KR20190046015A - Pharmaceutical composition for use in preventing or treating osteoporosis containing eucalyptol as an active ingredient - Google Patents
Pharmaceutical composition for use in preventing or treating osteoporosis containing eucalyptol as an active ingredient Download PDFInfo
- Publication number
- KR20190046015A KR20190046015A KR1020170139074A KR20170139074A KR20190046015A KR 20190046015 A KR20190046015 A KR 20190046015A KR 1020170139074 A KR1020170139074 A KR 1020170139074A KR 20170139074 A KR20170139074 A KR 20170139074A KR 20190046015 A KR20190046015 A KR 20190046015A
- Authority
- KR
- South Korea
- Prior art keywords
- pharmaceutical composition
- preventing
- pharmaceutically acceptable
- formula
- compound represented
- Prior art date
Links
- 208000001132 Osteoporosis Diseases 0.000 title claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 25
- 239000004480 active ingredient Substances 0.000 title claims description 10
- 229960005233 cineole Drugs 0.000 title abstract description 29
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 title abstract description 28
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 title abstract description 28
- 230000004072 osteoblast differentiation Effects 0.000 claims abstract description 20
- 102000015775 Core Binding Factor Alpha 1 Subunit Human genes 0.000 claims abstract description 14
- 108010024682 Core Binding Factor Alpha 1 Subunit Proteins 0.000 claims abstract description 14
- 101150118728 Dlx5 gene Proteins 0.000 claims abstract description 13
- 230000014509 gene expression Effects 0.000 claims abstract description 10
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 10
- 239000003550 marker Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 30
- 102000002260 Alkaline Phosphatase Human genes 0.000 claims description 16
- 108020004774 Alkaline Phosphatase Proteins 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 13
- 235000013376 functional food Nutrition 0.000 claims description 11
- 230000036541 health Effects 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 10
- 239000003826 tablet Substances 0.000 claims description 8
- 102100027641 DNA-binding protein inhibitor ID-1 Human genes 0.000 claims description 7
- 101710152088 DNA-binding protein inhibitor ID-1 Proteins 0.000 claims description 7
- 102000004067 Osteocalcin Human genes 0.000 claims description 7
- 108090000573 Osteocalcin Proteins 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 102100022373 Homeobox protein DLX-5 Human genes 0.000 claims description 5
- 101000901627 Homo sapiens Homeobox protein DLX-5 Proteins 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 5
- 108010061414 Hepatocyte Nuclear Factor 1-beta Proteins 0.000 claims description 4
- 102100022123 Hepatocyte nuclear factor 1-beta Human genes 0.000 claims description 4
- 239000007902 hard capsule Substances 0.000 claims description 3
- 239000007901 soft capsule Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 abstract description 30
- 210000000963 osteoblast Anatomy 0.000 abstract description 25
- 230000004069 differentiation Effects 0.000 abstract description 14
- 210000002997 osteoclast Anatomy 0.000 abstract description 14
- 239000003814 drug Substances 0.000 abstract description 9
- 230000011164 ossification Effects 0.000 abstract description 9
- 230000001965 increasing effect Effects 0.000 abstract description 7
- 230000001737 promoting effect Effects 0.000 abstract description 6
- 101150047694 ID1 gene Proteins 0.000 abstract description 5
- 230000002308 calcification Effects 0.000 abstract description 3
- 235000013402 health food Nutrition 0.000 abstract description 3
- 230000008685 targeting Effects 0.000 abstract description 2
- 101710189683 Alkaline protease 1 Proteins 0.000 abstract 1
- 101710154562 Alkaline proteinase Proteins 0.000 abstract 1
- 101710170876 Antileukoproteinase Proteins 0.000 abstract 1
- 208000010392 Bone Fractures Diseases 0.000 abstract 1
- 101710112538 C-C motif chemokine 27 Proteins 0.000 abstract 1
- 206010017076 Fracture Diseases 0.000 abstract 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 30
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 25
- 210000000988 bone and bone Anatomy 0.000 description 17
- 235000010323 ascorbic acid Nutrition 0.000 description 15
- 229960005070 ascorbic acid Drugs 0.000 description 15
- 239000011668 ascorbic acid Substances 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 238000011282 treatment Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 238000010186 staining Methods 0.000 description 7
- 150000004820 halides Chemical class 0.000 description 6
- 239000007788 liquid 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
- 230000002265 prevention Effects 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 description 4
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 229940112869 bone morphogenetic protein Drugs 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- -1 pyrosulfate Chemical compound 0.000 description 4
- 238000003753 real-time PCR Methods 0.000 description 4
- 239000000243 solution 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
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 102100025368 Runt-related transcription factor 2 Human genes 0.000 description 3
- 101710102802 Runt-related transcription factor 2 Proteins 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 3
- 229940077388 benzenesulfonate Drugs 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 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
- 235000009508 confectionery Nutrition 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 229940041476 lactose 100 mg Drugs 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000005728 strengthening Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- QRXMUCSWCMTJGU-UHFFFAOYSA-N 5-bromo-4-chloro-3-indolyl phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP(O)(=O)O)=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-N 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- 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 2
- 208000020084 Bone disease Diseases 0.000 description 2
- 206010065687 Bone loss Diseases 0.000 description 2
- 208000018084 Bone neoplasm Diseases 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
- 229920002261 Corn starch Polymers 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
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 244000166124 Eucalyptus globulus Species 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 244000269722 Thea sinensis Species 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- RGCKGOZRHPZPFP-UHFFFAOYSA-N alizarin Chemical compound C1=CC=C2C(=O)C3=C(O)C(O)=CC=C3C(=O)C2=C1 RGCKGOZRHPZPFP-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 239000007758 minimum essential medium Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 208000028169 periodontal disease Diseases 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000013616 tea Nutrition 0.000 description 2
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- 150000000193 1,8-cineol derivatives Chemical class 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- JKYKXTRKURYNGW-UHFFFAOYSA-N 3,4-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C(O)=C(O)C(S(O)(=O)=O)=C2 JKYKXTRKURYNGW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000000972 4,5-dimethylthiazol-2-yl group Chemical group [H]C([H])([H])C1=C(N=C(*)S1)C([H])([H])[H] 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- CNNSWSHYGANWBM-UHFFFAOYSA-N 6-chloro-2,3-dimethylquinoxaline Chemical compound C1=C(Cl)C=C2N=C(C)C(C)=NC2=C1 CNNSWSHYGANWBM-UHFFFAOYSA-N 0.000 description 1
- 206010000372 Accident at work Diseases 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 206010006326 Breath odour Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000579895 Chlorostilbon Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-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
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 235000004692 Eucalyptus globulus Nutrition 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 244000060234 Gmelina philippensis Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000016921 Integrin-Binding Sialoprotein Human genes 0.000 description 1
- 108010028750 Integrin-Binding Sialoprotein Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- 208000023178 Musculoskeletal disease Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 206010049088 Osteopenia Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010039203 Road traffic accident Diseases 0.000 description 1
- 229920002472 Starch Polymers 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-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 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
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- YTIVTFGABIZHHX-UHFFFAOYSA-L acetylenedicarboxylate(2-) Chemical compound [O-]C(=O)C#CC([O-])=O YTIVTFGABIZHHX-UHFFFAOYSA-L 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 235000013334 alcoholic beverage Nutrition 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 230000037180 bone health Effects 0.000 description 1
- 230000010478 bone regeneration Effects 0.000 description 1
- 230000010072 bone remodeling Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 208000019664 bone resorption disease Diseases 0.000 description 1
- 230000037118 bone strength Effects 0.000 description 1
- 230000008416 bone turnover Effects 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 229940037448 calcitonin preparations Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012136 culture method Methods 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 229910052876 emerald Inorganic materials 0.000 description 1
- 239000010976 emerald Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- NCAUKTRHFNKPLU-UHFFFAOYSA-N eucalyptolic acid Natural products COc1cc(C=CC(=O)OC2C(O)CC3(C)C(CCC4(C)C3CC=C5C6CC(C)(C)CCC6(CCC45C)C(=O)O)C2(C)C)ccc1O NCAUKTRHFNKPLU-UHFFFAOYSA-N 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- ZEQMQPCXFPCFDI-UHFFFAOYSA-N formaldehyde;2-hydroxypropane-1,2,3-tricarboxylic acid;propan-2-one Chemical compound O=C.CC(C)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O ZEQMQPCXFPCFDI-UHFFFAOYSA-N 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 208000037824 growth disorder Diseases 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 235000001497 healthy food Nutrition 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000077 insect repellent Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003098 myoblast Anatomy 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000012149 noodles Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 210000004409 osteocyte Anatomy 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid 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
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000013550 pizza Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000012257 pre-denaturation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 235000013580 sausages Nutrition 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 1
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 235000011888 snacks Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/306—Foods, ingredients or supplements having a functional effect on health having an effect on bone mass, e.g. osteoporosis prevention
Abstract
Description
본 발명은 유칼립톨 또는 이의 약학적으로 허용 가능한 유도체를 유효성분으로 함유하는 골다공증의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for the prevention or treatment of osteoporosis comprising eucalyptol or a pharmaceutically acceptable derivative thereof as an active ingredient.
