬ－３３）は、炎症に関連するインターロイキン－１ファミリーに属するサイトカインである。ＩＬ－３３は、上皮細胞や血管内皮細胞で恒常的に発現しており、感染、物理的又は化学的ストレス等によって細胞外に放出される。放出されたＩＬ－３３は、その受容体を発現する免疫系細胞を介してアレルギー性の炎症応答を引き起こすことが知られている。 Interleukin-33 (IL-33) is a cytokine belonging to the interleukin-1 family, which is associated with inflammation. IL-33 is constantly expressed in epithelial cells and vascular endothelial cells, and is released extracellularly by infection, physical or chemical stress, and the like. Released IL-33 is known to trigger an allergic inflammatory response via immune system cells expressing its receptor.
例えば、ＩＬ－３３は、アトピー性皮膚炎の病変部Ｔｈ２細胞の遊走を通じて、アトピー性皮膚炎の発症に関わることが知られている（非特許文献２）。 For example, IL-33 is known to be involved in the onset of atopic dermatitis through the migration of Th2 cells in lesions of atopic dermatitis (Non-Patent Document 2).
そのほかにも、乾癬、喘息、関節リウマチ、全身性硬化症、潰瘍性大腸炎、クローン病、多発性硬化症、強直性脊椎炎、肝繊維症等の炎症性疾患にＩＬ－３３が関与することが示唆されている。 In addition, IL-33 is involved in inflammatory diseases such as psoriasis, asthma, rheumatoid arthritis, systemic sclerosis, ulcerative colitis, Crohn's disease, multiple sclerosis, ankylosing spondylitis, and liver fibrosis. is suggested.
炎症性皮膚疾患や喘息等の炎症にはステロイド製剤が用いられる。ステロイド製剤はＩＬ－３３による炎症を抑制する。しかし、ステロイド製剤の継続使用では、表皮のバリア機能の低下や、ステロイド抵抗性が生じることが知られている。また、ＴＳＬＰとＩＬ－３３の両方の発現量の増加が、重症の喘息においてステロイド抵抗性に関与することも知られている（非特許文献３）。そこで、ステロイドとは別の、ＴＳＬＰ又はＩＬ－３３の発現を抑制する薬剤が望まれていた。 Steroid preparations are used for inflammation such as inflammatory skin diseases and asthma. Steroid preparations suppress inflammation caused by IL-33. However, continuous use of steroid preparations is known to cause a decline in the barrier function of the epidermis and steroid resistance. It is also known that increased expression levels of both TSLP and IL-33 are involved in steroid resistance in severe asthma (Non-Patent Document 3). Therefore, a drug other than steroids that suppresses the expression of TSLP or IL-33 has been desired.
その一方で、皮膚の炎症においては、炎症を抑える他に、表皮のバリア機能を改善して、皮膚の乾燥や外部から皮膚内への刺激因子の侵入を防ぐことも重要である。表皮のバリア機能に関わる代表的なタンパク質の一つがフィラグリンである。フィラグリンは、表皮の顆粒細胞で産生される塩基性タンパク質である。ヒトにおいては、フィラグリンは分子量約４００ｋＤａのプロフィラグリンとして産生された後、プロフィラグリンの脱リン酸化とプロテアーゼによる分解を経て、３７ｋＤａのフィラグリンモノマーとなる。フィラグリンモノマーはケラチンフィラメント同士を凝集させる線維間凝集物質として働く。さらに、角層の外層部では、フィラグリンは分解されて、アミノ酸、ウロカニン酸糖を含む天然保湿因子（ＮＭＦ）となる。 On the other hand, in the case of skin inflammation, in addition to suppressing inflammation, it is also important to improve the barrier function of the epidermis to prevent skin dryness and the entry of irritating factors into the skin from the outside. One of the representative proteins involved in the barrier function of the epidermis is filaggrin. Filaggrin is a basic protein produced in granule cells of the epidermis. In humans, filaggrin is produced as profilaggrin with a molecular weight of approximately 400 kDa, and then undergoes dephosphorylation of profilaggrin and decomposition by protease to become filaggrin monomers of 37 kDa. Filaggrin monomer acts as an interfiber aggregation substance that aggregates keratin filaments together. Furthermore, in the outer layer of the stratum corneum, filaggrin is decomposed into natural moisturizing factor (NMF) containing amino acids and urocanic acid sugars.
従って、炎症性皮膚疾患等の改善のために、フィラグリンの産生を促進することも重要な課題の一つであった。 Therefore, promoting the production of filaggrin has been an important issue in order to improve inflammatory skin diseases and the like.
本発明は、新たなＴＳＬＰ遺伝子発現抑制用組成物、ＩＬ－３３遺伝子発現抑制用組成物、又はフィラグリン産生促進用組成物の提供に関する。 The present invention relates to the provision of a new composition for suppressing TSLP gene expression, a composition for suppressing IL-33 gene expression, or a composition for promoting filaggrin production.
本発明者らは、鋭意検討を行った結果、トレハロース又はその誘導体で対象を処置又は処理することにより、胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子及びＩＬ－３３遺伝子の発現が抑制されることを見出した。
また、本発明者らは、トレハロース又はその誘導体で対象を処置又は処理することにより、フィラグリンの産生が促進されることを見出した。
本発明は、これらの知見に基づいて完成されたものである。
As a result of extensive studies, the present inventors have found that the expression of the thymic stromal lymphopoietic factor (TSLP) gene and the IL-33 gene is suppressed by treating a subject with trehalose or its derivatives. I discovered that.
The present inventors have also discovered that filaggrin production is promoted by treating or treating a subject with trehalose or a derivative thereof.
The present invention was completed based on these findings.
本発明は、トレハロース又はその誘導体を含有する、胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現抑制用、ＩＬ－３３遺伝子発現抑制用、又はフィラグリン産生促進用である、組成物に関する。
また、本発明は、トレハロース又はその誘導体を有効成分として含有する、炎症性皮膚疾患、瘢痕、又は皮膚のひび割れ若しくはあかぎれ、を改善又は予防するための医薬組成物に関する。
The present invention relates to a composition containing trehalose or a derivative thereof for suppressing thymic stromal lymphopoietic factor (TSLP) gene expression, suppressing IL-33 gene expression, or promoting filaggrin production.
The present invention also relates to a pharmaceutical composition for improving or preventing inflammatory skin diseases, scarring, or cracking or chapped skin, which contains trehalose or a derivative thereof as an active ingredient.
本発明の組成物により、細胞におけるＴＳＬＰ遺伝子及びＩＬ－３３遺伝子の発現が抑制される。従って、本発明の組成物は、ＴＳＬＰ関連状態又はＩＬ－３３関連状態の改善又は予防に有用である。
また本発明の組成物により、細胞におけるフィラグリンの産生が促進される。さらに産生されたフィラグリンの一部は分解して天然保湿因子（ＮＭＦ）となる。従って、本発明の組成物は、皮膚バリア機能低下状態の改善又は予防に有用である。
The composition of the present invention suppresses the expression of the TSLP gene and IL-33 gene in cells. Accordingly, the compositions of the present invention are useful for ameliorating or preventing TSLP-related conditions or IL-33-related conditions.
The composition of the present invention also promotes filaggrin production in cells. Furthermore, some of the filaggrin produced is degraded to become natural moisturizing factor (NMF). Therefore, the composition of the present invention is useful for improving or preventing a state of decreased skin barrier function.
本発明の構成の医薬組成物は、炎症性皮膚疾患、瘢痕、又は皮膚のひび割れ若しくはあかぎれを改善又は予防する。従って、本発明の医薬組成物は、これら皮膚の状態の処置に有用である。 Pharmaceutical compositions in accordance with the invention improve or prevent inflammatory skin diseases, scarring, or cracking or chapped skin. Accordingly, the pharmaceutical compositions of the present invention are useful in treating these skin conditions.
本明細書において、「改善」とは、疾患、症状、健康状態若しくは審美的状態の治癒、好転若しくは緩和、又は、疾患、症状、健康状態若しくは審美的状態の悪化の防止若しくは遅延、あるいは、疾患若しくは症状の進行の逆転、防止若しくは遅延を表す。
本明細書において、「予防」とは、疾患若しくは症状の発症の防止、又は疾患若しくは症状の発症のリスクを低下させることを表す。
As used herein, "improvement" refers to curing, improving or alleviating a disease, symptom, health condition or aesthetic condition, or preventing or delaying deterioration of a disease, symptom, health condition or aesthetic condition, or or the reversal, prevention or delay of the progression of symptoms.
As used herein, "prevention" refers to preventing the onset of a disease or symptom, or reducing the risk of developing a disease or symptom.
本明細書において、「対象」とは、本発明の組成物又は医薬組成物によって処理又は処置される、個体、器官、組織又は細胞を表す。 As used herein, "subject" refers to an individual, organ, tissue or cell treated or treated by the composition or pharmaceutical composition of the invention.
本明細書において、「瘢痕」（Scar）とは、身体の任意の組織の損傷又は疾患の部位に生じた線維性組織を表す。瘢痕には肥厚性瘢痕及びケロイドが包含される。 As used herein, "scar" refers to fibrous tissue produced at the site of injury or disease in any tissue of the body. Scars include hypertrophic scars and keloids.
本明細書において、「トレハロース」とは、２つのα－グルコースが１，１－グリコシド結合した二糖類であり、α，α－トレハロースとも呼ばれる。本明細書のトレハロースは無水物、二水和物等の水和物を包含する。 As used herein, "trehalose" is a disaccharide in which two α-glucoses are bonded with a 1,1-glycoside, and is also called α,α-trehalose. Trehalose herein includes anhydrous forms and hydrates such as dihydrates.
