CN101410100B - 利用木酚素类化合物治疗痤疮的方法及含有该化合物的组合物 - Google Patents
利用木酚素类化合物治疗痤疮的方法及含有该化合物的组合物 Download PDFInfo
- Publication number
- CN101410100B CN101410100B CN200580002069.7A CN200580002069A CN101410100B CN 101410100 B CN101410100 B CN 101410100B CN 200580002069 A CN200580002069 A CN 200580002069A CN 101410100 B CN101410100 B CN 101410100B
- Authority
- CN
- China
- Prior art keywords
- acne
- lignan compounds
- present
- macelignan
- lignan
- 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
- 208000002874 Acne Vulgaris Diseases 0.000 title claims abstract description 77
- 206010000496 acne Diseases 0.000 title claims abstract description 77
- -1 lignan compounds Chemical class 0.000 title abstract description 73
- 229930013686 lignan Natural products 0.000 title abstract description 67
- 235000009408 lignans Nutrition 0.000 title abstract description 67
- 239000000203 mixture Substances 0.000 title abstract description 32
- 238000000034 method Methods 0.000 title abstract description 26
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 60
- 238000011282 treatment Methods 0.000 claims abstract description 17
- QDDILOVMGWUNGD-UONOGXRCSA-N 4-[(2S,3R)-4-(1,3-benzodioxol-5-yl)-2,3-dimethylbutyl]-2-methoxyphenol Chemical class C1=C(O)C(OC)=CC(C[C@H](C)[C@H](C)CC=2C=C3OCOC3=CC=2)=C1 QDDILOVMGWUNGD-UONOGXRCSA-N 0.000 claims description 29
- 241000186427 Cutibacterium acnes Species 0.000 claims description 29
- 229940055019 propionibacterium acne Drugs 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 22
- 229940124597 therapeutic agent Drugs 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 10
- 241000894006 Bacteria Species 0.000 abstract description 36
- 230000002401 inhibitory effect Effects 0.000 abstract description 12
- 239000003795 chemical substances by application Substances 0.000 abstract description 6
- 239000003242 anti bacterial agent Substances 0.000 abstract 1
- QDDILOVMGWUNGD-UHFFFAOYSA-N Macelignan Natural products C1=C(O)C(OC)=CC(CC(C)C(C)CC=2C=C3OCOC3=CC=2)=C1 QDDILOVMGWUNGD-UHFFFAOYSA-N 0.000 description 37
- 238000004519 manufacturing process Methods 0.000 description 22
- 239000000839 emulsion Substances 0.000 description 18
- 210000000582 semen Anatomy 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 241000191967 Staphylococcus aureus Species 0.000 description 11
- 239000000287 crude extract Substances 0.000 description 10
- 239000000284 extract Substances 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- 241000191963 Staphylococcus epidermidis Species 0.000 description 9
- 238000011160 research Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 210000003491 skin Anatomy 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 208000020154 Acnes Diseases 0.000 description 7
- 150000005692 lignans Chemical class 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 241000196324 Embryophyta Species 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 235000013372 meat Nutrition 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 235000013311 vegetables Nutrition 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 210000003780 hair follicle Anatomy 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000007670 refining Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 241000191940 Staphylococcus Species 0.000 description 4
- 244000309464 bull Species 0.000 description 4
- 238000005100 correlation spectroscopy Methods 0.000 description 4
- 239000002537 cosmetic Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 235000013399 edible fruits Nutrition 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 231100000915 pathological change Toxicity 0.000 description 4
- 230000036285 pathological change Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000004342 Benzoyl peroxide Substances 0.000 description 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010015150 Erythema Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241000498779 Myristica Species 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 230000002421 anti-septic effect Effects 0.000 description 3
- 229960003328 benzoyl peroxide Drugs 0.000 description 3
- 235000019400 benzoyl peroxide Nutrition 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012459 cleaning agent Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 210000001732 sebaceous gland Anatomy 0.000 description 3
- 210000002374 sebum Anatomy 0.000 description 3
- 235000013599 spices Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 229940111630 tea tree oil Drugs 0.000 description 3
- 239000010677 tea tree oil Substances 0.000 description 3
- 238000012795 verification Methods 0.000 description 3
- FJBQYOWYDLEAKI-UHFFFAOYSA-N (2,3-dimethyl-4-phenylbutyl)benzene Chemical compound C=1C=CC=CC=1CC(C)C(C)CC1=CC=CC=C1 FJBQYOWYDLEAKI-UHFFFAOYSA-N 0.000 description 2
- WRYLYDPHFGVWKC-UHFFFAOYSA-N 4-terpineol Chemical compound CC(C)C1(O)CCC(C)=CC1 WRYLYDPHFGVWKC-UHFFFAOYSA-N 0.000 description 2
- 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
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 206010048768 Dermatosis Diseases 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 244000270834 Myristica fragrans Species 0.000 description 2
- 235000009421 Myristica fragrans Nutrition 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- 231100000321 erythema Toxicity 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 235000020710 ginseng extract Nutrition 0.000 description 2
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 2
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000001702 nutmeg Substances 0.000 description 2
- 229940126701 oral medication Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229940109850 royal jelly Drugs 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 239000000344 soap Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- WRYLYDPHFGVWKC-SNVBAGLBSA-N 4-Terpineol Natural products CC(C)[C@]1(O)CCC(C)=CC1 WRYLYDPHFGVWKC-SNVBAGLBSA-N 0.000 description 1
- KBIWNQVZKHSHTI-UHFFFAOYSA-N 4-n,4-n-dimethylbenzene-1,4-diamine;oxalic acid Chemical compound OC(=O)C(O)=O.CN(C)C1=CC=C(N)C=C1 KBIWNQVZKHSHTI-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 102000003952 Caspase 3 Human genes 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- 241000931705 Cicada Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- TULNGKSILXCZQT-IMJSIDKUSA-N Cys-Asp Chemical compound SC[C@H](N)C(=O)N[C@H](C(O)=O)CC(O)=O TULNGKSILXCZQT-IMJSIDKUSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 231100000111 LD50 Toxicity 0.000 description 1
- 240000006417 Leucas aspera Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241001081833 Myristicaceae Species 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 206010058667 Oral toxicity Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 208000028804 PERCHING syndrome Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 244000220503 Persea thunbergii Species 0.000 description 1
- 235000004267 Persea thunbergii Nutrition 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 206010042566 Superinfection Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000003915 air pollution Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 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
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000007799 cork Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002481 ethanol extraction Methods 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000000745 gonadal hormone Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000013101 initial test Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 230000002879 macerating effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000037311 normal skin Effects 0.000 description 1
- 229940098295 nutmeg extract Drugs 0.000 description 1
- 231100000418 oral toxicity Toxicity 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical compound CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 229940043263 traditional drug Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9789—Magnoliopsida [dicotyledons]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/005—Antimicrobial preparations
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Birds (AREA)
- Communicable Diseases (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Oncology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medical Informatics (AREA)
- Alternative & Traditional Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cosmetics (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Abstract
本发明涉及利用通式1所示的木酚素类化合物治疗痤疮的方法以及组合物,更详细地说,本发明涉及含有所述通式1所示的木酚素类化合物的针对痤疮诱发菌的抗菌用组合物以及利用该组合物治疗痤疮的方法。本发明的通式1所示的木酚素类化合物具有优异的抑制痤疮诱发菌生长的抗菌活性,并且具有优异的热稳定性,所以可有效用于针对痤疮诱发菌的抗菌剂以及痤疮治疗剂。
Description
技术领域
本发明涉及利用以下述通式1表示的木酚素类化合物治疗痤疮的方法,并涉及含有所述木酚素类化合物的组合物。更详细地说,本发明涉及针对痤疮诱发菌的抗菌用组合物,该组合物含有以通式1表示的木酚素类化合物;本发明还涉及利用该组合物治疗痤疮的方法。
背景技术
痤疮起因于毛囊和皮脂腺的炎症性疾病,其导致青春期和年轻年龄段的人在面部皮肤毛囊出现炎症,是一种极为常见的皮肤疾病。然而,最近由于空气污染、性激素不均衡、药品滥用、压力、内脏疾病等原因,罹患痤疮人群的年龄段正在扩大。处于青春期时,男性和女性的男性荷尔蒙分泌均是旺盛的,这刺激了存在于毛囊附近的皮脂腺,结果皮脂腺增大,分泌出大量的皮脂。与此同时,毛孔入口的角质层变厚,粘着力变大,毛孔变窄或者被堵塞。其结果是,皮脂堵在毛囊内,由于栖息在毛囊内的细菌的繁殖而发展成炎症。
引起痤疮和炎症的微生物包括痤疮丙酸菌(Propionibacterium acnes)以及金黄色葡萄球菌(Staphylococcus aureus)和表皮葡萄球菌(Staphylococcus epidermis)等葡萄球菌(Raman A.et al.,Lett.Appl.Microbiol.,21:242-245,1995)。这些微生物在正常的皮肤内也存在,特别是痤疮丙酸菌是引起痤疮的主要菌。上述微生物首先通过毛囊管侵入到毛囊中,在毛囊深处栖息的同时分解皮脂,生成游离脂肪酸,如果这里发生葡萄球菌的二次感染,则会出现红肿并产生脓。
为了抑制这些引起痤疮和毛囊皮脂腺炎症性皮肤疾病的病原菌,迄今为止有采用过氧化苯甲酰、水杨酸、苯扎氯铵、苯酚、四环素或者红霉素等抗菌药来抑制上述病菌的方法。利用四环素等抗生素的方法在皮 肤治疗方面虽然有效,但是已知这样对诱发痤疮丙酸菌中出现抗药性菌株的可能性大,而且很可能诱发光过敏作用等副作用(Gollnick,H.et al.,Dermatology.,196:119-125,1998)。此外已知,水杨酸制剂的主要作用是去除角蛋白,不能用于化脓性皮肤炎,有时还引起皮肤发红和红斑。另外,有大量报道指出抑制化脓菌的过氧化苯甲酰制剂出现过敏性皮肤炎以及红斑等的副作用,而且在功效方面也不能完全治愈痤疮。
另外,最近在利用茶树油(tea tree oil)、王浆(royal jelly extract)、人参提取物(ginseng extract)等天然物治疗痤疮,但是,上述天然物基本都不是单一物质,所以在制成皮肤外用剂和化妆品这些制剂时,有时由于添加的其他物质而出现抗菌活性急剧下降的情况,此外,这些天然物的抗菌谱不宽,所以存在对诱发痤疮的葡萄球菌不能表现出有效的抗菌作用的问题。特别是,从天然物得到的抗菌物质,在加热时,其中相当一部分的有效成分由于挥发而消失,或者存在热稳定性差、抗菌活性急剧下降的倾向,存在难以制成制剂的问题(Higaki,S.et al.,J.Dermatology.,23:310-314,1996)。
木酚素是苯基正丙烷通过正丙基侧链的β位键合的天然物的总称,在其药效方面,公开了降血糖功能(韩国公开公报第2003-0064919号)、消炎功能(韩国公开公报第2003-0035124号)等。肉豆蔻木酚素(macelignan)是从植物肉豆蔻(Myristica fragrans)中发现的代表性木酚素类化合物(Tuchinda P.et al.,Phytochemistry,59:169-173,2002),有报道指出其对诱导细胞凋亡的半胱氨酰天冬氨酸蛋白酶-3(caspase-3)具有活化作用(ParkB.Y.et al.,Biol.Pharm.Bull.,27(8):1305-1307,2004),并具有抗氧化作用(Sadhu,S.K.et al.,Chem.Pharm.Bull.,51(9):595-598,2003)等。但是,迄今尚没有关于以所述肉豆蔻木酚素为代表的下述通式1的木酚素类化合物针对痤疮诱发菌的抗菌活性的报道的例子。
发明内容
此处,本发明的发明人为了从天然物中得到对所述痤疮诱发菌具有强有力的抗菌活性的化合物,经过长期探索,结果确认,从植物肉豆蔻 (Myristica fragrance)分离的木酚素类化合物对痤疮诱发菌表现出卓越的抗菌活性以及热稳定性,从而完成了本发明。
本发明的目的是提供以下述通式1表示的木酚素类化合物,其对痤疮诱发菌表现出优秀的抗菌活性,并提供含有上述化合物的针对痤疮诱发菌的抗菌用组合物以及痤疮治疗用组合物。
此外,本发明的目的是提供抑制痤疮诱发菌的生长的方法以及治疗痤疮的方法,所述方法中,将以下述通式1表示的木酚素类化合物施用至需要这些物质的个体。
此外,本发明的目的是提供利用以下述通式1表示的木酚素类化合物制备针对痤疮诱发菌的抗菌剂以及痤疮治疗剂的用途。
为了达成所述技术课题,本发明提供抗菌用组合物以及痤疮治疗用组合物,所述组合物含有以下述通式1表示的木酚素(lignan;2,3-二苄基丁烷;2,3-dibenzylbutane)类化合物或其可药用盐作为有效成分,对选自由痤疮丙酸菌、表皮葡萄球菌以及金黄色葡萄球菌组成的组中的痤疮诱发菌表现出抗菌活性。
(所述通式1中,R1、R2是C1-5烷氧基或羟基基团,R3是 或 )
此外,本发明提供对选自痤疮丙酸菌、表皮葡萄球菌以及金黄色葡萄球菌等痤疮诱发菌的生长进行抑制的方法以及治疗痤疮的方法,其中,将有效量的以所述通式1表示的木酚素类化合物施用至需要这些物质的个体。
此外,本发明提供以所述通式1表示的木酚素类化合物的用途,其用于制造针对选自由痤疮丙酸菌、表皮葡萄球菌以及金黄色葡萄球菌组成的组中的痤疮诱发菌的抗菌剂以及痤疮治疗剂。
本发明中,″有效量″是指本发明的木酚素类化合物在作为给药对象的个体内表现出针对痤疮诱发菌的抗菌活性、能够有效治疗痤疮的量。此外,本发明中,″个体(subject)″是指哺乳动物,特别是包括人类的动物。所述个体有时也指需要治疗的患者(patient)。
下面详细说明本发明。
本发明的特征在于,提供以通式1所示的木酚素类化合物对痤疮诱发菌的抗菌活性用途。
本发明的木酚素类化合物以下述通式1表示。
(R1、R2是C1-5烷氧基或羟基基团,R3是 或 )
本发明优选的木酚素类化合物可以是通式1中所述R1为甲氧基、R2为羟基、R3为 的化合物,即下述化学式1表示的肉豆蔻木酚素[(8R,8′S)-7-(3,4-亚甲基二氧苯基)-7′-(4-羟基-3-甲氧基苯基)-8,8′-二甲基丁烷]。
本发明的木酚素类化合物可以以盐的形式、优选可药用盐的形式使用。所述盐优选为通过可药用游离酸(free acid)形成的酸加成盐。所述游离酸可以使用有机酸和无机酸。所述有机酸包括柠檬酸、醋酸、乳酸、酒石酸、马来酸、富马酸、甲酸、丙酸、乙二酸、三氟乙酸、苯甲酸、葡糖酸、甲磺酸、乙醇酸、琥珀酸、4-甲基苯磺酸、谷氨酸以及天冬氨酸,但不限于此。此外,所述无机酸包括盐酸、溴酸、硫酸以及磷酸,但不限于此。
利用以往提取分离物质的方法可以从植物或者植物的一部分中获得本发明的木酚素类化合物。为了获得目的提取物,可将茎、根或者叶经适宜脱水、浸软或者仅经脱水后,利用本发明所属技术领域的技术人员公知的精制方法,精制目的提取物。此外,与上述通式1所示的木酚素类化合物相应的合成化合物或者这些化合物的衍生物一般是可以购买到的物质,或者是可以利用公知的合成方法化学制造的。
所述通式1表示的本发明的木酚素类化合物可以从植物肉豆蔻(Myristica fragnance Houtt.)分离精制(Jung Yun Lee et al.,Kor.J.Pharmacogn.21(4):270-273,1990)。优选从肉豆蔻(nutmeg)或假种皮(aril)分离、精制获得。所述肉豆蔻是指植物肉豆蔻的成熟果实或果实中的种子。此外,本发明的木酚素类化合物可以从肉豆蔻经压榨获得的油中分离精制。此外,也可由作为其他肉豆蔻科植物的长形肉豆蔻(Myristicaargentea Warb)等分离精制(Filleur,F.et al.,Natural Product Letters,16:1-7,
2002)。进一步也可以从厚朴(Machilus thunbergii)(Park B.Y.et al.,Biol.Pharm.Bull.,27(8):1305-1307,2004)、蜂巢草(Leucas aspera)分离精制(Sadhu,S.K.et al.,Chem.Pharm.Bull.,51(9):595-598,2003)。
作为用于本发明的木酚素类化合物的分离的提取溶剂,可使用水或者C1-C6有机溶剂。优选单独使用或者混合使用蒸馏水、甲醇、乙醇、丙醇、异丙醇、丁醇、丙酮、乙醚、苯、氯仿、醋酸乙酯、二氯甲烷、己烷、环己烷、石油醚等各种溶剂。从植物肉豆蔻提取物分离精制本发明的木酚素类化合物时,可以单独或者同时使用填充有硅胶(silica gel)或者活性氧化铝(alumina)等各种合成树脂的柱色谱(column chromatography)以及高效液相色谱(HPLC)等。不过,有效成分的提取以及分离精制方法不一定限定为上述方法。
这样,本发明的木酚素类化合物可以以分离、精制的纯化合物形式使用,进一步,也可以以含有该化合物的提取物的形式使用。例如,如上所述,可以以植物肉豆蔻的种子、果实或者假种皮提取物的形式使用,或者以植物肉豆蔻的种子经压榨得到的油的形式使用。如上所述,所述提取物可以通过用水或者C1-C6有机溶剂提取植物肉豆蔻来获得。所述提取物优选由植物肉豆蔻的种子获得,即为肉豆蔻提取物(nutmeg extract)。
本发明的一个实施例中,从植物肉豆蔻(Myristica fragrance)果实(肉豆蔻)的乙醇提取物中分离、精制上述通式1表示的木酚素类化合物中代表性的化合物,即上述化学式1表示的肉豆蔻木酚素(macelignan)(参见实施例1)。
本发明的通式1所示的木酚素类化合物对痤疮丙酸菌等痤疮诱发菌表现出卓越的抗菌活性,并且热稳定性优异,即使加热也能维持该抗菌活性(参见实施例3)。
研究本发明的木酚素类化合物对于引起痤疮的病原菌即痤疮丙酸菌、金黄色葡萄球菌和表皮葡萄球菌是否有抗菌活性,结果表明其具有高的抗菌活性(参见图6以及表2)。特别是对于已知作为痤疮的主因菌的痤疮丙酸菌,经证明其最小抑菌浓度(MIC)为2μg/ml,显示出比以往作为痤疮治疗剂而大量使用的药剂更好的抗菌活性。也就是说,以往作为痤疮 治疗剂使用的过氧化苯甲酰对痤疮丙酸菌的最小抑菌浓度(MIC)是500μg/ml~1000μg/ml(Decker,LC.et al.,Antimicro.Agents.Chemother.,33(3):326-330,1989),苯扎氯铵的最小抑菌浓度(MIC)为200μg/ml~300μg/ml(Gloor,M.et al.,Arch.Dermatol.Res.,265(2):207-212,1979),茶树油成分松油烯-4-醇(Terpinen-4-ol)的最小抑菌浓度(MIC)为300μg/ml~500μg/ml(Raman,A.et al.,Lett.Appl.Microbiol.,21(4):242-245,1995),所以本发明的木酚素类化合物与所述公知的痤疮治疗剂相比,对痤疮诱发菌表现出了更优秀的抗菌活性。此外,本发明的木酚素类化合物对痤疮丙酸菌的最小抑菌浓度是64μg/ml,其抗菌活性甚至是肉豆蔻粗提物的约30倍以上,抗菌活性出色(参见下面的比较例1)。此外,制造含有本发明的木酚素类化合物的化妆水以及乳剂并进行抗菌活性实验,结果表明,所述化妆水及乳剂对痤疮诱发菌的抗菌活性极为出色(参见表5以及表7)。
上述这些结果意味着本发明的木酚素类化合物对引起痤疮的病因菌即痤疮丙酸菌、金黄色葡萄球菌和表皮葡萄球菌的抗菌活性出色,具有治疗痤疮的效果。本发明首次探明了这种通式1所示的本发明的木酚素类化合物对痤疮诱发菌的抗菌活性。此外还得知了本发明的木酚素类化合物的抗菌活性远高于以往作为痤疮治疗剂而使用的化合物的抗菌活性,与以往的痤疮治疗剂相比,本发明的木酚素类化合物可以用作具有优秀效果的痤疮治疗剂。
因此,以本发明的上述通式1所示的木酚素类化合物或者其可药用盐作为有效成分的抗菌用组合物以及痤疮治疗用组合物在临床给药时,可以口服或者非口服给药,并且可以以常规药物制剂的形式进行应用。
当本发明化合物以常规药物形式进行制剂时,可以使用通常使用的填充剂、增量剂、粘合剂、润湿剂、崩解剂、表面活性剂等稀释剂或者赋型剂进行调制。用于口服给药的固体制剂包括片剂、丸剂、散剂、颗粒剂、胶囊剂等,对于这种固体制剂,可以在上述的木酚素类化合物中混合至少一种赋型剂进行调制,所述赋型剂例如为淀粉、碳酸钙、蔗糖或者乳糖、明胶等。
此外,除简单的赋型剂外,还可以使用润滑剂等,所述润滑剂例如 为硬脂酸镁或滑石。用于口服给药的液体制剂包括悬浊剂、内溶液剂(internal solution)、油剂(emulsion)、糖浆剂等,除广泛使用的单纯稀释剂如水、液体石蜡之外,其同时还可含有多种多样的赋型剂,例如可包含湿润剂、甜味剂、芳香剂、防腐剂等。用于非口服给药的制剂包括经灭菌的水溶液、非水性溶剂、悬浊剂、油剂(emulsion)、冻干制剂、软膏剂、乳剂(cream)。作为非水性溶剂、悬浊剂,其中可使用丙二醇、聚乙二醇、橄榄油等植物油、油酸乙酯等注射用酯等。
此外,本发明的抗菌用组合物以及痤疮治疗用组合物可以进行非口服给药,非口服给药可以通过皮下注射、静脉注射、肌内注射或者胸内注射的注入方式进行。为了制成非口服给药用剂型,将上述通式1的木酚素类化合物与稳定剂或者缓冲剂一起在水中混合,制成溶液或者悬浊液,将其制成安瓿或者小瓶的单位给药形式。对于剂量单位,例如可以是单剂量的1、2、3或4倍,或者1/2、1/3或1/4倍。单剂量优选为含有一次施用的有效药物,这通常相当于1日给药量的全部、1/2、1/3或者1/4。
对于本发明的通式1所示的木酚素类化合物的有效容量,1次服用量为0.1mg/kg~50mg/kg,优选为1mg/kg~10mg/kg,1天可服用1~3次。对于特定患者,剂量水平根据患者的体重、年龄、性别、健康状态、食物、给药时间、给药方法、排泄率、疾病的严重程度等进行改变。
将本发明的通式1所示的木酚素类化合物对小鼠口服给药,进行毒性实验,结果表明,口服毒性实验的50%致死量(LD50)大于等于2000mg/kg。
特别是,含有本发明的通式1所示的木酚素类化合物的抗菌用组合物以及痤疮治疗用组合物可以制剂化为皮肤涂敷用药品,也就是软膏、乳剂形式,相对于制剂物总重量,可以根据剂型适当地配合0.001重量%~10.0重量%、优选0.001重量%~5.0重量%的本发明的化合物。这是因为,添加量少于0.001重量%时,抗菌活性降低,添加量超过10.0重量%时,抗菌活性并不会因为仅增加该添加量而存在明显差别。
含有本发明的上述通式1所示的木酚素(lignan)类化合物的针对痤疮诱发菌的抗菌剂以及痤疮治疗剂包括痤疮皮肤用化妆品。所述痤疮皮肤用化妆品包括肥皂等清洁剂以及乳剂、化妆水等。
含有本发明的通式1所示的木酚素(lignan)类化合物的化妆品可以制备成多种多样的制剂形式使用,例如肥皂、液态以及乳剂形式的洁面剂等多种多样形式的清洁剂或者乳剂、化妆水、凝胶体、水溶性液体、精油、水包油型以及油包水型等剂型,但是,本发明所属技术领域的技术人员能够极容易地确定以什么样的剂型进行制造使用。此外,可轻松地添加到洁面泡沫、乳液、精油等基础化妆品中作为痤疮皮肤用化妆品使用。
相对于清洁剂或者化妆品总重量,本发明的通式1所示的木酚素类化合物根据剂型可在0.001重量%~10.0重量%、优选0.001重量%~5.0重量%的范围内进行适当的配合。这是因为,添加量少于0.001重量%时,抗菌活性降低,添加量大于10.0重量%时,抗菌活性不会因为仅增加该添加量而存在明显差别。
附图说明
图1是本发明的木酚素类化合物的13C-NMR光谱;
图2是本发明的木酚素类化合物的1H-NMR光谱;
图3是本发明的木酚素类化合物的1H-1H COSY光谱;
图4是本发明的木酚素类化合物的1H-13C HMBC光谱;
图5是本发明的木酚素类化合物的EI-Mass光谱;
图6是图表,表示根据活菌数测定法测定本发明木酚素类化合物对痤疮丙酸菌的抗菌活性的结果(◆对照组的二甲基亚砜、■0.002%浓度的肉豆蔻木酚素试样、▲0.001%浓度的肉豆蔻木酚素试样、●0.0005%浓度的肉豆蔻木酚素试样)。
图7是图表,表示根据活菌数测定法测定本发明的肉豆蔻粗提物对痤疮丙酸菌的抗菌活性的结果(◆对照组的二甲基亚砜、■0.02%浓度的肉豆蔻粗提物试样、▲0.01%浓度的肉豆蔻粗提物试样、●0.005%浓度的肉豆蔻粗提物试样)。
具体实施方式
下面根据实施例对本发明进行更详细的说明。
但是,下面的实施例仅仅是本发明的举例,本发明的内容并不被限定为下面的实施例。此外,下面的实施例以及实验例等中,没有特别明示为体积%的百分比(%)表示重量%。此外,所有的活性分析均重复实施至少3次,其结果以平均值±标准偏差表示。此外,利用Students′s t-test进行统计分析,p值<0.05的情况下,认为具有统计学上的明显差异。
<实施例1>由肉豆蔻分离、精制木酚素类化合物
<1-1>肉豆蔻木酚素的分离以及精制
在经干燥粉碎的100g(干燥重量)肉豆蔻中加入400ml 75体积%的乙醇,在常温放置二天之后,利用沃特曼(Whatman)2号滤纸过滤该溶液。重复上述过程2次之后,将乙醇过滤液真空浓缩,进行冷冻干燥之后,利用硅胶柱色谱分离法,用己烷和乙酸乙酯以20∶1的比率混合的溶剂进行洗脱,用真空旋转浓缩器完全除去溶剂,制造肉豆蔻粗提物。将上述肉豆蔻粗提物在TLC板上用己烷和乙酸乙酯以10∶1的比例混合的溶剂系统进行分离,通过TLC板分析法对其确认。将通过TLC板分析法确认的提取物的抗菌活性物质用己烷和乙酸乙酯以10∶1混合的溶剂系统展开,调整抗菌活性物质的展开距离与溶剂的展开距离的比例为0.2,再用甲醇和水的比率为8∶2(体积/体积)的展开溶剂进行薄层色谱分析(TLC,RP-18gel 60F254,Merck),分离Rf=0.2、在紫外线波长(254nm、365nm,VL-6-LC、Vilberlourmat)有强吸收带的单一物质。
<1-2>结构分析
为了确定在实施例<1-1>被分离的单一物质的结构,分别用600MHz和150MHz(溶剂:DMSO)测定1H-NMR光谱和13C-NMR光谱,分别示于图1和图2。为了以13C-NMR光谱和1H-NMR光谱的结果为基础测定1H-1H的相关关系和1H-13C的相关关系,测定了1H-1H COSY光谱和1H-13C HMBC光谱,其结果示于图3和图4。综合分析1H-NMR、13C-NMR、1H-1H COSY、 1H-13C HMBC,结果示于表1。
表1
<1-3>质量分析
此外,为了分析上述分离的单一物质的质量,将测定的EI/MS的结果示于图5。根据EI/MS,[M]+出现在m/z328,由此确定本化合物分子量为328,分子式是C20H24O4。
将上述的1H-NMR、13C-NMR、1H-1H COSY、1H-13C HMBC以及EI/MS的结果与已经发表的研究报告(Woo,W.S.et al.,Phytochemistry,26:1542-1543,1987)进行比较分析、鉴定,结果确认到在实施例<1-1>中分离的单一物质是用上述化学式1表示的肉豆蔻木酚素(macelignan)化合物。
<实施例2>抗菌活性的研究
<2-1>通过活菌数测定法测定木酚素类化合物抑制痤疮诱发菌生长的效果
将上述实施例<1-1>制造的肉豆蔻木酚素化合物溶解在二甲基亚砜 中,制造浓度为0.002%、0.001%、0.0005%的试样。将痤疮丙酸菌用所制造的试样稀释成2×105CFU/ml,向各个试管中添加100μl,在37℃分别进行2小时、4小时、8小时、12小时、16小时、20小时、24小时的反应之后,将各试样依次10倍梯度稀释,进行倾注平板法(pour plate method)培养,培养于37℃恒温箱中进行,测定作为代表性的痤疮诱发菌的痤疮丙酸菌的活菌数。其结果如图6所示。
由图6可知,根据活菌数测定法测定活菌数的结果表明,肉豆蔻木酚素化合物的浓度为0.002%(20μg/ml)时,2小时内基本杀灭了细菌,浓度为0.001%(10μg/ml)时,8小时内基本杀灭了细菌。该结果意味着,采用以肉豆蔻木酚素化合物作为原料的口服药物或经皮施用的药物作为痤疮治疗剂的情况下,若为口服药物,则通常考虑每隔8小时服用,若为软膏或贴剂,则考虑每隔约2小时~4小时使用,此时所述药剂对作为代表性痤疮诱发菌的痤疮丙酸菌表现出极为有效的杀菌活性。
<2-2>木酚素类化合物的最小抑菌浓度(Minimum InhibitoryConcentration,MIC)测定
将实施例<1-1>制造的肉豆蔻木酚素化合物溶解在0.5%的甲醇中,分别在每个准备好的试管中加入1ml血液平板培养基(BHI broth,脑心浸出液),仅在最初的试管中分别加入1ml 2%浓度的肉豆蔻木酚素类化合物,以2倍梯度依次稀释。分别向各个试管中添加100μl痤疮丙酸菌,使该稀释液中痤疮丙酸菌浓度为2×105CFU/ml,在37℃培养至少24小时,测定不产生混浊的最小抑菌浓度,并示于表2。按同一方法测定对金黄色葡萄球菌、表皮葡萄球菌的最小抑菌浓度,其结果示于表2。
表2对痤疮诱发菌的最小抑菌浓度的测定结果(单位:μg/ml)
<比较例1>肉豆蔻粗提物抗菌活性的研究
对于在上述实施例<1-1>分离肉豆蔻木酚素的过程中制造的肉豆蔻粗提物,以上述实施例<2-1>公开的方法,测定其对痤疮诱发菌的生长的 抑制效果,结果示于图7。此外,以实施例<2-1>公开的方法测定肉豆蔻粗提物对痤疮诱发菌的最小抑菌浓度,结果确认到对痤疮丙酸菌、金黄色葡萄球菌、表皮葡萄球菌的最小抑菌浓度分别是64μg/ml、250μg/ml、250μg/ml。
<实施例3>木酚素类化合物的热稳定性
将上述实施例<1-1>制造的肉豆蔻木酚素化合物溶解在二甲基亚砜中,制造0.1%浓度的试样,分别在60℃、70℃、80℃、90℃、100℃以及121℃进行30分钟的热处理,以打孔扩散法(well diffusion assay)测定抗菌活性,结果示于下述的表3中。
表3
从上述表3可知,进行从60℃到121℃的热处理以后,抗菌活性也几乎没有减少。从而,确认了本发明的木酚素类化合物在高温处理过程中稳定。
<实施例4>含有肉豆蔻木酚素的化妆水的制造以及其抗菌活性的研究
<4-1>含有肉豆蔻木酚素的化妆水的制造
利用本发明的肉豆蔻木酚素化合物,制造具有下面表4的组成的化妆水。将实施例<1-1>分离的肉豆蔻木酚素化合物制成4种浓度(1.0%、0.1%、0.01%、0.001%),分别在一定量的水中溶解后,与磷酸水溶液混合。将乙醇与甘油、丙二醇混合后,加入到前面制造的混合物中,混合的同时追加香料、防腐剂,用蒸馏水调整重量后,均匀混合。
表4
<4-2>抗菌活性的研究
在每个试管中分别添加4ml上述实施例<4-1>制造的含有不同浓度的肉豆蔻木酚素的化妆水,在该试管中添加1ml含有痤疮丙酸菌等痤疮诱发菌的液体,振荡培养,24小时之后测定活菌数。其结果示于下面的表5。
表5
从上述表5的结果可知,与不含肉豆蔻木酚素化合物的成分的化妆水相比,本发明的药用化妆水对痤疮丙酸菌等痤疮诱发菌的抗菌活性极高。
<实施例5>含肉豆蔻木酚素的乳剂的制造及其抗菌活性的研究
<5-1>含肉豆蔻木酚素的乳剂的制造
利用本发明的肉豆蔻木酚素化合物,制造具有下面表6组成的乳剂。首先,在75℃~80℃使B表示的物质熔融,在同样的温度使C表示的物质中的鲸蜡醇和防腐剂熔融。使C在B中乳化,分别向其中加入浓度为3.0%、0.1%、0.01%、0.001%的以A表示的肉豆蔻木酚素化合物,混合,最后加入香料,用蒸馏水进行定量,制得所述乳剂。
表6
<5-2>抗菌活性的研究
在每个试管中分别添加4ml上述实施例<5-1>制造的含有不同浓度的肉豆蔻木酚素化合物的乳剂,在该试管中添加1ml含有痤疮丙酸菌等痤疮诱发菌的液体,振荡培养,24小时之后测定活菌数。其结果示于下面的表7。
表7
从上述表7的结果可知,与不含肉豆蔻木酚素的成分的乳剂相比,本发明实施例的乳剂对痤疮丙酸菌等痤疮诱发菌的抗菌活性极高。
<实施例6>木酚素类化合物的浓度对痤疮患者的临床试验
<6-1>口服给药
使用实施例<1-1>分离精制的肉豆蔻木酚素,实施临床试验治疗痤疮。试验对象选择受痤疮困扰的十几岁到三十几岁的30名男女,1天2次,每次600mg,给药4周之后,将结果示于表8。与给药前的病变的个数相比,给药4周后的病变的个数明显减少,在统计学上有明显差别(p值<0.05)。
表8口服给药时痤疮病变个数的测定
<6-2>经皮施用
使用上述实施例<5-1>制造的含有肉豆蔻木酚素的乳剂,实施对痤疮 预防以及治疗的临床试验。试验对象选择受痤疮困扰的十几岁到三十几岁的30名男女,1天2次每次定量用于皮肤,4周之后,将结果示于表9。与研究开始前的病变的个数相比,给药4周后的病变的个数明显减少,在统计学上有明显差别(p值<0.05)。
表9经皮施用时的痤疮病变的个数测定
<制造例1>本发明的痤疮治疗剂的制造
<1-1>片剂的制造
将25mg本发明的肉豆蔻木酚素与26mg直接成片用赋型剂乳糖、3.5mg Avicel(微晶纤维素)、1.5mg作为崩解助剂的乙醇酸淀粉钠、以及8mg作为粘合剂的直接成片用L-HPC(低取代羟丙纤维素)一起放进U型混合机混合20分钟。混合完毕之后,追加1mg作为润滑剂的硬脂酸镁,混合3分钟。经定量试验和抗湿试验后进行制片,然后进行包衣,得到片剂。
<1-2>糖浆剂的制造
用下述方法制造含有2%(W/V)本发明的肉豆蔻木酚素或者其可药用盐作为有效成分的糖浆剂:将2g本发明肉豆蔻木酚素的酸加成盐、0.8g糖精、以及25.4g糖溶解在80g温水中。将上述溶液冷却后,在其中混合8.0g甘油、0.04g香料、4.0g乙醇、0.4g山梨酸以及适量的蒸馏水。向上述混合物添加水使达到100ml。
<1-3>胶囊剂的制造
将50mg本发明的肉豆蔻木酚素、50mg乳糖、46.5mg淀粉、1mg滑石以及适量的硬脂酸镁进行混合,然后将其填充到硬凝胶胶囊中,制造胶囊剂。
<1-4>针剂的制造
按下面的方法制造含有10mg有效成分的针剂。将1g本发明的肉豆蔻木酚素的盐酸盐、0.6g氯化钠以及0.1g抗坏血酸溶解在蒸馏水中,制造 100ml溶液。将所述溶液装瓶,在20℃加热灭菌30分钟。
产业上的可利用性
根据上述研究,本发明的通式1所示的木酚素类化合物对痤疮丙酸菌(Propionibacterium acnes)、表皮葡萄球菌(Staphylococcus epidermis)、金黄色葡萄球菌(Staphylococcus aureus)等痤疮诱发菌具有出色的抗菌活性,并具有出色的热稳定性。因而,本发明的木酚素类化合物作为针对痤疮诱发菌的抗菌剂以及痤疮治疗剂极为有用。
Claims (2)
1.化学式1所示的肉豆蔻木酚素类化合物在制备针对痤疮丙酸菌的抗菌剂中的用途,
所述化学式1为:
2.化学式1所示的肉豆蔻木酚素类化合物在制备痤疮治疗剂中的用途,所述治疗剂通过抑制痤疮丙酸菌生长来治疗痤疮,
所述化学式1为:
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020040001207 | 2004-01-08 | ||
KR10-2004-0001207 | 2004-01-08 | ||
KR1020040001207A KR100567431B1 (ko) | 2004-01-08 | 2004-01-08 | 리그난계 화합물을 유효성분으로 함유하는 여드름 치료 또는 예방용 조성물 |
PCT/KR2005/000045 WO2005070402A1 (en) | 2004-01-08 | 2005-01-07 | Method and composition for treating acne using lignan compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101410100A CN101410100A (zh) | 2009-04-15 |
CN101410100B true CN101410100B (zh) | 2015-05-06 |
Family
ID=34805985
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200580002069.7A Active CN101410100B (zh) | 2004-01-08 | 2005-01-07 | 利用木酚素类化合物治疗痤疮的方法及含有该化合物的组合物 |
Country Status (5)
Country | Link |
---|---|
US (1) | US8642646B2 (zh) |
JP (1) | JP4547388B2 (zh) |
KR (1) | KR100567431B1 (zh) |
CN (1) | CN101410100B (zh) |
WO (1) | WO2005070402A1 (zh) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100579752B1 (ko) * | 2004-09-07 | 2006-05-15 | 황재관 | 리그난계 화합물을 함유하는 염증성 질환의 치료 또는예방용 약학적 조성물 |
KR100830192B1 (ko) * | 2005-09-22 | 2008-05-19 | (주)바이오케어 | 메이스리그난 또는 이의 약제학적으로 허용 가능한 염을유효성분으로 함유하는 PPARα에 의해 매개되는 질환의예방 또는 치료용 조성물 |
KR100646574B1 (ko) | 2005-11-30 | 2006-11-23 | 황재관 | 항암제로 유발되는 독성의 억제제 및 이를 함유하는 항암제조성물 |
KR101404398B1 (ko) * | 2007-06-20 | 2014-06-09 | (주)뉴트리 | 주름개선 화장료 조성물 |
CN101827579B (zh) | 2007-10-17 | 2013-01-23 | 生物关怀有限公司 | 木酚素系化合物或含有该化合物的肉豆蔻提取物或肉豆蔻假种皮提取物的新用途 |
FR2933300B1 (fr) * | 2008-07-02 | 2012-10-19 | Europ Finances | Compositions comprenant au moins une lignane et/ou neolignane en association avec un compose actif contre l'acne |
KR101062670B1 (ko) | 2009-06-01 | 2011-09-06 | (주)아모레퍼시픽 | 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난을 유효성분으로 포함하는 에이엠피케이의 활성화에 의해 매개되는 비만 관련 질환의 예방 또는 치료용 조성물 |
CA3047701C (en) * | 2016-12-22 | 2021-03-09 | Muhammed Majeed | Natural molecules from artocarpus hirsutus: method of isolation and anti-acne potential thereof |
CN113613666A (zh) * | 2018-10-26 | 2021-11-05 | 延世大学校产学协力团 | 包含肉豆蔻提取物或肉豆蔻木酚素作为有效成分的用于缓解由环境污染因素引起的皮肤刺激及保护皮肤的组合物 |
KR102047459B1 (ko) | 2018-12-24 | 2019-11-21 | 한국식품연구원 | 락토바실러스 플랜타룸 WiKim0088 |
CN112294796B (zh) * | 2020-11-06 | 2023-04-21 | 中国水产科学研究院长江水产研究所 | 安五脂素在抗水产动物嗜水气单胞菌感染中的应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1988001509A1 (en) * | 1986-08-25 | 1988-03-10 | Chemex Pharmaceuticals, Inc. | Pharmacologically active compositions of catecholic butanes with zinc |
WO1988003806A1 (en) * | 1986-11-19 | 1988-06-02 | Chemex Pharmaceuticals, Inc. | Pharmacologically active compositions of catecholic butanes with zinc |
EP0297733A2 (en) * | 1987-06-03 | 1989-01-04 | Block Drug Company, Inc. | Pharmaceutical compositions comprising catecholic butanes |
WO2003028692A2 (fr) * | 2001-10-03 | 2003-04-10 | Sederma | Traitement de l'acne a l'aide d'acide oleanolique |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3164854B2 (ja) * | 1991-10-31 | 2001-05-14 | 雪印乳業株式会社 | 皮膚衛生用シート |
JP2711630B2 (ja) * | 1994-04-07 | 1998-02-10 | 株式会社大阪薬品研究所 | 皮膚外用剤 |
-
2004
- 2004-01-08 KR KR1020040001207A patent/KR100567431B1/ko active IP Right Grant
-
2005
- 2005-01-07 CN CN200580002069.7A patent/CN101410100B/zh active Active
- 2005-01-07 WO PCT/KR2005/000045 patent/WO2005070402A1/en active Application Filing
- 2005-01-07 US US10/585,553 patent/US8642646B2/en active Active
- 2005-01-07 JP JP2006549118A patent/JP4547388B2/ja not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1988001509A1 (en) * | 1986-08-25 | 1988-03-10 | Chemex Pharmaceuticals, Inc. | Pharmacologically active compositions of catecholic butanes with zinc |
WO1988003806A1 (en) * | 1986-11-19 | 1988-06-02 | Chemex Pharmaceuticals, Inc. | Pharmacologically active compositions of catecholic butanes with zinc |
EP0297733A2 (en) * | 1987-06-03 | 1989-01-04 | Block Drug Company, Inc. | Pharmaceutical compositions comprising catecholic butanes |
WO2003028692A2 (fr) * | 2001-10-03 | 2003-04-10 | Sederma | Traitement de l'acne a l'aide d'acide oleanolique |
Also Published As
Publication number | Publication date |
---|---|
WO2005070402A1 (en) | 2005-08-04 |
CN101410100A (zh) | 2009-04-15 |
JP4547388B2 (ja) | 2010-09-22 |
US20090192217A1 (en) | 2009-07-30 |
US8642646B2 (en) | 2014-02-04 |
KR20050073027A (ko) | 2005-07-13 |
KR100567431B1 (ko) | 2006-04-04 |
JP2007524666A (ja) | 2007-08-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101410100B (zh) | 利用木酚素类化合物治疗痤疮的方法及含有该化合物的组合物 | |
WO2008140200A1 (en) | External compositions for the skin | |
KR20130142696A (ko) | 흰점박이꽃무지를 유효성분으로 포함하는 염증성 질환의 예방 및 치료용 조성물 | |
KR102112736B1 (ko) | 탈모 방지 또는 발모 촉진용 조성물 | |
KR100973221B1 (ko) | 판두라틴 에이 또는 그의 유도체의 신규한 용도 | |
KR20170040002A (ko) | 홍삼 에탄올 추출물의 부탄올 분획물을 포함하는 여드름 개선용 화장료 조성물 | |
KR101715294B1 (ko) | 디오스민 또는 이의 염을 유효성분으로 함유하는 피부보습 개선, 피부각질 제거, 피부탄력 증진, 홍반 억제, 피부주름 개선 또는 피부광노화 개선 효과를 갖는 조성물 | |
KR101796866B1 (ko) | 시멘, 베헨산, 2-메톡시나프탈렌, 티몰 및 이들의 염으로 이루어진 군에서 선택된 어느 하나 이상을 유효성분으로 함유하는 피부보습 개선, 피부각질 제거, 피부탄력 증진, 홍반 억제, 피부주름 개선 또는 피부광노화 개선 효과를 갖는 조성물 | |
KR100776755B1 (ko) | 생약 추출물을 함유하는 가려움증 억제 및 완화용 조성물 | |
KR101346412B1 (ko) | 탱자나무 속 식물 및/또는 치자 속 식물의 과실 추출물을 포함하는 항진균용 조성물 | |
KR102221627B1 (ko) | 붉나무 추출물을 유효성분으로 포함하는 조성물 | |
KR102263330B1 (ko) | 식물 제형의 상승작용적 조합을 통한 트리글리세리드 합성의 억제를 위한 조성물 및 방법 | |
KR102260228B1 (ko) | 케나프 종자 추출물을 유효성분으로 함유하는 항균용 조성물 | |
JP5542145B2 (ja) | イワヤツデ抽出物およびそれから分離した活性成分を含む抗菌性薬学組成物 | |
JP2005029556A (ja) | 皮膚老化防止剤 | |
KR20110049272A (ko) | 항균활성을 갖는 깻잎 추출물을 함유하는 조성물 | |
KR20040056079A (ko) | 여드름 예방 및 치료용 화장료 조성물 | |
CN105473139A (zh) | 用于有效治疗、预防或改善痤疮的二氢卟吩e6 | |
JP2788166B2 (ja) | 活性酸素消去用の組成物 | |
KR102249708B1 (ko) | 파시플로라 콰드랭귤라리스의 꽃 추출물을 포함하는 두피 상태 개선용 조성물 | |
KR102598905B1 (ko) | 퀼라야 추출물을 함유하는 소취용 조성물 | |
KR101785096B1 (ko) | 호로파 추출물을 포함하는 뇌암 치료용 조성물 및 미백 기능성 화장품 | |
KR20190009097A (ko) | 에틸바닐린을 유효성분으로 함유하는 근력강화, 근육증강, 근육분화, 근육재생 또는 근감소증 억제효과를 갖는 조성물 | |
KR20080090745A (ko) | 항산화 효과를 갖는 순비기나무 추출물을 유효성분으로함유하는 화장료 조성물 | |
KR20100041258A (ko) | 제이에스원의 신규한 용도 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
TR01 | Transfer of patent right | ||
TR01 | Transfer of patent right |
Effective date of registration: 20181119 Address after: Seoul, South Kerean Co-patentee after: NEWTREE INDUSTRY CO., LTD. Patentee after: AAT Cox Tek Co., Ltd. Address before: Gyeonggi Do, South Korea Co-patentee before: NEWTREE INDUSTRY CO., LTD. Patentee before: Huang Zaikuan |