최근 각종 산업재해 및 교통사고가 증가하고 고령화 사회로 접어들면서 골다공증 및 그에 따른 골절등에 의한 근골격계 질환이 증가하고 있다. 이와 같은 골질환등의 예방과 치료를 위해 골 재생 능력유도를 위한 다양한 형태의 뼈이식제와 조골세포의 활성향상 및 파골세포의 활성을 저하시키기 위한 새로운 형태의 관련질환 치료제들이 개발되고 있다. 또한, 골종양, 골결손이 심한 부위를 채울 수 있는 신생골을 능동적으로 유도하기 위하여 줄기세포와 조골세포를 이용하여 다양한 연구들이 시도되고 있다.BACKGROUND ART [0002] As various industrial accidents and traffic accidents have increased and an aging society has recently been developed, musculoskeletal diseases caused by osteoporosis and fractures resulting from such diseases have been increasing. In order to prevent and treat bone diseases and the like, there have been developed various types of bone grafting agents for inducing bone regeneration ability, new types of related diseases for improving osteoclast activity and osteoclast activity. In addition, various studies using stem cells and osteoblasts have been attempted to actively induce new bone that can fill a bone tumor or bone defect.
골의 재형성 과정은 오래된 골이 주기적으로 새로운 골로 전환되는 과정으로, 이 과정은 증식, 분화 및 세포외기질의 석회화유도 등의 단계를 거쳐 진행된다. 일반적으로 성인의 골 형성과 흡수 과정은 중간엽줄기세포 유래의 조골세포와 조혈모세포 유래의 파골세포의 상호작용에 의해 균형을 이루면서 골의 건강을 유지하는데, 조골세포의 활성도가 낮아져 골 형성이 감소 되거나 파골세포의 활성도가 강해져 골 흡수가 증가 되는 등의 조골세포와 파골세포 간의 활성 불균형이 일어나게 되면 조직 내 화학조성에는 큰 변화가 없지만 골 질량이 감소하여 골다공증(osteoporosis)과 같은 골 대사질환이 유발될 수 있다.The bone remodeling process is a process in which old bone is periodically converted into a new bone, and this process proceeds through steps such as proliferation, differentiation, and induction of calcification of the extracellular matrix. In general, the bone formation and absorption process of adult is balanced by the interaction of osteoblasts derived from mesenchymal stem cells with osteoblast-derived osteoblasts, maintaining bone health, lowering osteoblast activity and reducing bone formation Or osteoclast activity increases osteoclast activity and increases osteoclast activity, there is no significant change in the chemical composition of the osteoblast and osteoclast. However, osteopenia such as osteoporosis is caused by decreased bone mass. .
골다공증은 유전적 요인이나 식이, 생활 방식과 같은 환경적 요인에 의해서도 영향을 받는 복합적인 질병으로, 특히 여성의 경우 폐경기에 이르면 호르몬의 변화에 의해 골 감소가 급격히 진행된다.Osteoporosis is a complex disease that is also influenced by genetic factors, environmental factors such as diet and lifestyle, and especially in women, bone turnover is dramatically accelerated by hormonal changes in menopause.
현재 시판되고 있는 골다공증 치료제는 비타민 D, 여성호르몬제, 비스포스포네이트제제, 선택적 에스트로겐 수용체 조절제, 칼시토닌 제제 등이 있는데 대부분 파골세포의 활성을 감소시켜 골 흡수를 조절함으로써 뼈의 소실을 막아주는 방식에 의하고 있다. 그러나 파골세포의 활성억제를 통한 골다공증 치료법들은 근본적으로 골다공증을 치료할 수 있는 치료법이 아니기 때문에 완치에 한계가 있으며 실질적인 골밀도 증가 및 골 강화가 이루어질 수 있는 조골세포 활성의 증가가 필수적으로 요구된다.Currently available osteoporosis drugs are vitamin D, female hormones, bisphosphonates, selective estrogen receptor modulators, and calcitonin preparations. Most of them are based on the way of preventing loss of bones by decreasing the activity of osteoclasts and regulating bone resorption . However, since osteoporosis treatments through inhibition of osteoclast activity are not fundamentally therapeutic methods for treating osteoporosis, there is a limit to cure and it is essential to increase osteoblast activity which can increase bone mass and bone strength.
또한, 골다공증은 약물의 단기 투여만으로는 치료할 수 없고 약물의 장기 투여가 필수적인 질환이므로, 약물을 장기 투여할 때에도 부작용이 없으면서 우수한 약효를 갖는 새로운 물질들의 개발이 요구되고 있다.In addition, osteoporosis is a disease that can not be treated only by short-term administration of a drug, and long-term administration of the drug is essential. Therefore, there is a need to develop new substances with superior drug efficacy without side effects when the drug is administered for a long period of time.
이에 따라, 최근에는 기존 치료법의 부작용 최소화와 골 소실을 최소화하면서 골 형성을 촉진할 수 있는 한약재 및 식품 등의 천연물 유래 활성성분을 이용한 대체요법 연구들이 활발히 진행되고 있다.Recently, alternative therapies using active ingredients derived from natural products such as herbal medicines and foods that can promote bone formation with minimal side effects and minimizing bone loss have been actively conducted.
한편, 유칼립톨(Eucalyptol)은 특유의 방향성 장뇌(樟腦) 비슷한 향기가 있고 자극성의 짜릿한 맛이 있으며 유칼리유(油)나 그외 다른 원료로부터 얻을 수 있는 무색의 액체로서, 향미료, 거담제, 국소소독제, 구충제로 사용되며, 수의학에서는 기관지염의 흡입제나 거담제로 사용된다고 알려져 있다.On the other hand, Eucalyptol is a colorless liquid having a characteristic aromatic camphor-like aroma, irritating, exhilarating taste, and obtainable from eucalyptus oil or other raw materials. It is a colorless liquid obtained from spices, It is known to be used as an insect repellent, and it is used in veterinary medicine as an inhalant or expectorant of bronchitis.
최근, 유칼립톨의 신장섬유증 예방 및 치료효과에 대한 연구가 진행된 바 있으며(특허문헌 1), 주로 구강청정용, 구강위생증진용, 구취억제용 조성물들의 성분으로 연구되어지고 있다.In recent years, studies on the prevention and treatment effects of eucalyptol for renal fibrosis have been made (Patent Document 1), and studies have been made mainly on compositions for oral cleaning, oral hygiene promotion, and bad breath suppressing compositions.
그러나 이러한 유칼립톨에 대한 조골세포의 증식 및 분화에 미치는 영향에 대한 연구결과는 아직 보고된 바 없다.However, no study has been reported on the effect of this eucalyptol on osteoblast proliferation and differentiation.