本明細書において、「トレハロース誘導体」とは、トレハロースの糖質誘導体であり、分子内にα，α－トレハロース構造に１個以上の糖モノマーが縮合した糖質である。トレハロース誘導体の具体例としては、特に限定されないが、例えば、特開平７－１４３８７６号公報、特開平８－７３５０４号公報、特許第３１８２６７９号公報、特開２０００－２２８９８０号公報などに記載される、α－マルトシルα－グルコシド、α－イソマルトシルα－グルコシドなどのモノ－グルコシルα，α－トレハロース；α－マルトトリオシルα－グルコシド（別名α－マルトシルα，α－トレハロース）、α－マルトシルα－マルトシド、α－イソマルトシルα－マルトシド、α－イソマルトシルα－イソマルトシドなどのジ－グルコシルα，α－トレハロース；α－マルトテトラオシルα－グルコシド（別名α－マルトトリオシルα，α－トレハロース）、α－マルトシルα－マルトトリオシド、α－パノシルα－マルトシドなどのトリ－グルコシルα，α－トレハロース；α－マルトペンタオシルα－グルコシド（別名α－マルトテトラオシルα，α－トレハロース）、α－マルトトリオシルα－マルトトリオシド、α－パノシルα－マルトトリオシドなどのテトラ－グルコシルα，α－トレハロースなど、グルコース重合度が３～６のα，α－トレハロースの糖質誘導体が挙げられる。
トレハロース又はその誘導体の由来や製法は特に限定されず、天然物由来であっても化学合成された物であってもよいが、リポ多糖（ＬＰＳ）その他の細胞毒性をもたらす物質の含有量が、細胞増殖を妨げない量以下であることが好ましい。
本明細書において、「トレハロース換算量」とは、トレハロース及びその誘導体から、水和水及びトレハロース以外の糖部分を差し引いた、トレハロース部分に相当する質量を表す。
As used herein, the term "trehalose derivative" refers to a carbohydrate derivative of trehalose, which is a carbohydrate in which one or more sugar monomers are condensed to an α,α-trehalose structure within the molecule. Specific examples of trehalose derivatives are not particularly limited, but include those described in JP-A-7-143876, JP-A-8-73504, JP-A-3182679, JP-A-2000-228980, etc. Mono-glucosyl α, α-trehalose such as α-maltosyl α-glucoside, α-isomaltosyl α-glucoside; α-maltotriosyl α-glucoside (also known as α-maltosyl α, α-trehalose), α-maltosyl α-maltoside Di-glucosyl α,α-trehalose such as , α-isomaltosyl α-maltoside, α-isomaltosyl α-isomaltoside; α-maltotetraosyl α-glucoside (also known as α-maltotriosyl α,α-trehalose), α- Tri-glucosyl α,α-trehalose such as maltosyl α-maltotrioside, α-panosyl α-maltoside; α-maltopentaosyl α-glucoside (also known as α-maltotetraosyl α,α-trehalose), α- Examples include carbohydrate derivatives of α,α-trehalose having a degree of glucose polymerization of 3 to 6, such as tetra-glucosyl α,α-trehalose such as maltotriosyl α-maltotrioside and α-panosyl α-maltotrioside.
The origin and manufacturing method of trehalose or its derivatives are not particularly limited, and may be derived from natural products or chemically synthesized, but the content of lipopolysaccharide (LPS) and other cytotoxic substances is The amount is preferably at most an amount that does not inhibit cell proliferation.
As used herein, "trehalose equivalent amount" refers to the mass equivalent to the trehalose moiety obtained by subtracting hydration water and sugar moieties other than trehalose from trehalose and its derivatives.
本明細書において、含有量の単位「質量％」は、「ｇ／１００ｇ」と同義である。
本明細書において、「ｖ／ｖ％」は、体積百分率を表し、「ｍＬ／１００ｍＬ」と同義である。
In this specification, the unit of content "mass%" has the same meaning as "g/100g".
In this specification, "v/v%" represents volume percentage and is synonymous with "mL/100mL".
［ＴＳＬＰ遺伝子発現抑制用、ＩＬ－３３遺伝子発現抑制用、又はフィラグリン産生促進用である、組成物］
本発明の組成物は、トレハロース及びトレハロース誘導体からなる群より選ばれる１種又は２種以上の化合物を含有することを特徴とする。
トレハロース又はトレハロース誘導体は、下記の実施例で示されるように、ＴＳＬＰ遺伝子の発現抑制効果、ＩＬ－３３遺伝子の発現抑制効果、及びフィラグリンの産生促進効果を有する。
[Composition for suppressing TSLP gene expression, suppressing IL-33 gene expression, or promoting filaggrin production]
The composition of the present invention is characterized by containing one or more compounds selected from the group consisting of trehalose and trehalose derivatives.
As shown in the Examples below, trehalose or trehalose derivatives have the effect of suppressing the expression of the TSLP gene, the effect of suppressing the expression of the IL-33 gene, and the effect of promoting the production of filaggrin.
（用途）
本発明の組成物は、ＴＳＬＰの発現量増加が関与する生理的状態である、ＴＳＬＰ関連状態の改善に有用である。ＴＳＬＰ関連状態としては、特に限定されないが、例えば、炎症性皮膚疾患、瘢痕、アレルギー性結膜炎、アレルギー性鼻炎、アレルギー性副鼻腔炎、喘息、慢性閉塞性肺疾患（ＣＯＰＤ）、好酸球性食道炎等が挙げられる。
(Application)
The composition of the present invention is useful for improving TSLP-related conditions, which are physiological conditions associated with increased expression of TSLP. TSLP-related conditions include, but are not limited to, inflammatory skin diseases, scarring, allergic conjunctivitis, allergic rhinitis, allergic sinusitis, asthma, chronic obstructive pulmonary disease (COPD), and eosinophilic esophagus. Examples include flame.
本発明の組成物は、ＩＬ－３３の発現量増加が関与する生理的状態である、ＩＬ－３３関連状態の改善に有用である。ＩＬ－３３関連状態としては、特に限定されないが、例えば、炎症性皮膚疾患、アレルギー性結膜炎、アレルギー性鼻炎、アレルギー性副鼻腔炎、喘息、慢性閉塞性肺疾患、全身性エリテマトーデス、潰瘍性大腸炎、クローン病、アナフィラキシーショック、天疱瘡、類天疱瘡、強皮症、強直性脊椎炎、肝線維症、肺線維症、急性腎障害、血管炎、癌等が挙げられる。 The composition of the present invention is useful for improving IL-33-related conditions, which are physiological conditions associated with increased expression of IL-33. IL-33-related conditions include, but are not limited to, inflammatory skin diseases, allergic conjunctivitis, allergic rhinitis, allergic sinusitis, asthma, chronic obstructive pulmonary disease, systemic lupus erythematosus, and ulcerative colitis. , Crohn's disease, anaphylactic shock, pemphigus, pemphigoid, scleroderma, ankylosing spondylitis, liver fibrosis, pulmonary fibrosis, acute kidney injury, vasculitis, cancer, etc.
本明細書において、炎症性皮膚疾患としては、特に限定されないが、国際疾病分類であるＩＣＤ－１０に例示される、アトピー性皮膚炎、脂漏性皮膚炎、おむつ皮膚炎、アレルギー性接触皮膚炎、刺激性接触皮膚炎（医薬品の接触等による皮膚炎を含む）、詳細不明の接触皮膚炎、剥脱性皮膚炎、摂取物質による皮膚炎、慢性単純性苔癬及び痒疹、掻痒症、又はその他の皮膚炎が挙げられる。 In this specification, inflammatory skin diseases include, but are not limited to, atopic dermatitis, seborrheic dermatitis, diaper dermatitis, and allergic contact dermatitis as exemplified by ICD-10, the International Classification of Diseases. , irritant contact dermatitis (including dermatitis due to contact with pharmaceuticals, etc.), unspecified contact dermatitis, exfoliative dermatitis, dermatitis due to ingested substances, lichen simplex chronicus and prurigo, pruritus, or other Examples include dermatitis.
本発明の組成物は、フィラグリンの分解によって生じる天然保湿因子（ＮＭＦ）の産生を促進するのにも有用である。さらに、本発明の組成物は、フィラグリン産生促進効果とＮＭＦ産生促進効果を通じて、皮膚バリア機能の低下を抑制する用途にも有用である。皮膚バリア機能の低下に起因する状態としては、特に限定されないが、例えばアトピー性皮膚炎等の炎症性皮膚疾患、ひび割れ、あかぎれ等が挙げられる。 Compositions of the invention are also useful for promoting the production of natural moisturizing factor (NMF), which results from the breakdown of filaggrin. Furthermore, the composition of the present invention is also useful for suppressing a decline in skin barrier function through the effect of promoting filaggrin production and the effect of promoting NMF production. Conditions caused by a decrease in skin barrier function include, but are not particularly limited to, inflammatory skin diseases such as atopic dermatitis, cracks, chapped skin, and the like.
（対象）
本発明の組成物が対象とする個体又は器官、組織若しくは細胞の由来は、特に限定されないが、好ましくは哺乳動物、より好ましくはヒトである。
本発明が対象とする器官又は組織は、好ましくは皮膚であり、より好ましくは皮膚上皮（表皮）である。
本発明の組成物が対象とする細胞は、特に限定されないが、好ましくは上皮細胞、より好ましくは皮膚上皮細胞（表皮細胞）である。ここで、対象となる細胞は、単離された器官又は組織に由来する細胞や単離細胞、幹細胞等から分化して得られた細胞、又は個体、器官若しくは組織中に存在する細胞であってもよい。
(subject)
The origin of the individual, organ, tissue or cell targeted by the composition of the present invention is not particularly limited, but is preferably a mammal, more preferably a human.
The organ or tissue targeted by the present invention is preferably skin, more preferably skin epithelium (epidermis).
The cells targeted by the composition of the present invention are not particularly limited, but are preferably epithelial cells, more preferably skin epithelial cells (epidermal cells). Here, the target cell is a cell derived from an isolated organ or tissue, a cell obtained by differentiation from an isolated cell, a stem cell, etc., or a cell existing in an individual, organ, or tissue. Good too.
（用量）
本発明の組成物のトレハロース及びその誘導体の総含有量は、当該組成物の形態、対象、使用目的等によって適宜調整される。
本発明の効果を顕著に奏する観点から、本発明の組成物は、上記の本発明の対象となる細胞に適用されるトレハロース及びその誘導体の総和の濃度が、トレハロース換算量で、１０ｍｇ／ｍＬ以上であり、好ましくは２０ｍｇ／ｍＬ以上、より好ましくは３０ｍｇ／ｍＬ以上、更に好ましくは５０ｍｇ／ｍＬ以上となるように調製される。
また、本発明の組成物は、特に限定されないが、上記の本発明の対象となる細胞に適用されるトレハロース及びその誘導体の総和の濃度が、トレハロース換算量で、例えば３００ｍｇ／ｍＬ以下であり、好ましくは２００ｍｇ／ｍＬ以下、より好ましくは１５０ｍｇ／ｍＬ以下、更に好ましくは１００ｍｇ／ｍＬ以下となるように調製される。
本明細書において、特定量の成分が「細胞に適用される」とは、その細胞（組織、器官又は個体中のものを含む）が特定量の成分に曝露されることを表す。
(dose)
The total content of trehalose and its derivatives in the composition of the present invention is appropriately adjusted depending on the form, object, purpose of use, etc. of the composition.
From the viewpoint of significantly exhibiting the effects of the present invention, the composition of the present invention is such that the total concentration of trehalose and its derivatives applied to the above-mentioned cells targeted by the present invention is 10 mg/mL or more in terms of trehalose. The concentration is preferably 20 mg/mL or more, more preferably 30 mg/mL or more, and even more preferably 50 mg/mL or more.
