KR102618628B1 - Pharmaceutical composition comprising high amount of an active ingredient derived from herbal substances - Google Patents
Pharmaceutical composition comprising high amount of an active ingredient derived from herbal substances Download PDFInfo
- Publication number
- KR102618628B1 KR102618628B1 KR1020210163840A KR20210163840A KR102618628B1 KR 102618628 B1 KR102618628 B1 KR 102618628B1 KR 1020210163840 A KR1020210163840 A KR 1020210163840A KR 20210163840 A KR20210163840 A KR 20210163840A KR 102618628 B1 KR102618628 B1 KR 102618628B1
- Authority
- KR
- South Korea
- Prior art keywords
- release
- weight
- tablet
- minutes
- dissolution
- Prior art date
Links
- 239000004480 active ingredient Substances 0.000 title claims abstract description 20
- 239000000126 substance Substances 0.000 title description 7
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 239000012676 herbal extract Substances 0.000 claims abstract description 41
- 238000002360 preparation method Methods 0.000 claims abstract description 27
- 239000000203 mixture Substances 0.000 claims abstract description 26
- 206010003246 arthritis Diseases 0.000 claims abstract description 25
- 238000009472 formulation Methods 0.000 claims abstract description 15
- 239000001856 Ethyl cellulose Substances 0.000 claims description 30
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 30
- 229920001249 ethyl cellulose Polymers 0.000 claims description 30
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 30
- DOUMFZQKYFQNTF-WUTVXBCWSA-N (R)-rosmarinic acid Chemical compound C([C@H](C(=O)O)OC(=O)\C=C\C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-WUTVXBCWSA-N 0.000 claims description 24
- 239000011248 coating agent Substances 0.000 claims description 22
- 238000000576 coating method Methods 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- ZZAFFYPNLYCDEP-HNNXBMFYSA-N Rosmarinsaeure Natural products OC(=O)[C@H](Cc1cccc(O)c1O)OC(=O)C=Cc2ccc(O)c(O)c2 ZZAFFYPNLYCDEP-HNNXBMFYSA-N 0.000 claims description 12
- DOUMFZQKYFQNTF-MRXNPFEDSA-N rosemarinic acid Natural products C([C@H](C(=O)O)OC(=O)C=CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-MRXNPFEDSA-N 0.000 claims description 12
- TVHVQJFBWRLYOD-UHFFFAOYSA-N rosmarinic acid Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=Cc2ccc(O)c(O)c2)C=O TVHVQJFBWRLYOD-UHFFFAOYSA-N 0.000 claims description 12
- 239000002775 capsule Substances 0.000 claims description 9
- 238000010998 test method Methods 0.000 claims description 7
- 238000011049 filling Methods 0.000 claims description 4
- 230000000694 effects Effects 0.000 abstract description 22
- 229940079593 drug Drugs 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 8
- 239000003826 tablet Substances 0.000 description 75
- 238000004090 dissolution Methods 0.000 description 48
- 201000008482 osteoarthritis Diseases 0.000 description 31
- 239000007950 delayed release tablet Substances 0.000 description 19
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 19
- 239000000284 extract Substances 0.000 description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 18
- 238000012360 testing method Methods 0.000 description 17
- 210000000845 cartilage Anatomy 0.000 description 15
- 239000007884 disintegrant Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- 239000011230 binding agent Substances 0.000 description 14
- 238000011156 evaluation Methods 0.000 description 14
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 12
- 235000012239 silicon dioxide Nutrition 0.000 description 12
- 238000010828 elution Methods 0.000 description 11
- 239000004615 ingredient Substances 0.000 description 11
- 239000008187 granular material Substances 0.000 description 10
- 210000003141 lower extremity Anatomy 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- 239000007939 sustained release tablet Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 229920002785 Croscarmellose sodium Polymers 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 9
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 9
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
- 229960001681 croscarmellose sodium Drugs 0.000 description 9
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 9
- 239000000314 lubricant Substances 0.000 description 9
- 235000019359 magnesium stearate Nutrition 0.000 description 9
- 102100027995 Collagenase 3 Human genes 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000000469 ethanolic extract Substances 0.000 description 8
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 7
- 102000004127 Cytokines Human genes 0.000 description 7
- 108090000695 Cytokines Proteins 0.000 description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 7
- 210000001264 anterior cruciate ligament Anatomy 0.000 description 7
- 230000002209 hydrophobic effect Effects 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 229960000913 crospovidone Drugs 0.000 description 6
- 238000007922 dissolution test Methods 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 230000005021 gait Effects 0.000 description 6
- 238000011532 immunohistochemical staining Methods 0.000 description 6
- 239000008108 microcrystalline cellulose Substances 0.000 description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 6
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 6
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 6
- 238000002271 resection Methods 0.000 description 6
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 5
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 208000030175 lameness Diseases 0.000 description 5
- 210000002540 macrophage Anatomy 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 229940079832 sodium starch glycolate Drugs 0.000 description 5
- 239000008109 sodium starch glycolate Substances 0.000 description 5
- 229920003109 sodium starch glycolate Polymers 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- JJYWRQLLQAKNAD-UHFFFAOYSA-N 2-methylpent-2-enoic acid Chemical compound CCC=C(C)C(O)=O JJYWRQLLQAKNAD-UHFFFAOYSA-N 0.000 description 4
- 102000000503 Collagen Type II Human genes 0.000 description 4
- 108010041390 Collagen Type II Proteins 0.000 description 4
- 108050005238 Collagenase 3 Proteins 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- 244000060234 Gmelina philippensis Species 0.000 description 4
- 101000577887 Homo sapiens Collagenase 3 Proteins 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000003463 adsorbent Substances 0.000 description 4
- 239000000090 biomarker Substances 0.000 description 4
- 210000003690 classically activated macrophage Anatomy 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 230000003111 delayed effect Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 210000002744 extracellular matrix Anatomy 0.000 description 4
- 239000007888 film coating Substances 0.000 description 4
- 238000009501 film coating Methods 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 4
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- OARRHUQTFTUEOS-UHFFFAOYSA-N safranin Chemical compound [Cl-].C=12C=C(N)C(C)=CC2=NC2=CC(C)=C(N)C=C2[N+]=1C1=CC=CC=C1 OARRHUQTFTUEOS-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 3
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 244000018436 Coriandrum sativum Species 0.000 description 3
- 235000002787 Coriandrum sativum Nutrition 0.000 description 3
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 3
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- -1 IL-1β Proteins 0.000 description 3
- MHQJUHSHQGQVTM-HNENSFHCSA-N Octadecyl fumarate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)\C=C/C(O)=O MHQJUHSHQGQVTM-HNENSFHCSA-N 0.000 description 3
- 102000016611 Proteoglycans Human genes 0.000 description 3
- 108010067787 Proteoglycans Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000013265 extended release Methods 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 210000003127 knee Anatomy 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 229940071138 stearyl fumarate Drugs 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- IHCCLXNEEPMSIO-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 IHCCLXNEEPMSIO-UHFFFAOYSA-N 0.000 description 2
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 2
- WROUWQQRXUBECT-UHFFFAOYSA-N 2-ethylacrylic acid Chemical compound CCC(=C)C(O)=O WROUWQQRXUBECT-UHFFFAOYSA-N 0.000 description 2
- VKOLYCXSNZEWFZ-UHFFFAOYSA-N 2-methylidenebutanoic acid;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCC(=C)C(O)=O VKOLYCXSNZEWFZ-UHFFFAOYSA-N 0.000 description 2
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 2
- 241000221079 Euphorbia <genus> Species 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 206010019909 Hernia Diseases 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 2
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 2
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 2
- 102100030416 Stromelysin-1 Human genes 0.000 description 2
- 101710108790 Stromelysin-1 Proteins 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 210000001612 chondrocyte Anatomy 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 2
- 241000411851 herbal medicine Species 0.000 description 2
- 238000007489 histopathology method Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 210000001258 synovial membrane Anatomy 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 1
- ZKRFOXLVOKTUTA-KQYNXXCUSA-N 9-(5-phosphoribofuranosyl)-6-mercaptopurine Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(NC=NC2=S)=C2N=C1 ZKRFOXLVOKTUTA-KQYNXXCUSA-N 0.000 description 1
- 102000051389 ADAMTS5 Human genes 0.000 description 1
- 108091005663 ADAMTS5 Proteins 0.000 description 1
- 102100032814 ATP-dependent zinc metalloprotease YME1L1 Human genes 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 102000016284 Aggrecans Human genes 0.000 description 1
- 108010067219 Aggrecans Proteins 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
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- 208000019300 CLIPPERS Diseases 0.000 description 1
- 229920002567 Chondroitin Polymers 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 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
- 208000035859 Drug effect increased Diseases 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 229920003135 Eudragit® L 100-55 Polymers 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 229920003114 HPC-L Polymers 0.000 description 1
- 101000627872 Homo sapiens 72 kDa type IV collagenase Proteins 0.000 description 1
- 101001033249 Homo sapiens Interleukin-1 beta Proteins 0.000 description 1
- 101001013150 Homo sapiens Interstitial collagenase Proteins 0.000 description 1
- 101000669513 Homo sapiens Metalloproteinase inhibitor 1 Proteins 0.000 description 1
- 108010034143 Inflammasomes Proteins 0.000 description 1
- 102100039065 Interleukin-1 beta Human genes 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 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 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 1
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 240000001439 Opuntia Species 0.000 description 1
- 235000013389 Opuntia humifusa var. humifusa Nutrition 0.000 description 1
- 208000008558 Osteophyte Diseases 0.000 description 1
- 235000004347 Perilla Nutrition 0.000 description 1
- 244000124853 Perilla frutescens Species 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 101800000795 Proadrenomedullin N-20 terminal peptide Proteins 0.000 description 1
- 108091008611 Protein Kinase B Proteins 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 241000304195 Salvia miltiorrhiza Species 0.000 description 1
- 235000011135 Salvia miltiorrhiza Nutrition 0.000 description 1
- 102000040739 Secretory proteins Human genes 0.000 description 1
- 108091058545 Secretory proteins Proteins 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 208000027520 Somatoform disease Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 230000003846 cartilage breakdown Effects 0.000 description 1
- 230000008355 cartilage degradation Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000021930 chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids Diseases 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000007580 dry-mixing Methods 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
- 201000010934 exostosis Diseases 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 1
- 230000001744 histochemical effect Effects 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 208000027753 pain disease Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000000252 photodiode array detection Methods 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000013441 quality evaluation Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229960004029 silicic acid Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 108091007196 stromelysin Proteins 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 210000005222 synovial tissue Anatomy 0.000 description 1
- 210000002437 synoviocyte Anatomy 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 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 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000009966 trimming Methods 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
Classifications
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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)
- A61K36/42—Cucurbitaceae (Cucumber family)
- A61K36/428—Trichosanthes
-
- 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)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/536—Prunella or Brunella (selfheal)
-
- 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)
- A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
- A61K36/716—Clematis (leather flower)
-
- 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
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Mycology (AREA)
- Alternative & Traditional Medicine (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Microbiology (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
본 개시의 일 측면은 유효성분으로 관절염 등의 치료 또는 개선에 유용한 위령선, 괄루근 및 하고초의 생약 추출물을 고함량 포함하는 제제에 관한 것이다. 본 개시의 일 측면에 따른 제제는 유효성분을 고함량 포함하면서도 크기가 작아 복약 편의성이 우수하고, 1일 2회 복용하더라도 우수한 관절염 치료 효과를 나타내는 방출 패턴 및 방출성을 가진다. 본 개시의 다른 측면은 위령선, 괄루근 및 하고초의 생약 추출물을 280-320 mg 포함하고, 1일 2회 복용하는 제제로 특정 방출 패턴을 가져 관절염 치료 효과가 뛰어난 제제에 관한 것이다.One aspect of the present disclosure relates to a preparation containing, as an active ingredient, a high content of herbal extracts of Uryeongseon, Brachialis root, and Herbal extract useful for treating or improving arthritis, etc. The formulation according to one aspect of the present disclosure contains a high content of the active ingredient and is small in size, providing excellent medication convenience, and has a release pattern and release property that shows an excellent arthritis treatment effect even when taken twice a day. Another aspect of the present disclosure relates to a preparation that contains 280-320 mg of herbal extracts of Euryeongseon, Brachialis root, and Herbal extracts of the herb, is taken twice a day, has a specific release pattern, and is excellent in treating arthritis.
Description
본 개시는 위령선, 괄루근 및 하고초의 생약추출물을 함유하는 제제에 관한 것이다. 특히, 본 개시는 하루 2회 복용 가능한 제제에 관한 것으로, 고함량을 포함하면서도 뛰어난 약효를 나타내는 방출 패턴을 가진 제제에 관한 것이다.The present disclosure relates to a preparation containing herbal extracts of Uryeongseon, Brachiorrhea root, and Herbaceous root. In particular, the present disclosure relates to a formulation that can be taken twice a day and has a release pattern that shows excellent drug efficacy while containing a high dose.
골관절염은 퇴행성 관절염으로 불리는 성인에서 가장 흔한 관절염이다. 골관절염은 고령화사회가 진행되면서 환자는 급격히 증가하고 있고, 환자 개인의 삶의 질 저하뿐 아니라 사회 경제적인 손실로도 이어지고 있다. Osteoarthritis, also called degenerative arthritis, is the most common form of arthritis in adults. The number of patients with osteoarthritis is rapidly increasing as the aging society progresses, leading not only to a decline in the quality of life of individual patients but also to social and economic losses.
관절염(arthritis)은 관절에 염증이 일어나는 질병을 말하며 매우 많은 종류가 있다. 가장 흔한 관절염은 퇴행성관절염 (osteoarthritis)이며 그외 류마티스관절염 (rheumatoid arthritis), 통풍, 건선관절염 등이 있다. 각 관절염은 그 발병원인이 다르지만 연골조직이 파괴되는 현상은 동일하다. Arthritis is a disease that causes inflammation in the joints, and there are many types. The most common form of arthritis is osteoarthritis, and others include rheumatoid arthritis, gout, and psoriatic arthritis. Each type of arthritis has different causes, but the phenomenon of destruction of cartilage tissue is the same.
퇴행성관절염(골관절염)은 관절염 중 가장 빈번하게 발생하는 대표적인 만성 관절질환이다. 퇴행성관절염은 뼈의 말단을 둘러싸고 있는 연골조직이 점차 마모되면서 관절 내 염증과 심한 통증을 일으키고 연골 밑 뼈가 비정상적으로 딱딱해지는 현상이 나타난다. 따라서 관절의 움직임으로 일어나는 마찰의 완충하는 역할을 하는 연골이 닳아 없어지게 되어 관절을 움직일 때 심한 통증과 운동장애가 나타나게 된다.Degenerative arthritis (osteoarthritis) is the most frequently occurring chronic joint disease among arthritis. In degenerative arthritis, the cartilage tissue surrounding the ends of the bones gradually wears away, causing inflammation and severe pain within the joint, and the bone under the cartilage becomes abnormally hard. Therefore, the cartilage, which acts as a buffer for friction caused by joint movement, wears away, causing severe pain and movement disorders when moving the joint.
퇴행성관절염을 제어하기 위한 많은 연구에도 불구하고, 아직 질병의 병리적 원인을 기반으로 한 근본적인 치료법은 개발되지 못하고 있으며 현재까지 수술적 방법 외에 비스테로이드성 진통소염제(NSAID), 질병 완화 골관절염치료제 (Disease-modifying osteoarthritis drug, DMOAD) 등 항염증 및 통증완화를 위한 약물요법이 주를 이룬다. 또한 히알루론산, 글루코사민, 콘드로이틴과 같은 연골보호제들이 개발되어 시판되고 있으나, 연골보호 및 재생유도 등에는 그 치료효과가 확립되지 않았다.Despite many studies to control degenerative arthritis, a fundamental treatment based on the pathological cause of the disease has not yet been developed. To date, in addition to surgical methods, non-steroidal analgesics and anti-inflammatory drugs (NSAIDs) and disease-relieving osteoarthritis treatment drugs (Disease) have been used to control degenerative arthritis. Drug therapy for anti-inflammatory and pain relief, such as -modifying osteoarthritis drug (DMOAD), is mainly used. In addition, cartilage protective agents such as hyaluronic acid, glucosamine, and chondroitin have been developed and are commercially available, but their therapeutic effects on cartilage protection and regeneration induction have not been established.
한편, 위령선, 괄루근 및 하고초의 복합 생약 추출물은 항염, 진통, 관절보호 및 면역억제 작용이 있는 것으로 알려져 있으며, 골관절염과 류마티스 관절염 치료제로 널리 사용되고 있다. Meanwhile, complex herbal extracts of Uryeongseon, Brachialis root, and Hagochoe are known to have anti-inflammatory, analgesic, joint-protective, and immunosuppressive effects, and are widely used as a treatment for osteoarthritis and rheumatoid arthritis.
이러한 생약 추출물을 고함량으로 포함하는 정제로 제조될 수 있는데 약효를 높이고자 단순히 용량을 높일 경우 그로 인한 부작용의 증가가 나타날 수 있다. 또한, 현재 시판되는 위령선, 괄루근 및 하고초의 복합 생약 추출물을 함유한 제제는 하루 3번 복용하도록 되어 있어 복용 편의성이 떨어진다. These herbal extracts can be manufactured into tablets containing a high content, but if the dosage is simply increased to increase the efficacy, an increase in side effects may occur. In addition, the currently commercially available preparations containing complex herbal extracts of Uryeongseon, Brachiorrhea root, and Hagocho are required to be taken three times a day, making them less convenient to take.
따라서 고함량 제제로 인한 부작용을 방지하고, 복용 편의성을 높이기 위하여 방출이 지연된 제제를 고려할 수 있으나, 본 발명자들이 실험을 통해 확인한 결과 위령선, 괄루근 및 하고초의 복합 생약 추출물 제제의 경우 예상치 못한 여러 문제점이 드러났다.Therefore, in order to prevent side effects caused by high-dose preparations and increase the convenience of administration, delayed-release preparations can be considered. However, the present inventors confirmed through experiments that there are many unexpected problems in the case of complex herbal extract preparations of Uryeongseon, Brachylus root, and Hagocho. This was revealed.
따라서 본 개시가 해결하고자 하는 과제는 유효성분으로 위령선, 괄루근 및 하고초 추출물을 고함량 함유하면서도, 제제 크기가 작아 복용하기 편하며, 바람직한 약효를 나타낼 수 있는 방출 패턴을 가져 1일 2회 복용 가능한 제제, 특히 정제를 제공하는 것이다.Therefore, the problem that the present disclosure aims to solve is to contain a high content of the extracts of the euphorbia gland, brachiorrhea root, and hagochoe as active ingredients, while being easy to take due to the small size of the preparation, and has a release pattern that can exhibit desirable medicinal effects, taking it twice a day. Possible formulations, especially tablets, are provided.
상기 과제를 해결하기 위하여, 본 발명의 일 측면은 유효성분으로 위령선, 괄루근 및 하고초의 생약추출물을 280-320 mg 포함하고, 유효성분의 함량은 코팅 전 나정 또는 공캡슐 충진 전 혼합물의 총 중량 대비 40 내지 90 중량%(바람직하게는, 50-90 중량%, 더욱 바람직하게는 60-90 중량%)이며, 에틸셀룰로오스, 메타크릴산에틸아크릴산공중합체 또는 이들의 혼합물을 포함하여 방출을 조절하는 것을 특징으로 하는 제제, 특히 정제를 제공한다. In order to solve the above problem, one aspect of the present invention includes 280-320 mg of herbal extracts of Uryeongseon, Guaru root, and Hagocho as active ingredients, and the content of the active ingredient is the total weight of the mixture before coating or empty capsule filling. It is 40 to 90% by weight (preferably, 50-90% by weight, more preferably 60-90% by weight) and includes ethylcellulose, ethyl methacrylic acid copolymer, or a mixture thereof to control release. Provided are preparations, particularly tablets, characterized in that.
본 발명자들은 위령선, 괄루근 및 하고초의 생약추출물을 고함량으로 포함하는 1일 2회 복용 제제를 제조하고자 하였으나, 연구 결과 예상치 못한 문제점이 드러났다. 구체적으로, 다양한 결합제를 사용하여 방출을 지연 또는 조절하는 것은 가능하였으나, 이 경우 포함된 모든 추출물을 완전히 용출시키기 어렵다는 문제점이 나타났다. 추가적인 연구에서 상대적으로 많은 부형제, 붕해제를 사용하여 추출물의 상대적 함량을 줄여 지연방출과 양호한 방출량을 달성할 수도 있었다. 그러나, 이 경우 복용해야 하는 1개 제제의 크기가 너무 커져 복용이 불편하였다. 즉, 위령선, 괄루근 및 하고초의 생약추출물의 특이적 물성으로 인하여, 고함량의 위령선, 괄루근 및 하고초 생약 추출물을 제제 중량 대비 높은 중량%로 포함하면서, 양호한 방출 패턴과 높은 방출성을 동시에 달성하는 것이 용이치 않았다.The present inventors attempted to manufacture a twice-daily formulation containing high doses of herbal extracts of Uryeongseon, Brachiocephalic hernia, and Herbal extracts, but unexpected problems were revealed as a result of the research. Specifically, it was possible to delay or control the release using various binders, but in this case, it was difficult to completely elute all the contained extracts. In additional studies, delayed release and good release amount could be achieved by reducing the relative content of the extract by using relatively more excipients and disintegrants. However, in this case, the size of one preparation to be taken was too large, making it inconvenient to take. In other words, due to the specific physical properties of the herbal extracts of Wiryeongseon, Brachiocephalic hernia, and Herbal extracts, the product contains a high content of Herbal extracts of Wiryeongseon, Brachiorrhea, and Herbal extracts at a high weight percent relative to the weight of the preparation, while providing a good release pattern and high release properties at the same time. It was not easy to achieve.
본 발명자들은 이러한 상호모순적인 문제점들을 결합제로 에틸셀룰로오스, 메타크릴산에틸아크릴산공중합체 또는 이들의 혼합물을 이용하여 해소할 수 있다는 점을 확인하여 본 발명의 일 측면을 완성하였다. The present inventors completed one aspect of the present invention by confirming that these contradictory problems can be solved by using ethylcellulose, ethyl methacrylic acid copolymer, or a mixture thereof as a binder.
본 발명의 위령선, 괄루근 및 하고초의 생약추출물로는 황갈색-갈색의 흡습성이 있는 가루 상태인 ‘위령선·괄루근·하고초30%에탄올엑스(40→1)’ 추출물이 사용될 수 있으며, 이러한 추출물은 예를 들어, 상기 위령선, 괄루근 및 하고초의 생약추출물은 한국 등록특허 제0180567호, 제0483707호 (WO2002-094301 A1) 등에 기재된 방법에 따라 제조된 생약 추출물일 수 있다. As a herbal extract of Wiryeongseon, Gwanrugeun, and Hedgehog herb of the present invention, the extract of 'Wiryeongseon, Hwaneurogeun, and Hedgehog herb 30% ethanol extract (40→1)', which is in the form of a yellow-brown, hygroscopic powder, can be used, and this extract For example, the herbal extracts of Wiryeongseon, Gwanrugeun and Hagocho may be herbal extracts prepared according to the method described in Korean Patent Nos. 0180567, 0483707 (WO2002-094301 A1), etc.
본 발명의 상기 2가지 결합제 성분들 중에서는 에틸셀룰로오스가 좀 더 바람직하며, 따라서 본 발명의 바람직한 일 태양은 유효성분으로 위령선, 괄루근 및 하고초의 생약추출물을 280-320 mg 포함하고, 유효성분의 함량은 코팅 전 나정의 총 중량 대비 40 내지 90 중량%(바람직하게는, 50-90 중량%, 더욱 바람직하게는 60-90 중량%)이며, 에틸셀룰로오스을 포함하여 방출을 조절하는 것을 특징으로 하는 제제, 특히 정제를 제공한다. Among the two binder components of the present invention, ethylcellulose is more preferable, and therefore, a preferred embodiment of the present invention contains 280-320 mg of herbal extracts of Wiryeongseon, Gwanrugeun, and Hagochoe as active ingredients, and the active ingredient The content is 40 to 90% by weight (preferably, 50-90% by weight, more preferably 60-90% by weight) relative to the total weight of the uncoated tablet before coating, and is characterized by controlling the release by including ethylcellulose. , especially tablets.
이러한 에틸셀룰로오스로는 toluene/ethanol 80:20(부피비) 혼합용매로 5 중량% 용액을 만들어 상온에서 점도 측정시 3-22 mPa.s의 점도를 가지는 것들이 사용될 수 있다.Such ethylcellulose can be used to have a viscosity of 3-22 mPa.s when a 5% by weight solution is prepared with a mixed solvent of toluene/ethanol 80:20 (volume ratio) and the viscosity is measured at room temperature.
본 발명자들은 위령선, 괄루근 및 하고초의 생약추출물을 280-320 mg 포함하며, 1일 2회 복용하는 제제를 개발하고자 하였다. 이에 다양한 방출 패턴(속도)를 가진 제제를 제조하여 평가하였는데, 후술하는 바와 같이, 특정 방출 패턴을 가질 경우 관절염 (예를 들어, 골관절염(퇴행관절질환), 류마티스관절염 등)의 치료 효과가 월등히 뛰어났다. 통상적으로 1일 2회 투여 제제의 경우에는, 후술하는 실시예 4-4와 유사하게, 장시간 동안 약효성분이 방출되도록 서방성을 조절하는 것이 일반적이다. 그러나, 매우 특이하게도, 도 4 내지 10에 나타나는 바와 같이, 위령선, 괄루근 및 하고초의 생약추출물의 관절염 치료 목적을 위해서는 약효 성분의 방출을 약간만 지연시키는 정도이어야 (도 4 참조) 하루 3번 복용하는 제제 대비 관절염 치료 효과가 상승하였다.The present inventors sought to develop a preparation that contains 280-320 mg of herbal extracts of Uryeongseon, Brachialis root, and Herbal extracts and is to be taken twice a day. Accordingly, preparations with various release patterns (rates) were manufactured and evaluated. As described later, when a specific release pattern is used, the treatment effect for arthritis (e.g., osteoarthritis (degenerative joint disease), rheumatoid arthritis, etc.) is significantly superior. It came out. Typically, in the case of a preparation administered twice a day, the sustained release is generally controlled so that the drug ingredient is released over a long period of time, similar to Example 4-4 described later. However, very specifically, as shown in FIGS. 4 to 10, for the purpose of treating arthritis with the herbal extracts of Uryeongseon, Brachiocephalicum, and Herbal Medicine Extracts, the release of the medicinal ingredients must be slightly delayed (see FIG. 4) and taken three times a day. The arthritis treatment effect increased compared to the formulation.
즉, 본 개시의 일 측면은 위령선, 괄루근 및 하고초의 생약추출물을 280-320 mg 포함하며, 1일 2회 복용하는 제제에 있어, 바람직한 관절염 치료 효과를 나타내는 용출 패턴을 제공하는 것이다. 본 발명의 우수한 관절염 치료 효과를 달성할 수 있는 용출 패턴은 37±0.5 ℃, 50rpm 속도의 패들(paddle) 시험법으로 물 900ml 매질의 조건으로 용출시험 시, 로즈마린산의 방출이 45분에 40~70% (더욱 바람직하게는 45~65%, 더욱 더 바람직하게는 45~60%), 90분에 75% 이상 (바람직하게는 80% 이상), 및 120분에 80% 이상 (바람직하게는 85% 이상)이다. That is, one aspect of the present disclosure is to provide a dissolution pattern that shows a desirable arthritis treatment effect in a preparation containing 280-320 mg of herbal extracts of Uryeongseon, Brachialis root, and Herbaceous herb, and taken twice a day. The dissolution pattern that can achieve the excellent arthritis treatment effect of the present invention is the paddle test method at 37 ± 0.5 ℃ and 50 rpm speed, and when dissolution is tested in 900 ml of water as a medium, the release of rosmarinic acid is 40 to 70% in 45 minutes. % (more preferably 45 to 65%, even more preferably 45 to 60%), 75% or more (preferably 80% or more) in 90 minutes, and 80% or more (preferably 85%) in 120 minutes. above).
이러한 방출 패턴을 달성할 수 있다면 앞서 언급된 또는 후술하는 결합제 또는 방출지연제 이외의 다른 첨가제들이 사용될 수 있다. 즉, 본 개시에 따른 특정 방출 패턴을 달성할 수 있는 조건이라면 전술한 또는 후술하는 특정 첨가제의 종류에 의해 본 발명의 범위가 한정되는 것은 아니다. 전술한 또는 후술하는 특정 첨가제는 본 개시의 더욱 바람직한 측면을 달성하기 위한 것일 뿐이다.Additives other than the binders or release retardants mentioned above or described below may be used if such a release pattern can be achieved. In other words, the scope of the present invention is not limited by the type of specific additives described above or below as long as it is possible to achieve a specific release pattern according to the present disclosure. The specific additives described above or below are merely intended to achieve more preferred aspects of the present disclosure.
즉, 본 발명의 다른 측면은 또한, 유효성분으로 ‘위령선·괄루근·하고초30%에탄올엑스(40→1)’ 추출물을 280-320 mg 포함한 제제이며, 1일 2회 복용하는 제제이고, 37±0.5 ℃, 50rpm 속도의 패들(paddle) 시험법으로 물 900ml 매질의 조건으로 용출시험 시, 로즈마린산(Rosmarinic Acid)의 방출이 45분에 40~70%, 90분에 75% 이상인(더욱 바람직하게는 45분에 40~70%, 90분에 75% 이상이고, 120분에 80% 이상인), 관절염 치료용 제제, 특히 정제를 제공한다. 여기에서, 바람직하게는, 상기 ‘위령선·괄루근·하고초30%에탄올엑스(40→1)’ 추출물의 함량은 코팅 전 나정 또는 공캡슐 충진 전 혼합물의 총 중량 대비 40 내지 90 중량% (바람직하게는, 50-90 중량%, 더욱 바람직하게는 60-90 중량%)이다. In other words, another aspect of the present invention is a preparation containing 280-320 mg of the extract of 'Uryeongseon, Gwanlugeun, and Coriander root 30% ethanol extract (40→1)' as an active ingredient, and is a preparation to be taken twice a day, When dissolving in 900 ml of water using the paddle test method at 37 ± 0.5 ℃ and 50 rpm, the release of Rosmarinic Acid was 40 to 70% in 45 minutes and 75% or more in 90 minutes (more preferably (40 to 70% in 45 minutes, 75% or more in 90 minutes, and 80% or more in 120 minutes), and preparations for treating arthritis, especially tablets. Here, preferably, the content of the extract of 'Wiryeongseon·Guarugeun·Hagocho 30% ethanol extract (40→1)' is 40 to 90% by weight (preferably) relative to the total weight of the mixture before coating or empty capsule filling. Preferably, 50-90% by weight, more preferably 60-90% by weight.
본 발명의 바람직한 태양에 있어, 상기 관절염 치료용 제제는 유효성분으로 위령선, 괄루근 및 하고초의 생약추출물을 280-320 mg 포함한 정제 또는 캅셀제인 제제이고, 1일 2회 복용하는 제제이고, 37±0.5 ℃, 50rpm 속도의 패들(paddle) 시험법으로 물 900ml 매질의 조건으로 용출시험 시, 로즈마린산의 방출이 45분에 45~65%, 90분에 80% 이상, 120분에 85% 이상(더욱 바람직하게는, 45분에 45~60%, 90분에 80% 이상, 120분에 85% 이상)이다. 여기에서, 바람직하게는, 상기 '위령선·괄루근·하고초30%에탄올엑스(40→1)' 추출물의 함량은 코팅 전 나정 또는 공캅셀의 중량을 제외한 캅셀 충진물의 총 중량 대비 40 내지 90 중량%(바람직하게는, 50-90 중량%, 더욱 바람직하게는 60-90 중량%)이다. In a preferred embodiment of the present invention, the formulation for treating arthritis is a tablet or capsule formulation containing 280-320 mg of herbal extracts of Euryeongseon, Brachialis root, and Herbaceae as active ingredients, and is a formulation to be taken twice a day, and the dosage is 37± When dissolution was tested under the conditions of 900 ml of water using the paddle test method at 0.5 ℃ and 50 rpm speed, the release of rosmarinic acid was 45-65% in 45 minutes, more than 80% in 90 minutes, and more than 85% in 120 minutes (more Preferably, 45 to 60% in 45 minutes, 80% or more in 90 minutes, and 85% or more in 120 minutes. Here, preferably, the content of the extract of 'Wiryeongseon·Guarugeun·Hagocho 30% ethanol extract (40→1)' is 40 to 90 weight compared to the total weight of the capsule filling excluding the weight of the uncoated tablet or empty capsule before coating. % (preferably 50-90% by weight, more preferably 60-90% by weight).
바람직하게, 본 발명의 바람직한 일 태양은 유효성분으로 '위령선·괄루근·하고초30%에탄올엑스(40→1)' 추출물을 280-320 mg 포함한 정제이고, 유효성분의 함량은 코팅 전 나정의 총 중량 대비 40 내지 90 중량%(바람직하게는, 50-90 중량%, 더욱 바람직하게는 60-90 중량%)이며, 1일 2회 복용하는 정제이고, 37±0.5 ℃, 50rpm 속도의 패들(paddle) 시험법으로 물 900ml 매질의 조건으로 용출시험 시, 로즈마린산의 방출이 45분에 40~70%, 90분에 75% 이상(더욱 바람직하게는 45분에 40~70%, 90분에 75% 이상이고, 120분에 80% 이상, 더욱 더 바람직하게는 45분에 45~65%, 90분에 80% 이상이고, 120분에 85% 이상)이며, 상기 방출 조절은 에틸셀룰로오스, 메타크릴산에틸아크릴산공중합체 또는 이들의 혼합물(더욱 바람직하게는, 에틸셀룰로오스)을 포함하여 이루어지는 것을 특징으로 하는 정제를 제공한다.Preferably, a preferred embodiment of the present invention is a tablet containing 280-320 mg of the extract of 'Wiryeongseon, Gwalugeun, and Coriander root 30% ethanol extract (40→1)' as an active ingredient, and the content of the active ingredient is the same as that of the uncoated tablet before coating. It is 40 to 90% by weight (preferably, 50-90% by weight, more preferably 60-90% by weight) relative to the total weight, is a tablet to be taken twice a day, and is administered at 37 ± 0.5 ° C. with a paddle speed of 50 rpm ( When dissolving in a 900 ml water medium using the paddle test method, the release of rosmarinic acid is 40-70% in 45 minutes and 75% or more in 90 minutes (more preferably 40-70% in 45 minutes, 75% in 90 minutes). % or more, more preferably 80% or more in 120 minutes, more preferably 45 to 65% in 45 minutes, 80% or more in 90 minutes, and 85% or more in 120 minutes), and the release control is performed using ethylcellulose, methacrylic A tablet comprising an acid ethyl acrylic acid copolymer or a mixture thereof (more preferably, ethylcellulose) is provided.
본 발명의 일 태양은, 유효성분으로 위령선, 괄루근 및 하고초의 생약추출물을 280-320 mg 포함한 정제이고, 유효성분의 함량은 코팅 전 나정의 총 중량 대비 40 내지 90 중량%(바람직하게는, 50-90 중량%, 더욱 바람직하게는 60-90 중량%)이며, 1일 2회 복용하는 정제이고, 37±0.5 ℃, 50rpm 속도의 패들(paddle) 시험법으로 물 900ml 매질의 조건으로 용출시험 시, 로즈마린산의 방출이 45분에 40~70%, 90분에 75% 이상, 120분에 80% 이상(더욱 바람직하게는 45분에 45~65%, 90분에 80% 이상이고, 120분에 85% 이상)이며, 에틸셀룰로오스을 이용하여 방출을 조정하는 것을 특징으로 하는 정제를 제공한다. 상기 에틸셀룰로오스의 함량은 코팅 전 나정의 총 중량 대비 0.1-10 중량%가 바람직하며, 0.4-5 중량%가 더욱 바람직하고, 0.8-3 중량%가 더욱 더 바람직하다. One aspect of the present invention is a tablet containing 280-320 mg of herbal extracts of Wiryeongseon, Guaru root and Hagocho as active ingredients, and the content of the active ingredient is 40 to 90% by weight relative to the total weight of the uncoated tablet before coating (preferably, 50-90% by weight, more preferably 60-90% by weight), is a tablet to be taken twice a day, and is tested for dissolution in 900ml water using the paddle test method at 37±0.5°C and 50rpm speed. , the release of rosmarinic acid is 40-70% at 45 minutes, 75% or more at 90 minutes, and 80% or more at 120 minutes (more preferably 45-65% at 45 minutes, 80% or more at 90 minutes, and 120 minutes or more). 85% or more), and provides a tablet characterized in that the release is adjusted using ethylcellulose. The content of ethylcellulose is preferably 0.1-10% by weight, more preferably 0.4-5% by weight, and even more preferably 0.8-3% by weight, based on the total weight of the uncoated tablet before coating.
본 발명의 일 태양에 있어, 상기 정제는 선택적으로 약학적으로 허용 가능한 부형제, 흡착제, 붕해제, 활택제 등을 추가로 포함할 수 있다. In one aspect of the present invention, the tablet may optionally further include pharmaceutically acceptable excipients, adsorbents, disintegrants, lubricants, etc.
본 발명의 일 측면에 있어, 방출조절제로는 폴리비닐피롤리돈, 에틸셀룰로오스, 메타크릴산에틸아크릴산공중합체, 히이드록시프로필메틸셀룰로오스, 히드록시프로필셀룰로오스, 아크릴산공중합체 등 다양한 물질이 사용될 수 있다. 다만, 정제의 크기를 줄이는 동시에 양호한 방출성을 달성할 수 있다는 측면에서는 에틸셀룰로오스, 메타크릴산에틸아크릴산공중합체 또는 이들의 혼합물이 바람직하다. 방출조절 물질은 코팅 전 나정의 총 중량 대비 0.1-10 중량%가 바람직하며, 0.4-5 중량%가 더욱 바람직하고, 0.8-3 중량%가 더욱 더 바람직하다. In one aspect of the present invention, various materials such as polyvinylpyrrolidone, ethylcellulose, ethyl methacrylic acid copolymer, hydroxypropylmethylcellulose, hydroxypropylcellulose, and acrylic acid copolymer can be used. there is. However, in terms of reducing the size of the tablet and achieving good release properties, ethylcellulose, ethyl methacrylic acid copolymer, or a mixture thereof is preferred. The release control material is preferably 0.1-10% by weight, more preferably 0.4-5% by weight, and even more preferably 0.8-3% by weight, relative to the total weight of the uncoated tablet before coating.
상기 부형제로는 미결정셀룰로오스, 유당, 만니톨 등을 사용할 수 있으며, 이러한 부형제의 함량은 코팅 전 나정 중량 대비 5-40 중량%가 바람직하며, 10-35 중량%가 더욱 바람직하고, 15-30 중량%가 더욱 더 바람직하다. Microcrystalline cellulose, lactose, mannitol, etc. can be used as the excipients. The content of these excipients is preferably 5-40% by weight, more preferably 10-35% by weight, and 15-30% by weight relative to the weight of the bare tablet before coating. is even more desirable.
상기 흡착제로는 경질무수규산 (소수성 경질무수규산 포함), 마그네슘 알루미늄 실리케이트 등을 사용할 수 있으며, 이러한 흡착제의 함량은 코팅 전 나정 중량 대비 0.5-9 중량%가 바람직하고, 1-7 중량%가 더욱 바람직하며, 2-5 중량%가 더욱 더 바람직하다.As the adsorbent, light anhydrous silicic acid (including hydrophobic light anhydrous silicic acid), magnesium aluminum silicate, etc. can be used. The content of such adsorbent is preferably 0.5-9% by weight, more preferably 1-7% by weight, based on the weight of the bare tablet before coating. Preferred, 2-5% by weight is even more preferred.
상기 붕해제로는 크로스카멜로오스나트륨, 전분 글리콜산 나트륨, 크로스포비돈, 저치환도히드록시프로필셀룰로오스 등을 사용할 수 있다. 다만, 정제의 크기를 줄이는 동시에 양호한 방출성을 달성할 수 있다는 측면에서는 크로스카르멜로오스나트륨, 저치환도히드록시프로필셀룰로오스 또는 이들의 혼합물이 바람직하다. 크로스카르멜로오스나트륨, 저치환도히드록시프로필셀룰로오스 또는 이들의 혼합물이 사용될 경우 유효성분의 함량이 높아지는 조건에서도 양호한 방출성이 달성된다. 붕해제로 크로스카르멜로오스나트륨 또는 저치환도하이드록시프로필셀룰로오스 중에서도, 본 발명의 목적상 특히 크로스카르멜로오스나트륨이 더욱 바람직하다. 이러한 붕해제의 함량은 코팅 전 나정 중량 대비 1-10 중량%가 바람직하고, 1-8 중량%가 더욱 바람직하며, 2-5 중량%가 더욱 더 바람직하다. As the disintegrant, croscarmellose sodium, sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, etc. can be used. However, in terms of being able to achieve good release properties while reducing the size of the tablet, croscarmellose sodium, low-substituted hydroxypropyl cellulose, or a mixture thereof is preferable. When croscarmellose sodium, low-substituted hydroxypropyl cellulose, or a mixture thereof is used, good release properties are achieved even under conditions where the content of the active ingredient is increased. Among croscarmellose sodium or low-substituted hydroxypropyl cellulose as a disintegrant, croscarmellose sodium is particularly more preferable for the purpose of the present invention. The content of this disintegrant is preferably 1-10% by weight, more preferably 1-8% by weight, and even more preferably 2-5% by weight, based on the weight of the bare tablet before coating.
상기 활택제로는 스테아릴퓨마레이트, 스테아르산마그네슘, 스테아린산, 탈크 등을 사용할 수 있으며, 이러한 활택제의 함량은 코팅 전 나정 중량 대비 0.1-4 중량%가 바람직하고, 0.2-2 중량%가 더욱 바람직하다. As the lubricant, stearyl fumarate, magnesium stearate, stearic acid, talc, etc. can be used. The content of such lubricant is preferably 0.1-4% by weight, more preferably 0.2-2% by weight, based on the weight of the bare tablet before coating. do.
본 발명의 일 태양에 있어, 본 발명에 따른 정제는 또한 외부 충격으로부터 보호, 외관, 방출의 조절 등 다양한 목적을 위해 코팅될 수 있다. 예를 들어, 나정은 필름형성제, 가소제, 부착방지체 등을 포함하는 코팅용 조성물을 이용하여 코팅될 수 있으며, 코팅물의 함량은 코팅 전 나정 총 중량을 기준으로 1-15 중량%, 바람직하게는 3-10 중량%의 양으로 코팅될 수 있다. 이러한 필름코팅 조성물(제품)로는 칼라콘 사에서 판매하는 폴리비닐알코올을 기본 코팅물질로 포함하는 다양한 코팅기제 제품이 사용될 수 있다. In one aspect of the invention, tablets according to the invention may also be coated for various purposes, such as protection from external impacts, appearance, and control of release. For example, the uncoated tablet can be coated using a coating composition containing a film former, a plasticizer, an anti-adhesion agent, etc., and the content of the coating is preferably 1-15% by weight based on the total weight of the uncoated tablet before coating. Can be coated in an amount of 3-10% by weight. As such a film coating composition (product), various coating base products sold by Colorcon Company containing polyvinyl alcohol as a basic coating material can be used.
본 발명의 바람직한 일 태양은, 유효성분으로 위령선, 괄루근 및 하고초의 생약추출물을 280-320 mg 포함한 정제이고, 유효성분의 함량은 코팅 전 나정의 총 중량 대비 40 내지 90 중량%(바람직하게는, 50-90 중량%, 더욱 바람직하게는 60-90 중량%)이며, 1일 2회 복용하는 정제이고, 37±0.5 ℃, 50rpm 속도의 패들(paddle) 시험법으로 물 900ml 매질의 조건으로 용출시험 시, 로즈마린산의 방출이 45분에 40~70%, 90분에 75% 이상, 120분에 80% 이상(더욱 바람직하게는 45분에 45~65%, 90분에 80% 이상이고, 120분에 85% 이상)이며, 에틸셀룰로오스을 이용하여 방출을 조정하고, 붕해제로 크로스카르멜로오스나트륨을 포함하는 것을 특징으로 하는 정제를 제공한다.A preferred embodiment of the present invention is a tablet containing 280-320 mg of herbal extracts of Uryeongseon, Guaru root, and Hagocho as active ingredients, and the content of the active ingredient is 40 to 90% by weight (preferably 40 to 90% by weight) relative to the total weight of the uncoated tablet before coating. , 50-90% by weight, more preferably 60-90% by weight), is a tablet to be taken twice a day, and is eluted in 900ml of water using the paddle test method at 37±0.5°C and 50rpm speed. During the test, the release of rosmarinic acid is 40-70% at 45 minutes, 75% or more at 90 minutes, 80% or more at 120 minutes (more preferably 45-65% at 45 minutes, 80% or more at 90 minutes, and 120% or more). 85% or more per minute), the release is adjusted using ethylcellulose, and a tablet is provided, characterized in that it contains croscarmellose sodium as a disintegrant.
본 발명에 따른 상기 제제는 물, 에탄올, 이소프로판올 등의 용매를 이용한 습식과립법 또는 압축력을 이용한 건식과립법으로 과립을 제조한 후 이 과립을 붕해제, 활택제 등의 후혼합 성분들과 혼합하여 정제 또는 캡슐제 등으로 제조될 수 있다. 본 발명에 따른 상기 제제는 과립 제조 과정없이 직타 방법으로 정제로 제조될 수 있다. 다만, 본 발명의 여러 목적 중 하나를 달성하기 위한 방출 패턴을 편차 없이 유지한다는 측면에서 습식과립법 정제가 바람직할 수 있다.The formulation according to the present invention is prepared by producing granules by a wet granulation method using a solvent such as water, ethanol, or isopropanol, or a dry granulation method using compression force, and then mixing the granules with post-mixing components such as a disintegrant and lubricant. It can be manufactured as tablets or capsules. The preparation according to the present invention can be manufactured into tablets by a direct compression method without a granule manufacturing process. However, wet granulation tablets may be preferable in terms of maintaining the release pattern without deviation to achieve one of the several purposes of the present invention.
따라서, 본 발명의 일 태양은 위령선, 괄루근 및 하고초의 생약추출물, 흡착제, 결합제, 임의로 부형제, 임의로 붕해제 등을 이용하여 과립을 제조하는 단계; 상기에서 제조된 과립에 약학적으로 허용 가능한 첨가제인 활택제, 붕해제 등을 후혼합하고 타정하여 정제를 제조하는 단계; 및 임의로 상기 정제를 코팅하는 단계를 포함하는 정제의 제조 방법을 제공한다.Accordingly, one aspect of the present invention includes the steps of preparing granules using herbal extracts of Wiryeongseon, Gwanrugeun, and H. aquifolia, an adsorbent, a binder, optionally an excipient, and optionally a disintegrant; Preparing tablets by post-mixing the granules prepared above with pharmaceutically acceptable additives such as lubricants and disintegrants and compressing them into tablets; and optionally coating the tablet.
본 개시의 일 측면은 고함량의 위령선, 괄루근 및 하고초의 생약추출물을 함유하고, 1일 2회 복용이 가능한 제제를 제공한다. 본 개시에 따른 제제는 특정 방출 패턴을 가져 1일 2회 복용하더라도 우수한 관절염 치료 효과를 나타낸다. 본 개시에 따른 일 측면의 제제는 또한 위령선, 괄루근 및 하고초의 생약추출물을 고함량 함유함으로써 크기가 작아 복약 편의성이 우수하다.One aspect of the present disclosure provides a preparation that contains a high content of herbal extracts of Uryeongseon, Brachiorrhea root, and Herbal extracts of Prickly pear, and can be taken twice a day. The formulation according to the present disclosure has a specific release pattern and exhibits excellent arthritis treatment effects even when taken twice a day. The formulation of one aspect according to the present disclosure also contains a high content of herbal extracts of euphorbia, brachialis root, and hagchoi, and thus is small in size and has excellent medication convenience.
본 명세서에 첨부되는 다음의 도면들은 전술한 발명의 내용과 함께 본 발명의 기술사상을 더욱 이해시키는 역할을 하는 것이므로, 본 발명은 그러한 도면에 기재된 사항에만 한정되어 해석되어서는 아니 된다.
도 1은 결합제 종류별 pH 1.2 매질에서의 용출패턴을 나타낸 그래프이다.
도 2는 에틸셀룰로오스 점도별 pH 6.8 매질에서의 용출패턴을 나타낸 그래프이다.
도 3은 본 발명 따른 실시예와 비교예의 물에서의 용출패턴을 나타낸 그래프이다.
도 4는 다양한 용출 패턴을 가진 제제들의 물에서의 용출패턴을 나타낸 그래프이다.
도 5는 다양한 용출 패턴을 가진 제제들이 Meniscectomy 및 전십자인대 절제술 실시 후 보행에 미치는 영향을 평가한 결과이다.
도 6은 다양한 용출 패턴을 가진 제제들이 관절염에 미치는 영향을 평가한 결과로, 체중 부하 검사(Incapacitance test) 결과이다.
도 7은 다양한 용출 패턴이 가진 제제들이 관절염 내 사이토카인들에 미치는 영향을 평가한 ELISA 분석 결과이다.
도 8은 다양한 용출 패턴이 가진 제제들이 관절염 내 바이오마커들에 미치는 영향을 평가한 면적조직화학 염색 분석 결과이다.
도 9는 다양한 용출 패턴이 가진 제제들의 효과를 조직병리학적 분석으로 OARSI score로서 평가한 결과이다.
도 10은 면역조직화학 분석 결과로, 시험 완료 후 Joint surface, cartilage 및 synovium의 Hematoxylin & Eosin (H&E) 및 Safranin-O 염색 결과이다.The following drawings attached to this specification serve to further understand the technical idea of the present invention along with the contents of the above-described invention, and therefore, the present invention should not be construed as limited to only the matters described in such drawings.
Figure 1 is a graph showing the elution pattern in pH 1.2 medium for each type of binder.
Figure 2 is a graph showing the dissolution pattern in pH 6.8 medium for each ethylcellulose viscosity.
Figure 3 is a graph showing the dissolution patterns in water of examples and comparative examples according to the present invention.
Figure 4 is a graph showing the dissolution patterns in water of agents with various dissolution patterns.
Figure 5 shows the results of evaluating the effects of agents with various dissolution patterns on gait after meniscectomy and anterior cruciate ligament resection.
Figure 6 shows the results of an incapacitance test evaluating the effects of agents with various dissolution patterns on arthritis.
Figure 7 shows the results of an ELISA analysis evaluating the effect of agents with various dissolution patterns on cytokines in arthritis.
Figure 8 shows the results of area histochemical staining analysis evaluating the effect of agents with various dissolution patterns on biomarkers in arthritis.
Figure 9 shows the results of evaluating the effects of agents with various dissolution patterns as OARSI scores through histopathological analysis.
Figure 10 shows the results of immunohistochemical analysis, showing the results of Hematoxylin & Eosin (H&E) and Safranin-O staining of the joint surface, cartilage, and synovium after completion of the test.
이하, 본 발명의 이해를 돕기 위하여 실시예 등을 들어 상세하게 설명하기로 한다. 그러나, 본 발명에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 하기 실시예들에 한정되는 것으로 해석되어서는 안 된다. 본 발명의 실시예들은 본 발명이 속한 분야에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, to aid understanding of the present invention, it will be described in detail through examples. However, the embodiments according to the present invention may be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the present invention are provided to more completely explain the present invention to those with average knowledge in the field to which the present invention pertains.
실시예 1: 다양한 결합제를 이용한 용출 패턴 확인Example 1: Confirmation of dissolution patterns using various binders
하기 표 1에 기재된 함량 및 성분을 이용하여 위령선·괄루근·하고초30%에탄올엑스(40→1) 추출물 함유 정제를 제조하였다. 추출물, 크로스포비돈, 소수성경질무수규산, 및 결합제를 혼합하였다. 그 후 스테아르산마그네슘을 첨가하여 혼합하고 타정하였다. Tablets containing 30% ethanol extract (40 → 1) extracts of Wiryeongseon, Gwarugeun, and Hedgehog herb were prepared using the contents and ingredients listed in Table 1 below. The extract, crospovidone, hydrophobic light anhydrous silicic acid, and binder were mixed. Afterwards, magnesium stearate was added, mixed, and tableted.
1-1Example
1-1
1-2Example
1-2
1-3Example
1-3
1-4Example
1-4
1-5Example
1-5
1-6Example
1-6
폴리비닐피롤리돈: Kollidon K30, 점도 약 5.5~8.5 cps (20℃, 10% w/v)Polyvinylpyrrolidone: Kollidon K30, viscosity approximately 5.5~8.5 cps (20℃, 10% w/v)
메타크릴산에틸아크릴산공중합체: Eudragit L100-55, 점도 약 50~200cpsMethacrylic acid ethyl acrylic acid copolymer: Eudragit L100-55, viscosity approximately 50~200cps
하이드록시프로필메틸셀룰로오스: Metolose, 점도 약 100cps (20℃/2% w/v)Hydroxypropylmethylcellulose: Metolose, viscosity about 100cps (20℃/2% w/v)
히드록시프로필셀룰로오스: Nisso HPC-L, 점도 약 6~10cps (20℃/2% w/v)Hydroxypropylcellulose: Nisso HPC-L, viscosity approximately 6~10cps (20℃/2% w/v)
아크릴산공중합체: Carbomer 971, 점도 약 4000~11000 (0.5%w/w)Acrylic acid copolymer: Carbomer 971, viscosity approximately 4000~11000 (0.5%w/w)
실험예 1: 결합제 종류별 용출 평가Experimental Example 1: Elution evaluation by binder type
대한민국약전 12개정 용출시험법에 의하여 상기 실시예 1에서 제조한 정제들의 용출시험을 하였다. 패들법을 사용하고 교반속도는 50rpm, 용출온도는 37.0±0.5℃에서 수행하였다. 용출액은 pH 1.2 900ml에서 실시하였다. 검액 안정성 개선을 위해 아세토니트릴로 전처리 후 분석하였다. 용출시험결과는 하기 표 2 및 도 1에 나타내었다. 용출률은 생약추출물의 활성성분인 로즈마린산의 시간에 따른 함량을 측정하였다. 로즈마린산의 함량은 문헌 J. Sep. Sci. 2015, 0, 1-8 (“Quality evaluation of Salvia miltiorrhiza Bge. by ultra high performance liquid chromatography with photodiode array detection and chemical fingerprinting coupled with chemometric analysis”)에 기재된 방법과 유사하게 측정하였다. The tablets prepared in Example 1 were tested for dissolution according to the dissolution test method of the 12th edition of the Korean Pharmacopoeia. The paddle method was used, the stirring speed was 50 rpm, and the elution temperature was 37.0 ± 0.5°C. Elution was performed at 900 ml at pH 1.2. To improve the stability of the sample solution, it was analyzed after pretreatment with acetonitrile. The dissolution test results are shown in Table 2 and Figure 1 below. The dissolution rate was measured by measuring the content of rosmarinic acid, the active ingredient in herbal medicine extract, over time. The content of rosmarinic acid is reported in J. Sep. Sci. It was measured similarly to the method described in 2015, 0, 1-8 (“Quality evaluation of Salvia miltiorrhiza Bge. by ultra high performance liquid chromatography with photodiode array detection and chemical fingerprinting coupled with chemometric analysis”).
1-1Example
1-1
1-2Example
1-2
1-3Example
1-3
1-4Example
1-4
1-5Example
1-5
1-6Example
1-6
상기 표 2에 나타나는 바와 같이, 실시예 1-1, 1-4, 1-6의 경우 용출 지연효과가 크고, 실시예 1-2와 1-3은 유사한 용출 지연효과를 보였다. 실시예 1-5는 용출 지연 효과가 적었다.As shown in Table 2, Examples 1-1, 1-4, and 1-6 showed a large dissolution delay effect, and Examples 1-2 and 1-3 showed similar dissolution delay effects. Examples 1-5 had little dissolution delay effect.
그러나, 실시예 1-2 및 1-3을 제외한 나머지 실시예들의 경우 아주 충분한 시간 동안 방출을 평가하여도 용출량이 80% 정도에 미치지 못하는 것으로 확인되어 실질적으로 이용이 불가능한 것으로 파악되었다. 이는 본 발명에서 사용된 특정 추출물의 물성과 고분자의 특유의 물성의 조합에 기인한 것으로 추측되며, 예를 들어, 생약 추출물의 겔화 등을 방지하는 기능과도 연관되어 있는 것으로 생각되나, 본 발명은 이러한 이론적 기전에 한정되는 것은 아니다. However, in the case of the remaining examples except for Examples 1-2 and 1-3, it was confirmed that the dissolution amount was less than 80% even when the release was evaluated for a very sufficient time, so it was found that it was practically impossible to use. This is presumed to be due to a combination of the physical properties of the specific extract used in the present invention and the unique physical properties of the polymer. For example, it is thought to be related to the function of preventing gelation of the herbal extract, etc., but the present invention It is not limited to these theoretical mechanisms.
실시예 1-3에서 사용된 메타크릴산에틸아크릴산공중합체의 경우 산성 매질에서는 바람직한 방출패턴을 보였으나, 다른 pH 매질에서 방출패턴이 달라져 방출을 조절하기 쉽지 않다는 문제가 있었고, 결과적으로 실시예 1-2의 에틸셀룰로오스 보다는 덜 바람직하였다. The methacrylic acid-ethylacrylic acid copolymer used in Examples 1-3 showed a desirable release pattern in an acidic medium, but there was a problem in that the release pattern was different in different pH media, making it difficult to control the release, and as a result, Example 1 It was less desirable than -2 ethylcellulose.
본 발명자들은 또한 다양한 평가를 수행하여 pH 1.2 매질에서는 실시예 1-2 또는 1-3과 같은 용출 패턴이 300 mg 함유 정제를 2회 복용하는 제제의 용출 패턴으로 바람직하다고 판단하였으며, 따라서 이러한 측면에서는 실시예 1-2 및 1-3 이외의 다른 결합제들은 방출을 너무 지연시킨다는 문제도 있다. The present inventors also performed various evaluations and determined that in a pH 1.2 medium, the dissolution pattern of Examples 1-2 or 1-3 is preferable as the dissolution pattern of a preparation containing 300 mg tablets taken twice. Therefore, in this respect, Binders other than Examples 1-2 and 1-3 also have the problem of delaying release too much.
결과적으로, 놀랍게도 위령선, 괄루근 및 하고초의 생약추출물 300 mg을 포함하고, 하루 2회 복용하는 제제의 방출조절 성분으로는 통상적으로 사용되는 HPMC 등보다 에틸셀룰로오스 및 메타크릴산에틸아크릴산공중합체이 바람직하며, 에틸셀룰로오스가 더욱 바람직하였다. As a result, surprisingly, ethylcellulose and ethyl acrylic acid copolymer of methacrylic acid are preferred as release-controlling ingredients of a preparation that contains 300 mg of herbal extracts of Uryeongseon, Brachialis root, and Herbal extracts and is taken twice a day, rather than the commonly used HPMC. , ethylcellulose was more preferable.
실시예 2: 에틸셀룰로오스를 이용한 지연 용출패턴 확인Example 2: Confirmation of delayed dissolution pattern using ethylcellulose
하기 표 3에 기재된 함량 및 성분을 이용하여 위령선·괄루근·하고초30%에탄올엑스(40→1) 추출물 함유 정제를 제조하였다. 먼저 이소프로필알콜에 에틸셀룰로오스를 녹여 결합액을 제조 후 추출물과 소수성경질무수규산을 결합액에 넣고 습식과립을 제조하였다. 상기 제조된 습식과립에 크로스포비돈 및 스테아린산마그네슘을 혼합하여 타정하였다.Tablets containing 30% ethanol extract (40 → 1) extracts of Wiryeongseon, Gwarugeun, and Coriander root were prepared using the contents and ingredients shown in Table 3 below. First, ethyl cellulose was dissolved in isopropyl alcohol to prepare a binding solution, and then the extract and hydrophobic light anhydrous silicic acid were added to the binding liquid to prepare wet granules. Crospovidone and magnesium stearate were mixed with the wet granules prepared above and compressed into tablets.
실험예 2: pH 6.8 매질에서의 에틸셀룰로오스 점도별 용출 평가Experimental Example 2: Elution evaluation by viscosity of ethylcellulose in pH 6.8 medium
대한민국약전 12개정 용출시험법에 의하여 상기 실시예 2-1 내지 2-4의 용출을 평가하였다. 패들법을 사용하고 교반속도는 50rpm, 용출온도는 37.0±0.5℃에서 수행하였다. 용출액은 pH 6.8 900ml에서 실시하였다. 검액 안정성 개선을 위해 아세토니트릴로 전처리 후 분석하였다. 로즈마린산의 용출시험결과는 하기 표 4 및 도 2에 나타내었다.The dissolution of Examples 2-1 to 2-4 was evaluated according to the dissolution test method of the 12th edition of the Korean Pharmacopoeia. The paddle method was used, the stirring speed was 50 rpm, and the elution temperature was 37.0 ± 0.5°C. The elution was performed at 900 ml at pH 6.8. To improve the stability of the sample solution, it was analyzed after pretreatment with acetonitrile. The dissolution test results of rosmarinic acid are shown in Table 4 and Figure 2 below.
상기 표 4에서 보는 바와 같이, 에틸셀룰로오스를 이용한 본 발명의 제제는 pH 6.8에서도 양호한 방출 패턴을 나타내었으며, pH 6.8에서도 100%에 가까운 방출을 나타낼 수 있었다. As shown in Table 4, the formulation of the present invention using ethylcellulose showed a good release pattern even at pH 6.8, and was able to exhibit a release close to 100% even at pH 6.8.
또한, 실시예 2-1에서 2-4로 갈수록 용출률이 느려지는 패턴이며 이는 에틸셀룰로오스의 점도가 높아지는 것과 일치함을 확인할 수 있었다.In addition, it was confirmed that the dissolution rate slowed down from Example 2-1 to 2-4, which was consistent with the increase in viscosity of ethylcellulose.
실시예 3 및 비교예 1: 여러 성분에 따른 용출성 평가Example 3 and Comparative Example 1: Evaluation of dissolution according to various components
하기 표 5에 기재된 함량 및 성분에 따라 정제를 제조하였다. 실시예 3은 위령선, 괄루근 및 하고초의 생약추출물, 소수성경질무수규산 및 에틸셀룰로오스를 습식과립화하는 방법으로 제조하였다. 상기 제조된 습식과립에 미결정셀룰로오스, 크로스카르멜로오스나트륨 및 스테아릴퓨마레이트를 혼합하여 타정하였다. 이렇게 제조된 코어에 코팅기제를 이용하여 코팅하였다. 비교예 1은 위령선, 괄루근 및 하고초의 생약추출물, 경질무수규산, 옥수수전분, 미결정셀룰로오스 및 전분글리콜산나트륨을 건식 혼합하는 방식으로 제조하였다. 상기 제조된 혼합물에 스테아르산마그네슘을 후혼합하여 타정하였다. 이렇게 제조된 코어에 코팅기제를 이용하여 코팅하였다.Tablets were prepared according to the contents and ingredients listed in Table 5 below. Example 3 was prepared by wet granulation of herbal extracts of Wiryeongseon, Gwanrugeun, and Hagochoe, hydrophobic light anhydrous silicic acid, and ethylcellulose. Microcrystalline cellulose, croscarmellose sodium, and stearyl fumarate were mixed into the wet granules prepared above and compressed into tablets. The core prepared in this way was coated using a coating agent. Comparative Example 1 was prepared by dry mixing the herbal extracts of Wiryeongseon, Gwanru root, and H. perilla, light anhydrous silicic acid, corn starch, microcrystalline cellulose, and sodium starch glycolate. Magnesium stearate was mixed with the mixture prepared above and compressed into tablets. The core prepared in this way was coated using a coating agent.
실험예 3: 실시예 3 및 비교예 1의 용출 평가Experimental Example 3: Dissolution evaluation of Example 3 and Comparative Example 1
대한민국약전 12개정 용출시험법에 의하여 상기 실시예 3, 비교예 1 및 비교예 2의 용출패턴을 평가하였다. 패들법을 사용하고 교반속도는 50rpm, 용출온도는 37.0±0.5℃에서 수행하였다. 용출액은 정제수 900ml에서 실시하였다. 검액 안정성 개선을 위해 아세토니트릴 및 pH 1.2 완충액으로 전처리 후 분석하였다. 로즈마린산의 용출시험결과는 하기 표 6 및 도 3에 나타내었다.The dissolution patterns of Example 3, Comparative Example 1, and Comparative Example 2 were evaluated according to the dissolution test method of the 12th edition of the Korean Pharmacopoeia. The paddle method was used, the stirring speed was 50 rpm, and the elution temperature was 37.0 ± 0.5°C. Elution was performed in 900 ml of purified water. To improve the stability of the sample solution, it was analyzed after pretreatment with acetonitrile and pH 1.2 buffer. The dissolution test results of rosmarinic acid are shown in Table 6 and Figure 3 below.
상기 표 6에 나타나는 바와 같이, 본 발명에 따른 제제는 물에서도 양호한 방출패턴을 나타내었다. 본 발명자들은 다양한 평가를 수행하여 용출 매질이 물일 경우 상기 실시예 3과 같은 용출패턴 (예를 들어, 45분에 40~70%, 90분에 75% 이상이면서, 더욱 바람직하게는 120분에 85% 이상)이 바람직한 것으로 파악하였으나, 상기와 같은 용출 패턴을 달성하는 것이 쉽지 않았다. 예를 들어, 비교예 1의 용출결과는 부형제 및 붕해제를 많이 사용하고 추출물의 함량을 낮추어 초기 용출률을 높였음에도 불구하고 최종 용출률이 높지 않음을 보여준다.As shown in Table 6, the formulation according to the present invention showed a good release pattern even in water. The present inventors performed various evaluations and found that when the dissolution medium was water, the dissolution pattern was the same as in Example 3 (e.g., 40 to 70% in 45 minutes, 75% or more in 90 minutes, and more preferably 85% in 120 minutes). % or more) was found to be desirable, but it was not easy to achieve the above dissolution pattern. For example, the dissolution results of Comparative Example 1 show that although the initial dissolution rate was increased by using more excipients and disintegrants and lowering the extract content, the final dissolution rate was not high.
실시예 4: 용출 패턴에 따른 약효 평가Example 4: Evaluation of drug efficacy according to dissolution pattern
하기 표 7과 같은 처방으로, 다양한 용출 패턴을 가진 위령선·괄루근·하고초 30% 에탄올엑스 (40→1) 정제들을 제조한 후에 용출 패턴이 약효에 미치는 영향을 평가하였다. 200mg 속방정, 300mg 속방정, 300mg 지연방출정, 및 300mg 서방정을 제조하였다. 먼저 물, 에탄올, 이소프로필알콜 또는 이들의 혼합 용매 중 적합한 용매에 결합제를 녹여 결합액을 제조하였다. 이후 추출물, 경질무수규산, 부형제 등을 결합액에 넣고 습식과립을 제조하였다. 상기 제조된 습식과립에 붕해제 및 활택제를 혼합하여 타정하였다. 이후 통상적인 방법으로 필름코팅을 수행하였다.With the prescription shown in Table 7 below, 30% ethanol extract (40 → 1) tablets of Wiryeongseon, Gwarugeun, and Hedgehog herbacea with various dissolution patterns were manufactured and then the effect of the dissolution pattern on drug efficacy was evaluated. 200mg immediate-release tablets, 300mg immediate-release tablets, 300mg delayed-release tablets, and 300mg sustained-release tablets were manufactured. First, a binding solution was prepared by dissolving the binder in a suitable solvent among water, ethanol, isopropyl alcohol, or a mixed solvent thereof. Afterwards, extract, light anhydrous silicic acid, and excipients were added to the binding solution to prepare wet granules. The wet granules prepared above were mixed with a disintegrant and a lubricant and compressed into tablets. Afterwards, film coating was performed using a conventional method.
4-1Example
4-1
4-2Example
4-2
4-3Example
4-3
4-4Example
4-4
실험예 4-1: 용출 평가Experimental Example 4-1: Dissolution evaluation
실험예 3과 동일한 방법으로 200mg 속방정, 300mg 속방정, 300mg 지연방출정, 및 300mg 서방정의 용출을 평가하였다. 즉, 패들법을 사용하고 교반속도는 50rpm, 용출온도는 37.0±0.5℃에서 수행하였다. 용출액은 정제수 900ml에서 실시하였다. 로즈마린산의 용출 결과를 하기 표 8 및 도 4에 종합하여 나타내었다. The dissolution of 200mg immediate-release tablets, 300mg immediate-release tablets, 300mg delayed-release tablets, and 300mg extended-release tablets was evaluated in the same manner as in Experimental Example 3. That is, the paddle method was used, the stirring speed was 50 rpm, and the elution temperature was 37.0 ± 0.5°C. Elution was performed in 900 ml of purified water. The dissolution results of rosmarinic acid are summarized in Table 8 and Figure 4 below.
평균 용출률이 80%에 도달하는 시점을 보았을 때 ‘200mg 속방정’ 30분, ‘300mg 속방정’ 45분, ‘300mg 지연방출정’ 90분, 및 ‘300mg 서방정’ 360분으로 확인되었다. 따라서 각 제형은 각각 속방정, 지연방출정, 서방정의 특성을 갖는다고 판단된다.When looking at the time when the average dissolution rate reached 80%, it was confirmed to be 30 minutes for the ‘200mg immediate-release tablet’, 45 minutes for the ‘300mg immediate-release tablet’, 90 minutes for the ‘300mg delayed-release tablet’, and 360 minutes for the ‘300mg sustained-release tablet’. Therefore, each dosage form is judged to have characteristics of immediate-release tablets, delayed-release tablets, and sustained-release tablets, respectively.
실험예 4-2: 골관절염 치료 효과 평가Experimental Example 4-2: Evaluation of osteoarthritis treatment effect
실험동물, 시험물질 및 시험 군Experimental animals, test substances and test groups
비글견(Beagle dog) 반월상 연골판 절제술 (meniscectomy) 및 전십자인대 절제술 (ACLT) 모델을 이용하여 골관절염 치료 효과를 평가하였다. 시험 물질로는 실시예 4에서 제조한, 200mg 속방정, 300mg 속방정, 300mg 지연방출정, 및 300mg 서방정을 이용하였다. 양성대조군으로는 화이자 사의 Celecoxib 제제 (제조(로트)번호: EF6274, 캡슐제)를 이용하였다. 음성대조군(Vehicle)으로는 하기 표 9와 같은 처방으로 이루어진 정제를 이용하였다.The effectiveness of osteoarthritis treatment was evaluated using the Beagle dog meniscectomy and anterior cruciate ligament resection (ACLT) models. As test materials, the 200mg immediate-release tablet, 300mg immediate-release tablet, 300mg delayed-release tablet, and 300mg sustained-release tablet prepared in Example 4 were used. As a positive control group, Pfizer's Celecoxib preparation (manufacturing (lot) number: EF6274, capsule) was used. As a negative control group (vehicle), tablets with the prescription shown in Table 9 below were used.
시험군의 구성은 하기 표 10과 같았다. The composition of the test group was as shown in Table 10 below.
(마리)number of animals
(number of animals)
(mg)dosage
(mg)
(정)dosage
(affection)
Beagle dog (Xi’an Dilepu Biology & Medicine Co., Ltd)에 상기 표 9의 투여 횟수에 따라 경구 투여하였으며, 8주 동안 투여하였다. 구체적으로 동물을 사육상자 내에서 자연스럽게 위치한 상태로 입을 벌린 후 시험물질을 혀의 안쪽에 넣고 입을 다물게 한 다음, 인후두부를 부드럽게 쓰다듬어 연하시켰다. 삼켰는지 확인하고, 주사기를 이용하여 물 약 10 mL을 먹였다.It was administered orally to a Beagle dog (Xi’an Dilepu Biology & Medicine Co., Ltd) according to the number of administrations in Table 9 above, and administered for 8 weeks. Specifically, the animal opened its mouth in a natural position in the breeding box, placed the test substance on the inside of the tongue, closed its mouth, and then gently stroked the larynx to swallow. After confirming that the patient had swallowed, approximately 10 mL of water was administered using a syringe.
Meniscectomy 및 전십자인대 절제Meniscectomy and anterior cruciate ligament resection
수술 전, clipper를 이용하여 동물의 양쪽 무릎 주변부를 제모하였다. 동물을 마취하고, Povidone 및 70 % alcohol을 이용하여 절개할 부위를 넓게 소독하였다. 그 다음, 우측 무릎의 피부를 절개하였다. 주변 조직을 둔성분리 (blunt dissection)하여, 대퇴부 말단의 관절면을 노출시켰다. 내측 관절면에 결손창을 만들고, 전십자인대를 절제하였다. 4-0 나일론을 사용하여 창상 봉합을 실시하였다. 좌측 무릎의 경우, 전십자인대 절제술만 실시하였다. Before surgery, the area around both knees of the animal was removed using a clipper. The animal was anesthetized, and the area to be incised was widely disinfected using Povidone and 70% alcohol. Next, an incision was made in the skin of the right knee. The surrounding tissues were bluntly dissected to expose the articular surface of the distal femur. A defect window was created on the medial articular surface, and the anterior cruciate ligament was resected. Wound closure was performed using 4-0 nylon. For the left knee, only anterior cruciate ligament resection was performed.
Meniscectomy 실시 1주 후, 해당 동물에 대하여 1회/일, 7일간 인위적 운동 (30 분/일)을 실시하였다.One week after meniscectomy, artificial exercise (30 minutes/day) was performed on the animal once per day for 7 days.
관찰 및 검사 항목Observation and inspection items
(1) 보행평가(1) Gait evaluation
상기 실시예 4에서 제조한 제형들이 골관절염 동물모델에의 효력을 평가하고자 보행 평가를 수행하였다. 시험물질 투여 전, 이후 2회/주 실시하였다. 하기 표 11의 평가 기준에 따라 보행 평가를 실시하고, 디지털카메라를 이용하여 영상을 촬영하였다. A gait evaluation was performed to evaluate the effectiveness of the formulations prepared in Example 4 on an osteoarthritis animal model. The test was conducted twice a week before and after administration of the test substance. Gait evaluation was performed according to the evaluation criteria in Table 11 below, and images were taken using a digital camera.
그 결과를 도 5에 나타내었다. 도 5에 나타나는 바와 같이, 300mg 지연방출정 (G6)의 결과가 가장 바람직하였다. 특히, 300mg 속방정 (G5) 및 300mg 서방정 (G7)과 비교하여 특정 용출 패턴을 가진 300mg 지연방출정 (G6)만 좋은 결과가 나타났으며, 이는 매우 특이적인 결과이었다. The results are shown in Figure 5. As shown in Figure 5, the results of the 300mg delayed-release tablet (G6) were most favorable. In particular, compared to the 300mg immediate-release tablet (G5) and 300mg sustained-release tablet (G7), only the 300mg delayed-release tablet (G6) with a specific dissolution pattern showed good results, which was a very specific result.
(2) Incapacitance test (2) Incapacitance test
상기 실시예 4에서 제조한 제형들이 골관절염 동물모델에의 체중 부하에 미치는 효과를 확인하였다. 뒷다리 체중 부하는 발 무게 측정기 (Incapacitance tester (1029-S, Linton instrumentation, USA)를 사용하여 측정하였다. 본 시험에서 골관절염이 유발된 비글견은 전십자인대절제술만 실시한 좌 후지에 비해 전십자인대절제술 및 내측반월판 절제를 동시에 시행한 우 후지에 더 심한 통증이 발생하므로, 좌 후지에 의지하여 서게 되고, 이에 따라 좌 후지 체중 부하 대비 우 후지의 체중 부하가 상대적으로 가볍게 측정되었다. 발의 무게 측정시 비글견의 배가 기기 센서에 닿지 않은 상태에서 양쪽 발의 무게 (g)를 각각 측정하였으며, 상기 측정된 발의 무게를 이용하여, 체중 부하율(%)을 하기 계산식 1의 방법으로 계산하였다. 상기 체중부하는 발로 지탱하여 누르는 힘으로, 정상적인 경우 양쪽 발의 무게가 균형을 이루어 한쪽 발의 체중 부하율(%) 은 50% 수준으로 나타나지만, 골관절염 유발에 의해 통증이 심해질수록 골관절염 유발 뒷다리의 체중 부하율 (%)이 낮아진다.The effect of the formulations prepared in Example 4 on weight bearing in an osteoarthritis animal model was confirmed. Weight bearing on the hind limbs was measured using a paw weight meter (Incapacitance tester (1029-S, Linton instrumentation, USA). In this test, beagle dogs with osteoarthritis underwent anterior cruciate ligament resection compared to the left hindlimb that underwent anterior cruciate ligament resection alone. Since more severe pain occurred in the right hind limb where the and medial meniscectomy were performed simultaneously, the beagle stood relying on the left hind limb, and as a result, the weight load on the right hind limb was measured to be relatively light compared to the weight load on the left hind limb. The weight (g) of both feet was measured in a state where the dog's stomach did not touch the device sensor, and using the measured weight of each foot, the weight bearing ratio (%) was calculated by the method of equation 1 below. With the force of supporting and pressing, normally, the weight of both feet is balanced and the weight bearing ratio (%) of one foot is around 50%. However, as the pain becomes worse due to osteoarthritis, the weight bearing ratio (%) of the hind limb caused by osteoarthritis decreases.
[계산식 1][Calculation Formula 1]
체중 부하율 (%) = [골관절염 유발 뒷다리의 무게 / (양발 뒷다리의 무게)] × 100Weight bearing ratio (%) = [Weight of the hind limbs causing osteoarthritis / (Weight of both hind limbs)] × 100
시험물질 투여 전 및 그 이후에는 1회/주, 8주간 Incapacitance tester를 이용하여 후지 체중 부하 분배율 수준을 측정하였다. 그 결과를 도 6에 나타내었다.Before and after administration of the test substance, the level of hindlimb weight bearing distribution ratio was measured using an Incapacitance tester once a week for 8 weeks. The results are shown in Figure 6.
도 6에 나타나는 바와 같이, 300mg 지연방출정 (G6)의 결과가 가장 바람직하였다. 특히, 300mg 속방정 (G5) 및 300mg 서방정 (G7)과 비교하여 특정 용출 패턴을 가진 300mg 지연방출정 (G6)만 좋은 결과가 나타났으며, 이는 매우 특이적인 결과이었다. As shown in Figure 6, the results of the 300mg delayed-release tablet (G6) were most favorable. In particular, compared to the 300mg immediate-release tablet (G5) and 300mg sustained-release tablet (G7), only the 300mg delayed-release tablet (G6) with a specific dissolution pattern showed good results, which was a very specific result.
(3) ELISA 분석 (3) ELISA analysis
관절염 발생과 관련된 바이오마커의 활성을 확인하고자 부검일에 채취한 관절액을 이용하여 관절액 내 바이오마커로 IL-1β, MMP-3 및 TNF-α 3종 Cytokine의 분석을 실시하였다. 분석은 상용화된 ELISA kit를 이용하였다. 그 결과를 도 7에 나타내었다.To confirm the activity of biomarkers related to the development of arthritis, three types of cytokines, IL-1β, MMP-3, and TNF-α, were analyzed as biomarkers in joint fluid using joint fluid collected on the day of autopsy. The analysis was performed using a commercially available ELISA kit. The results are shown in Figure 7.
골관절염이 유발되는 유력한 기전 중 하나는 TNF-α, IL-1β, IL-6와 같은 전염증성사이토카인(pro-inflammatory cytokine)의 생성이 증가하고 콜라게네이즈(collagenase), 스트로멜라이신(stromelysin) 등과 같은 MMP들의 분비가 증가되어 관절 연골의 손상을 유발한다는 것이다. 즉, 골관절염 발병시 MMP-3, MMP-9, 및 MMP-13 등의 발현이 증가하며, 이러한 MMP들의 증가로 인해 연골을 구성하는 콜라겐 기질(collagen matrix)를 손상시켜 퇴행성관절염을 악화시키는 것으로 알려져 있다. 또, 대표적 연골세포외기질인 aggrecan과 제 2형 콜라젠(type II collagen)의 분해에 있어 ADAMTS5와 MMP13이 퇴행성관절염의 진행에 결정적인 역할을 한다는 사실이 규명된 바 있다. One of the influential mechanisms causing osteoarthritis is increased production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, as well as collagenase and stromelysin. The secretion of MMPs such as these increases, causing damage to joint cartilage. In other words, when osteoarthritis develops, the expression of MMP-3, MMP-9, and MMP-13 increases, and this increase in MMPs is known to worsen degenerative arthritis by damaging the collagen matrix that makes up cartilage. there is. In addition, it has been established that ADAMTS5 and MMP13 play a critical role in the progression of degenerative arthritis in the decomposition of aggrecan and type II collagen, representative cartilage extracellular matrices.
관절염 진행 경로에는 여러 가지 원인이 있다. 그 중에서 중요한 원인을 차지하고 있는 것은 macrophage (대식세포)의 활성에 관한 것이다. 활액에 존재하고 있는 macrophage가 PAMPs, DAMPs 및 inflammasome에 의하여 활성이 촉진이 되게 되면, 염증에 관련된 역할을 하는 M1 macrophage로 polarization 되게 된다. 이러한 M1-macrophage는 염증성 cytokine (예를 들어, IL-1B, IL-6, TNF-α), 성장인자, MMPs (ex: MMP1, MMP2, MMP3, MMP13) 및 TIMP를 분비하게 되며, 그 결과 인해 염증. 연골 분해 및 osteophyte formation이 야기된다. 이러한 cytokine, MMPs 및 분비성 단백질들은 autocrine 형태로 macrophage를 M1 형태로의 활성을 유지시키며, M1-macrophage는 TGF-β, JNK, Akt, NF-κB 및 beta-catenin의 신호전달을 포함한 연골세포의 신호전달 경로를 변경함으로써 세포외 기질 (ECM) 성분의 분해를 촉진시킨다. 이렇게 분해된 ECM은 DAMP 역할을 함으로써 다시 대식세포 활성화와 M1-macrophage로의 polarization을 자극하여, 염증과 연골 분해의 반복을 초래한다. There are several causes of arthritis progression. Among them, the most important cause is the activity of macrophages. When macrophages existing in synovial fluid are activated by PAMPs, DAMPs, and inflammasomes, they are polarized into M1 macrophages, which play a role in inflammation. These M1-macrophages secrete inflammatory cytokines (e.g., IL-1B, IL-6, TNF-α), growth factors, MMPs (e.g., MMP1, MMP2, MMP3, MMP13), and TIMP, and as a result, Inflammation. Cartilage breakdown and osteophyte formation occur. These cytokines, MMPs, and secretory proteins maintain the activity of macrophages in the autocrine form in the M1 form, and M1-macrophages control chondrocytes including signaling of TGF-β, JNK, Akt, NF-κB, and beta-catenin. By altering signaling pathways, it promotes the degradation of extracellular matrix (ECM) components. By acting as a DAMP, the decomposed ECM stimulates macrophage activation and polarization into M1-macrophages, resulting in repeated inflammation and cartilage degradation.
이러한 관절염에 원인이 되는 macrophage에서 분비하는 주된 cytokine (IL-1β, TNF-α)및 MMPs (MMP3)의 관절액 내에서 level을 ELISA 검사를 통하여 확인한 결과, 유발군 (G2) 대비 G3, G4, G5, G6 및 G7에서 IL-1β의 level이 유의하게 감소하였고, TNF-α의 level은 유발군 (G2) 대비 시험군 G3, G4, G5 및 G6에서 유의하게 감소하였다. MMP3의 관절액 내의 level은 유발군 (G2) 대비 시험군 G3, G4, G5, G6 및 G7 유의하게 감소하였다. 도 7에 나타나는 바와 같이, 300mg 지연방출정 (G6)의 결과가 가장 바람직하였다. 특히, 300mg 속방정 (G5) 및 300mg 서방정 (G7)과 비교하여 특정 용출 패턴을 가진 300mg 지연방출정 (G6)만 좋은 결과가 나타났으며, 이는 매우 특이적인 결과이었다. 이러한 결과를 통하여 염증성 cytokine 및 MMP3의 level이 감소하여 ELISA 검사상 관절염 완화에 도움을 준 것으로 사료된다. As a result of checking the levels of the main cytokines (IL-1β, TNF-α) and MMPs (MMP3) secreted by macrophages that cause arthritis in the joint fluid through ELISA test, G3, G4, and G5 compared to the induced group (G2) , the level of IL-1β was significantly decreased in G6 and G7, and the level of TNF-α was significantly decreased in the test groups G3, G4, G5, and G6 compared to the induced group (G2). The level of MMP3 in joint fluid was significantly decreased in test groups G3, G4, G5, G6, and G7 compared to the induced group (G2). As shown in Figure 7, the results of the 300mg delayed-release tablet (G6) were most favorable. In particular, compared to the 300mg immediate-release tablet (G5) and 300mg sustained-release tablet (G7), only the 300mg delayed-release tablet (G6) with a specific dissolution pattern showed good results, which was a very specific result. Based on these results, it is believed that the levels of inflammatory cytokines and MMP3 were reduced, helping to alleviate arthritis according to the ELISA test.
(4) 면역조직화학 염색(4) Immunohistochemical staining
또, 관절염 발생과 관련된 바이오마커로 MMP-13 저해 효과 및 Collagen type II의 생성 효과 확인을 위해 면역조직화학염색 (IHC) 마커로 Collagen type II 및 MMP-13의 분석을 실시하였다. In addition, to confirm the inhibitory effect of MMP-13 and the production effect of Collagen type II as a biomarker related to the development of arthritis, analysis of Collagen type II and MMP-13 was performed using immunohistochemical staining (IHC) markers.
부검일에 관절액을 채취한 다음, 동물을 안락사시킨 후, 결손부의 육안 관찰을 실시하고 사진을 촬영하였다. 결손부를 적출하여 10 % 중성 완충포르말린용액에 고정하였다. 채취한 관절액은 분석 전까지 -70 ℃ 이하로 설정되어 있는 초저온 냉동고에 보관하였다. 고정된 조직은 탈회, 삭정, 탈수, 파라핀 포매, 박절 등 일반적인 조직처리 과정을 거쳐 조직병리학적 검사를 위한 검체를 제작하였다. 그 뒤, Hematoxylin & Eosin (H&E), Safranin-O 및 면역조직화학염색 (Collagen type II 및 MMP-13)을 실시하고 염색을 실시하고, 광학 현미경 (Olympus BX53, Japan)을 이용하여 조직병리학적 변화를 관찰하며, Image analyzer (Zen 2.3 blue edition, Carl Zeiss, Germany)를 이용하여 면역조직화학염색의 분석을 실시한다.Joint fluid was collected on the day of necropsy, the animal was euthanized, the defect was visually observed, and photographs were taken. The defect was extracted and fixed in 10% neutral buffered formalin solution. The collected joint fluid was stored in an ultra-low temperature freezer set to -70°C or lower until analysis. The fixed tissue went through general tissue processing procedures such as decalcification, trimming, dehydration, paraffin embedding, and sectioning to prepare a specimen for histopathological examination. Afterwards, Hematoxylin & Eosin (H&E), Safranin-O, and immunohistochemical staining (Collagen type II and MMP-13) were performed, and histopathological changes were performed using an optical microscope (Olympus BX53, Japan). Observe and perform immunohistochemical staining analysis using an Image analyzer (Zen 2.3 blue edition, Carl Zeiss, Germany).
면역조직화학 염색의 경우, MMP13 (R&D System, MAB511-500), Collagen II (abcan, ab34712)를 1 차 항체로 사용하며, MMP13의 경우, DAKO, Envision+System-HRP labelled polymer anti-mouse(K4001), Collagen II의 경우, DAKO, Envision+System-HRP labelled polymer anti-rabbit(K4003)를 2 차 항체로 사용하였다. 이후 DAB로 염색한 후, Hematoxylin으로 대비염색을 진행하였다.For immunohistochemical staining, MMP13 (R&D System, MAB511-500) and Collagen II (abcan, ab34712) are used as primary antibodies. For MMP13, DAKO, Envision+System-HRP labeled polymer anti-mouse (K4001) ), For Collagen II, DAKO, Envision+System-HRP labeled polymer anti-rabbit (K4003) was used as a secondary antibody. After staining with DAB, counterstaining was performed with Hematoxylin.
그 결과를 도 8에 나타내었다. The results are shown in Figure 8.
도 8에 나타나는 바와 같이, 300mg 지연방출정 (G6)은 양호한 결과를 나타내었다. 특히, 300mg 속방정 (G5) 및 300mg 서방정 (G7)과 비교하여 특정 용출 패턴을 가진 300mg 지연방출정 (G6)만 좋은 결과가 나타났으며, 이는 매우 특이적인 결과이었다.As shown in Figure 8, 300mg delayed-release tablet (G6) showed good results. In particular, compared to the 300mg immediate-release tablet (G5) and 300mg sustained-release tablet (G7), only the 300mg delayed-release tablet (G6) with a specific dissolution pattern showed good results, which was a very specific result.
(5) 조직 병리 분석 실험 (5) Histopathological analysis experiments
H&E 염색 후 OARSI score 항목 중 관절면에서 Cartilage structure 및 chondrocyte 수준을 확인했으며, 관절강에서 synovial lining, inflammatory cell infiltration 및 Synovial hyperplasia 수준을 확인했다. Safranin-O 염색 후 OARSI score 항목중 관절면에서 Proteoglycan 수준을 확인했다. 해당평가 방법은 The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the dog (Osteoarthritis Cartilage. 2010 Oct;18 Suppl 3:S66-79.)을 참고하여 점수화하였다.After H&E staining, among the OARSI score items, cartilage structure and chondrocyte levels were confirmed on the joint surface, and the levels of synovial lining, inflammatory cell infiltration, and synovial hyperplasia were confirmed in the joint space. After Safranin-O staining, the level of Proteoglycan in the joint surface was confirmed among the OARSI score items. The corresponding evaluation method was scored by referring to The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the dog (Osteoarthritis Cartilage. 2010 Oct;18 Suppl 3:S66-79.).
결과를 도 9 및 10에 나타내었다. 도 9에 나타나는 바와 같이, 300mg 지연방출정 (G6)은 양호한 결과를 나타내었다. 특히, 300mg 속방정 (G5) 및 300mg 서방정 (G7)과 비교하여 특정 용출 패턴을 가진 300mg 지연방출정 (G6)만 좋은 결과가 나타났으며, 이는 매우 특이적인 결과이었다. The results are shown in Figures 9 and 10. As shown in Figure 9, 300mg delayed-release tablet (G6) showed good results. In particular, compared to the 300mg immediate-release tablet (G5) and 300mg sustained-release tablet (G7), only the 300mg delayed-release tablet (G6) with a specific dissolution pattern showed good results, which was a very specific result.
또한 도 10에 나타난 바와 같이 Safranin-O 염색 결과, 골관절염 유발군은 정상 연골 조직이 유발에 의해 파괴되어 프로테오글리칸 조직의 손상 수준이 증가하였다. 이에 반해 약물 투여군의 경우 염색된 프로테오글리칸 조직이 활막 주변에 많이 분포하였다. H&E 염색에서는 정상군의 연골 조직 대비 골관절염 유발된 군은 관절면의 균열 및 침식이 깊게 나타났으며 약물 투여군의 경우 이러한 관절면의 손상 수준이 감소 되었음을 확인하였다. 정상군의 관절 활막 조직 대비 골관절염이 유도된 군은 관절 주변에 활막 세포의 과다 침투로 인한 손상 증가로 융모 수준이 증가 하였으며 약물 투여군의 경우 이러한 연골 및 뼈의 침윤이 상대적으로 감소한 것을 확인하였다. 또한 300mg 지연방출정 (G6)은 양호한 결과를 나타내었다. 특히, 300mg 속방정 (G5) 및 300mg 서방정 (G7)과 비교하여 특정 용출 패턴을 가진 300mg 지연방출정 (G6)만 좋은 결과가 나타났으며, 이는 매우 특이적인 결과이었다.Additionally, as shown in Figure 10, as a result of Safranin-O staining, in the osteoarthritis-induced group, normal cartilage tissue was destroyed by the induction, and the level of damage to the proteoglycan tissue increased. On the other hand, in the drug administration group, stained proteoglycan tissue was widely distributed around the synovial membrane. In H&E staining, compared to the cartilage tissue of the normal group, the osteoarthritis-induced group showed deeper cracks and erosion of the joint surface, and it was confirmed that the level of damage to the joint surface was reduced in the drug-administered group. Compared to the joint synovial tissue of the normal group, the group with induced osteoarthritis had an increased level of villi due to increased damage due to excessive infiltration of synovial cells around the joint, and in the drug-administered group, it was confirmed that this infiltration of cartilage and bone was relatively reduced. Additionally, 300mg delayed-release tablet (G6) showed good results. In particular, compared to the 300mg immediate-release tablet (G5) and 300mg sustained-release tablet (G7), only the 300mg delayed-release tablet (G6) with a specific dissolution pattern showed good results, which was a very specific result.
Claims (10)
에틸셀룰로오스를 포함하여 방출을 조절하며,
37±0.5 ℃, 50rpm 속도의 패들(paddle) 시험법으로 물 900ml 매질의 조건으로 용출시험 시, 로즈마린산의 방출이 45분에 45~65%, 90분에 80% 이상, 120분에 85% 이상인 관절염 치료용 제제.It is a tablet or capsule preparation that contains 280-320 mg of herbal extracts of Euryeongseon, Brachialis root, and Herbaceae as active ingredients, and is taken twice a day.
Contains ethylcellulose to control release,
When dissolving in 900 ml of water using the paddle test method at 37 ± 0.5 ℃ and 50 rpm, the release of rosmarinic acid was 45 to 65% in 45 minutes, more than 80% in 90 minutes, and more than 85% in 120 minutes. Preparations for treating arthritis.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020230145116A KR20230153973A (en) | 2020-11-24 | 2023-10-26 | Pharmaceutical composition comprising high amount of an active ingredient derived from herbal substances |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020200159042 | 2020-11-24 | ||
KR20200159042 | 2020-11-24 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020230145116A Division KR20230153973A (en) | 2020-11-24 | 2023-10-26 | Pharmaceutical composition comprising high amount of an active ingredient derived from herbal substances |
Publications (2)
Publication Number | Publication Date |
---|---|
KR20220071956A KR20220071956A (en) | 2022-05-31 |
KR102618628B1 true KR102618628B1 (en) | 2023-12-27 |
Family
ID=81754875
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020210163840A KR102618628B1 (en) | 2020-11-24 | 2021-11-24 | Pharmaceutical composition comprising high amount of an active ingredient derived from herbal substances |
KR1020230145116A KR20230153973A (en) | 2020-11-24 | 2023-10-26 | Pharmaceutical composition comprising high amount of an active ingredient derived from herbal substances |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020230145116A KR20230153973A (en) | 2020-11-24 | 2023-10-26 | Pharmaceutical composition comprising high amount of an active ingredient derived from herbal substances |
Country Status (3)
Country | Link |
---|---|
KR (2) | KR102618628B1 (en) |
CN (1) | CN116744908A (en) |
WO (1) | WO2022114795A1 (en) |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR0180567B1 (en) * | 1995-12-29 | 1999-03-20 | 김준웅 | Method for extracting and purifying effective reactive from compound crude drug |
KR100483707B1 (en) | 2001-05-18 | 2005-04-18 | 에스케이케미칼주식회사 | Cartilage protective ingredients from medicinal plants and their composition |
KR20110009379A (en) * | 2009-07-22 | 2011-01-28 | 한국맥널티 주식회사 | Galenical extract-containing tablet having shortened disintergration time |
KR101559339B1 (en) * | 2014-02-03 | 2015-10-12 | 에스케이케미칼주식회사 | Fast-release tablet comprising high amounts of herbal substances |
KR101761983B1 (en) * | 2014-08-25 | 2017-08-07 | 아주대학교산학협력단 | Fast dissolving oral thin film composite and preparing method thereof |
KR101923403B1 (en) * | 2017-01-12 | 2018-11-29 | (주)넥스팜코리아 | Oral composition of sustained-release formular containing limaprost or limaprost alfadex |
-
2021
- 2021-11-24 CN CN202180091670.7A patent/CN116744908A/en active Pending
- 2021-11-24 WO PCT/KR2021/017444 patent/WO2022114795A1/en active Application Filing
- 2021-11-24 KR KR1020210163840A patent/KR102618628B1/en active IP Right Grant
-
2023
- 2023-10-26 KR KR1020230145116A patent/KR20230153973A/en active Application Filing
Also Published As
Publication number | Publication date |
---|---|
KR20230153973A (en) | 2023-11-07 |
CN116744908A (en) | 2023-09-12 |
KR20220071956A (en) | 2022-05-31 |
WO2022114795A1 (en) | 2022-06-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2287333T5 (en) | Modified release tamsulosin tablets | |
EP2428204A2 (en) | pH sensitive matrix formulation | |
ES2642788T3 (en) | Manufacture of granules without active substance and tablets comprising the same | |
KR101234254B1 (en) | Aceclofenac sustained-release formulation for providing pharmaceutical clinical effects with once-a-day dosing | |
EP2448561B1 (en) | Solid pharmaceutical fixed dose compositions comprising irbesartan and amlodipine, their preparation and their therapeutic application | |
US20100204333A1 (en) | Novel Pharmaceutical Modified Release Dosage Form Cyclooxygenase Enzyme Inhibitor | |
JP2023026623A (en) | Pharmaceutical formulation with excellent dissolution property containing esomeprazole and sodium bicarbonate | |
AU2014299447B2 (en) | Pharmaceutical capsule composite formulation comprising tadalafil and tamsulosin | |
AU2017304029B2 (en) | Formulation having improved pH-dependent drug-release characteristics, containing esomeprazole or pharmaceutically acceptable salt thereof | |
KR20040006887A (en) | Compositions for controlled release acetaminophen dosage forms | |
JP2020535113A (en) | A pharmaceutical composition containing esomeprazole and a multi-unit spherical tablet containing a pharmaceutically acceptable salt thereof, and a method for producing the same. | |
WO2004078111A2 (en) | Extended release minocycline compositions and processes for their preparation | |
KR102618628B1 (en) | Pharmaceutical composition comprising high amount of an active ingredient derived from herbal substances | |
ES2963886T3 (en) | Tablets containing tamsulosin and solifenacin | |
KR20190098525A (en) | Pharmaceutical sustained-release composition containing lacosamide | |
Singh et al. | Formulation and in vitro evaluation of bilayer tablets of lansoprazole and amoxycillin trihydrate for the treatment of peptic ulcer | |
KR20130117128A (en) | Sustained release tablets containing levodropropizine and manufacturing method for the same | |
KR20200116867A (en) | Pharmaceutical composition comprising esomeprazole, or pharmaceutically acceptable salt thereof with dual release profile | |
RU2367438C2 (en) | Controlled release trimetazidine matrix tablet | |
AU2018332417B2 (en) | Pharmaceutical composition for treating acute and chronic pain, containing polmacoxib and tramadol | |
KR20220071957A (en) | Pharmaceutical composition comprising high amount of an active ingredient derived from herbal substances | |
Mehetre et al. | A study on Formulation and Evaluation of Gastroretentive tablet incorporating Ciprofloxacin Hydrochloride | |
CN114762687A (en) | Premix of potassium ion competitive acid retarder and preparation thereof | |
KR20200121591A (en) | Pharmaceutical Composition Comprising Aceclofenac and Method of Preparing Thereof | |
US20090202633A1 (en) | Extended release formulations of guaifenesin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A201 | Request for examination | ||
A302 | Request for accelerated examination | ||
E902 | Notification of reason for refusal | ||
E701 | Decision to grant or registration of patent right | ||
GRNT | Written decision to grant |