본 발명자들은 근본적으로 골다공증을 치료하기 위해 실질적인 골밀도 증가 및 골 강화를 위해 조골세포의 활성을 증가시키고, 장기간 복용하여도 부작용이 적은 새로운 약학적 조성물을 개발하기 위해 노력하던 중, 유칼립톨 또는 이의 약학적으로 허용 가능한 유도체들이 조골세포의 증식 및 분화를 촉진함을 확인함으로써 본 발명을 완성하였다.The inventors of the present invention have been intensively working to develop a new pharmaceutical composition which increases osteoblast activity and increases the osteoblast activity for bone strengthening and bone strengthening in order to treat osteoporosis, The present inventors have accomplished the present invention by confirming that allowable derivatives promote the proliferation and differentiation of osteoblasts.
따라서, 본 발명의 목적은 골다공증 예방 및 치료 효능이 우수하고 장기간 복용하여도 부작용이 적은 약학적 조성물 및 건강기능식품을 제공하는 것이다.Accordingly, an object of the present invention is to provide a pharmaceutical composition and a health functional food having excellent osteoporosis prevention and treatment efficacy and having little side effects even when taken for a long time.
상기 목적을 달성하기 위해,In order to achieve the above object,
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 유도체를 유효성분으로 함유하는 골다공증의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating osteoporosis, which comprises a compound represented by the following formula (1) or a pharmaceutically acceptable derivative thereof as an active ingredient.
상기 화학식 1로 표시되는 화합물은 유칼립톨(eucalyptol)로 명명될 수 있다.The compound represented by the above formula (1) may be named eucalyptol.
상기 약학적 조성물은 조골세포 분화를 촉진시키는 것을 특징으로 할 수 있다. The pharmaceutical composition may be characterized in promoting osteoblast differentiation.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 유도체의 농도는 0.01 내지 5 μM 인 것을 특징으로 할 수 있다.The concentration of the compound represented by Formula 1 or a pharmaceutically acceptable derivative thereof may be 0.01 to 5 μM.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 유도체는 Runx2(runt-related transcription factor 2), Id1(inhibitor of DNA binding 1), Dlx5(distal-less homeobox 5), OC(osteocalcin) 및 ALP(alkaline phosphatase) 중 어느 하나 이상의 조골세포 분화 마커 유전자의 발현량을 증가시키는 것을 특징으로 할 수 있다.The compound represented by Formula 1 or a pharmaceutically acceptable derivative thereof may be selected from Runx-related transcription factor 2 (Runx2), inhibitor of DNA binding 1, Dlx5 (distal-less homeobox 5), osteocalcin and an alkaline phosphatase (osteoclast differentiation marker gene).
상기 약학적 조성물은 산제, 과립제, 정제, 경질 캡슐제, 연질 캐슐제 또는 주사제의 형태로 제형화되는 것을 특징으로 할 수 있다.The pharmaceutical composition may be formulated in the form of powders, granules, tablets, hard capsules, soft capsules or injections.
또한, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 유도체를 유효성분으로 함유하는 골다공증의 예방 또는 개선용 건강기능식품을 제공한다.The present invention also provides a health functional food for preventing or ameliorating osteoporosis, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable derivative thereof as an active ingredient.
[화학식 1][Chemical Formula 1]
상기 화학식 1로 표시되는 화합물은 유칼립톨(eucalyptol)로 명명될 수 있다.The compound represented by the above formula (1) may be named eucalyptol.
상기 건강기능식품은 조골세포 분화를 촉진시키는 것을 특징으로 할 수 있다.The health functional food may be characterized by promoting osteoblast differentiation.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 유도체의 농도는 0.01 내지 5 μM 인 것을 특징으로 할 수 있다.The concentration of the compound represented by Formula 1 or a pharmaceutically acceptable derivative thereof may be 0.01 to 5 μM.
본 발명에 따른 약학적 조성물은 조골세포 분화 마커 유전자인 Id1, Dlx5, Runx2, ALP, OC의 발현량을 증가시키고, 조골세포의 석회화를 증가시킴으로써 조골세포의 분화를 촉진하는 효과가 있어 골다공증의 예방 또는 치료용 의약품 또는 건강식품으로 널리 이용될 수 있다.The pharmaceutical composition according to the present invention increases the expression level of the osteoblast differentiation marker genes Id1, Dlx5, Runx2, ALP, and OC and increases osteoblast calcification, thereby promoting osteoblast differentiation. Thus, osteoporosis prevention Or therapeutic medicines or health foods.
또한, 파골세포를 표적으로 하기보다는 조골세포의 활성을 증가시킴으로써 골형성을 촉진시켜 근본적으로 골다공증을 치료할 수 있으며, 2차 골절 예방효과를 나타낼 수 있는 장점이 있다.In addition, rather than targeting osteoclasts, osteoblast activity can be increased to promote osteogenesis, thereby osteoporosis can be fundamentally treated, and secondary osteoporosis can be effectively prevented.
도 1은 유칼립톨(eucalyptol)의 농도에 따른 MTT 분석의 결과 그래프이다.
도 2는 유칼립톨(eucalyptol)에 의한 조골세포 분화 마커의 발현정도를 시간에 따라 비교한 <실험예 2>에 따른 결과이다.
도 3은 <실험예 3>에 따른 알리자린 레드 에스 염색(Alizarin red s staining, ALP staining)의 결과를 나타낸 사진이다.
도 4는 ALP 활성도 정도를 계산하여 나타낸 그래프이다.Figure 1 is a graph of the results of MTT analysis according to the concentration of eucalyptol.
FIG. 2 shows the results of Experimental Example 2 in which the expression level of osteoblast differentiation markers by eucalyptol was compared over time.
FIG. 3 is a photograph showing the results of Alizarin red staining (ALP staining) according to Experimental Example 3.
4 is a graph showing the ALP activity level calculated.
이하, 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail.
본 명세서 및 청구범위에 사용되는 용어나 단어는 통상적이거나 사전적인 의미로 한정해서 해석되어서는 아니되며, 발명자는 그 자신의 발명을 가장 최선의 방법으로 설명하기 위해 용어의 개념을 적절하게 정의할 수 있다는 원칙에 입각하여 본 발명의 기술적 사상에 부합하는 의미와 개념으로 해석되어야만 한다.The terms and words used in the present specification and claims should not be construed as limited to ordinary or dictionary meanings and the inventor may properly define the concept of the term to describe its invention in the best possible way It should be construed as meaning and concept consistent with the technical idea of the present invention.
본 발명은 골다공증의 예방 또는 치료용 약학적 조성물 및 건강기능식품에 관한 것이다.The present invention relates to a pharmaceutical composition and a health functional food for preventing or treating osteoporosis.
본 명세서에서 용어 골다공증은 뼈의 양이 감소하고 질적인 변화로 인하여 뼈의 강도가 약해진 상태를 의미하고, 골다공증의 예방, 개선 및 치료라 함은 골 밀도 저하, 골 손실로 인한 각종 질병을 모두 포함하는 것으로 해석된다.As used herein, the term osteoporosis refers to a state in which the amount of bone is reduced and the strength of the bone is weakened due to a qualitative change, and the prevention, improvement and treatment of osteoporosis includes all kinds of diseases caused by decreased bone density and bone loss .
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 유도체를 유효성분으로 함유하는 골다공증의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating osteoporosis, which comprises a compound represented by the following formula (1) or a pharmaceutically acceptable derivative thereof as an active ingredient.
[화학식 1][Chemical Formula 1]
상기 화학식 1로 표시되는 화합물은 유칼립톨 (eucalyptol)로 명명될 수 있다.The compound represented by the above formula (1) may be named eucalyptol.
상기 화학식 1로 표시되는 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 아세트산, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 다이하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.The compound represented by the formula (1) can be used in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chloro Such as benzenesulfonate, benzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.
본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 디클로로메탄, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다.The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile and the like, Followed by filtration and drying, or by distillation of the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻는다.In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
상기 화학식 1로 표시되는 화합물인 유칼립톨은 공지된 방법에 의해 천연물로부터 추출된 것이나 합성된 것을 사용할 수 있으며, 그 제조방법이나 기원은 한정되지 않는다.Eucalyptol, which is a compound represented by the general formula (1), can be extracted from natural products or synthesized by a known method, and the production method and origin are not limited.
유칼립톨은 유칼립투스(Eucalyptus globulus)의 잎에서 추출하여 오일을 정류 및 블렌딩한 에센셜오일로서, 항염증, 항통증, 항바이러스, 해열 작용 등 다양한 생리 활성이 알려져 있는 물질이다.Eucalyptol is an essential oil extracted from eucalyptus ( Eucalyptus globulus ) leaves and purified and blended with oil. It is known for various physiological activities such as anti-inflammatory, anti-inflammatory, antiviral and antipyretic action.
상기 약학적 조성물은 조골세포 분화를 촉진시키는 것을 특징으로 할 수 있다. The pharmaceutical composition may be characterized in promoting osteoblast differentiation.
조골세포의 분화를 촉진시키는 화합물은 골다공증 및 골절 등과 같은 질환 및 증상의 예방 또는 치료에 사용될 수 있을 뿐만 아니라, 골 강화를 목적으로 하는 치주질환 치료에도 사용될 수 있으며(Zhang et al., ShanghaiKou Qiang Yi Xue 7(2), pp99-103, 1998; Cahill et al, Biol Blood Marrow Transplant 10(10), pp709-717, 2004), 화상으로 비롯되는 골 성장 장애 치료에 유용하게 사용될 수 있다는 연구도 보고된바 있다(Klein et al.,Osteoporos Int. 16(6), pp631-635, 2005).Compounds that promote osteoclast differentiation can be used not only for the prevention or treatment of diseases and symptoms such as osteoporosis and fracture but also for the treatment of periodontal disease for the purpose of bone strengthening (Zhang et al., Shanghai Kou Qiang Yi It has also been reported that it may be useful for the treatment of bone growth disorders resulting from burns, as reported by Xue 7 (2), pp 99-103, 1998; Cahill et al, Biol Blood Marrow Transplant 10 (10), pp709-717, (Klein et al., Osteoporos Int. 16 (6), pp. 631-635, 2005).
상기 약학적 조성물은 조골세포 등의 부족으로 인한 골 형성에 문제가 있는 질환에 제한 없이 사용될 수 있으며, 구체적으로 에스트로겐의 부족으로 인한 인터루킨-1(IL-1)에 의한 골 파괴와 염증성 질환 등이 포함될 수 있고, 과도한 파골 세포의 골 흡수에 의한 골다공증, 뼈전이암 병소(bone metastatic lesion), 원발성으로 뼈에 생성된 종양, 류마티스성 또는 퇴행성 관절염, 치주질환, 염증성 치조골 흡수질환, 염증성 뼈 흡수 질환 및 파제트병(Paget's disease) 등과 같은 병리학적 골 질환으로 골 파괴를 촉진하는 질환이 포함될 수 있다.The pharmaceutical composition can be used without limitation in diseases causing bone formation due to deficiency of osteoblasts and the like. More specifically, the pharmaceutical composition can be used for the treatment of bone destruction and inflammatory diseases caused by interleukin-1 (IL-1) And can be used to treat osteoporosis, bone metastatic lesion, primary bone tumor, rheumatic or degenerative arthritis, periodontal disease, inflammatory alveolar bone disease, inflammatory bone resorption disease And Paget's < Desc /
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 유도체의 농도는 0.01 내지 5 μM 인 것을 특징으로 할 수 있다.The concentration of the compound represented by Formula 1 or a pharmaceutically acceptable derivative thereof may be 0.01 to 5 μM.
만일 농도가 0.01 μM 미만일 경우 약학적인 효과가 미미하게 나타날 수 있고, 5 μM를 초과할 경우 세포독성이 나타날 수 있는 문제점이 있다.If the concentration is less than 0.01 μM, the pharmacological effect may be insignificant, and if the concentration is more than 5 μM, the cytotoxicity may occur.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 유도체는 Runx2(runt-related transcription factor 2), Id1(inhibitor of DNA binding 1), Dlx5(distal-less homeobox 5), OC(osteocalcin) 및 ALP(alkaline phosphatase) 중 어느 하나 이상의 조골세포 분화 마커 유전자의 발현량을 증가시키는 것을 특징으로 할 수 있다.The compound represented by
조골세포 분화는 호르몬, 뼈형성단백질(bone morphogenetic proteins:BMPs)과 같은 사이토카인, Runx2(runt-related transcription factor 2), Id1(inhibitor of DNA binding 1), Dlx5(distal-less homeobox 5), OC(osteocalcin), ALP(alkaline phosphatase)과 같은 다양한 전사인자에 의해서 조절된다. 그 중에서도 Id1, Dlx5, Runx2는 조골세포 분화 초기에 발현되는 필수적인 유전자로 이들 유전자의 발현은 조골세포 분화가 가속화됨을 의미한다.Osteoblast differentiation can be induced by a combination of hormones, cytokines such as bone morphogenetic proteins (BMPs), runt-related transcription factor 2 (Runx2), inhibitor of DNA binding 1, Dlx5 (distal-less homeobox 5) (osteocalcin), and alkaline phosphatase (ALP). Among them, Id1, Dlx5, and Runx2 are essential genes that are expressed at the early stage of osteoblast differentiation. Expression of these genes means that osteoblast differentiation is accelerated.
구체적으로, Runx2(runt-related transcription factor 2)는 조골세포 분화에 있어 중요한 조절자로 많이 알려져 있으며 다분화능세포 또는 조골전구세포에서 ALP(alkaline phosphatase), OC(osteocalcin) 그리고 골격시알로단백질(bone sialoprotein)과 같은 유전자를 조절함으로써 조골세포 분화를 촉진하는 유전자이다.Runx-related transcription factor 2 (Runx2) is known to be an important regulator of osteoblast differentiation, and it is known that ALP (alkaline phosphatase), OC (osteocalcin) and bone sialoprotein ) To control osteoblast differentiation.
Id1(inhibitor of DNA binding 1)은 조골세포에서 세포의 성장과 분화 사이의 균형에 영향을 미치는 전사인자이고, 조골세포 특이적 분화에 있어서 초기 단계에 중요한 역할을 하는 것으로 알려져 있다. 뿐만 아니라 근원세포, 중간엽 줄기세포에서 조골세포 분화로 전환될 때 Id1(inhibitor of DNA binding 1) 유전자 발현의 조절에 따라 분화가 촉진된다. Id1 (inhibitor of DNA binding 1) is a transcription factor that affects the balance between cell growth and differentiation in osteoblasts and is known to play an important role in the early stages of osteoblast-specific differentiation. In addition, differentiation is promoted by the regulation of Id1 (inhibitor of DNA binding 1) gene expression when transformed into osteoblast differentiation from myoblast and mesenchymal stem cells.
Dlx5(distal-less homeobox 5) 또한 뼈에 의해 유도되며 Runx2(runt-related transcription factor 2)의 프로모터에 직접적으로 결합하여 전사를 조절하고, 조골세포 분화의 후기 표지 유전자인 OC(osteocalcin)의 유전자 발현을 조절함으로써 조골세포 분화를 조절한다.Dlx5 (distal-less homeobox 5) is also induced by bone and directly binds to the promoter of Runx2 (runt-related transcription factor 2) to regulate transcription, and gene expression of OC (osteocalcin), the late marker gene of osteoblast differentiation To control osteoblast differentiation.
상기 약학적 조성물은 임상 투여시에 경구 또는 비경구로 투여가 가능하며, 일반적인 의약품 제제의 형태로 사용될 수 있다.The pharmaceutical composition can be administered orally or parenterally at the time of clinical administration and can be used in the form of a general pharmaceutical preparation.
상기 약학적 조성물은 산제, 과립제, 정제, 경질 캡슐제, 연질 캐슐제 또는 주사제의 형태로 제형화되는 것을 특징으로 할 수 있다.The pharmaceutical composition may be formulated in the form of powders, granules, tablets, hard capsules, soft capsules or injections.
보다 상세하게는, 각각 통상적인 방법에 따라 산제, 과립제, 정제, 캡슐, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 멸균 주사용액, 사전 충전식 주사 용액제의 형태 또는 동결건조된 형태로 제형화할 수 있으나, 이에 제한되는 것은 아니다.More specifically, the pharmaceutical composition of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, external preparations, suppository sterilized injection solutions, But the present invention is not limited thereto.
제형화할 경우에는 통상 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조될 수 있다.In the case of formulation, it may be prepared using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and the like which are usually used.
경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 유효 성분에 적어도 하나 이상의 부형제, 예컨대, 전분, 칼슘 카르보네이트, 수크로오스, 락토오스, 젤라틴 등을 혼합하여 제조할 수 있다. 또한, 단순한 부형제 이외에도 마그네슘 스테아레이트, 탈크와 같은 윤활제도 사용될 수 있다.Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one or more excipients such as starch, calcium carbonate, sucrose, lactose, gelatin, . In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.
경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 통상적으로 사용되는 단순 희석제인 물, 액체 파라핀 이외에 다양한 부형제, 예컨대 습윤제, 감미제, 방향제, 보존제 등이 함께 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제, 좌제 등이 포함된다.Examples of the liquid preparation for oral administration include suspensions, solutions, emulsions and syrups. Various excipients such as wetting agents, sweetening agents, fragrances, preservatives, etc. may be included in addition to water and liquid paraffin which are simple diluents commonly used have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.
본 발명의 약학적 조성물의 바람직한 투여량은 환자의 상태 및 체중, 증상의 정도, 약물 형태, 투여 경로 및 기간에 따라 적절하게 선택될 수 있다.A preferable dosage of the pharmaceutical composition of the present invention can be appropriately selected depending on the condition and the weight of the patient, the degree of symptoms, the drug form, the administration route and the period.
또한, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 유도체를 유효성분으로 함유하는 골다공증의 예방 또는 개선용 건강기능식품을 제공한다.The present invention also provides a health functional food for preventing or ameliorating osteoporosis, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable derivative thereof as an active ingredient.
[화학식 1][Chemical Formula 1]
상기 화학식 1로 표시되는 화합물은 유칼립톨 (eucalyptol)로 명명될 수 있다.The compound represented by the above formula (1) may be named eucalyptol.
상기 건강기능식품은 조골세포 분화를 촉진시키는 것을 특징으로 할 수 있다.The health functional food may be characterized by promoting osteoblast differentiation.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 유도체의 농도는 0.01 내지 5 μM 인 것을 특징으로 할 수 있다.The concentration of the compound represented by
만일 농도가 0.01 μM 미만일 경우 약학적인 효과가 미미하게 나타날 수 있고, 5 μM를 초과할 경우 세포독성이 나타날 수 있는 문제점이 있다.If the concentration is less than 0.01 μM, the pharmacological effect may be insignificant, and if the concentration is more than 5 μM, the cytotoxicity may occur.
상기 건강기능식품은, 비제한적으로 각종 음료, 껌, 차, 과자, 비타민 복합체, 건강 보조식품 등의 형태로 제조될 수 있다.The health functional food may be manufactured in the form of, but not limited to, various drinks, gum, tea, confectionery, vitamin complex, health supplement, and the like.
또한, 상기 건강기능식품은 골다공증 개선을 목적으로 건강식품에 첨가되는 경우도 포함하며, 식품의 종류에 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.In addition, the health functional food includes a case where it is added to health food for the purpose of improving osteoporosis, and there is no particular limitation on the kind of food. Examples of the food to which the above substances can be added include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, Alcoholic beverages, and vitamin complexes, all of which include healthy foods in a conventional sense.
상기 건강기능식품의 바람직한 섭취량은 섭취자의 상태 및 체중, 증상의 정도, 식품 형태, 섭취 기간에 따라 다르며 적절하게 선택될 수 있다.The preferred amount of the health functional food to be consumed depends on the condition and the weight of the recipient, the degree of symptoms, the type of food, the period of consumption, and may be appropriately selected.
골의 형성과정에 조골세포의 분화는 유전형질의 발현에 의해 조절되며, 배양방법에 따라 고유의 특성을 가진다. 골세포의 분화 및 골 형성에 관여하는 중요한 신호전달체계는 대표적으로 변화 성장 인자-β(transforming growth factor-β: TGF-β)와 뼈형성단백질(bone morphogenetic protein: BMP), 윈트/베타-카테닌(Wnt/β-catenin), 섬유아세포 증식인자(fibroblast growth factor: FGF), 헤지호그(hedgehog), 노치(notch) 등이 알려져 있다.The differentiation of osteoblasts during bone formation is controlled by the expression of genotypes and has inherent characteristics depending on the culture method. Important signaling pathways involved in osteocyte differentiation and osteogenesis are transforming growth factor-beta (TGF-beta), bone morphogenetic protein (BMP), and beta-catenin , Fibroblast growth factor (FGF), hedgehog, and notch are known.
이러한 신호전달체계는 골세포 분화과정 동안 Runx2(Runt-related transcription factor 2) 및 Dlx5(Distalless-related homeobox 5) 등과 같은 골 형성과 관련한 다양한 전사인자의 발현과 활성화를 유도하며, ALP(alkaline phosphatase), Id1(inhibitor of DNA binding 1), OC(Osteocalcin) 등의 골 분화 관련 유전자를 발현시킨다. 이러한 조골세포에서의 분화 유도 물질로는 아스코르브산(ascorbic acid:AA), 베타-글리세로포스페이트(β-glycerophosphate:β-GP), 덱사메타손(dexamethasone) 등이 알려져 있다.These signaling pathways induce the expression and activation of various transcription factors related to osteogenesis such as Runx2 (Runt-related transcription factor 2) and Dlx5 (Distalless-related homeobox 5) during osteoclast differentiation, and ALP (alkaline phosphatase) , Id1 (inhibitor of DNA binding 1), and OC (osteocalcin). As a differentiation inducer in such osteoblasts, ascorbic acid (AA), beta-glycerophosphate (beta -GP), dexamethasone and the like are known.
본 발명에서는 골조직에 존재하는 조골세포와 유사한 MC3T3-E1 전조골세포(preosteoblasts)를 이용하여 유칼립톨이 조골세포의 증식 및 분화에 미치는 영향을 알아보기 위한 실험을 진행하였으며, 그 결과 유칼립톨은 조골세포의 증식 및 분화에 긍정적인 효과를 나타냄을 확인할 수 있었다.In the present invention, experiments were conducted to examine the effect of eucalyptol on the proliferation and differentiation of osteoblast using MC3T3-E1 preosteoblasts similar to osteoblasts present in bone tissue. As a result, eucalyptol It was confirmed that the cell proliferation and differentiation were positively effected.
이하, 본 발명을 구체적으로 설명하기 위해 실시예 및 실험예를 들어 상세하게 설명하기로 한다. 그러나 본 발명에 따른 실시예 및 실험예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 아래에서 상술하는 실시예 및 실험예들은 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해서 제공되는 것이다.Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, and thus are not limitative of the present invention, It is provided for a complete description.
<< 실험예Experimental Example 1> 세포독성실험 1> Cytotoxicity experiment
1-1. 실험방법1-1. Experimental Method
(1) 실험재료 및 세포배양(1) Experimental materials and cell culture
세포배양에 사용된 알파-최소필수영양배지(alpha-minimum essential medium, α-MEM), 소태아혈청(fetal bovine serum: FBS), 항생제(antibiotics), trypsin-EDTA는 GibcoBRL (GibcoBRL, Grandisland, N.Y., USA)로부터 구입하였다. 세포증식측정에 사용된 3-(4,5-디메틸-티아졸-2-일)-2,5-디페닐테트라졸리움-브로마이드(MTT)시약은 Sigma사 (SigmaChem. Co., St.Louis. Mo., USA)의 제품을 사용하였다. ALP 효소 측정과 염색에 사용된 시약은 모두 Sigma사 (SigmaChem. Co., St.Louis. Mo., USA)로부터 특급시약을 사용하였고 PCR실험에 사용된 프라이머는 Bioneer사 (Bioneer.Co., Upland, CA, USA)로부터 합성을 하였고, RNA측정은 Takara kit (Takara BioInc., Shiga, Japan)의 제품을 구입하여 사용하였다. 본 연구에 사용한 MC3T3-E1 세포는 쥐 두개관(mouse calvaria)유래의 조골세포로서 ATCC (American Type Culture Collection, Manassas, VA, USA)로부터 구입하였다. (FBS), antibiotics, and trypsin-EDTA were purchased from GibcoBRL (GibcoBRL, Grandisland, NY), which were used for cell culture. , USA). The 3- (4,5-dimethyl-thiazol-2-yl) -2,5-diphenyltetololium bromide (MTT) reagent used in the cell proliferation assay was purchased from Sigma Co. (St. Mo., USA) was used. The reagents used for ALP enzyme determination and staining were all reagents from Sigma Chemical Co., St. Louis, Mo., USA. The primers used in the PCR experiments were Bioneer, Inc., Upland (Takara Bio Inc., Shiga, Japan) was used for RNA measurement. The MC3T3-E1 cells used in this study were obtained from ATCC (American Type Culture Collection, Manassas, VA, USA) as osteoblast cells derived from mouse calvaria.
MC3T3-E1 세포는 10% 소태아혈청(fetal bovine serum: FBS)과 1% 항생제페니실린-스트렙토마이신(Phenicilin-streptomycin: P/S)가 포함된 알파-최소필수영양배지(alpha-minimum essential medium, α-MEM)에서 배양하였다. 37 ℃, 5% CO2 조건을 유지하는 인큐베이터(Model3154, FormaScientific, USA)에서 배양하였으며, 세포가 충분한 증식이 일어나면 5 mM 베타-글리세로포스페이트(β-glycerophosphate:β-GP)와 50 μg/mL 아스코르브산(ascorbic acid: AA)을 함유한 배지로 교환하여 2-3일 간격으로 계대 배양하면서 실험에 사용하였다.MC3T3-E1 cells were cultured in an alpha-minimum essential medium containing 10% fetal bovine serum (FBS) and 1% antibiotic penicillin-streptomycin (P / S) alpha-MEM). The cells were cultured in an incubator (Model3154, FormaScientific, USA) maintained at 37 ° C and 5% CO 2. When cells were sufficiently proliferated, cells were treated with 5 mM β-glycerophosphate (β-GP) The medium was replaced with medium containing ascorbic acid (AA), and subcultured at 2-3 days intervals.
(2) MTT 분석(2) MTT analysis
세포독성 실험을 위하여 MC3T3-E1세포를 48_웰 플레이트에 2x104/웰로 배양시켰다. 0, 5, 10, 20 μM 농도의 유칼립톨로 배양액에 첨가한 다음 37 ℃ 5% CO2 인큐베이터에서 24시간 배양하였다.. 배양액을 제거하고 0.5 mg/ml농도로 MTT를 처리하여 37 ℃ CO2 5%에서 30분간 배양하였다. 30분후 MTT를 제거한 뒤 디메틸설폭사이드(DMSO)를 넣고 540 nm에서 흡광도를 측정하였다.For cytotoxicity experiments, MC3T3-E1 cells were cultured in 48-well plates at 2 × 10 4 / well. 0, 5, 10 and 20 μM was added to the culture medium to yukal riptol of concentration and then 37 ℃ were cultured for 24 hours in 5% CO 2 incubator. The culture solution was removed and processed for MTT was 0.5 mg / ml concentration of 37 CO 2 ℃ 5% for 30 minutes. After 30 minutes, MTT was removed, dimethylsulfoxide (DMSO) was added, and absorbance was measured at 540 nm.
1-2. 실험결과1-2. Experiment result
유칼립톨(eucalyptol)의 세포 독성을 확인하기 위하여 MC3T3-E1 세포에서 진행된 MTT 분석의 결과를 도 1에 나타내었다.The results of MTT analysis conducted in MC3T3-E1 cells to confirm the cytotoxicity of eucalyptol are shown in FIG.
나타낸 바와 같이, 유칼립톨 5μM 이하의 농도에서 세포 활성도가 가장 높았으며, 10μM의 농도 이상일 때 세포 활성도가 낮아 지는 것을 확인할 수 있었다. 특히, 20μM부터는 급격히 낮아지는 것을 알 수 있었다.As shown, the cell activity was highest at a concentration of 5 μM or less of eucalyptol, and the cell activity was decreased at a concentration of 10 μM or more. In particular, it was found that the concentration rapidly decreased from 20 μM.
<< 실험예Experimental Example 2> 유칼립톨(eucalyptol) 처리에 따른 조골세포 분화 2> Osteoblast differentiation by eucalyptol treatment 마커의Marker 발현 분석 Expression analysis
2-1. 실험방법: 실시간 중합효소 연쇄반응(RT-PCR, Real-time polymerase chain reaction)2-1. Real-time polymerase chain reaction (RT-PCR)
RT-PCR을 하기 위해 먼저 cDNA를 합성하였다. RNA 추출을 위하여 배양한 것을 300μl Tri-solution (Bioscience technology)을 처리하고, 세포를 스크래퍼로 긁어 모아 10분간 반응시킨 후 60μl의 클로로폼을 첨가한 다음, 볼텍스(Vortex)로 강하게 혼합 후 10분간 반응시켰다. 원심분리(14500rpm, 4℃, 15min) 후 RNA가 있는 상층액 부분을 다른 튜브에 옮겨 이소프로필 알콜 150μl를 첨가 후 4 °C에 30분간 반응시켰다. 다시 원심분리 후, 상층액을 제거하고 70% 에탄올로 펠렛을 2~3회 정도 세정 후 원심분리 (13000rpm, 4℃, 10min) 하였다. 에탄올을 제거하고 실온에서 20분간 건조한 다음, 3차 증류수로 4 ℃에서 30분간 녹인 후 260~280nm에서 흡광도 값을 측정하고, 분리된 RNA로 TOP script™RT DryMIX (Enzynomics)를 사용하여 42 ℃에서 60분, 95 ℃에서 5분간 cDNA를 합성하였다.CDNA was synthesized first for RT-PCR. Cells were scraped with scraper for 10 minutes, and then 60 μl of chloroform was added. After vigorous mixing with Vortex, the cells were incubated for 10 min. . After centrifugation (14500 rpm, 4 ° C, 15 min), the RNA supernatant was transferred to another tube and 150 μl of isopropyl alcohol was added, followed by reaction at 4 ° C for 30 min. After centrifugation again, the supernatant was removed, and the pellet was washed with 70% ethanol 2-3 times and centrifuged (13000 rpm, 4 ° C, 10 min). After ethanol was removed, it was dried at room temperature for 20 minutes and then dissolved in tertiary distilled water at 4 ° C for 30 minutes. Absorbance was measured at 260-280 nm and TOPScript ™ RT DryMIX (Enzynomics) CDNA was synthesized for 5 minutes at 95 ° C for 60 minutes.
유전자의 발현을 측정하기 위하여 Emerald Amp GT PCR Master Mix (Takara Bio Inc, Japen) 10μl, 프라이머 (β-actin, Id-1, Dlx5, Runx2, O.C) 2μl, 3 D.W 7μl, cDNA 1μl를 혼합하여 RT-PCR을 이용하여 반응 시켰다. 반응시킨 후 1% 아가로스 겔(Agarose gel) 전기영동에 의해 확인분리 하였다. 분석에 사용한 각각의 프라이머의 염기서열 및 반응 조건을 표 1 및 표 2에 나타내었다.10 μl of Emerald Amp GT PCR Master Mix (Takara Bio Inc, Japan), 2 μl of primers (β-actin, Id-1, Dlx5, Runx2, OC) 3 DW and 1 μl of cDNA were mixed and reacted using RT-PCR. After the reaction, they were identified by 1% agarose gel electrophoresis. The nucleotide sequences of the respective primers used in the analysis and the reaction conditions are shown in Tables 1 and 2.
gene
gene
DenaturationPre-
Denaturation
ExtensionPost-
Extension
2-2. 실험결과2-2. Experiment result
유칼립톨과 아스코르브산 + 베타-글리세로포스페이트 (AA + β-GP, Ascorbic acid + β-glycerophosphate)의 상관관계를 알아보기 위해, PT-PCR을 이용하여 각각의 유전자들을 발현 시킨 것을 1% 아가로스 겔(Agarose gel)로 전기 영동한 것의 밴드 결과를 도 2에 나타내었다.In order to investigate the correlation between eucalyptol and ascorbic acid + beta-glycerophosphate (AA + beta -GP, Ascorbic acid + beta -glycerophosphate), the expression of each gene was analyzed by PT-PCR using 1% agarose The band results of electrophoresis on a gel (agarose gel) are shown in Fig.
β-actin을 사용했을 때에는 모두 일정한 밴드가 나왔고, β-actin을 제외한 나머지 유전자인 Id-1, Dlx5, Runx2, OC 모두 아스코르브산 + 베타-글리세로포스페이트를 첨가하지 않았을 때보다 첨가 했을 때가 더 높게 나타났으며, 유칼립톨 역시 첨가하지 않았을 때보다 첨가 하였을 때가 높게 나타남을 확인할 수 있었다. 또한 아스코르브산 + 베타-글리세로포스페이트와 유칼립톨을 각각 따로 첨가했을 때 보다 함께 첨가 했을 때 그 효과는 더 높게 나온 것을 볼 수 있었다. All of Id-1, Dlx5, Runx2, and OC, which are genes other than β-actin, were higher than when no ascorbic acid + beta-glycerophosphate was added And the addition of Eucalyptol was higher than that of Eucalyptol. It was also found that the effect was higher when the ascorbic acid + beta-glycerophosphate and eucalyptol were added together than when they were added separately.
<< 실험예Experimental Example 3> 알리자린 3> Alizarin 레드Red 에스s 염색(Alizarin red s staining, ALP staining) 분석 Analysis of staining (Alizarin red staining, ALP staining)
3-1. 실험방법3-1. Experimental Method
ALP 효소의 염색 정도를 측정하기 위해, 24 웰에 1x105 cells/웰로 분주하고 시료 농도에 따른 효소활성 정도를 BCIP/NBT(sigma aldrich, St, Louis, MO)를 사용하여 측정하였다. 제조사의 지침에 따라 먼저, 배지를 제거하고 고정액(citrate-acetone-formaldehyde)을 첨가하여 약 30초간 실온에 보관하였다가 45초간 증류수로 세척하였다. 준비된 BCIP/NBT(sigma ardrich)를 첨가하여 약 15분간 실온에서 방치한 뒤 2분간 증류수로 세척하고 적색 부위를 관찰하였다.In order to measure the degree of staining of ALP enzyme, each well was divided into 24 wells at 1 × 10 5 cells / well. The degree of enzyme activity according to the sample concentration was measured using BCIP / NBT (Sigma aldrich, St, Louis, MO). Following the manufacturer's instructions, the medium was first removed, citrate-acetone-formaldehyde was added, and the mixture was stored at room temperature for about 30 seconds and washed with distilled water for 45 seconds. The prepared BCIP / NBT (sigma ardrich) was added, and the mixture was allowed to stand at room temperature for about 15 minutes, washed with distilled water for 2 minutes, and the red region was observed.
3-2. 실험결과3-2. Experiment result
MC3T3-E1에 물질을 첨가했을 때의 조골세포의 활성도를 알아보기 위하여, 아스코르브산 + 베타-글리세로포스페이트, 유칼립톨, 아스코르브산 + 베타-글리세로포스페이트 + 유칼립톨 순으로하여 첨가하였고, 그 결과를 도 3 및 도 4에 나타내었다.In order to investigate the activity of osteoblasts when the substance was added to MC3T3-E1, it was added in the order of ascorbic acid + beta-glycerophosphate, eucalyptol, ascorbic acid + beta-glycerophosphate + eucalyptol, Are shown in Fig. 3 and Fig.
먼저, 도 3에 나타난 바와 같이, 아스코르브산 + 베타-글리세로포스페이트, 유칼립톨을 첨가하지 않은 것(control)과 비교하여, 아스코르브산 + 베타-글리세로포스페이트 또는 유칼립톨을 각각 첨가 했을 때 염색된 정도가 훨씬 큰 것을 확인할 수 있었다. 또한 아스코르브산 + 베타-글리세로포스페이트와 유칼립톨을 함께 첨가했을 때 염색정도가 더 진했음을 볼 수 있었다.First, as shown in Fig. 3, when ascorbic acid + beta-glycerophosphate or eucalyptol was added, respectively, as compared with the control without addition of ascorbic acid + beta-glycerophosphate and eucalyptol (control) Which is much larger. When ascorbic acid + beta - glycerophosphate and eucalyptol were added together, the degree of dyeing was increased.
또한, 도 4는 활성도 정도를 계산하여 그래프로 나타낸 것으로, 도 3과 비교하여 염색 된 것이 진할수록 활성도는 높은 것을 알 수 있었으며, 아스코르브산 + 베타-글리세로포스페이트와 유칼립톨을 함께 첨가 했을 때 그 효과는 배로 증가하는 것을 볼 수 있었다.FIG. 4 is a graph showing the degree of activity. FIG. 4 is a graph showing the degree of activity. As shown in FIG. 3, the more active the dye is, the higher the activity is. Ascorbic acid plus beta-glycerophosphate and eucalyptol Was increased by a factor of two.
한편, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.Meanwhile, the compound represented by
<제제예> <Formulation example>
1-1. 산제의 제조1-1. Manufacture of Powder
화학식 1의 화합물 500 ㎎ 500 mg of the compound of formula (1)
유당 100 ㎎ Lactose 100 mg
탈크 10 ㎎ 10 mg of talc
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다. The above components are mixed and filled in airtight bags to prepare powders.
1-2. 정제의 제조1-2. Manufacture of tablets
화학식 1의 화합물 500 ㎎ 500 mg of the compound of formula (1)
옥수수전분 100 ㎎ Corn starch 100 mg
유당 100 ㎎ Lactose 100 mg
스테아린산 마그네슘 2 ㎎ 2 mg of magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다. After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.
1-3. 캅셀제의 제조1-3. Manufacture of capsules
화학식 1의 화합물 500 ㎎ 500 mg of the compound of formula (1)
옥수수전분 100 ㎎ Corn starch 100 mg
유당 100 ㎎ Lactose 100 mg
스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다. The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.
1-4. 주사제의 제조1-4. Injection preparation
화학식 1의 화합물 500 ㎎500 mg of the compound of formula (1)
주사용 멸균 증류수 적량 Sterile sterilized water for injection
pH 조절제 적량pH adjuster
통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조한다. (2 ml) per ampoule in accordance with the usual injection method.
1-5. 액제의 제조1-5. Manufacture of liquid agent
화학식 1의 화합물 100 ㎎ 100 mg of the compound of formula (1)
이성화당 10 g 10 g per isomer
만니톨 5 g 5 g mannitol
정제수 적량Purified water quantity
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬 향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ㎖로 조절한 후 갈색 병에 충진하여 멸균시켜 액체를 제조한다.Each component was added to purified water in accordance with the usual liquid preparation method and dissolved, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was adjusted to 100 ml with purified water, The liquid is prepared by sterilization.
Claims (8)
[화학식 1]
1. A pharmaceutical composition for preventing or treating osteoporosis, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable derivative thereof as an active ingredient.
[Chemical Formula 1]
상기 약학적 조성물은 조골세포 분화를 촉진시키는 것을 특징으로 하는 골다공증의 예방 또는 치료용 약학적 조성물.
The method according to claim 1,
A pharmaceutical composition for preventing or treating osteoporosis, wherein the pharmaceutical composition promotes osteoblast differentiation.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 유도체의 농도는 0.01 내지 5 μM 인 것을 특징으로 하는 골다공증의 예방 또는 치료용 약학적 조성물.
The method according to claim 1,
The pharmaceutical composition for preventing or treating osteoporosis, wherein the concentration of the compound represented by the formula (1) or a pharmaceutically acceptable derivative thereof is 0.01 to 5 μM.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 유도체는 Runx2(runt-related transcription factor 2), Id1(inhibitor of DNA binding 1), Dlx5(distal-less homeobox 5), OC(osteocalcin) 및 ALP(alkaline phosphatase) 중 어느 하나 이상의 조골세포 분화 마커 유전자의 발현량을 증가시키는 것을 특징으로 하는 골다공증의 예방 또는 치료용 약학적 조성물.
The method according to claim 1,
The compound represented by Formula 1 or a pharmaceutically acceptable derivative thereof may be selected from Runx-related transcription factor 2 (Runx2), inhibitor of DNA binding 1, Dlx5 (distal-less homeobox 5), osteocalcin wherein the expression level of the osteoblast differentiation marker gene is at least one of alkaline phosphatase and alkaline phosphatase.
상기 약학적 조성물은 산제, 과립제, 정제, 경질 캡슐제, 연질 캐슐제 또는 주사제의 형태로 제형화되는 것을 특징으로 하는 약학적 조성물.
The method according to claim 1,
Wherein said pharmaceutical composition is formulated in the form of powders, granules, tablets, hard capsules, soft capsules or injections.
[화학식 1]
A health functional food for preventing or ameliorating osteoporosis, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable derivative thereof as an active ingredient.
[Chemical Formula 1]
상기 건강기능식품은 조골세포 분화를 촉진시키는 것을 특징으로 하는 건강기능식품.
The method according to claim 6,
Wherein said health functional food promotes osteoblast differentiation.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 유도체의 농도는 0.01 내지 5 μM 인 것을 특징으로 하는 건강기능식품.The method according to claim 6,
Wherein the concentration of the compound represented by Formula 1 or a pharmaceutically acceptable derivative thereof is 0.01 to 5 μM.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170139074A KR101984541B1 (en) | 2017-10-25 | 2017-10-25 | Pharmaceutical composition for use in preventing or treating osteoporosis containing eucalyptol as an active ingredient |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170139074A KR101984541B1 (en) | 2017-10-25 | 2017-10-25 | Pharmaceutical composition for use in preventing or treating osteoporosis containing eucalyptol as an active ingredient |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20190046015A true KR20190046015A (en) | 2019-05-07 |
| KR101984541B1 KR101984541B1 (en) | 2019-05-31 |
Family
ID=66656399
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020170139074A KR101984541B1 (en) | 2017-10-25 | 2017-10-25 | Pharmaceutical composition for use in preventing or treating osteoporosis containing eucalyptol as an active ingredient |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR101984541B1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR0167896B1 (en) * | 1995-10-11 | 1999-02-01 | 김광호 | Subscription communication method for portable phone |
| KR20160063716A (en) | 2014-11-27 | 2016-06-07 | 한림대학교 산학협력단 | Composition with eucalyptol for prevention and treatment of diabetic renal fibrosis |
| KR101632111B1 (en) * | 2014-07-30 | 2016-06-20 | 원광대학교산학협력단 | Composition for preventing and treating osteoporosis |
| KR101665234B1 (en) * | 2015-02-10 | 2016-10-12 | 순천향대학교 산학협력단 | Compositions and health functional food for the prevention of bone loss |
| KR20170135681A (en) * | 2016-05-31 | 2017-12-08 | 주식회사 성균바이오텍 | Novel compound for promoting osteoblast differentiation and inhibiting adipocyte differentiation, preparation method thereof and its use |
-
2017
- 2017-10-25 KR KR1020170139074A patent/KR101984541B1/en active IP Right Grant
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR0167896B1 (en) * | 1995-10-11 | 1999-02-01 | 김광호 | Subscription communication method for portable phone |
| KR101632111B1 (en) * | 2014-07-30 | 2016-06-20 | 원광대학교산학협력단 | Composition for preventing and treating osteoporosis |
| KR20160063716A (en) | 2014-11-27 | 2016-06-07 | 한림대학교 산학협력단 | Composition with eucalyptol for prevention and treatment of diabetic renal fibrosis |
| KR101665234B1 (en) * | 2015-02-10 | 2016-10-12 | 순천향대학교 산학협력단 | Compositions and health functional food for the prevention of bone loss |
| KR20170135681A (en) * | 2016-05-31 | 2017-12-08 | 주식회사 성균바이오텍 | Novel compound for promoting osteoblast differentiation and inhibiting adipocyte differentiation, preparation method thereof and its use |
Non-Patent Citations (2)
| Title |
|---|
| Kyung-Mi Chang 외. Chemical Constituents of Chrysanthemum indicum L. Flower Oil and Effect on Osteoblastic MC3T3-E1 Cells. Food Sci. Biotechnol. Vol. 19, No. 3. 2010년, pp. 815-819* * |
| R.C. Muhlbauer 외. Common herbs, essential oils, and monoterpenes potently modulate bone metabolism. Bone. Vol. 32. 2003년, pp. 372-380* * |
Also Published As
| Publication number | Publication date |
|---|---|
| KR101984541B1 (en) | 2019-05-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR20170137201A (en) | Derivatives used in the treatment of muscle atrophy | |
| KR101673265B1 (en) | A pharmaceutical composition for preventing or treating IL-6-mediated disease, comprising extract, fraction, or compounds derived from Ampelopsis brevipedunculata | |
| KR101984541B1 (en) | Pharmaceutical composition for use in preventing or treating osteoporosis containing eucalyptol as an active ingredient | |
| KR101656834B1 (en) | A composition for preventing and treating bone disease comprising colforsin daropate | |
| KR100575479B1 (en) | Food compositions containing furan derivatives and pharmaceutically acceptable salts thereof for prevention and treatment osteoporosis | |
| JP2006515276A (en) | Furan derivative having preventive and therapeutic effects on osteoporosis and pharmaceutical composition containing the same | |
| KR102158980B1 (en) | Pharmaceutical composition for preventing or treating osteoporosis containing azelaic acid as an active ingredient | |
| KR102063962B1 (en) | Pharmaceutical composition for use in preventing or treating osteoporosis containing camphene as an active ingredient | |
| KR102015488B1 (en) | Pharmaceutical composition for use in preventing or treating osteoporosis containing trimethylpyrazine as an active ingredient | |
| JP2020521785A (en) | Pharmaceutical composition for prevention or treatment of bone-related diseases | |
| KR102161111B1 (en) | Pharmaceutical composition for preventing or treating osteoporosis containing linalool as an active ingredient | |
| KR102139994B1 (en) | Pharmaceutical composition for use in preventing or treating osteoporosis containing stigmasterol as an active ingredient | |
| KR102347731B1 (en) | Composition for activating zinc transporter | |
| KR20190044986A (en) | Pharmaceutical composition for use in preventing or treating osteoporosis containing betaine as an active ingredient | |
| KR101502465B1 (en) | A pharmaceutical composition comprising Alpinia Officinarum extracts for prevention and treatment of bone diseases or anti-vascular calcification activity | |
| KR101305555B1 (en) | Composition for treatment and prevention of bone diseases comprising extract of magnoliae flos's active components | |
| KR101826109B1 (en) | Food composition for improvement of osteoporosis and pharmaceutical compositions for prevention or treatment of osteoporosis with gossypetin | |
| KR102600931B1 (en) | Pharmaceutical composition for USE IN preventing or treating METABOLIC BONE DISEASE comprising Azulene as an active ingredient | |
| KR101677967B1 (en) | Pharmaceutical composition for preventing and treating bone disease comprising aminobenzoate derivatives | |
| KR102521988B1 (en) | Pharmaceutical composition for treating or preventing cancer comprising gamma-glutamyltyrosine | |
| KR101264014B1 (en) | Composition for Preventing or Treating Bone Disease Comprising of Aminocoumarins | |
| KR101320975B1 (en) | Composition for treatment and prevention of bone diseases comprising extract of magnoliae flos's active components | |
| KR102416464B1 (en) | Composition for preventing or treating inflammatory kidney diseases comprising LGK974 | |
| WO2023136578A1 (en) | Prdx1 mutant for preventing or treating bone disease and use thereof | |
| WO2004094446A1 (en) | Remedies for diseases caused by strengthened vascular smooth muscle using 14-membered ring macrolide compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant |