CN102988406B - 用于抑制发炎的医药组合物及套组 - Google Patents
用于抑制发炎的医药组合物及套组 Download PDFInfo
- Publication number
- CN102988406B CN102988406B CN201110320388.XA CN201110320388A CN102988406B CN 102988406 B CN102988406 B CN 102988406B CN 201110320388 A CN201110320388 A CN 201110320388A CN 102988406 B CN102988406 B CN 102988406B
- Authority
- CN
- China
- Prior art keywords
- hyaluronic acid
- vitamin
- composition
- medical composition
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 206010061218 Inflammation Diseases 0.000 title claims abstract description 26
- 230000004054 inflammatory process Effects 0.000 title claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 3
- 230000002401 inhibitory effect Effects 0.000 title abstract 3
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 68
- 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 claims abstract description 66
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 66
- 229940088594 vitamin Drugs 0.000 claims abstract description 26
- 229930003231 vitamin Natural products 0.000 claims abstract description 26
- 235000013343 vitamin Nutrition 0.000 claims abstract description 26
- 239000011782 vitamin Substances 0.000 claims abstract description 26
- 150000003722 vitamin derivatives Chemical class 0.000 claims abstract description 25
- 239000000203 mixture Substances 0.000 claims description 57
- 238000002347 injection Methods 0.000 claims description 22
- 239000007924 injection Substances 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 19
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 11
- 229930003316 Vitamin D Natural products 0.000 claims description 10
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 10
- 239000011710 vitamin D Substances 0.000 claims description 10
- 235000019166 vitamin D Nutrition 0.000 claims description 10
- 150000003710 vitamin D derivatives Chemical class 0.000 claims description 10
- 229940046008 vitamin d Drugs 0.000 claims description 10
- 206010003246 arthritis Diseases 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 6
- 201000005569 Gout Diseases 0.000 claims description 3
- 230000002926 anti-osteoarthritic effect Effects 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 14
- 239000003937 drug carrier Substances 0.000 abstract 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 16
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 16
- 238000000034 method Methods 0.000 description 15
- 201000008482 osteoarthritis Diseases 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 230000000694 effects Effects 0.000 description 12
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 11
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 9
- 210000002950 fibroblast Anatomy 0.000 description 9
- 239000001963 growth medium Substances 0.000 description 9
- 210000002437 synoviocyte Anatomy 0.000 description 9
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 8
- 229930003268 Vitamin C Natural products 0.000 description 8
- 229930003427 Vitamin E Natural products 0.000 description 8
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 8
- 230000028709 inflammatory response Effects 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 239000011718 vitamin C Substances 0.000 description 8
- 235000019154 vitamin C Nutrition 0.000 description 8
- 239000011709 vitamin E Substances 0.000 description 8
- 235000019165 vitamin E Nutrition 0.000 description 8
- 229940046009 vitamin E Drugs 0.000 description 8
- 239000002609 medium Substances 0.000 description 7
- 102000003777 Interleukin-1 beta Human genes 0.000 description 6
- 108090000193 Interleukin-1 beta Proteins 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000012360 testing method 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
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- OVBPIULPVIDEAO-LBPRGKRZSA-N Folic acid Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 4
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 4
- -1 aminomethyl folic acid Chemical compound 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 229960000304 folic acid Drugs 0.000 description 4
- 235000019152 folic acid Nutrition 0.000 description 4
- 239000011724 folic acid Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 2
- 208000006820 Arthralgia Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- 206010018634 Gouty Arthritis Diseases 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 208000004575 Infectious Arthritis Diseases 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102000000588 Interleukin-2 Human genes 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 230000002917 arthritic effect Effects 0.000 description 2
- 208000025255 bacterial arthritis Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 208000037976 chronic inflammation Diseases 0.000 description 2
- 230000006020 chronic inflammation Effects 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 239000000644 isotonic solution Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 2
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 210000001258 synovial membrane Anatomy 0.000 description 2
- 229940036220 synvisc Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 229940125725 tranquilizer Drugs 0.000 description 2
- 239000003204 tranquilizing agent Substances 0.000 description 2
- 230000002936 tranquilizing effect Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 230000007923 virulence factor Effects 0.000 description 2
- 239000000304 virulence factor Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-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
- 241000561734 Celosia cristata Species 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010057254 Connective tissue inflammation Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001188 articular cartilage Anatomy 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
- 239000000872 buffer Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 210000001520 comb Anatomy 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000002316 cosmetic surgery Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 229960002986 dinoprostone Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 238000012407 engineering method Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000006624 extrinsic pathway Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003230 hygroscopic agent Substances 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 239000011229 interlayer Substances 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011785 micronutrient Substances 0.000 description 1
- 235000013369 micronutrients Nutrition 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000007981 phosphate-citrate buffer Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(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- Chemical compound [Na+].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 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000001171 synovial bursa Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000003954 umbilical cord Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- 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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及一种用于抑制发炎的医药组合物,其包含:(a)玻尿酸、(b)维生素、及(c)医药可接受载剂。本发明还提供一种用于抑制发炎的套组,至少包括含有有效剂量的玻尿酸的第一部分以及含有有效剂量的维生素的第二部分。本发明并用维生素与玻尿酸,可提供增进的抗发炎效果,从而能够以较低的玻尿酸剂量提供所欲的抗发炎效果,减轻或免除玻尿酸进入人体后所可能引起的暂时性发炎反应。
Description
技术领域
本发明关于一种用于抑制发炎的医药组合物,尤其关于抗关节炎的医药组合物。
背景技术
关节炎是一常见的慢性疾病,其因关节软骨退化或结缔组织发炎而造成关节疼痛,进而影响关节的正常活动。依据发生部位与原因,关节炎共可分为一百多种类型,最常见者包括骨关节炎(退化性关节炎)、类风湿性关节炎、痛风性关节炎、细菌性关节炎、僵直性脊椎关节炎、及红斑性狼疮等。
针对关节炎的治疗,一般于初期先采取保守性、非手术性的疗法,例如药物治疗与注射剂治疗,当初期治疗未见成效时,才会采用外科手术的治疗方式。已知药物治疗包括使用类固醇与非类固醇的抗发炎药物,其中,类固醇药物虽具止痛效果快且显著的优点,但会引起许多副作用,例如骨质疏松症、伤口不易愈合、上消化道出血,甚至会加重如高血压或糖尿病等疾病的症状,故已逐渐不被纳入药物治疗的行列。至于非类固醇药物,虽也具良好的止痛效果,但若长期使用,则会产生诸如消化性溃疡、下肢水肿及肾脏功能损伤等副作用,故于实际应用上也多受限制。
玻尿酸(hyaluronicacid),又称“透明质酸”或“醣醛酸”,已知其具抗发炎效果,故已广泛被运用于抑制骨关节炎的注射剂中。其中,将含有玻尿酸的注射液直接注射至患者的关节,以适度减缓发炎及病患的疼痛感。玻尿酸的作用机制迄今并不明确,但已知其另可作为一种润滑剂以帮助关节活动,同时达到改善关节功能的效果。然而,业经发现,玻尿酸虽可有效减轻疼痛,但其于进入人体后,有时反而会在数日内引起暂时性发炎反应,严重者甚至造成慢性发炎(此可参见Leopoldetal.,Increasedfrequencyofacutelocalreactiontointra-articularhylanGF-20(Synvisc)inpatientsreceivingmorethanonecourseoftreatment.JBoneJointSurg,2002;84:1619-23;Bernardeauetal.,Acutearthritisafterintra-articularhyaluronateinjection:onsetofeffusionswithoutcrystal.AnnRheumDis,2001;60:518-20;以及Kroesenetal.,Inductionofanacuteattackofcalciumpyrophosphatedihydratearthritisbyintra-articularinjectionofhylanG-F20(Synvisc).ClinRheumatol,2000;19:147-9等文献)。因此,若能以较低玻尿酸剂量提供所欲的抗发炎效果,则可减缓、甚至避免玻尿酸进入人体的后所可能引起的后续发炎反应。
已有文献报导一种改进玻尿酸制剂的方法,其利用化学合成方式,将玻尿酸通过一多胜肽连结至具有抗发炎活性的胺基甲基叶酸(methotrexate,MTX)上以形成一共轭物(conjugate),由此制得的产物具有改良的抗发炎效果(此可参见Hommaetal.,Novelhyaluronicacid-methotrexateconjugatesforosteoarthritistreatment,BioorganicandMedicinalChemistry,17(2009),4647-4656的文献)。惟,根据该文献的教示,单纯混合玻尿酸与胺基甲基叶酸所形成的混合物并无法达到改良效果,其使得合成该共轭物成为必要的手段。然而,制备该共轭物必须使用多胜肽原料且涉及繁复的合成步骤,此势必增加玻尿酸制剂的制造成本,不仅于量产制程上造成困难,也增加使用者的经济负担,故在临床应用上多有局限。
本发明人发现,并用维生素与玻尿酸,可提供增进的抗发炎效果,从而能够以较低的玻尿酸剂量提供所欲的抗发炎效果,减轻或免除玻尿酸进入人体后所可能引起的暂时性发炎反应。
发明内容
为了改进传统玻尿酸制剂的缺点,本发明的目的在于提供一种用于抑制发炎的医药组合物,其包含:(a)玻尿酸、(b)维生素、及(c)医药可接受载剂。
本发明的另一目的在于提供一种抑制发炎的方法,其包含使患者施用一有效量的上述医药组合物。
本发明的又一目的在于提供一种用于抑制发炎的套组,其包含一包含有效剂量的玻尿酸的第一部分,以及一包含有效剂量的维生素的第二部分。
本发明的详细技术及较佳实施方式,将描述于以下内容中,以供本发明所属领域具通常知识者据以明了本发明的特征。
附图说明
图1所示为经维生素C处理的纤维母细胞样滑膜细胞(fibroblast-likesynoviocytes)中发炎介质肿瘤坏死因子-α(TNF-α)的表现量的统计直条图;
图2所示为经维生素C处理的纤维母细胞样滑膜细胞中发炎介质介白素-1β(IL-1β)的表现量的统计直条图;
图3所示为经维生素D处理的纤维母细胞样滑膜细胞中TNF-α的表现量的统计直条图;
图4所示为经维生素D处理的纤维母细胞样滑膜细胞中发炎介质IL-1β的表现量的统计直条图;
图5所示为经维生素E处理的纤维母细胞样滑膜细胞中TNF-α的表现量的统计直条图;以及
图6所示为经维生素E处理的纤维母细胞样滑膜细胞中发炎介质IL-1β的表现量的统计直条图。
具体实施方式
于本文中(尤其后附申请专利范围中),除非另外说明,所使用的“一”、“该”及类似用语应理解为包含单数及复数形式。
如上述,于玻尿酸进入人体后,有时会于数日内引起暂时性发炎反应,甚至造成慢性发炎,不利于所欲提供的抗发炎效益;另一方面,已有文献所提出的制备玻尿酸与胺基甲基叶酸的共轭物的改良方法,则具诸多限制。本发明通过玻尿酸与维生素的并用,可以简易手段改进现有玻尿酸制剂的缺点。
因此,本发明提供一种用于抑制发炎的医药组合物,其包含:(a)玻尿酸、(b)维生素、及(c)医药可接受载剂。
玻尿酸为构成细胞外基质的主要成分的一,广布于内皮组织、结缔组织、表皮组织及神经组织中,且对于细胞的增生及迁移等生理活动至关重要。此外,由于玻尿酸为皮肤真皮层内的重要保湿成分,且具有优异的黏容性与伸缩性,是一种非常理想的填充物质,故常用于美容产品及整形手术中。
玻尿酸是一不具硫元素的糖胺聚醣,其基本结构是由两个双糖单位D-葡萄糖醛酸及N-乙酰葡糖胺组成的大型多醣类,具如下式(I)的化学式:
玻尿酸可自天然物质中制备,例如由鸡冠、脐带、软骨及皮肤等活体部分萃取而得,也可由化学合成或利用酵母菌等微生物通过培养或基因工程方法生产。市售的玻尿酸制剂也可作为本发明医药组合物中玻尿酸的来源,例如含玻尿酸钠水溶液的制剂,包括ARTZ 及等,或包含交联玻尿酸衍生物水溶液的制剂,包括及
适用于本发明医药组合物的成份(a)的玻尿酸并无特别限制,但较佳具平均分子量约3万至约1000万道尔顿(Dalton),更佳为具平均分子量约50万至约600万道尔顿。此外,玻尿酸可为不形成盐的游离状态,也可形成药学上可容许的盐。玻尿酸于药学上可容许的盐包括与无机碱所形成的盐,例如钠盐或钾盐等碱金属离子盐、镁盐或钙盐等碱土金属离子盐、以及铵盐等;或者与有机碱所形成的盐,例如与二乙醇胺、环己胺或胺基酸等所形成的盐。
维生素(或称维他命)为生物体所须的微量营养成分,其无法由生物体生产,必须通过如饮食等外部途径而获得。尽管维生素无法像醣类、蛋白质及脂肪般于生物体中产生能量,但其对生物体的新陈代谢具有重要的调节作用。本发明人研究发现,如后附实施例所示,相较于单独施用维生素或玻尿酸,当合并使用玻尿酸与维生素时,可意外地提供增进的抗发炎效果,从而可以较低玻尿酸剂量提供所欲的抗发炎效果,减缓、甚至避免玻尿酸进入人体后所可能引起的后续发炎反应。
本发明医药组合物的成份(b)较佳一选自以下群组的维生素:维生素A、维生素B、维生素C、维生素D、维生素E、及前述的任意组合。成份(b)更佳选自以下群组:维生素C、维生素D、维生素E、及前述的任意组合。
于本发明医药组合物中,成份(a)与(b)的含量配比并无特别限制。其中,当成份(b)为维生素C或维生素E的至少一者时,成份(a)与(b)的重量比通常为1∶1至1000∶1,较佳为1∶1至10∶1。当成份(b)为维生素D时,成份(a)与(b)的重量比通常为1000∶1至100000∶1,较佳为8000∶1至15000∶1。
本发明医药组合物可使用于兽医与人类医药上,且可呈任何形式,并以任何合宜的方式施用。举例言之,但不以此为限,该医药组合物可以口服、皮下、静脉或关节内注射等投药方式施用的。视使用形式及用途而定,可于本发明医药组合物中包含一成份(c)医药可接受载剂。
以制备适于口服投药的药剂形式为例,可于本发明医药组合物中含有不会对玻尿酸及维生素产生不利影响的医药可接受载剂,例如:溶剂、油性溶剂、稀释剂、安定剂、吸收延迟剂、崩散剂、乳化剂、抗氧化剂、黏合剂、润滑剂、吸湿剂等。可利用任何合宜的方法,将该组合物制成适于口服投药的形式,例如:锭剂、胶囊剂、颗粒剂、散剂、流浸膏剂、溶液剂、糖浆剂、悬液剂、乳剂、及酊剂等等。
至于适于皮下、静脉或关节内注射的药剂形式,则可于本发明医药组合物中含有一或多种例如pH值调整剂、等渗透压剂或安定剂等添加剂(如硫酸氢钠、双氢硫酸钠、磷酸二氢钠、磷酸氢钠或氯化钠等),以及如等张溶液、注射用水、生理食盐水或盐类缓冲液(如磷酸盐缓冲液或柠檬酸盐缓冲液)等溶剂,以制成如静脉输注液、乳剂静脉输注液、干粉注射剂、悬液注射剂、或干粉悬液注射剂等。
本发明医药组合物可视需要另含有调味剂、调色剂、着色剂等添加剂,以提高所得药剂服用时的口适感及视觉感受;另可添加适当的保存剂、防腐剂、抗菌剂、抗真菌剂等,以改善所得药剂的储存性。
视需要地,可于本发明医药组合物中并含一或多种其他活性成分,以进一步加强组合物的功效或增加制剂配方的运用灵活性与调配度。举例言之,可于本发明医药组合物含有一或多种如下活性成分:类固醇抗发炎药物、非类固醇抗发炎药物、葡萄糖胺(glucosamine)、以及其他活性成分等,只要该其他活性成分对玻尿酸及维生素的效益没有不利的影响即可。
由于本发明医药组合物可提供增进的抗发炎效果,故可用于抑制发炎,尤其可用于抑制关节炎,包括骨关节炎(退化性关节炎)、类风湿性关节炎、痛风性关节炎、细菌性关节炎、僵直性脊椎关节炎、及红斑性狼疮等,较佳用于抑制骨关节炎及类风湿性关节炎。于一实施方式中,是将本发明医药组合物制成注射剂的药剂形式,以供用于关节注射的治疗方法。
相较于现有玻尿酸制剂对于类风湿性关节炎无法达成显著的治疗效果,本发明医药组合物的一有利的处在于,可通过抑制膝关节滑囊细胞分泌肿瘤坏死因子(TNF)(肿瘤坏死因子为类风湿性关节炎重要的致病因子),提供优异的抑制类风湿性关节炎的功效,因此,尤其可用于类风湿性关节炎的治疗。另,本发明医药组合物也可通过抑制第一型介白素(IL-1)来达到抑制发炎的效果。退化性关节炎近年来被认为是一种非典型的发炎疾病,通过抑制第一型介白素,也可减缓退化性关节炎的进展,进而达到治疗退化性关节炎的目的。
此外,本发明组合物除可有效减轻患者的关节疼痛及改善关节活动度外,也可预防关节炎的发生。再者,不同于已知玻尿酸与胺基甲基叶酸的组合,需通过多胜肽的繁复手段以形成共轭物方可提供所欲的抗发炎效果,于本发明医药组合物中,玻尿酸及维生素仅需简单混合即可,故具有制程简便、适于大规模量产的优点。
由于本发明医药组合物可改善现有玻尿酸制剂的缺点,故也可应用于玻尿酸的任何已知用途,而不限于抗关节炎。举例言之,可将本发明组合物运用于美容产品或整形外科,例如可将其添加于皮肤保养品或脸部的玻尿酸注射剂中。
本发明也提供一种抑制发炎的方法,其包含使患者施用一有效量的本发明的医药组合物。于本发明的一实施方式中,以注射剂的型式,将本发明医药组合物注射至患者的关节中,以达成治疗关节炎的效果。
本发明也提供一种用于抑制发炎的套组,其包含:含有效剂量的玻尿酸的第一部分、以及含有效剂量的维生素的第二部分。其中,该套组中玻尿酸与维生素的种类、性质、来源与用量比例等皆如上文所述。
于本发明套组中,该第一部分与第二部分的形式并无特殊限制。举例言之,于供关节内注射投药的套组中,该第一部分及第二部分可呈溶液形式并分别置于不同灭菌包装(例如塑胶瓶或如安瓶的玻璃瓶)中,且各包装可包含多次投药剂量、但较佳为单次投药剂量的第一部分或第二部分。于此,本发明套组可更包含一注射针筒(例如一次性注射针筒),或视需要更包含一使用说明书。于进行关节内注射投药时,可依该使用说明书的指示(包括如套组的操作方式及溶液混合的比例等信息),将该两部分装入该注射针筒中以施用药剂。
另一方面,于供口服投药的套组中,该第一部分及第二部分可各自独立呈锭剂或胶囊的形式,且该二部分可依单次投药剂量或多次投药剂量分别置于不同包装中。于此,本发明套组可视需要包含一使用说明书,于进行口服投药时,可依该使用说明书的指示(包括如投药时程及建议剂量等信息),合并该两部分进行服用。
以下列具体实施方式以进一步例示说明本发明。其中该些实施方式仅提供作为说明,而非用以限制本发明的范畴。
[制备例]玻尿酸关节注射液的制备
于一预装式玻尿酸注射针器内,添加浓度为0.5至2毫克的玻尿酸(平均分子量为60至80万道尔顿)、等张溶液1毫升及0.01至1毫克的维生素C或维生素E、或10-4至10-5毫克的维生素D,再添加总量为5至20毫克的氯化钠、硫酸氢钠及双氢硫酸钠,最后添加2毫升注射用水作为赋型剂,以制得玻尿酸关节注射液,并置于4℃的避光环境下储存。
[实施例1]玻尿酸关节注射液的细胞试验
实验A、细胞培养
收集来自五个罹患有退化性关节炎的病患的纤维母细胞样滑膜细胞(fibroblast-likesynoviocytes,FLS)并进行培养。首先,将病患的关节滑膜(synovium)切成小碎片,再使其悬浮于一DMEM(Dulbeccomodifiedeagle’smedium)培养基中,并于37℃、5%的二氧化碳的环境中培养3天。该培养基含有1.5克/升碳酸氢钠(S6297,Sigma-Aldrich,StLouis,密苏里州,美国)、1%盘尼西林-链霉素-新霉素(P4083,Sigma-Aldrich)、以及10%胎牛血清(04-001-1A,BiologicalIndustries,GrandIsland,纽约州,美国)。
以磷酸盐缓冲液(PBS)洗去未附着的细胞,并更换培养基,再培养留下的附着的细胞历时2周。重复上述程序3至6次,存留下的细胞即为纤维母细胞样滑膜细胞,将其用于以下试验。
实验B、细胞处理
于不含血清的培养基中培养实验A制得的纤维母细胞样滑膜细胞历时24小时,再分别于如下四种培养基中培养24小时:(1)仅含有10%胎牛血清的DMEM培养基,此作为控制组;2)含有10%胎牛血清的DMEM培养基及玻尿酸(平均分子量为60至80万道尔顿);3)含有10%胎牛血清的DMEM培养基及维生素C或维生素D或维生素E;以及4)含有10%胎牛血清的DMEM培养基、玻尿酸(平均分子量为60至80万道尔顿)以及维生素C或维生素D或维生素E。以上四种培养基中玻尿酸与维生素的剂量浓度如以上制备例所示。
接着,分别收集上述四组细胞并离心,再收集上清液,以进行以下试验。
实验C、与关节炎相关的蛋白质的定量
发炎反应为一复杂的过程,其中包含产生自由基分子(例如:一氧化氮及过氧化氢等)及细胞激素(cytokine)(例如:前列腺素2(PGE2)、肿瘤坏死因子-α(TNF-α)、干扰素-γ(IFN-γ)、介白素-2(IL-2,Interleukin-2)、及介白素-1β(IL-1β))等。因此,借助测量与发炎反应相关的自由基分子或细胞激素,即可得知发炎反应的程度。
于此实验中,使用夹层结合蛋白质分析套组(sandwichbindingproteinassaykit或sandwichELISAkits,购自eBioscience公司),并依据厂商的使用手册,利用标准曲线以测定实验B所收集上清液中二个与退化性关节炎相关的细胞激素的浓度,以观察其表现程度,借此判断细胞的发炎情形,该二细胞激素分别为肿瘤坏死因子-α(标准品购自88-7340,eBioscience)及介白素-1β(88-7010,标准品购自eBioscience公司)。各样本皆进行两次试验,并使用一酶免疫吸附分析(ELISA)读取器(SunriseRemote,TECAN)进行测定。结果如表1至表3及图1至图6所示。
表1
表2
表3
[试验结果]
由表1至表3及图1至图6显示,来自退化性关节炎患者的关节细胞会分泌大量的发炎介质TNF-α及IL-1β,说明其发炎情况严重,而结合玻尿酸与维生素,则可有效抑制该发炎介质的表现。其中,如图1、3及5所示,本发明结合玻尿酸与维生素,可有效抑制TNF-α(类风湿性关节炎重要的致病因子)表现,故可提供优异的抑制关节炎、尤其是类风湿性关节炎的功效。此外,如图2、4及6所示,本发明结合玻尿酸与维生素,也可通过抑制IL-1β表现而达到抑制发炎、尤其是抑制退化性关节炎的效果。以上试验数据,也显示本发明医药组合物能够提供不可预期的增进抗发炎的效果。
上述实施例仅用以例示说明本发明的原理及功效,而非用于限制本发明。任何熟于此项技艺的人士均可在不违背本发明的技术原理及精神的情况下,对上述实施例进行修改及变化。
Claims (7)
1.一种用于抑制发炎的医药组合物,其特征包含:
(a)玻尿酸;
(b)维生素;及
(c)医药可接受载剂;
其中,成份(b)为维生素D;成份(a)与(b)的重量比为1000:1至100000:1;且该医药组合物呈供关节内注射投药的药剂形式。
2.如权利要求1所述的医药组合物,其特征在于:成份(a)的平均分子量为3万至1000万道尔顿。
3.如权利要求1所述的医药组合物,其特征在于:成份(a)的平均分子量为50万至600万道尔顿。
4.如权利要求1至3中任一项所述的医药组合物,其特征在于:该医药组合物用于抗关节炎。
5.如权利要求4所述的医药组合物,其特征在于:该医药组合物用于抗骨关节炎、抗类风湿性关节炎或抗痛风性关节炎。
6.如权利要求5所述的医药组合物,其特征在于:该医药组合物用于抗类风湿性关节炎。
7.一种用于抑制发炎的套组,其特征包含:
第一部分,包含有效剂量的玻尿酸;以及
第二部分,包含有效剂量的维生素;
其中,该维生素为维生素D;成份(a)与(b)的重量比为1000:1至100000:1;且该第一及第二部分别呈供注射投药的溶液形式,且该套组更包含一个注射针筒。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
TW100133355A TWI466675B (zh) | 2011-09-16 | 2011-09-16 | 用於抑制發炎之醫藥組合物 |
TW100133355 | 2011-09-16 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102988406A CN102988406A (zh) | 2013-03-27 |
CN102988406B true CN102988406B (zh) | 2016-03-02 |
Family
ID=45507432
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201110320388.XA Expired - Fee Related CN102988406B (zh) | 2011-09-16 | 2011-10-20 | 用于抑制发炎的医药组合物及套组 |
Country Status (6)
Country | Link |
---|---|
US (2) | US8835405B2 (zh) |
EP (1) | EP2570118B1 (zh) |
JP (1) | JP5639604B2 (zh) |
CN (1) | CN102988406B (zh) |
ES (1) | ES2701787T3 (zh) |
TW (1) | TWI466675B (zh) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100383139C (zh) | 2005-04-07 | 2008-04-23 | 天津和美生物技术有限公司 | 可抑制细胞释放肿瘤坏死因子的哌啶-2,6-二酮衍生物 |
WO2014165713A2 (en) * | 2013-04-03 | 2014-10-09 | Cedars-Sinai Medical Center | Treatment of inflammatory conditions by modulation of hyaluronan and hyaluronidase activity |
WO2014172784A1 (en) * | 2013-04-25 | 2014-10-30 | Aluron Biopharma Inc. | Crosslinked hyaluronic acid compositions |
US20150010606A1 (en) * | 2013-07-08 | 2015-01-08 | Arthrex, Inc. | Intra-articular injection and implant attachment of molecule consisting of lubricin and extracellular superoxide dismutase or hyaluronic acid and extracellular superoxide dismutase |
US9603867B2 (en) * | 2015-03-03 | 2017-03-28 | Yung Shin Pharm. Ind. Co., Ltd. | Pharmaceutical composition for improving wound healing or prophylactically preventing or inhibiting scar formation |
US10149868B2 (en) * | 2016-05-31 | 2018-12-11 | Tco Co., Ltd. | Use of Streptococcus thermophilis TCI633 in treating arthritis |
IT201700117361A1 (it) * | 2017-10-17 | 2019-04-17 | Alfakjn S R L | Composizione liquida per uso come antiinfiammatorio |
CN110038027A (zh) * | 2018-01-16 | 2019-07-23 | 菲利达生技股份有限公司 | 用于抑制发炎的医药组合物 |
TWI663979B (zh) * | 2018-03-20 | 2019-07-01 | 菲利達生技股份有限公司 | 用於抗發炎之套組 |
DE112019006563T5 (de) * | 2019-01-06 | 2021-10-21 | Huseyin Coban | Verwendung von vitamin d als intraartikuläre injektion zur behandlung der arthrose (osteoarthrose) |
JP7461006B2 (ja) * | 2019-01-24 | 2024-04-03 | 国立大学法人大阪大学 | 関節炎の予防又は治療剤 |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1340994C (en) * | 1989-09-21 | 2000-05-16 | Rudolf Edgar Dr. Falk | Treatment of conditions and disease |
US5834444A (en) | 1991-07-03 | 1998-11-10 | Hyal Pharmaceutical Corporation | Hyaluronic acid and salts thereof inhibit arterial restenosis |
US6645948B2 (en) * | 1998-03-24 | 2003-11-11 | George D. Petito | Nutritional composition for the treatment of connective tissue |
US6924273B2 (en) * | 2000-10-03 | 2005-08-02 | Scott W. Pierce | Chondroprotective/restorative compositions and methods of use thereof |
US20020099032A1 (en) | 2000-11-10 | 2002-07-25 | Kiyotsugu Higashi | Preparations and method of producing the same |
JP3510861B2 (ja) | 2001-01-31 | 2004-03-29 | リバテープ製薬株式会社 | 美容食品 |
JP2004137183A (ja) | 2002-10-17 | 2004-05-13 | Kotobuki Seiyaku Kk | グリコサミノグリカン又はその塩を含む経口投与用医薬品、健康食品又は栄養薬品組成物 |
JP4143387B2 (ja) | 2002-11-21 | 2008-09-03 | 株式会社アセロラフーズ | 健康食品 |
CN1314361C (zh) * | 2003-04-02 | 2007-05-09 | 李安虎 | 一种关节保健饮品或食品及其制备方法 |
CA2534033A1 (fr) | 2003-07-30 | 2005-02-10 | Anteis S.A. | Matrice complexe a usage biomedical |
US20070224278A1 (en) * | 2003-11-12 | 2007-09-27 | Lyons Robert T | Low immunogenicity corticosteroid compositions |
WO2006043965A1 (en) * | 2004-10-14 | 2006-04-27 | Allergan, Inc. | Therapeutic ophthalmic compositions containing retinal friendly excipients and related methods |
JP2006316053A (ja) | 2005-04-13 | 2006-11-24 | Hayashibara Biochem Lab Inc | 細胞障害抑制剤とその用途 |
DE202005012510U1 (de) | 2005-08-09 | 2007-01-04 | Almapharm Christian F.A. Botzenhardt Gmbh + Co | Präparat umfassend Hyaluronsäure, Emu-Öl und Vitamin K |
ITPD20060219A1 (it) | 2006-05-31 | 2007-12-01 | Fidia Farmaceutici | Composizioni farmaceutiche contenenti acido ialuronico solfatato nel trattamento dell'osteoartrosi |
MX2009013265A (es) * | 2007-06-06 | 2010-01-25 | Novus Int Inc | Suplementos alimenticios para la promocion de crecimiento, reparacion y mantenimiento de huesos y articulaciones. |
FR2919185B1 (fr) | 2007-07-23 | 2010-09-10 | Ard Sa | Utilisation d'acide hyaluronique pour la preparation de compositions destinees a l'amelioration notamment de l'etat des muqueuses |
WO2010054125A1 (en) * | 2008-11-05 | 2010-05-14 | Georgia Tech Research Corporation | Formulations and uses of 24r, 25-dihydroxyvitamin d3 as an anti-apoptotic |
FR2948286B1 (fr) | 2009-07-27 | 2011-08-26 | Jean-Noel Thorel | Composition injectable associant un agent de comblement et un milieu de croissance des fibroblastes |
US20110117207A1 (en) * | 2009-11-17 | 2011-05-19 | U.S. Nutraceuticals, LLC d/b/a Valensa International State of Incorporation: | Use of eggshell membrane formulations to alleviate joint pain |
PT2455066T (pt) | 2010-11-08 | 2018-12-06 | Epitech Group S P A | Preparação farmacológica para utilização tópica contendo n-palmitoil-vanilamida |
US8623839B2 (en) | 2011-06-30 | 2014-01-07 | Depuy Mitek, Llc | Compositions and methods for stabilized polysaccharide formulations |
-
2011
- 2011-09-16 TW TW100133355A patent/TWI466675B/zh not_active IP Right Cessation
- 2011-10-20 CN CN201110320388.XA patent/CN102988406B/zh not_active Expired - Fee Related
- 2011-12-23 US US13/336,178 patent/US8835405B2/en not_active Expired - Fee Related
-
2012
- 2012-01-05 EP EP12150251.2A patent/EP2570118B1/en not_active Not-in-force
- 2012-01-05 ES ES12150251T patent/ES2701787T3/es active Active
- 2012-02-06 JP JP2012023099A patent/JP5639604B2/ja not_active Expired - Fee Related
-
2014
- 2014-08-06 US US14/452,836 patent/US9662350B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
TW201313236A (zh) | 2013-04-01 |
ES2701787T3 (es) | 2019-02-25 |
JP2013063943A (ja) | 2013-04-11 |
JP5639604B2 (ja) | 2014-12-10 |
EP2570118B1 (en) | 2018-09-19 |
CN102988406A (zh) | 2013-03-27 |
TWI466675B (zh) | 2015-01-01 |
US20130072452A1 (en) | 2013-03-21 |
EP2570118A1 (en) | 2013-03-20 |
US8835405B2 (en) | 2014-09-16 |
US9662350B2 (en) | 2017-05-30 |
US20150094279A1 (en) | 2015-04-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102988406B (zh) | 用于抑制发炎的医药组合物及套组 | |
CN108125980A (zh) | 用于稳定的多糖制剂的组合物和方法 | |
CN105796589A (zh) | 用于治疗关节的组合物和方法 | |
EA029237B1 (ru) | Вязкие смазки, содержащие хондроитин сульфат и производные гиалуроновой кислоты | |
JP5513430B2 (ja) | 炎症を抑制するための薬剤組成物及び方法 | |
CN104138469A (zh) | 治疗ii型糖尿病和逆转胰岛素抵抗的药物复合制剂及其制备方法 | |
CN102274174A (zh) | 苯并咪唑类药物油混悬剂 | |
CN108283643A (zh) | 一种噻嗪二酮类化合物在制备预防或治疗类风湿性关节炎的药物中的应用 | |
CN107753504A (zh) | 用于疼痛、瘙痒和发炎的锶基组合物和调配物 | |
CN114191425A (zh) | 2,4-二羟基苯甲酸在治疗铁过载疾病食品药品中的应用 | |
CN101426490A (zh) | 包含α-酮戊二酸/盐的组合物及其用于调节肌肉性能的用途 | |
CN108354898A (zh) | 一种治疗类风湿性关节炎的透皮给药制剂及其制备方法 | |
CA3123849A1 (en) | Strontium based compositions and formulations for pain, pruritus, and inflammation | |
CN105982911A (zh) | 一种氨基葡萄糖和玻璃酸钠组合的高粘弹性注射液的制备方法 | |
US20160051582A1 (en) | Pharmaceutical composition for treatment of chronic pain | |
CN101721422B (zh) | 治疗关节炎的药物及其制备方法 | |
CN205964694U (zh) | 超声电动微针经皮给药装置 | |
CN103238839A (zh) | 用于保养关节的含胶原蛋白的食品组成物 | |
CN1107501C (zh) | 阿苯达唑乳剂 | |
CN110038027A (zh) | 用于抑制发炎的医药组合物 | |
RU2395278C1 (ru) | Способ получения комплексного препарата для профилактики и лечения патологий обмена веществ и нарушений функций иммунной системы животных | |
KR101462212B1 (ko) | 염증 억제용 약제학적 조성물 및 방법 | |
CN103263405B (zh) | 用于治疗糖尿病的药物组合物及其应用 | |
CN107198692A (zh) | 五加苷元在制备治疗糖尿病药物中的应用 | |
CN1240389C (zh) | 磺酰化乙酰氨基葡萄糖药物组合物及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160302 Termination date: 20201020 |