Furthermore, the composition of the present invention is such that, although not particularly limited, the total concentration of trehalose and its derivatives applied to the target cells of the present invention is, for example, 300 mg/mL or less in terms of trehalose, The concentration is preferably adjusted to 200 mg/mL or less, more preferably 150 mg/mL or less, even more preferably 100 mg/mL or less.
As used herein, "applying a specified amount of a component to a cell" means that the cell (including in a tissue, organ, or individual) is exposed to the specified amount of the component.
（形態）
本発明の組成物の形態は、特に限定されないが、例えば、医薬品、医薬部外品、化粧品、食品等である。
また、本発明の組成物は、例えば、細胞培養用品として、コラーゲンゲル、コラーゲンスポンジ等の細胞支持体、培地、培地添加用サプリメント、血清等；研究用試薬等であり得る。
本発明の組成物の形態は、好ましくは医薬品、医薬部外品又は化粧品である。
(form)
The form of the composition of the present invention is not particularly limited, and includes, for example, pharmaceuticals, quasi-drugs, cosmetics, foods, and the like.
Furthermore, the composition of the present invention can be used as, for example, cell culture supplies such as cell supports such as collagen gels and collagen sponges, culture media, supplements for medium addition, serum, etc.; research reagents, etc.
The composition of the present invention is preferably in the form of a pharmaceutical, quasi-drug, or cosmetic.
本発明の組成物を医薬品、医薬部外品又は化粧品に用いる場合、基剤又は担体、保存剤、乳化剤、着色剤、防腐剤、界面活性剤、紫外線吸収剤、酸化防止剤、保湿剤、紫外線吸収剤、香料、防腐防黴剤、体質顔料、着色顔料、アルコール、多価アルコール、水、油剤、増粘剤、粉体、キレート剤、酵素、動植物エキス類、ｐＨ調整剤等の成分のうち、１種単独又は２種以上を組み合わせて含んでいてもよい。本発明の組成物が医薬品又は医薬部外品の形態である場合、その具体的な形態は、下記の［医薬組成物］に記載した形態と同じである。 When the composition of the present invention is used in pharmaceuticals, quasi-drugs, or cosmetics, bases or carriers, preservatives, emulsifiers, colorants, preservatives, surfactants, ultraviolet absorbers, antioxidants, humectants, ultraviolet rays, etc. Among ingredients such as absorbents, fragrances, preservatives, fungicides, extender pigments, coloring pigments, alcohol, polyhydric alcohols, water, oils, thickeners, powders, chelating agents, enzymes, animal and plant extracts, and pH adjusters. , may be contained alone or in combination of two or more. When the composition of the present invention is in the form of a drug or quasi-drug, its specific form is the same as the form described in [Pharmaceutical Composition] below.
［医薬組成物］
本発明の医薬組成物は、トレハロース及びトレハロース誘導体からなる群より選ばれる１種又は２種以上の化合物を有効成分として含有することを特徴とする。
ここで、「医薬組成物」とは、医薬品及び医薬部外品を包含する。
本発明の医薬組成物は、上記の組成物と同じくＴＳＬＰ遺伝子発現抑制効果、ＩＬ－３３遺伝子発現抑制効果、及びフィラグリン産生促進効果を有する。
[Pharmaceutical composition]
The pharmaceutical composition of the present invention is characterized by containing as an active ingredient one or more compounds selected from the group consisting of trehalose and trehalose derivatives.
Here, the "pharmaceutical composition" includes pharmaceuticals and quasi-drugs.
The pharmaceutical composition of the present invention has the same effects as the above compositions in suppressing TSLP gene expression, suppressing IL-33 gene expression, and promoting filaggrin production.
（対象）
本発明の医薬組成物が対象とする個体は、特に限定されないが、好ましくは哺乳動物、より好ましくはヒトである。
(subject)
Individuals targeted by the pharmaceutical composition of the present invention are not particularly limited, but are preferably mammals, and more preferably humans.
（適用症）
本発明の医薬組成物は、上記のＴＳＬＰ関連状態、ＩＬ－３３関連状態、又は皮膚バリア機能低下状態の改善に有用である。即ち、本発明の医薬組成物が処置又は予防に用いられ得る具体的な疾患としては、炎症性皮膚疾患、瘢痕、皮膚のひび割れ若しくはあかぎれ、アレルギー性結膜炎、アレルギー性鼻炎、アレルギー性副鼻腔炎、喘息、慢性閉塞性肺疾患（ＣＯＰＤ）、好酸球性食道炎、全身性エリテマトーデス、潰瘍性大腸炎、クローン病、アナフィラキシーショック、天疱瘡、類点疱瘡、強皮症、強直性脊椎炎、肝線維症、肺線維症、急性腎障害、血管炎、又は癌が挙げられる。中でも、本発明の医薬組成物は、炎症性皮膚疾患、瘢痕又は皮膚のひび割れ若しくはあかぎれの処置又は予防に好適に用いられる。
(Applicable indications)
The pharmaceutical composition of the present invention is useful for improving the above-mentioned TSLP-related conditions, IL-33-related conditions, or impaired skin barrier function. That is, specific diseases for which the pharmaceutical composition of the present invention can be used to treat or prevent include inflammatory skin diseases, scars, cracked or chapped skin, allergic conjunctivitis, allergic rhinitis, allergic sinusitis, Asthma, chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, anaphylactic shock, pemphigus, melioidosis, scleroderma, ankylosing spondylitis, liver Fibrosis, pulmonary fibrosis, acute kidney injury, vasculitis, or cancer. Among these, the pharmaceutical composition of the present invention is suitably used for the treatment or prevention of inflammatory skin diseases, scars, or skin cracks or chapped skin.
（用量）
本発明の医薬組成物のトレハロース及びその誘導体の総含有量は、その剤形及び使用目的によって適宜調整され得るが、医薬組成物の全量に対して、トレハロース換算量で、例えば５質量％以上であり、好ましくは６質量％以上、より好ましくは８質量％以上、更に好ましくは１０質量％以上である。
トレハロース及びその誘導体の総含有量は、医薬組成物の全量に対して、トレハロース換算量で、例えば、８０質量％以下、７０質量％以下、６０質量％以下、５０質量％以下、４０質量％以下、３０質量％以下、２０質量％以下、又は１５質量％以下である。
(dose)
The total content of trehalose and its derivatives in the pharmaceutical composition of the present invention can be adjusted as appropriate depending on its dosage form and purpose of use, but it is, for example, 5% by mass or more in terms of trehalose based on the total amount of the pharmaceutical composition. The content is preferably 6% by mass or more, more preferably 8% by mass or more, and still more preferably 10% by mass or more.
The total content of trehalose and its derivatives is, for example, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less in terms of trehalose based on the total amount of the pharmaceutical composition. , 30% by mass or less, 20% by mass or less, or 15% by mass or less.
なお、医薬組成物が貼付剤である場合における医薬組成物の全量とは、外用剤のうち、患部に吸収され得る部分の総重量である。即ち、医薬組成物中の支持体、ライナー（剥離体）、テープ、布等の有効成分を含まない材料を除いた、残部の総重量である。 In addition, when the pharmaceutical composition is a patch, the total amount of the pharmaceutical composition is the total weight of the portion of the external preparation that can be absorbed into the affected area. That is, it is the total weight of the remainder of the pharmaceutical composition excluding materials that do not contain active ingredients, such as supports, liners (release bodies), tapes, cloths, etc.
（剤形）
本発明の医薬組成物の剤型としては、例えば、皮膚外用製剤（例：外用固形剤、外用液剤、スプレー剤、軟膏剤、クリーム剤、ゲル剤、貼付剤等）、眼科用製剤（例：点眼剤、眼軟膏剤等）、経口投与用製剤（例：錠剤、カプセル剤、顆粒剤、散剤、経口液剤、シロップ剤、経口ゼリー剤等）、口腔用製剤（例：口腔用錠剤、口腔用スプレー剤、口腔用半固形剤、含嗽剤等）、注射用製剤（例：注射剤等）、透析用製剤（例：透析用剤等）、吸入用製剤（例：吸入剤等）、耳科用製剤（例：点耳剤等）、鼻科用製剤（例：点鼻剤等）、直腸用製剤（例：坐剤、直腸用半固形剤、腸注剤等）、及び膣用製剤（例：膣錠、膣用坐剤等）等が挙げられる。
(Dosage form)
The dosage form of the pharmaceutical composition of the present invention includes, for example, skin preparations for external use (e.g. solid preparations for external use, liquid preparations for external use, sprays, ointments, creams, gels, patches, etc.), ophthalmological preparations (e.g. eye drops, eye ointments, etc.), oral preparations (e.g. tablets, capsules, granules, powders, oral liquids, syrups, oral jelly, etc.), oral preparations (e.g. oral tablets, oral jelly, etc.) sprays, oral semi-solid preparations, gargles, etc.), injection preparations (e.g. injections, etc.), dialysis preparations (e.g. dialysis preparations, etc.), inhalation preparations (e.g. inhalants, etc.), otology (e.g., ear drops, etc.), nasal preparations (e.g., nasal drops, etc.), rectal preparations (e.g., suppositories, rectal semisolid preparations, enteral injections, etc.), and vaginal preparations (e.g., suppositories, rectal semisolid preparations, enteral injections, etc.). Examples: vaginal tablets, vaginal suppositories, etc.).
本発明の医薬組成物は、好ましくは外用製剤であり、より好ましくは皮膚外用製剤である。
本発明の医薬組成物が皮膚外用製剤の場合、その剤形は、好ましくは軟膏剤、クリーム剤、ゲル剤、又は貼付剤である。皮膚外用製剤の剤形を以下に示す。
The pharmaceutical composition of the present invention is preferably a preparation for external use, more preferably a preparation for external use on the skin.
When the pharmaceutical composition of the present invention is a preparation for external use on the skin, its dosage form is preferably an ointment, cream, gel, or patch. The dosage form of the preparation for external use on the skin is shown below.
＜皮膚外用製剤の剤形＞
（１）外用固形剤
外用固形剤は、頭皮を含む皮膚又は爪に、塗布又は散布する固形の製剤であり、外用散剤等が含まれる。外用散剤とは、粉末状の外用固形剤をいう。
（２）外用液剤
外用液剤は、頭皮を含む皮膚又は爪に塗布する液状の製剤であり、リニメント剤、ローション剤等が含まれる。リニメント剤とは、皮膚にすり込んで用いる液状又は泥状の外用液剤をいう。ローション剤とは、有効成分を水性の液に溶解又は乳化もしくは微細に分散させた外用液剤をいう。
（３）スプレー剤
スプレー剤は、有効成分を霧状、粉末状、泡沫状、又はペースト状等として皮膚に噴霧する製剤であり、外用エアゾール剤、ポンプスプレー剤等が含まれる。
（４）軟膏剤
軟膏剤は、皮膚に塗布する、有効成分を基剤に溶解又は分散させた半固形の製剤であり、油脂性軟膏剤、水溶性軟膏剤等が含まれる。
（５）クリーム剤
クリーム剤は、皮膚に塗布する、水中油型又は油中水型に乳化した半固形の製剤であり、油中水型に乳化した親油性の製剤については油性クリーム剤とも呼ばれることもある。
（６）ゲル剤
ゲル剤は、皮膚に塗布するゲル状の製剤であり、水性ゲル剤、油性ゲル剤等が含まれる。
（７）貼付剤
貼付剤は、皮膚に貼付する製剤であり、テープ剤、パップ剤等が含まれる。貼付剤は、通常、高分子化合物又はこれらの混合物を基剤とし、有効成分を基剤と混和し均質として、支持体又はライナー（剥離体）に展延して成形されたものをいう。貼付剤には、必要に応じて、粘着剤や吸収促進剤等の添加剤を用いることもできる。テープ剤とは、ほとんど水を含まない基剤を用いる貼付剤をいい、プラスター剤、硬膏剤等が含まれる。テープ剤は、通常、樹脂、プラスチック、ゴム等の非水溶性の天然又は合成高分子化合物を基剤とし、有効成分をそのまま、又は有効成分に添加剤を加え、全体を均質とし、布に展延又はプラスチック製フィルム等に展延もしくは封入して成形することにより製造することができる。パップ剤とは、水を含む基剤を用いる貼付剤をいう。
<Dosage form of external skin preparation>
(1) Solid preparations for external use Solid preparations for external use are solid preparations that are applied or sprinkled on the skin including the scalp or the nails, and include powders for external use. Powder for external use refers to a powdered solid preparation for external use.
(2) External liquid preparations External liquid preparations are liquid preparations that are applied to the skin including the scalp or nails, and include liniments, lotions, and the like. Liniment refers to a liquid or slurry external preparation that is rubbed into the skin. Lotion refers to a liquid preparation for external use in which active ingredients are dissolved, emulsified, or finely dispersed in an aqueous liquid.
(3) Sprays Sprays are preparations in which the active ingredient is sprayed onto the skin in the form of a mist, powder, foam, or paste, and include external aerosols, pump sprays, and the like.
(4) Ointment Ointment is a semi-solid preparation in which an active ingredient is dissolved or dispersed in a base and is applied to the skin, and includes oil-based ointments, water-soluble ointments, and the like.
(5) Creams Creams are semi-solid formulations emulsified in oil-in-water or water-in-oil type that are applied to the skin. Lipophilic formulations emulsified in water-in-oil type are also called oil-based creams. Sometimes.
(6) Gel Gel is a gel-like preparation that is applied to the skin, and includes aqueous gels, oil-based gels, and the like.
(7) Patch A patch is a preparation that is applied to the skin, and includes tapes, poultices, and the like. A patch is usually formed by using a polymer compound or a mixture thereof as a base, mixing an active ingredient with the base to make it homogeneous, and spreading the mixture onto a support or a liner (releasable body). Additives such as adhesives and absorption enhancers can also be used in the patch, if necessary. Tapes refer to patches that use a base that contains almost no water, and include plasters, plasters, and the like. Tapes are usually based on water-insoluble natural or synthetic polymer compounds such as resins, plastics, and rubbers, and are made by adding the active ingredients as they are or adding additives to the active ingredients to make the whole homogeneous, and then spreading it on cloth. It can be manufactured by spreading or enclosing it in a plastic film or the like and molding it. Poultice refers to a patch that uses a base containing water.
（基剤又は担体）
本発明の医薬組成物は、有効成分である当該物質を、通常、各種の添加剤又は溶媒等の薬学的に許容される基剤又は担体と共に製剤化したうえで、全身的又は局所的に、経口又は非経口の形（例えば、外用）で投与される。
ここで、薬学的に許容される担体とは、一般的に医薬品の製剤に用いられる、有効成分以外の物質を意味する。薬学的に許容される担体は、その製剤の投与量において薬理作用を示さず、無害で、有効成分の治療効果を妨げないものが好ましい。また、薬学的に許容される担体は、有効成分及び製剤の有用性を高める、製剤化を容易にする、品質の安定化を図る、又は使用性を向上させる等の目的で用いることもできる。具体的には、薬事日報社２０１６年刊「医薬品添加物事典２０１６」（日本医薬品添加剤協会編集）等に記載されているような物質を、適宜目的に応じて選択すればよい。
(base or carrier)
In the pharmaceutical composition of the present invention, the substance as an active ingredient is usually formulated together with a pharmaceutically acceptable base or carrier such as various additives or solvents, and then administered systemically or locally. Administered in oral or parenteral form (eg, externally).
Here, the term "pharmaceutically acceptable carrier" means a substance other than the active ingredient that is generally used in pharmaceutical preparations. Preferably, the pharmaceutically acceptable carrier is one that does not exhibit pharmacological effects at the dosage of the formulation, is harmless, and does not interfere with the therapeutic effects of the active ingredient. Furthermore, pharmaceutically acceptable carriers can also be used for purposes such as increasing the usefulness of active ingredients and formulations, facilitating formulation, stabilizing quality, or improving usability. Specifically, substances such as those listed in "Dictionary of Pharmaceutical Excipients 2016" (edited by Japan Pharmaceutical Excipients Association) published by Yakuji Nipposha in 2016 may be appropriately selected depending on the purpose.
本発明の医薬組成物が皮膚外用製剤である場合、用いられる基剤又は担体としては、特に限定されないが、例えば、油溶性の基剤又は担体として、ワセリン、精製ワセリン、パラフィン、流動パラフィン、ラノリン、精製ラノリン、炭化水素、高級アルコール類、植物油、動物油等の脂肪油；脂肪酸エステル類、プラスチベース、グリコール類、高級脂肪酸等が挙げられる。また、特に限定されないが、水溶性の基材又は担体として、マクロゴール２００、マクロゴール４００、マクロゴール１５００、マクロゴール１５４０、マクロゴール４０００、マクロゴール２００００等のマクロゴール類（ポリエチレングリコール類）；濃グリセリン、プロピレングリコール等の多価アルコール類；ポビドン、ポリビニルアルコール等の水溶性高分子等が挙げられる。さらに、基剤又は担体としては、特に限定されないが、例えば、水溶性溶媒としてエタノール、イソプロピルアルコール、水、グリセリン、プロピレングリコール、ポリエチレングリコール類等、油溶性溶媒としてセバシン酸ジエチル、アジピン酸ジイソプロピル、トリ（カプリル・カプリン酸）グリセリン等の液状の油等が挙げられる。
当該皮膚外用製剤には、これらの基剤又は担体から、１種又は２種以上を適宜選択して用いることができる。
When the pharmaceutical composition of the present invention is a preparation for external use on the skin, the base or carrier used is not particularly limited, but examples of oil-soluble bases or carriers include petrolatum, purified petrolatum, paraffin, liquid paraffin, and lanolin. , refined lanolin, hydrocarbons, higher alcohols, fatty oils such as vegetable oils and animal oils; fatty acid esters, plastibase, glycols, and higher fatty acids. In addition, although not particularly limited, as a water-soluble base material or carrier, macrogols (polyethylene glycols) such as macrogol 200, macrogol 400, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 20000; Examples include polyhydric alcohols such as concentrated glycerin and propylene glycol; water-soluble polymers such as povidone and polyvinyl alcohol. Furthermore, the base or carrier is not particularly limited, but for example, water-soluble solvents such as ethanol, isopropyl alcohol, water, glycerin, propylene glycol, polyethylene glycols, etc., and oil-soluble solvents such as diethyl sebacate, diisopropyl adipate, and Liquid oils such as (caprylic/capric acid) glycerin, etc. are mentioned.
One or more of these bases or carriers can be appropriately selected and used in the skin external preparation.
（その他成分）
本発明の医薬組成物には、必要に応じて、さらに懸濁剤、増粘剤、安定化剤、湿潤剤、保存剤、乳化剤、懸濁化剤、ｐＨ調整剤等の１種又は２種以上を含有してもよい。
(Other ingredients)
The pharmaceutical composition of the present invention may optionally contain one or more of suspending agents, thickeners, stabilizers, wetting agents, preservatives, emulsifiers, suspending agents, pH adjusters, etc. It may contain the above.
（用法）
本発明の医薬組成物が皮膚外用製剤である場合は、対象の年齢、性別等、に応じて適宜変更し得るが、例えば、１日数回（例えば、約１～５回、好ましくは１～３回）、適量（例えば、約０．０５～５ｇ）を患部に投与（塗布等）することができる。
(Usage)
When the pharmaceutical composition of the present invention is a preparation for external use on the skin, it may be changed as appropriate depending on the age, sex, etc. of the subject, but for example, An appropriate amount (for example, about 0.05 to 5 g) can be administered (applied, etc.) to the affected area.
本発明の医薬組成物が皮膚外用製剤である場合は、製剤の塗布による１０ｃｍ２当たりの１回の投与量は、特に限定されないが、例えば、トレハロース換算量で、０．１ｍｇ以上、好ましくは１ｍｇ以上、より好ましくは５ｍｇ以上、更に好ましくは１０ｍｇ以上、更により好ましくは１００ｍｇ以上であり、５，０００ｍｇ以下、好ましくは１，０００ｍｇ以下、より好ましくは５００ｍｇ以下である。 When the pharmaceutical composition of the present invention is a preparation for external use on the skin, the dosage per 10 cm 2 of the preparation is not particularly limited, but for example, the amount of trehalose equivalent is 0.1 mg or more, preferably 1 mg. As mentioned above, the amount is more preferably 5 mg or more, still more preferably 10 mg or more, even more preferably 100 mg or more, and 5,000 mg or less, preferably 1,000 mg or less, and more preferably 500 mg or less.
（他の医薬との組み合わせ）
本発明の医薬組成物は、ステロイド製剤と併用することができる。本発明の医薬組成物は、フィラグリン産生促進を通じて皮膚のバリア機能を改善する。そのため、このような併用は、ステロイド製剤による皮膚のバリア機能の低下を改善する観点から、皮膚疾患、好ましくは皮膚炎症性疾患に対して好適である。
本発明の医薬組成物は、ＴＳＬＰとＩＬ－３３の両方を抑制する。そのため、このような併用は、ＴＳＬＰ及びＩＬ－３３の発現量増加によってもたらされるステロイド抵抗性を改善する観点から、喘息又は慢性閉塞性肺疾患、好ましくは重度喘息に対して好適である。
(Combination with other medicines)
The pharmaceutical composition of the present invention can be used in combination with steroid preparations. The pharmaceutical composition of the present invention improves skin barrier function by promoting filaggrin production. Therefore, such a combination is suitable for skin diseases, preferably skin inflammatory diseases, from the viewpoint of improving the decrease in skin barrier function caused by steroid preparations.
Pharmaceutical compositions of the invention inhibit both TSLP and IL-33. Therefore, such a combination is suitable for asthma or chronic obstructive pulmonary disease, preferably severe asthma, from the viewpoint of improving steroid resistance caused by increased expression levels of TSLP and IL-33.
以下に、本発明及び本発明の好ましい実施態様を示す。
＜１＞
トレハロース及びその誘導体からなる群より選ばれる１種又は２種以上の化合物を含有する、胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現抑制用、ＩＬ－３３遺伝子発現抑制用、又はフィラグリン産生促進用である、組成物。
＜２＞
ＴＳＬＰ関連状態、ＩＬ－３３関連状態、又は皮膚バリア機能低下状態を改善又は予防するための、＜１＞に記載の組成物。
＜３＞
処置又は処理する対象となる細胞に適用されるトレハロース及びその誘導体の総和の濃度が、トレハロース換算量で、１０ｍｇ／ｍＬ以上であって、好ましくは２０ｍｇ／ｍＬ以上、より好ましくは３０ｍｇ／ｍＬ以上、更に好ましくは５０ｍｇ／ｍＬ以上、
３００ｍｇ／ｍＬ以下であって、好ましくは２００ｍｇ／ｍＬ以下、より好ましくは１５０ｍｇ／ｍＬ以下、更に好ましくは１００ｍｇ／ｍＬ以下となるように調製された、＜１＞又は＜２＞に記載の組成物。
＜４＞
対象が、哺乳動物、好ましくはヒトの、個体又は器官、組織若しくは細胞である、＜１＞～＜３＞のいずれか１に記載の組成物。
＜５＞
医薬品、医薬部外品、化粧品、食品、細胞培養用品、又は研究用試薬である、＜１＞～＜４＞のいずれか１に記載の組成物。
＜６＞
炎症性皮膚疾患、瘢痕、皮膚のひび割れ若しくはあかぎれ、アレルギー性結膜炎、アレルギー性鼻炎、アレルギー性副鼻腔炎、喘息、慢性閉塞性肺疾患（ＣＯＰＤ）、好酸球性食道炎、全身性エリテマトーデス、潰瘍性大腸炎、クローン病、アナフィラキシーショック、天疱瘡、類点疱瘡、強皮症、強直性脊椎炎、肝線維症、肺線維症、急性腎障害、血管炎、又は癌を、改善又は予防するための、＜１＞～＜５＞のいずれか１に記載の組成物。
＜７＞
トレハロース及びその誘導体の総含有量が、組成物の全量に対して、トレハロース換算量で、５質量％以上であり、好ましくは６質量％以上、より好ましくは８質量％以上、更に好ましくは１０質量％以上、
８０質量％以下であり、７０質量％以下、６０質量％以下、５０質量％以下、４０質量％以下、３０質量％以下、２０質量％以下、又は１５質量％以下である、＜１＞～＜６＞のいずれか１に記載の組成物。
The present invention and preferred embodiments of the present invention are shown below.
<1>
Containing one or more compounds selected from the group consisting of trehalose and its derivatives, for suppressing thymic stromal lymphopoietic factor (TSLP) gene expression, suppressing IL-33 gene expression, or promoting filaggrin production. A composition for use.
<2>
The composition according to <1>, for improving or preventing a TSLP-related condition, an IL-33-related condition, or a condition of decreased skin barrier function.
<3>
The total concentration of trehalose and its derivatives applied to cells to be treated or treated is 10 mg/mL or more, preferably 20 mg/mL or more, more preferably 30 mg/mL or more, in terms of trehalose. More preferably 50 mg/mL or more,
The composition according to <1> or <2>, prepared to have a concentration of 300 mg/mL or less, preferably 200 mg/mL or less, more preferably 150 mg/mL or less, even more preferably 100 mg/mL or less. .
<4>
The composition according to any one of <1> to <3>, wherein the subject is an individual or an organ, tissue or cell of a mammal, preferably a human.
<5>
The composition according to any one of <1> to <4>, which is a pharmaceutical, quasi-drug, cosmetic, food, cell culture product, or research reagent.
<6>
Inflammatory skin diseases, scarring, cracked or chapped skin, allergic conjunctivitis, allergic rhinitis, allergic sinusitis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis, systemic lupus erythematosus, ulcers To improve or prevent sexual colitis, Crohn's disease, anaphylactic shock, pemphigus, melioidosis, scleroderma, ankylosing spondylitis, liver fibrosis, pulmonary fibrosis, acute kidney injury, vasculitis, or cancer. The composition according to any one of <1> to <5>.
<7>
The total content of trehalose and its derivatives is 5% by mass or more in terms of trehalose based on the total amount of the composition, preferably 6% by mass or more, more preferably 8% by mass or more, and even more preferably 10% by mass. %that's all,
80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, or 15% by mass or less, <1> to < The composition according to any one of Item 6>.
＜８＞
トレハロース及びその誘導体からなる群より選ばれる１種又は２種以上の化合物を有効成分として含有する、炎症性皮膚疾患、瘢痕、又は皮膚のひび割れ若しくはあかぎれ、を改善又は予防するための医薬組成物。
＜９＞
トレハロース及びその誘導体の総含有量が、医薬組成物の全量に対して、トレハロース換算量で、５質量％以上であり、好ましくは６質量％以上、より好ましくは８質量％以上、更に好ましくは１０質量％以上、
８０質量％以下であり、７０質量％以下、６０質量％以下、５０質量％以下、４０質量％以下、３０質量％以下、２０質量％以下、又は１５質量％以下である、＜８＞に記載の医薬組成物。
＜１０＞
皮膚外用製剤であって、好ましくは外用固形剤、外用液剤、スプレー剤、軟膏剤、クリーム剤、ゲル剤、又は貼付剤である、＜８＞又は＜９＞に記載の医薬組成物。
<8>
A pharmaceutical composition for improving or preventing inflammatory skin diseases, scars, or skin cracks or chapping, which contains as an active ingredient one or more compounds selected from the group consisting of trehalose and its derivatives.
<9>
The total content of trehalose and its derivatives is 5% by mass or more, preferably 6% by mass or more, more preferably 8% by mass or more, and even more preferably 10% by mass, based on the total amount of the pharmaceutical composition. Mass% or more,
80 mass% or less, 70 mass% or less, 60 mass% or less, 50 mass% or less, 40 mass% or less, 30 mass% or less, 20 mass% or less, or 15 mass% or less, described in <8> Pharmaceutical composition.
<10>
The pharmaceutical composition according to <8> or <9>, which is an external preparation for skin use, preferably a solid preparation for external use, a liquid preparation for external use, a spray, an ointment, a cream, a gel, or a patch.
＜１１＞
胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現抑制、ＩＬ－３３遺伝子発現抑制、又はフィラグリン産生促進のための、トレハロース又はその誘導体の使用。
＜１２＞
処置又は処理する対象となる細胞に適用されるトレハロース及びその誘導体の総和の濃度が、トレハロース換算量で、１０ｍｇ／ｍＬ以上であって、好ましくは２０ｍｇ／ｍＬ以上、より好ましくは３０ｍｇ／ｍＬ以上、更に好ましくは５０ｍｇ／ｍＬ以上、
３００ｍｇ／ｍＬ以下であって、好ましくは２００ｍｇ／ｍＬ以下、より好ましくは１５０ｍｇ／ｍＬ以下、更に好ましくは１００ｍｇ／ｍＬ以下である、＜１１＞に記載の使用。
<11>
Use of trehalose or a derivative thereof for suppressing thymic stromal lymphopoietic factor (TSLP) gene expression, suppressing IL-33 gene expression, or promoting filaggrin production.
<12>
The total concentration of trehalose and its derivatives applied to cells to be treated or treated is 10 mg/mL or more, preferably 20 mg/mL or more, more preferably 30 mg/mL or more, in terms of trehalose. More preferably 50 mg/mL or more,
The use according to <11>, wherein the concentration is 300 mg/mL or less, preferably 200 mg/mL or less, more preferably 150 mg/mL or less, even more preferably 100 mg/mL or less.
＜１３＞
ＴＳＬＰ関連状態、ＩＬ－３３関連状態、又は皮膚バリア機能低下状態を改善又は予防するために用いるトレハロース又はその誘導体。
＜１４＞
炎症性皮膚疾患、瘢痕、又は皮膚のひび割れ若しくはあかぎれの処置のために用いるトレハロース又はその誘導体。
＜１５＞
上記＜１３＞又は＜１４＞において、使用濃度は、トレハロース換算量で、５質量％以上でり、好ましくは６質量％以上、より好ましくは８質量％以上、更に好ましくは１０質量％以上、
８０質量％以下であり、７０質量％以下、６０質量％以下、５０質量％以下、４０質量％以下、３０質量％以下、２０質量％以下、又は１５質量％以下である、トレハロース又はその誘導体。
<13>
Trehalose or a derivative thereof used for improving or preventing a TSLP-related condition, an IL-33-related condition, or a condition of decreased skin barrier function.
<14>
Trehalose or its derivatives for use in the treatment of inflammatory skin diseases, scars, or cracked or chapped skin.
<15>
In <13> or <14> above, the concentration used is 5% by mass or more, preferably 6% by mass or more, more preferably 8% by mass or more, still more preferably 10% by mass or more, in terms of trehalose.
Trehalose or a derivative thereof, which is 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, or 15% by mass or less.
＜１６＞
胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現抑制、ＩＬ－３３遺伝子発現抑制、又はフィラグリン産生促進の方法であって、それを必要とする対象にトレハロース又はその誘導体を有効量で投与することを含む、方法。
＜１７＞
対象となる細胞に適用されるトレハロース及びその誘導体の総和の濃度が、トレハロース換算量で、１０ｍｇ／ｍＬ以上であって、好ましくは２０ｍｇ／ｍＬ以上、より好ましくは３０ｍｇ／ｍＬ以上、更に好ましくは５０ｍｇ／ｍＬ以上、３００ｍｇ／ｍＬ以下であって、好ましくは２００ｍｇ／ｍＬ以下、より好ましくは１５０ｍｇ／ｍＬ以下、更に好ましくは１００ｍｇ／ｍＬ以下である、＜１６＞に記載の方法。
<16>
A method for suppressing thymic stromal lymphopoietic factor (TSLP) gene expression, suppressing IL-33 gene expression, or promoting filaggrin production, comprising administering an effective amount of trehalose or a derivative thereof to a subject in need thereof. including methods.
<17>
The total concentration of trehalose and its derivatives applied to the target cells is 10 mg/mL or more, preferably 20 mg/mL or more, more preferably 30 mg/mL or more, still more preferably 50 mg in terms of trehalose. /mL or more and 300mg/mL or less, preferably 200mg/mL or less, more preferably 150mg/mL or less, and still more preferably 100mg/mL or less.
＜１８＞
ＴＳＬＰ関連状態、ＩＬ－３３関連状態、又は皮膚バリア機能低下状態を改善又は予防するための方法であって、それを必要とする対象にトレハロース又はその誘導体を有効量で投与することを含む、方法。
＜１９＞
炎症性皮膚疾患、瘢痕、又は皮膚のひび割れ若しくはあかぎれの処置又は予防のための方法であって、それを必要とする対象にトレハロース又はその誘導体を有効量で投与することを含む、方法。
＜２０＞
製剤の塗布による１０ｃｍ２当たりの１回の投与量は、トレハロース換算量で、０．１ｍｇ以上であって、好ましくは１ｍｇ以上、より好ましくは５ｍｇ以上、更に好ましくは１０ｍｇ以上、更に好ましくは１００ｍｇ以上、５，０００ｍｇ以下であって、好ましくは１，０００ｍｇ以下、より好ましくは５００ｍｇ以下、である、＜１８＞又は＜１９＞に記載の方法。
＜２１＞
前記処置又は予防が、胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現抑制、ＩＬ－３３遺伝子発現抑制、又はフィラグリン産生促進によって行われる、＜１８＞～＜２０＞のいずれか１に記載の方法。
<18>
A method for improving or preventing a TSLP-related condition, an IL-33-related condition, or a reduced skin barrier function condition, the method comprising administering an effective amount of trehalose or a derivative thereof to a subject in need thereof. .
<19>
A method for the treatment or prevention of inflammatory skin diseases, scarring, or cracking or chapped skin, the method comprising administering to a subject in need thereof an effective amount of trehalose or a derivative thereof.
<20>
A single dose per 10 cm 2 of the preparation applied is 0.1 mg or more, preferably 1 mg or more, more preferably 5 mg or more, still more preferably 10 mg or more, still more preferably 100 mg or more in terms of trehalose. , 5,000 mg or less, preferably 1,000 mg or less, more preferably 500 mg or less, the method according to <18> or <19>.
<21>
The treatment or prevention according to any one of <18> to <20>, wherein the treatment or prevention is performed by suppressing thymic stromal lymphopoietic factor (TSLP) gene expression, suppressing IL-33 gene expression, or promoting filaggrin production. Method.
＜２２＞
胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現抑制用、ＩＬ－３３遺伝子発現抑制用、又はフィラグリン産生促進用の医薬を製造するための、トレハロース又はその誘導体の使用。
＜２３＞
炎症性皮膚疾患、瘢痕、又は皮膚のひび割れ若しくはあかぎれの処置又は予防用の医薬を製造するための、トレハロース又はその誘導体の使用。
<22>
Use of trehalose or a derivative thereof for producing a medicament for suppressing thymic stromal lymphopoietic factor (TSLP) gene expression, suppressing IL-33 gene expression, or promoting filaggrin production.
<23>
Use of trehalose or a derivative thereof for the manufacture of a medicament for the treatment or prevention of inflammatory skin diseases, scarring, or cracking or chapped skin.
［試験例１．トレハロースの遺伝子発現に対する効果の検証］
下記のように、正常ヒト皮膚上皮細胞を用いて、トレハロースによる遺伝子発現に与える効果をｉｎ ｖｉｔｒｏで検証した。
[Test Example 1. Verification of the effect of trehalose on gene expression]
As described below, the effect of trehalose on gene expression was verified in vitro using normal human skin epithelial cells.
（方法）
（１）ＭＣＤＢ Ｔｙｐｅ－ＩＩ培地（特許第３０６６６２４号公報の増殖培地２）に対して、６．６ｇ／Ｌ ＨＥＰＥＳ、０．０６ｍＭ ＣａＣｌ２、１００ｍｇ／Ｌカナマイシン、１．２ｇ／Ｌ ＮａＨＣＯ３、０．１μＭ インスリン、１００μＭモノエタノールアミン、１００μＭ ｏ－ホスホエタノールアミン、０．５μｇ／ｍＬヒドロコルチゾン、５０ｍｇタンパク質／ｍＬウシ脳視床下部抽出液（ＢＨＥ）を含有する培地（ｐＨ７．２）を調製した。正常ヒト皮膚上皮細胞（ＮＨＫ）を、前記培地中で、コンフルエントになるまで３７℃で単層培養した。
（２）（１）の培地を、０、３０又は１００ｍｇ／ｍＬのトレハロースを含有する培地に置換して、３７℃で４８時間インキュベートした。
（３）各条件の細胞を回収し、RNeasy Mini Kit（QIAGEN社製）を用いてｍＲＮＡを抽出した。ｍＲＮＡからiScript cDNA Synthesis kit（B10-RAD社製）を用いてｃＤＮＡを調製した。各処理はそれぞれのマニュアルに従って行った。
（４）（３）で得られたｃＤＮＡに対して、ＴＳＬＰ、フィラグリン、及びＩＬ－３３遺伝子に対するＴａｑＭａｎ ＰＣＲ用プライマー（Thermo fisher Scientific社製、プライマーコード：Hs00263639-m1（TSLP）、Hs00856927-g1（フィラグリン）、Hs04931857-m1（IL-33））を用いて、定量ＰＣＲ（ｑＰＣＲ）を行った。反応には、Fast Start Universl Probe Master (Rox)（Roche社製）、StepOnePlue Real time PCR system（Applied Biosystems社製）を用いた。各条件で用いたサンプル数は３であった。
(Method)
(1) For MCDB Type-II medium (growth medium 2 of Patent No. 3066624), 6.6 g/L HEPES, 0.06 mM CaCl 2 , 100 mg/L kanamycin, 1.2 g/L NaHCO 3 , 0 A medium (pH 7.2) was prepared containing .1 μM insulin, 100 μM monoethanolamine, 100 μM o-phosphoethanolamine, 0.5 μg/mL hydrocortisone, and 50 mg protein/mL bovine brain hypothalamic extract (BHE). Normal human skin epithelial cells (NHK) were cultured in monolayer at 37° C. in the above medium until confluent.
(2) The medium in (1) was replaced with a medium containing 0, 30 or 100 mg/mL trehalose, and incubated at 37°C for 48 hours.
(3) Cells under each condition were collected, and mRNA was extracted using RNeasy Mini Kit (manufactured by QIAGEN). cDNA was prepared from mRNA using iScript cDNA Synthesis kit (manufactured by B10-RAD). Each treatment was performed according to the respective manual.
(4) For the cDNA obtained in (3), use TaqMan PCR primers for TSLP, filaggrin, and IL-33 genes (manufactured by Thermo Fisher Scientific, primer code: Hs00263639-m1 (TSLP), Hs00856927-g1 ( Quantitative PCR (qPCR) was performed using Hs04931857-m1 (IL-33)). For the reaction, Fast Start Universl Probe Master (Rox) (manufactured by Roche) and StepOnePlue Real time PCR system (manufactured by Applied Biosystems) were used. The number of samples used under each condition was three.
（結果）
ｑＰＣＲの結果を図１に示す。３０ｍｇ／ｍＬ又は１００ｍｇ／ｍＬトレハロースで処理した場合、トレハロースなしの対照（vehicle）に比べてＴＳＬＰ遺伝子及びＩＬ－３３遺伝子のｍＲＮＡ発現量が顕著に減少した。
また、フィラグリン遺伝子については、１００ｍｇ／ｍＬトレハロース処理によってｍＲＮＡ発現量が顕著に増加した。３０ｍｇ／ｍＬトレハロースで処理した場合にも、トレハロースなしの培地で処理した場合に対してフィラグリン遺伝子のｍＲＮＡの発現量が５倍程度に増加した。
(result)
The qPCR results are shown in Figure 1. When treated with 30 mg/mL or 100 mg/mL trehalose, the mRNA expression levels of the TSLP gene and IL-33 gene were significantly reduced compared to the control (vehicle) without trehalose.
Furthermore, regarding the filaggrin gene, the mRNA expression level was significantly increased by treatment with 100 mg/mL trehalose. Even when treated with 30 mg/mL trehalose, the expression level of filaggrin gene mRNA increased about 5 times compared to when treated with a medium without trehalose.
以上から、トレハロースは皮膚上皮細胞のＴＳＬＰ遺伝子及びＩＬ－３３遺伝子の発現を抑制し、またフィラグリン遺伝子の発現を促進することが明らかとなった。 From the above, it has been revealed that trehalose suppresses the expression of the TSLP gene and IL-33 gene in skin epithelial cells, and also promotes the expression of the filaggrin gene.
［試験例２．トレハロースのフィラグリン産生促進効果の検証］
下記のように、皮膚組織のｉｎ ｖｉｔｒｏモデルである三次元培養皮膚に対して、トレハロースを含有するクリーム剤を塗布して、そのフィラグリン産生効果を検証した。
[Test Example 2. Verification of the filaggrin production promoting effect of trehalose]
As described below, a cream containing trehalose was applied to three-dimensional cultured skin, which is an in vitro model of skin tissue, and its filaggrin production effect was verified.
（方法）
＜１．三次元培養皮膚の作製＞
（１）まず、以下の表１の組成でゲル溶液Ｉを作製した。
(Method)
<1. Preparation of three-dimensional cultured skin>
(1) First, gel solution I was prepared with the composition shown in Table 1 below.
（２）続いて、得られたゲル約１ｍＬをセルカルチャーインサートであるトランズウェル－コルコラーゲンコートインサート（カタログ番号： ３４９２、Costar社製；ポアサイズ：３.０μｍ、表面積：４．６７ｃｍ２）に注ぎ、インキュベーターに５分以上静置した。５×１０５個／ｍＬの細胞密度で正常ヒト皮膚線維芽細胞（ＮＨＤＦ、Cambrex社製）を懸濁した、１０ｖ／ｖ％ＦＣＳ及び１ｖ／ｖ％ＡＢＡＭ（Antibiotics-Antimycotic solution, 100x，ThermoFisher Scientific社製）を含むＤＭＥＭ５ｍＬを、２９ｍＬのゲル溶液Ｉに加えた。この細胞を含むゲル溶液約３．５ｍＬを上記セルカルチャーインサートに加え、３７℃インキュベーターに３０分間静置してゲル化した。 (2) Next, approximately 1 mL of the obtained gel was poured into a cell culture insert, Transwell-Col collagen coated insert (catalog number: 3492, manufactured by Costar; pore size: 3.0 μm, surface area: 4.67 cm 2 ). , and left in an incubator for 5 minutes or more. Normal human dermal fibroblasts (NHDF, manufactured by Cambrex) were suspended at a cell density of 5 × 10 cells/mL in 10 v/v% FCS and 1 v/v% ABAM (Antibiotics-Antimycotic solution, 100x, ThermoFisher Scientific). 5 mL of DMEM containing (manufactured by) was added to 29 mL of gel solution I. Approximately 3.5 mL of the gel solution containing these cells was added to the above cell culture insert, and the gel solution was allowed to stand in a 37° C. incubator for 30 minutes to form a gel.
（３）次に、上記のＮＨＤＦを含むコラーゲンゲル（層状の真皮細胞構造体）を、５０μｇ／ｍｌアスコルビン酸、１０ｖ／ｖ％ＦＣＳ、１ｖ／ｖ％ＡＢＡＭを含むＤＭＥＭ培地を用いて５日間前培養した後、コラーゲンゲル表面にＭＣＤＢ培地に懸濁したヒト正常皮膚上皮細胞を１．２８×１０５個／ｃｍ２となるように播種し、セルカルチャーインサートの外液及びインサート内にＭＣＤＢ Ｔｙｐｅ－ＩＩ培地（特許第３０６６６２４号公報の増殖培地２）とＥＧＭを等量混ぜた培地を加えて、３７℃で２日間培養した。なお、ＥＧＭの組成は表２のとおりである。 (3) Next, the collagen gel (layered dermal cell structure) containing the above NHDF was prepared for 5 days using a DMEM medium containing 50 μg/ml ascorbic acid, 10 v/v% FCS, and 1 v/v% ABAM. After culturing, human normal skin epithelial cells suspended in MCDB medium were seeded on the surface of the collagen gel at a density of 1.28 x 10 5 cells/cm 2 , and MCDB Type- A medium containing equal amounts of II medium (growth medium 2 of Patent No. 3,066,624) and EGM was added and cultured at 37° C. for 2 days. Note that the composition of EGM is as shown in Table 2.
（４）角化培地（ＣＭ培地）に交換し、セルカルチャーインサートの多孔質膜が角化培地の気液界面に位置するようにセルカルチャーインサートを配置した。その状態で３７℃、７～１４日間気液界面培養することにより分化誘導を行い、三次元培養皮膚を得た。なお、培養開始から２日ごとに培地交換を行った。なお、ＣＭ培地の組成は表３のとおりである。 (4) The cell culture medium was replaced with a cornification medium (CM medium), and the cell culture insert was placed so that the porous membrane of the cell culture insert was positioned at the air-liquid interface of the cornification medium. Under this condition, differentiation was induced by culturing at an air-liquid interface for 7 to 14 days at 37°C to obtain three-dimensionally cultured skin. Note that the medium was replaced every two days from the start of culture. The composition of the CM medium is shown in Table 3.
＜２．培養皮膚の処置＞
（５）塗布用のサンプルとして、基剤にVanicream Moisturizing Skin Cream（Vanicream社製）を使用し、基剤のみのクリーム（ビヒクル）、トレハロースを１００ｍｇ／ｍＬ含有するクリーム、及びヘパリン類似物質（Heparinoid）を３０ｍｇ／ｍＬ含有するクリームを調製した。これら３種類のクリーム１００ｍｇを、（４）で得られた三次元培養皮膚の表皮上（面積：４．６７ｃｍ２）に塗布し、（４）と同じ培地で、さらに３７℃１週間インキュベートした。
<2. Cultured skin treatment>
(5) As samples for application, Vanicream Moisturizing Skin Cream (manufactured by Vanicream) was used as the base, a cream containing only the base (vehicle), a cream containing 100 mg/mL of trehalose, and a heparin-like substance (Heparinoid) A cream containing 30 mg/mL of was prepared. 100 mg of these three types of creams were applied onto the epidermis (area: 4.67 cm 2 ) of the three-dimensionally cultured skin obtained in (4), and further incubated at 37° C. for one week in the same medium as in (4).
＜３．培養皮膚の染色＞
（６）（５）で得られた三次元培養皮膚の組織切片を作製した。得られた組織切片を常法によりヘマトキシリン・エオジン（ＨＥ）染色を行った。また、得られた組織切片に、一次抗体として抗フィラグリン抗体（抗FillagrinマウスIgG抗体(AKH1)、Santa Cruz社製、製品番号sc-66192）を用いて、フィラグリン染色を行った。
<3. Staining of cultured skin>
(6) Tissue sections of the three-dimensional cultured skin obtained in (5) were prepared. The obtained tissue sections were stained with hematoxylin and eosin (HE) using a conventional method. In addition, filaggrin staining was performed on the obtained tissue sections using an anti-filagrin antibody (anti-filagrin mouse IgG antibody (AKH1), manufactured by Santa Cruz, product number sc-66192) as a primary antibody.
（結果）
得られたそれぞれの三次元培養皮膚の組織切片の染色像を、図２に示した。フィラグリン染色像に示されるように、１００ｍｇ／ｍＬトレハロース含有クリームで処理した場合、３０ｍｇ／ｍＬヘパリン類似物質で処置を行った場合やビヒクルと比べて、フィラグリンの層の厚みが増し、またフィラグリン量が増加していることが分かった。従って、トレハロースが表皮組織のフィラグリン量を増加させることが明らかとなった。
(result)
The stained images of the obtained tissue sections of the three-dimensionally cultured skin are shown in FIG. 2. As shown in the filaggrin staining images, when treated with 100 mg/mL trehalose-containing cream, the thickness of the filaggrin layer increased and the amount of filaggrin increased compared to treatment with 30 mg/mL heparin-like substance or vehicle. It was found that it is increasing. Therefore, it was revealed that trehalose increases the amount of filaggrin in epidermal tissue.
［試験例３．皮膚病変に対する効果の検証（ヒトを対象とした評価）］
以下では、塗布剤として、Gauglitzらの総説（Molecular Medicine, 2011, Vol.17, No.1-2, p.113-125）のSilicone gel sheetingに類似したゲルにトレハロースを添加し、患者に処置を行った例を示す。具体的には、塗布剤として、１０％トレハロースジェル（トレハロースを終濃度１００ｍｇ／ｍＬとなるように、アイ・ティー・オー社製のＩＴＯジェルベースに加え、１０００ｒｐｍの撹拌機で混合したもの）を用いた。当該ジェルは、水、グリセリン、カルボマー、ポリアクリル酸ナトリウム、メチルパラベン、プロピルパラベンを含有する。
[Test Example 3. Verification of effects on skin lesions (evaluation on humans)]
Below, as a liniment, trehalose is added to a gel similar to the silicone gel sheeting described in the review by Gauglitz et al. (Molecular Medicine, 2011, Vol. 17, No. 1-2, p. 113-125), and the patient is treated with the gel. An example is shown below. Specifically, as a coating agent, 10% trehalose gel (trehalose was added to ITO gel base manufactured by ITO to give a final concentration of 100 mg/mL and mixed with a stirrer at 1000 rpm) was used. Using. The gel contains water, glycerin, carbomer, sodium polyacrylate, methylparaben, propylparaben.
（１．瘢痕に対する効果の検証）
表４に記載の患者の瘢痕部に、１０％トレハロースジェルを、１日１回入浴後に適量（約１～約１０ｍｇ／ｃｍ２）塗布してもらった。塗布後に患部はラップで覆われ、固定された。処置前及び表４に記載する処置後の各時点の瘢痕の状態を、瘢痕・ケロイド治療研究会が定めるガイドラインであるＪＳＷ Ｓｃａｒ Ｓｃａｌｅ ２０１１に従ってスコア化した。処方及びスコア付けは、患者の同意を得て医師が行った。結果を同じ表４に示した。また、症例１及び３の瘢痕の経過を示す写真を図３に示した。トレハロース含有製剤の塗布により、いずれの症例においても、瘢痕の状態が通常よりも速やかに改善していた。
(1. Verification of effect on scarring)
An appropriate amount (about 1 to about 10 mg/cm 2 ) of 10% trehalose gel was applied to the scarred area of the patients listed in Table 4 after bathing once a day. After application, the affected area was covered with plastic wrap and fixed. The scar condition before the treatment and at each time point after the treatment listed in Table 4 was scored according to JSW Scar Scale 2011, a guideline established by the Scar and Keloid Treatment Study Group. Prescription and scoring were performed by a physician with patient consent. The results are shown in Table 4. Furthermore, photographs showing the progress of scarring in Cases 1 and 3 are shown in FIG. Application of the trehalose-containing preparation improved the scar condition more quickly than usual in all cases.
ＴＳＬＰは、瘢痕組織で発現量が増加し、瘢痕組織への線維芽細胞の浸潤を増加させることが示唆されている（Journal of Investigative Dermatology, Vol. 136, No. 2, 507-515 (2016)）。試験例１の結果を考慮すると、トレハロースがＴＳＬＰの発現を抑制することによって、線維芽細胞が瘢痕組織へ浸潤するのを抑制し、その結果瘢痕組織の線維化を抑制したと推察される。 It has been suggested that the expression level of TSLP increases in scar tissue and increases the infiltration of fibroblasts into scar tissue (Journal of Investigative Dermatology, Vol. 136, No. 2, 507-515 (2016) ). Considering the results of Test Example 1, it is inferred that trehalose suppressed the infiltration of fibroblasts into the scar tissue by suppressing the expression of TSLP, and as a result, suppressed fibrosis of the scar tissue.
（２．炎症性皮膚疾患に対する効果の検証）
表５に記載の患者の患部に、１０％トレハロースジェルを、各症例で示した回数で、適量（約１～約１０ｍｇ／ｃｍ２）を単純塗布してもらった。処方及び評価は、患者又は保護者の同意を得て医師が行った。処置後の患部の評価結果を、同じ表５に記載した。また、症例７の経過を示す写真を図４に示した。上記症例の皮膚の炎症は、保湿のみでは回復しないレベルのものであったが、１０％トレハロースジェルの塗布により、いずれの症例も症状が顕著に改善していた。
(2. Verification of effects on inflammatory skin diseases)
An appropriate amount (about 1 to about 10 mg/cm 2 ) of 10% trehalose gel was simply applied to the affected area of the patients listed in Table 5 at the number of times indicated for each case. Prescription and evaluation were performed by a physician with the consent of the patient or guardian. The evaluation results of the affected area after treatment are listed in the same Table 5. Furthermore, photographs showing the progress of case 7 are shown in FIG. The skin inflammation in the above cases was at a level that could not be recovered by moisturizing alone, but the symptoms were significantly improved in all cases by application of 10% trehalose gel.
上記結果と試験例１及び２の結果を合わせて考慮すると、トレハロースがＴＳＬＰ遺伝子及びＩＬ－３３遺伝子の発現抑制によって皮膚の炎症を抑えたと推察される。さらに、トレハロースがフィラグリン産生を促進した結果、皮膚バリア機能が改善し、皮膚の乾燥及び刺激因子の侵入による炎症悪化を防いだものと推察される。 Considering the above results together with the results of Test Examples 1 and 2, it is inferred that trehalose suppressed skin inflammation by suppressing the expression of the TSLP gene and IL-33 gene. Furthermore, as a result of trehalose promoting filaggrin production, it is presumed that the skin barrier function was improved and inflammation aggravation caused by skin dryness and entry of irritating factors was prevented.
（３．表皮の荒れに対する効果の検証）
両手指先に同程度のひび割れが見られた２名（症例８：５０代女性、症例９：３歳男性）を対象とした。症例８では、１日１回（夜）、対象の右親指は上記と同じ１０％トレハロースジェルを塗布した後ラップで覆い、対象の左親指は白色ワセリン（商品名：プロペト）を塗布した後ラップで覆ってもらった。日中は、両手ともに白色ワセリンを塗布してもらった。症例９では、対象の右手には上記と同じ１０％トレハロースジェルを適量塗布した後、白色ワセリンを塗布してもらった。対象の左手には白色ワセリンのみを適量塗布してもらった。これらの塗布は、毎日就寝前１回とした。日中は両手ともに０．３％ヘパリン類似物質油性クリームを塗布してもらった。処方及び評価は、患者又は保護者の同意を得て医師が行った。
(3. Verification of effect on rough epidermis)
The subjects were two people (Case 8: female in her 50s, Case 9: 3-year-old male) who had cracks of the same degree on the fingertips of both hands. In case 8, once a day (at night), the subject's right thumb was covered with plastic wrap after applying the same 10% trehalose gel as above, and the subject's left thumb was covered with plastic wrap after applying white petrolatum (trade name: Propeto). I had it covered. During the day, white petrolatum was applied to both hands. In case 9, the subject's right hand was coated with an appropriate amount of the same 10% trehalose gel as described above, and then white petrolatum was applied. Subjects were asked to apply an appropriate amount of white petrolatum to their left hand. These applications were applied once every day before going to bed. During the day, a 0.3% heparin-like oil cream was applied to both hands. Prescription and evaluation were performed by a physician with the consent of the patient or guardian.
その結果、症例８では、処置から２週間後に１０％トレハロースジェルで処置をした右手側のひび割れはほとんど見られなかったが、対照の左手側にはひび割れが残っていた。また、症例９では、処置５日後に同様に右手側のひび割れはほぼ閉塞したが、対照の左手側はひび割れが顕著に残っていた（図５）。ワセリンには保湿効果があることから、トレハロースによるひび割れの状態の改善は、保湿以外の効果も寄与しているといえる。 As a result, in case 8, almost no cracks were observed on the right hand side treated with 10% trehalose gel two weeks after the treatment, but cracks remained on the left hand side of the control. Furthermore, in Case 9, the crack on the right hand side was similarly almost closed 5 days after the treatment, but the crack remained prominent on the left hand side of the control (FIG. 5). Since Vaseline has a moisturizing effect, it can be said that effects other than moisturizing also contribute to the improvement of the cracked condition by trehalose.
上記結果に試験例１及び２の結果を合わせて考慮すると、トレハロースのフィラグリン産生促進効果によってバリア機能が改善して皮膚の乾燥が抑えられ、最終的にひび割れの状態が改善したものと推察される。さらに、トレハロースのＴＳＬＰ遺伝子及びＩＬ－３３遺伝子発現の抑制によるひび割れ部分の炎症抑制効果もまた、ひび割れの状態の改善に寄与したものと推察される。 Considering the above results together with the results of Test Examples 1 and 2, it is inferred that the filaggrin production promoting effect of trehalose improves the barrier function, suppresses skin dryness, and ultimately improves the condition of cracks. . Furthermore, it is presumed that the anti-inflammation effect of trehalose in the cracked area by suppressing the expression of the TSLP gene and IL-33 gene also contributed to the improvement of the condition of the crack.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2019199175A JP7396585B2 (en) | 2019-10-31 | 2019-10-31 | Composition for suppressing TSLP gene expression, suppressing IL-33 gene expression, or promoting filaggrin production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2019199175A JP7396585B2 (en) | 2019-10-31 | 2019-10-31 | Composition for suppressing TSLP gene expression, suppressing IL-33 gene expression, or promoting filaggrin production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2021070661A JP2021070661A (en) | 2021-05-06 |
| JP7396585B2 true JP7396585B2 (en) | 2023-12-12 |
Family
ID=75712689
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2019199175A Active JP7396585B2 (en) | 2019-10-31 | 2019-10-31 | Composition for suppressing TSLP gene expression, suppressing IL-33 gene expression, or promoting filaggrin production |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP7396585B2 (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004071472A1 (en) | 2003-02-13 | 2004-08-26 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | SKIN PREPARATION FOR EXTERNAL USE CHARACTERIZED BY CONTAINING SUGAR DERIVATIVE OF α,α-TREHALOSE |
| WO2004076602A1 (en) | 2003-02-27 | 2004-09-10 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Method of preventing lipids constituting lipid membrane from degradation and use thereof |
| JP2006045186A (en) | 2004-07-05 | 2006-02-16 | Fancl Corp | Lamella structure regenerating agent and skin care preparation for external use |
| JP2006188672A (en) | 2004-12-06 | 2006-07-20 | Hayashibara Biochem Lab Inc | Radical formation inhibitor |
| JP2007269692A5 (en) | 2006-03-31 | 2009-03-12 | ||
| WO2012077622A1 (en) | 2010-12-08 | 2012-06-14 | 株式会社ネクスト２１ | Therapeutic or prophylactic agent for keloid or hypertrophic scar, and agent for inhibiting tissue hypertrophy in injured part of airway |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4871624B2 (en) | 2006-03-31 | 2012-02-08 | ポーラ化成工業株式会社 | Cosmetics for softening the skin |
-
2019
- 2019-10-31 JP JP2019199175A patent/JP7396585B2/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004071472A1 (en) | 2003-02-13 | 2004-08-26 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | SKIN PREPARATION FOR EXTERNAL USE CHARACTERIZED BY CONTAINING SUGAR DERIVATIVE OF α,α-TREHALOSE |
| WO2004076602A1 (en) | 2003-02-27 | 2004-09-10 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Method of preventing lipids constituting lipid membrane from degradation and use thereof |
| JP2006045186A (en) | 2004-07-05 | 2006-02-16 | Fancl Corp | Lamella structure regenerating agent and skin care preparation for external use |
| JP2006188672A (en) | 2004-12-06 | 2006-07-20 | Hayashibara Biochem Lab Inc | Radical formation inhibitor |
| JP2007269692A5 (en) | 2006-03-31 | 2009-03-12 | ||
| WO2012077622A1 (en) | 2010-12-08 | 2012-06-14 | 株式会社ネクスト２１ | Therapeutic or prophylactic agent for keloid or hypertrophic scar, and agent for inhibiting tissue hypertrophy in injured part of airway |
Non-Patent Citations (9)
| Title |
|---|
| Cosmetics，2019年，6，62(pp.1-10)，doi:10.3390/cosmetics6040062 |
| Experimental Eye Research，2010年，91，pp.567-577 |
| Histol Histopathol，2019年，34，pp.611-618 |
| IOVS，2011年，52(9)，pp.6987-6993 |
| J Cell Physiol，2018年，233，pp.6524-6543 |
| J Nutr Biochem，2017年，45，pp.15-23 |
| Molecular Medicine Reports，2019年，19，pp.2087-2096 |
| Oncotarget，2016年，7(31)，pp.50682-50697 |
| The Journal of Spinal Cord Medicine，2019年，42(3)，pp.387-394 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2021070661A (en) | 2021-05-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8496917B2 (en) | Compositions and methods for improving skin appearance | |
| RU2673066C2 (en) | New medicines for topical application based on sulphated hyaluronic acid as stimulating or inhibiting agents of cytokine activity | |
| KR20070089907A (en) | Fetal skin cell protein compositions for the treatment of skin conditions, diseases or disorders, methods of making the same and methods of using the same | |
| JP5891651B2 (en) | Skin preparation for normalization of stratum corneum cell differentiation | |
| EP2839833B1 (en) | Topical pharmaceutical composition, method for producing the topical pharmaceutical composition, use of the topical pharmaceutical composition and method for the topical treatment of psoriasis, atopic dermatitis or chronic eczema | |
| US20130183257A1 (en) | Compositions and methods for improving skin appearance | |
| WO2019151285A1 (en) | Skin composition for external use | |
| WO2015168574A1 (en) | Epithelial ion channel (enac) blockers to treat psoriasis | |
| JP7396585B2 (en) | Composition for suppressing TSLP gene expression, suppressing IL-33 gene expression, or promoting filaggrin production | |
| CN108451952B (en) | A composition for treating skin immunological diseases and its preparation method | |
| CN115068407A (en) | Baricitinib gel and preparation method and application thereof | |
| TWI468184B (en) | Pharmaceutical composition and medical cosmetics | |
| JP2021510159A (en) | Topical dermatological composition containing cerduratinib and its use | |
| JPH10175868A (en) | Water (of chinese medicine idea) improving composition | |
| JP3827259B2 (en) | Keratinization promoter | |
| JP6656890B2 (en) | Filaggrin production promoter | |
| US10438128B2 (en) | Treatment of autoimmune and inflammatory diseases with the arsenic compounds AS2O3 and/or AS2O5 administered locally | |
| US12059430B2 (en) | Storage stable formulations of sulfated glycosaminoglycans and fragments derived therefrom for the treatment of pain and other medical conditions | |
| WO2021235275A1 (en) | Hyaluronic acid production promotor and collagen production promotor | |
| KR20130056825A (en) | Composition for preventing or treating or improvingatopic dermatitis comprising immunosuppressant and transglutaminase 2 inhibitor | |
| CN119606879A (en) | Antipruritic gel containing 3-hydroxydecanoic acid microemulsion and preparation method thereof | |
| CN118384153A (en) | Application of cimicifuga rhizome glycoside in preparing medicine for preventing and treating atopic dermatitis | |
| WO2014076642A1 (en) | Topical composition for the transepidermal or transdermal delivery of paracetamol | |
| WO2021007330A1 (en) | Cerdulatinib-containing topical skin pharmaceutical compositions and uses thereof | |
| CN107308145A (en) | Insoral as skin anti-inflammatory preparation purposes |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220714 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20230411 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230516 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230706 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230915 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231017 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20231109 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20231121 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 7396585 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |