WO2010133907A1 - Hexadentate chelators in inflammatory bowel disease - Google Patents
Hexadentate chelators in inflammatory bowel disease Download PDFInfo
- Publication number
- WO2010133907A1 WO2010133907A1 PCT/IB2009/005637 IB2009005637W WO2010133907A1 WO 2010133907 A1 WO2010133907 A1 WO 2010133907A1 IB 2009005637 W IB2009005637 W IB 2009005637W WO 2010133907 A1 WO2010133907 A1 WO 2010133907A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hdc
- pharmaceutical composition
- ibd
- colitis
- use according
- Prior art date
Links
- 208000022559 Inflammatory bowel disease Diseases 0.000 title claims abstract description 34
- 239000002738 chelating agent Substances 0.000 title claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 7
- GCTFIRZGPIUOAK-UHFFFAOYSA-N n-[[3,5-bis[[(2,3-dihydroxybenzoyl)amino]methyl]phenyl]methyl]-2,3-dihydroxybenzamide Chemical compound OC1=CC=CC(C(=O)NCC=2C=C(CNC(=O)C=3C(=C(O)C=CC=3)O)C=C(CNC(=O)C=3C(=C(O)C=CC=3)O)C=2)=C1O GCTFIRZGPIUOAK-UHFFFAOYSA-N 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 4
- 230000009885 systemic effect Effects 0.000 claims description 4
- GRUVVLWKPGIYEG-UHFFFAOYSA-N 2-[2-[carboxymethyl-[(2-hydroxyphenyl)methyl]amino]ethyl-[(2-hydroxyphenyl)methyl]amino]acetic acid Chemical group C=1C=CC=C(O)C=1CN(CC(=O)O)CCN(CC(O)=O)CC1=CC=CC=C1O GRUVVLWKPGIYEG-UHFFFAOYSA-N 0.000 claims description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 241000792859 Enema Species 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 206010009887 colitis Diseases 0.000 claims description 3
- 239000007920 enema Substances 0.000 claims description 3
- 229940095399 enema Drugs 0.000 claims description 3
- 230000002496 gastric effect Effects 0.000 claims description 3
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 3
- ZSTXLRNCUHUSRX-UHFFFAOYSA-N n-[2-[bis[2-[(2,3-dihydroxybenzoyl)amino]ethyl]amino]ethyl]-2,3-dihydroxybenzamide Chemical compound OC1=CC=CC(C(=O)NCCN(CCNC(=O)C=2C(=C(O)C=CC=2)O)CCNC(=O)C=2C(=C(O)C=CC=2)O)=C1O ZSTXLRNCUHUSRX-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- 208000027496 Behcet disease Diseases 0.000 claims description 2
- 208000009137 Behcet syndrome Diseases 0.000 claims description 2
- 206010009895 Colitis ischaemic Diseases 0.000 claims description 2
- 206010056979 Colitis microscopic Diseases 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 206010036774 Proctitis Diseases 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 208000008609 collagenous colitis Diseases 0.000 claims description 2
- 201000008243 diversion colitis Diseases 0.000 claims description 2
- 230000007071 enzymatic hydrolysis Effects 0.000 claims description 2
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 claims description 2
- 239000006260 foam Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 208000027138 indeterminate colitis Diseases 0.000 claims description 2
- 230000001524 infective effect Effects 0.000 claims description 2
- 208000004341 lymphocytic colitis Diseases 0.000 claims description 2
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 2
- 206010036784 proctocolitis Diseases 0.000 claims description 2
- 208000017048 proctosigmoiditis Diseases 0.000 claims description 2
- 230000028327 secretion Effects 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- RICKKZXCGCSLIU-UHFFFAOYSA-N 2-[2-[carboxymethyl-[[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]methyl]amino]ethyl-[[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]methyl]amino]acetic acid Chemical group CC1=NC=C(CO)C(CN(CCN(CC(O)=O)CC=2C(=C(C)N=CC=2CO)O)CC(O)=O)=C1O RICKKZXCGCSLIU-UHFFFAOYSA-N 0.000 claims 1
- 239000002775 capsule Substances 0.000 claims 1
- 239000006071 cream Substances 0.000 claims 1
- 239000000499 gel Substances 0.000 claims 1
- 159000000011 group IA salts Chemical class 0.000 claims 1
- 239000002674 ointment Substances 0.000 claims 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 34
- 229910052742 iron Inorganic materials 0.000 description 14
- -1 2-hydroxypyridyl moieties Chemical group 0.000 description 12
- 239000002552 dosage form Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 208000007502 anemia Diseases 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 0 CC(C)(CC(C)(C)NC(*)=O)CN(CC(C)(C)CNC(*)=O)CC(C)(*)CC(C)(C)NC(*)=O Chemical compound CC(C)(CC(C)(C)NC(*)=O)CN(CC(C)(C)CNC(*)=O)CC(C)(*)CC(C)(C)NC(*)=O 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 229920000881 Modified starch Polymers 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 125000006290 2-hydroxybenzyl group Chemical group [H]OC1=C(C([H])=C([H])C([H])=C1[H])C([H])([H])* 0.000 description 3
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 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 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000370 acceptor Substances 0.000 description 3
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 3
- 229960002170 azathioprine Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 239000003246 corticosteroid Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229960000598 infliximab Drugs 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 3
- 229960004963 mesalazine Drugs 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- NBGAYCYFNGPNPV-UHFFFAOYSA-N 2-aminooxybenzoic acid Chemical class NOC1=CC=CC=C1C(O)=O NBGAYCYFNGPNPV-UHFFFAOYSA-N 0.000 description 2
- LLUPVLHZPBTXOG-UHFFFAOYSA-N 4-amino-3-hydroxypyridine-2-carboxylic acid Chemical class NC1=CC=NC(C(O)=O)=C1O LLUPVLHZPBTXOG-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 108010008165 Etanercept Proteins 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 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 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 206010022971 Iron Deficiencies Diseases 0.000 description 2
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- HYMLWHLQFGRFIY-UHFFFAOYSA-N Maltol Natural products CC1OC=CC(=O)C1=O HYMLWHLQFGRFIY-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- RADKZDMFGJYCBB-UHFFFAOYSA-N Pyridoxal Chemical compound CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 125000005518 carboxamido group Chemical group 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 239000008199 coating composition Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 229930182912 cyclosporin Natural products 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium;phosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229940043353 maltol Drugs 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 235000021391 short chain fatty acids Nutrition 0.000 description 2
- 150000004666 short chain fatty acids Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 2
- 229960001940 sulfasalazine Drugs 0.000 description 2
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- FYGHSUNMUKGBRK-UHFFFAOYSA-N trimethylbenzene Natural products CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 2
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- 150000005206 1,2-dihydroxybenzenes Chemical class 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- WJTJFWHHNYHKMI-UHFFFAOYSA-N 2,3-dihydroxy-n,n-dimethylbenzamide Chemical compound CN(C)C(=O)C1=CC=CC(O)=C1O WJTJFWHHNYHKMI-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- FPDYOSFKYCMRME-UHFFFAOYSA-N 2-hydroxyisoquinolin-1-one Chemical compound C1=CC=C2C(=O)N(O)C=CC2=C1 FPDYOSFKYCMRME-UHFFFAOYSA-N 0.000 description 1
- GGLYFICJPRFUQP-UHFFFAOYSA-N 5-[(2,3-dihydroxybenzoyl)amino]-2,2-bis[3-[(2,3-dihydroxybenzoyl)amino]propyl]pentanoic acid Chemical compound C=1C=CC(O)=C(O)C=1C(=O)NCCCC(CCCNC(=O)C=1C(=C(O)C=CC=1)O)(C(=O)O)CCCNC(=O)C1=CC=CC(O)=C1O GGLYFICJPRFUQP-UHFFFAOYSA-N 0.000 description 1
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 101150009724 CYBA gene Proteins 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 239000000055 Corticotropin-Releasing Hormone Substances 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
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- PMVSDNDAUGGCCE-TYYBGVCCSA-L Ferrous fumarate Chemical compound [Fe+2].[O-]C(=O)\C=C\C([O-])=O PMVSDNDAUGGCCE-TYYBGVCCSA-L 0.000 description 1
- 206010016880 Folate deficiency Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- OWYWGLHRNBIFJP-UHFFFAOYSA-N Ipazine Chemical compound CCN(CC)C1=NC(Cl)=NC(NC(C)C)=N1 OWYWGLHRNBIFJP-UHFFFAOYSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 206010025476 Malabsorption Diseases 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- RTHRFGXUVDBBLZ-UHFFFAOYSA-N OC(CN(CC(O)=O)Cc1ccccc1O)CN(CC(O)=O)Cc1ccccc1O Chemical compound OC(CN(CC(O)=O)Cc1ccccc1O)CN(CC(O)=O)Cc1ccccc1O RTHRFGXUVDBBLZ-UHFFFAOYSA-N 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- 206010047626 Vitamin D Deficiency Diseases 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 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 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 230000004721 adaptive immunity Effects 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011942 biocatalyst Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229940105270 carbocaine Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229960003115 certolizumab pegol Drugs 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 238000002655 chelation therapy Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)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)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 238000013479 data entry Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- FWZTTZUKDVJDCM-CEJAUHOTSA-M disodium;(2r,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol;iron(3+);oxygen(2-);hydroxide;trihydrate Chemical compound O.O.O.[OH-].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[Na+].[Na+].[Fe+3].[Fe+3].[Fe+3].[Fe+3].[Fe+3].O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 FWZTTZUKDVJDCM-CEJAUHOTSA-M 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- 210000001842 enterocyte Anatomy 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 239000011773 ferrous fumarate Substances 0.000 description 1
- 235000002332 ferrous fumarate Nutrition 0.000 description 1
- 229960000225 ferrous fumarate Drugs 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound 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 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 239000007887 hard shell capsule Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940048921 humira Drugs 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- UAVPUGHKHGVUEZ-UHFFFAOYSA-N hydroxy(pyridin-2-yl)carbamic acid Chemical compound OC(=O)N(O)C1=CC=CC=N1 UAVPUGHKHGVUEZ-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 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 1
- 229960002182 imipenem Drugs 0.000 description 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940032961 iron sucrose Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- INWLQCZOYSRPNW-UHFFFAOYSA-N mepivacaine Chemical compound CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C INWLQCZOYSRPNW-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 244000005706 microflora Species 0.000 description 1
- 235000020802 micronutrient deficiency Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000004677 mucosal permeability Effects 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960005027 natalizumab Drugs 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 238000011903 nutritional therapy Methods 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
- 229960002700 octreotide Drugs 0.000 description 1
- QQBDLJCYGRGAKP-FOCLMDBBSA-N olsalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=C(C(O)=CC=2)C(O)=O)=C1 QQBDLJCYGRGAKP-FOCLMDBBSA-N 0.000 description 1
- 229960004110 olsalazine Drugs 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000037039 plant physiology Effects 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- TYPBXRFGTISSFB-UHFFFAOYSA-M potassium;3-morpholin-4-ylpropane-1-sulfonic acid;hydroxide Chemical compound [OH-].[K+].OS(=O)(=O)CCCN1CCOCC1 TYPBXRFGTISSFB-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000000541 pulsatile effect Effects 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- GGOZGYRTNQBSSA-UHFFFAOYSA-N pyridine-2,3-diol Chemical compound OC1=CC=CN=C1O GGOZGYRTNQBSSA-UHFFFAOYSA-N 0.000 description 1
- 150000005299 pyridinones Chemical class 0.000 description 1
- 229960003581 pyridoxal Drugs 0.000 description 1
- 235000008164 pyridoxal Nutrition 0.000 description 1
- 239000011674 pyridoxal Substances 0.000 description 1
- 150000003223 pyridoxals Chemical class 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- JTSSMMKHJYRYEG-UHFFFAOYSA-N scandine Natural products C12=CC=CC=C2NC(=O)C2(C(=O)OC)C1(C13)CCN3CC=CC1(C=C)C2 JTSSMMKHJYRYEG-UHFFFAOYSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- MBYLVOKEDDQJDY-UHFFFAOYSA-N tris(2-aminoethyl)amine Chemical compound NCCN(CCN)CCN MBYLVOKEDDQJDY-UHFFFAOYSA-N 0.000 description 1
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/0031—Rectum, anus
-
- 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
- A61K9/08—Solutions
Definitions
- the present invention relates the use of non-labile, hexadentate chelators for the manufacturing of a pharmaceutical composition to treat a subject affected by an inflammatory bowel disease (IBD).
- IBD inflammatory bowel disease
- Induction therapies for IBD include aminosalicylates such as mesalazine and prodrug thereof (e.g. sulfasalazine), antibiotics for mild mucosal disease, nutritional therapy including elemental or polymeric formulas (e.g. CarbopolTM), corticosteroids for moderate disease, and infliximab for corticosteroid-resistant or fistulizing disease.
- aminosalicylates such as mesalazine and prodrug thereof (e.g. sulfasalazine), antibiotics for mild mucosal disease, nutritional therapy including elemental or polymeric formulas (e.g. CarbopolTM), corticosteroids for moderate disease, and infliximab for corticosteroid-resistant or fistulizing disease.
- Aminosalicylates, mercaptopurine, azathioprine, methotrexate, and infliximab are generally used in maintenance therapy.
- IBD Ididodeficiency .
- Anemia in IBD patients is a problem of multifactorial origin, including blood loss, malabsorption of iron, and anemia of inflammation.
- the oxidative stress of IBD patients may be further enhanced by iron in the intestinal wall (Liu-Brohy L, et al. Dig Dis Sci 1996; 41: 2078-86), for instance from the heme extravasation within the mucosa and in the gut lumen and, additionally, by an increased mucosal permeability to iron.
- iron in the intestinal wall Liu-Brohy L, et al. Dig Dis Sci 1996; 41: 2078-86
- the effects of oral ferrous fumarate and intravenous iron sucrose on clinical disease and plasma redox status in IBD patients havee been investigated by Kari et all. Scandin J Gastroent. 2005, 40(9): 1058-65.
- 5-aminosalicylic acid has chelating properties which may contribute to its therapeutic efficacy.
- the invention refers to pharmaceutical compositions and methods to treat patients with inflammatory bowel disease (IBD) by administering a therapeutically effective amount of non-hydrolizable, potent and selective hexadentate chelators (HDC).
- IBD inflammatory bowel disease
- HDC non-hydrolizable, potent and selective hexadentate chelators
- the invention refers to the use of HDC having high stability, selectivity and potency in chelation OfFe 3+ and Al 3+ while possessing limited (if any) systemic absorption, so that local activity in the intestinal tract is performed without interfering with the body iron balance, especially in iron-deficiency anemic patients.
- the invention refers to the use of hydroxyphenolaminocarboxylate and their N-analogs (i.e. hydroxypyridylaminocarboxylate) for the manufacturing of a pharmaceutical composition for the treatment of IBD.
- hydroxyphenolaminocarboxylate and their N-analogs i.e. hydroxypyridylaminocarboxylate
- the invention refers to the use of TREN and TREN-HOPOs or MECAM and ME-HOPOs chelators for the manufacturing of a pharmaceutical composition for the treatment of IBD.
- the present invention refers to the use of hexadentate chelators (HDC) for the manufacturing of a pharmaceutical composition for the treatment of a patient with an inflammatory bowel disease (IBD).
- HDC hexadentate chelators
- the invention relates of HDC matching the afore mentioned criteria, hence being characterized by two 2-hydroxybenzyl or 2-hydroxypyridyl moieties; two acetic acid moieties; these linked by an ethylenediamine or propylenediamine bridge, optionally substituted.
- Such HDC are preferentially represented by substances of formula (I):
- each m 1, 2 ; each R independently represents H, C 1-5 -alkyl, -hydroxylalkyl, - perfluoalkyl, OR', COR', OSO 2 R', OPO 3 R' 2 , NR' 2 , or halogen;
- R' represents H, d- 6 -alkyl, or C 2 -is-acyl
- Y represents -(CRH) 0 -CH 2 -
- o 0, 1
- R represents H, OH, or O-Ci-5-alkyl.
- An exemplary substance of formula (I) is an aminophenolcarboxylate, such as the ⁇ iV J -bis(2-hydroxybenzyl)-ethylenediamine- ⁇ iV"-diacetic acid (HBED):
- Other substances of formula (I) have a substituted 2-hydroxybenzyl such as N,N'- bisCl ⁇ -dihydroxybenzy ⁇ -ethylenediamine-i ⁇ N'-diacetic acid (DHBED); ⁇ N'-bis(2- hydroxybenzyl-5 -carboxymethyl)-ethylenediamine-iV, TV '-diacetic acid (NMCBED) ; and ⁇ iV'-bis(2-hydroxybenzyl-3 ! ,5-dimethyl)-ethylenediamine- ⁇ N'-diacetic acid (H-3,5-DMBED):
- DHBED N,N'- bisCl ⁇ -dihydroxybenzy ⁇ -ethylenediamine-i ⁇ N'-diacetic acid
- NMCBED ⁇ N'-bis(2- hydroxybenzyl-5 -carboxymethyl)-ethylenediamine-iV, TV '-diacetic acid
- H-3,5-DMBED 2-hydroxybenzyl
- aminohydroxypyridylcarboxylates e.g. from pyridoxal, such as the ⁇ iV'-dipyridoxylethylenediamine- ⁇ iV'-diacetic acid (PLED):
- PLED Furhter aminohydroxypyridylcarboxylates are conceived with modified pyridoxal, such as ⁇ N'-bis(5-deoxypyridoxyl)ethylenediamine-iy;iV'-diacetic acid (DPLED); and its 5,5'-diphosphate ester (P5PLED):
- modified pyridoxal such as ⁇ N'-bis(5-deoxypyridoxyl)ethylenediamine-iy;iV'-diacetic acid (DPLED); and its 5,5'-diphosphate ester (P5PLED):
- the afore mendioned substances may have a propylene bridge instead of ethylene bridge, such as ⁇ iV'-bis(2-hydroxyben2yl)-propylenediamine-iV,N'-diacetic acid (HBPD); ⁇ iV'-bis(5-deoxypyridoxyl)propylenediamine-iV,iV'-diacetic acid (DPLPD):
- HBPD ⁇ iV'-bis(2-hydroxyben2yl)-propylenediamine-iV,N'-diacetic acid
- DPLPD ⁇ iV'-bis(5-deoxypyridoxyl)propylenediamine-iV,iV'-diacetic acid
- the propylene bridge can be modified, such as in JV, ⁇ -bis(2-hydroxybenzyl)-2- hydroxy- 1 ,3 -propylenediamine- ⁇ N '-diacetic acid (HBHPD) :
- One or more labile hydrogen in compound of formula (I) and analogs thereof may be substitute with physiological cations of inorganic and/or organic bases or amino acids, e.g Li + , K + , Na + , Ca 2+ , Mg 2+ , ammonium, substituted ammines, morpholine, glucamine, or lysine.
- the invention relates of HDC matching the afore mentioned criteria, being characterized by a TRENCAM or MECAM structure, or a hydroxypyridone (TREN-HOPO; ME-HOPO) analog thereof.
- HDC are preferentially represented by substances of formulae (II) and (III):
- each each n 1, 2 ; and each X independently represents one of the following group:
- TREN-HOPOs include JV, JV', JV"-tris[(l -methyl-2 ⁇ >xo-3-hy(toxy-2,3-dihydropyridin- 4-yl)carboxamidoethyl] -amine (TREN-Me-3,2-HOPO); and JV,JV',JV"-tris[(l-hydioxy- 2-oxo- 1 ,2-dihydropyridine-6-carboxamido)ethyl] -amine (TREN- 1 ,2-HOPO):
- N, N ', N"-t ⁇ s [(2-oxo-3 -hydroxy-2,3 -dihydropyridiny ⁇ carboxamidoethyl] -amine (TREN-2,1 -HOPO); and analog 2-hydroxy-isoquinolin-l-one (TREN- 1,2-HOIQO):
- TREN-2.1-H0P0 The substances of formula (II) may be also in "hybird form" combining one or more group (a) to (e), such as in ⁇ iV J -bis-[(2 5 3-dihydroxybenzoyl)-2-aminoethyl]- ⁇ ' ' "- [(1- hydroxy-2-oxo- 1 ,2-dihydropyridine-6-carboxamido)ethyl] -amine (TRENCAM- 1 ,2- HOPO); or in the folly tris-differentiated (TRENC AM-Me-3,2-HOPO-l,2-HOPO):
- the substances of formula (II) may have propylene bridge instead of ethylene, such as in iV ) iV' ) N"-tris-[(2,3-dihydroxybenzoyl)-3-aminopropyl]-amine (TRPNCAM):
- the compound of formula (II) can be prepared by know methods, e.g. those disclosed in WO9700245, as well as in Inorg. Chem., 2000, 39(16), 3624-31; Inorg.
- a TREN-like HDC may also have a different core, the central N(CH 2 CH 2 NH)- moiety can be substituted with another triamine moiety as in CYCAM (Inorg. Chem., 2001, 40(16),3922-35).
- CYCAM Inorg. Chem., 2001, 40(16),3922-35.
- exemplary substances of formula (III) include the N,N',N"-t ⁇ s(2,3- dihydroxybenzoyl)triaminomethylbenzene (MECAM) :
- Exemplary ME-HOPO have a hydroxypiridinone group instead of catechols, as in N, N ', iV"-tris [( 1 -methyl-2-oxo-3 -hydroxy-2,3 -dihydropyridin-4-yl)carboxamido] - trimethylbenzene (ME-Me-3 ,2-HOPO); N,N',N"-t ⁇ s[(l -hydroxy-2-oxo- 1 ,2- dihydropyridin-3-yl)carboxamido]- trimethylbenzene (ME-l,2-H0P0):
- Hydribs compounds of formula (III) with mixed groups (a), (b), (c), (d) and (e) are also included; as well as their homologues (MPCAM), and combination thereof.
- the compound of formula (HI) can be prepared by know methods, e.g. found in the references cited by Raymond et al. (Inorg. Chem. 2001, 40, 3922-35), as well as in J Organomet Chem. 1999, 575(1), 149-52.
- HDC of formulae (II-III) include CacCAM and pyridinone analogs thereof linked to a CO 2 H functionalized triamine backbone such as disclosed by Imbert d et al. (New J. Chem., 2000, 24, 281-8). Also in the compounds of formulae (II) and (III), on or more labile hydrogen may be substitute with physiologically compatible cations.
- compositions comprising the suitable HDC as disclosed before can be prepared by know methods.
- the compositions can be administered orally and in a variety of dosage forms including, but not limited to, tablets, soft gelatin capsules, hard shell capsules, suspensions, solutions, and emulsions.
- compositions typically include a pharmaceutically acceptable carrier and optionally one or more pharmaceutically acceptable excipients, including diluents, binders, plasticizers, lubricants, disintegrants, colorants, stabilizers, surfactants, etc.
- carrier includes, but is not limited to, diluents, binders, lubricants, disintegrators, fillers, solubilizing agents, pH modifying agents, preservatives, stabilizers, such as anti-oxidants, wetting or emulsifying agents, suspending agents and coating compositions.
- Carrier also includes all components of any coating composition, which may include plasticizers, pigments, colorants, stabilizing agents, glidants, pore formers and surfactants.
- Diluents also referred to as "fillers,” are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules.
- Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar.
- Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms.
- Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid, methacrylic acid and methyl methacrylate polymers and copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.
- Lubricants are used to facilitate tablet manufacture.
- suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.
- Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch and modified starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross-linked PVP (PolyplasdoneTM XL).
- Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.
- compositions can be also formulated as a suppository or enema or foam for rectal administration.
- compositions can be orally or rectally administered with immediate release as well as in controlled release dosage form, i.e. a dosage form for which the HDC release accomplish the therapeutic or convenience objectives not offered by conventional immediate release dosage forms such as solutions or promptly dissolving dosage forms.
- Delayed release, extended release, and pulsatile release forms and their combinations are types of controlled release dosage forms.
- double-coated tablets and/or granules are also included. Exemplary such controlled release formulations are, e.g., disclosed by Gazzaniga et al. (Expert Opin Drug Deliv.
- a composition of invention typically contains from 10 mg to 1000 g, more typically from 20 mg to 500 mg, preferably from 100 mg to 250 mg of a HDC.
- Further embodiments of the present invention further comprise one or more additional therapeutic such as, e.g., an immunosuppressive, an anti- inflammatory, a steroid, an immunomodulatory agent, a cytokine, and a TNF antagonist.
- immunosuppressives include azathioprine, methotrexate, cyclosporine,
- Exemplary antiinflammatories include 5-aminosalicylic acid, sulfasalazine and olsalazine.
- Exemplary steroids include corticosteroids, glucocorticosteroids, prednisone, prednisolone, hydrocortisone, methylprednisolone, dexamethasone and ACTH.
- Exemplary immunomodulatory agents include PVAC, anti-CD40 ligand, anti-CD40, natalizumab (AntegrenTM), anti-VCAMI and anti-ICAMl.
- Exemplary cytokines include IL-IO.
- TNF antagonists include infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira), and CDP870.
- a pharmaceutical composition comprising a HDC in association with an effective amount of a further active ingredient(s), e.g.
- the weight ratio of the HDC to the further active ingredient(s) may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a HDC is combined with a second active ingredient the weight ratio in range from about 1000:1 to about 10:1.
- Combinations of a HDC and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active is used.
- a method for the treatment of a subject with an inflammatory bowel disease such as ulcerative colitis, Crohn's disease, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, infective colitis, proctitis, proctosigmoiditis, indeterminate colitis, and the so-called irritable bowel syndrome (IBS), alias spastic colitis,
- IBD inflammatory bowel disease
- IBS irritable bowel syndrome
- the subject is a mammalian, typically a human.
- the HDC may be taken once, twice, three times a day.
- the dosages of HDC may vary from 10 mg through to 1 g per day, more typically 20 mg to 500 mg per day, still more typically 100 mg to 250 mg per day.
- the HDC are administered once a daily.
- the dosage may commence at a low level, such as daily and may be elevated to a higher dosage, such as twice or three times daily if required.
- Administration is typically over a period of from 30 days to 60 days or more, including indefinitely for the lifetime of the patient. More typically, a method of the invention results in relief of symptoms when the HDC are administered over a period of from 60 days to 120 days. After relief or symptoms is achieved, administration of the IC may be ceased, tapered, or reduced to lower maintenance dosages for an indefinite period.
- a further form of the invention provides a pack including a plurality of compositions of the first embodiment in individual dosages having different amounts of HDC packaged in such a way that dosages of the HDC are taken according to a predetermined schedule by a person to whom the dosages are administered.
- HDC decrease the pro-inflammatory presence OfFe 3+ and Al 3+ within the intestinal epithelium, hence providing a complementary therapy to IBD patients.
- HDC may have the ancillary capacity to suppress the abnormal, pro-pathogenic microflora in gut. Chelating potency and selectivity
- Fe 3+ complexes with HDC [Fe 3+ -HDC] are prepared in a 10:1 ligandaron molar ratio (total iron concentration 4.4 x 10 "5 M) in 0.1 m MOPS-KOH buffer, pH 7.4. This solution is titrated against maltol resulting in the partial dissociation of Fe 3+ -HDC complex with formation of an orange Fe 3+ - maltol complex.
- the spectrophotometric data is inserted into the COMPTl program to evaluate the affinity constants of the complex.
- pFe 3+ plots are calculated from pKa and KFQ 3+ values using the program SPECIAZl with metal and HDC concentration,
- KF G Q S KF G Q S values of complexes, K for Fe 3+ -OH interactions, and pKa values as data entry.
- HDC has for Fe 3+ . This required the calculation of the proton-independent solubility coefficients for each HDC using the proton-dependent solubility constants (pH 7.0) for each HDC and pK values with reference N,N-dimethyl-2,3-dihydroxybenzamide (Loomis & Raymond, Inorg Chem, 1991; 30:906-11; Reid et al. Nature, 1993;
- a proton-dependent solubility constant at pH 7.4 for a HDC is calculated. This value is used to determine the free Fe 3+ concentration expressed as pFe 3+ (-log 10 [Fe 3+ ]) in the model system. Thus, the larger the Fe 3+ value, the lower the concentration of free Fe 3+ in solution, indicating the HDC affinity for iron.
- a "soft metal" such as Zn 2+ , with the aim to determine both activity and selectivity, since a low competition with essential metal such as Zn 2+ is desired.
- the proposed HDC will display high affinity and specificity for Fe 3+ and Al 3+ , with a pFe 3+ higher than 20, or even higher than 25; a pAl 3+ higher than 15, or even higher than 20; and with a pZn 2+ lower than 12.
- a HDC lead shall behave oppositely, i.e. must have a poor GI absorption in order to preserve the body iron of the IBD patient.
- Veber's rule (Veber et al.; J Med Chem. 2002, 45, 2615-23) which permit the provisional calculation of oral availability can be applied in inverted way
- HDC lead i) 11 or higher rotatable bonds (RB); ii) Topological polar surface area (TPSA) equal to or more than 140; A2
- TPSA Polar surface area
- Ertl Rohde & Selzer J. Med. Chem. 2000, 43, 3714-3717; or Clark J Pharm Sci 1999, 88: 815-821
- H-boundtot is the total H-acceptor and donor bounds, estimated or calculated with "MarvinView - Hydrogen Bond Donor-Acceptor (HBDA) Plugin” (ChemAxon). Stability issue
- the stability test in simulate gastric environment shall be carried out on HDC hits.
- HDC For oral administration, 150 mg of a HDC is filled in gelatine hard capsule, size 1 (Coni-SnapTM, Capsugel, Bornem, Belgium) along with customary excipients.
- a HDC 1500 mg is adjusted with diluted NaOH until dissolution; then water, EDTA, Na metabisulphite, parabens, and methyl cellulose are added under continuous stirring to a final volume of 1500 ml.
- the solution is well mixed by shaking and packaged as 100 ml doses in Wheaton enema bottles.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Pharmaceutical compositions comprising a hexadentate chelators as novel tool for the treatment of a patient with an inflammatory bowel disease (IBD).
Description
HEXADENTATE CHELATORS IN INFLAMMATORY BOWEL DISEASE
FIELD OF THE INVENTION
The present invention relates the use of non-labile, hexadentate chelators for the manufacturing of a pharmaceutical composition to treat a subject affected by an inflammatory bowel disease (IBD).
BACKGROUND OF THE INVENTION
Patients with IBD have recurrent symptoms with high morbidity. Decisions about drug therapy in the management of patients with IBD are complex and depend on location, e.g. gastroduodenal vs small intestinal vs colon, and disease behaviour such as inflammatory/mucosal vs stricturing vs perforating in each patient.
Induction therapies for IBD include aminosalicylates such as mesalazine and prodrug thereof (e.g. sulfasalazine), antibiotics for mild mucosal disease, nutritional therapy including elemental or polymeric formulas (e.g. Carbopol™), corticosteroids for moderate disease, and infliximab for corticosteroid-resistant or fistulizing disease. Aminosalicylates, mercaptopurine, azathioprine, methotrexate, and infliximab are generally used in maintenance therapy.
Patients with IBD are also at risk for the development of micronutrient deficiencies including folate, vitamin D and iron deficiencies which require close nutritional monitoring. Anemia in IBD patients is a problem of multifactorial origin, including blood loss, malabsorption of iron, and anemia of inflammation.
A review of anemia in IBD, its pathogenetic features, epidemiology, diagnosis and therapy based on evidence from recent studies is the focus of an article by Giannini &
Martes, Minerva Gastroenterol Dietol. 2006, 52(3), 275-291. It is thought that anemia is also due to inhibitory effects of inflammatory cytokines, predominantly interleukin-6 (IL-6) on iron transport in enterocytes and macrophages.
However, an iron therapy will reinforce the intestinal inflammation by catalysing
ROS production. The oxidative stress of IBD patients may be further enhanced by iron in the intestinal wall (Liu-Brohy L, et al. Dig Dis Sci 1996; 41: 2078-86), for instance from the heme extravasation within the mucosa and in the gut lumen and, additionally, by an increased mucosal permeability to iron.
The effects of oral ferrous fumarate and intravenous iron sucrose on clinical disease and plasma redox status in IBD patients havee been investigated by Kari et all. Scandin J Gastroent. 2005, 40(9): 1058-65. Furthermore, 5-aminosalicylic acid has chelating properties which may contribute to its therapeutic efficacy. The possible role of iron in IBD is in fact supported by the beneficial effects of iron chelation therapy with desferoxamine in a open study on ulcerative colitis (Rampton DS et al. Aliment Pharmacol Ther. 2000; 14:1163-8).
However, the works of Jun CD at al. (Exper MoI Med. 2005; 37(4):297-310; Life Scien. 2007; 80(5):436-45; J Cell Biochem. 2007; 102(6): 1442-57) pointed out that desferoxamine may trigger the mucosal adaptive immunity. Although these studies are inconclusive, the hydroxamate drugs may present a further limitation due to their relative instability in the condition found in stomach (unpublished data), so that a controlled/targeted delivery system would be required.
Instead, a new generation of chelating drugs having optimized characteristics to treat and without the afore limitations in pharmacokinetic profile was still in need. SUMMARY OF THE INVENTION
The invention refers to pharmaceutical compositions and methods to treat patients with inflammatory bowel disease (IBD) by administering a therapeutically effective amount of non-hydrolizable, potent and selective hexadentate chelators (HDC). In one aspect, the invention refers to the use of HDC having high stability, selectivity and potency in chelation OfFe3+ and Al3+ while possessing limited (if any) systemic absorption, so that local activity in the intestinal tract is performed without interfering with the body iron balance, especially in iron-deficiency anemic patients.
In another aspect, the invention refers to the use of hydroxyphenolaminocarboxylate and their N-analogs (i.e. hydroxypyridylaminocarboxylate) for the manufacturing of a pharmaceutical composition for the treatment of IBD.
In another aspect, the invention refers to the use of TREN and TREN-HOPOs or MECAM and ME-HOPOs chelators for the manufacturing of a pharmaceutical composition for the treatment of IBD. These and other aspects will be further illustrated in the foregoing disclosure.
DETAILED DESCRIPTION OF THE INVENTION
The present invention refers to the use of hexadentate chelators (HDC) for the manufacturing of a pharmaceutical composition for the treatment of a patient with an inflammatory bowel disease (IBD). A suitable HDC for the present invention shall possess the following features:
- it possesses high affinity and specificity for Fe3+ and Al3+, with an overall a ρFe3+ value > 20, preferably > 25; and ρAl3+ value > 15, preferably > 20.
- it forms a 1:1 HDC-Fe and HDC-Al complex, in order to avoid Fe3+ and Al3+ redistribution or the formation of partially chelated, reactive complexes; - it is highly hydrophilic and/or has a high molecular weight, so to provide a low, if any, systemic availability; his structure is non-acid labile, meaning that its hexadentate structure shall resist to the acidic and enzymatic hydrolysis from the gastric secretion. In a first aspect, the invention relates of HDC matching the afore mentioned criteria, hence being characterized by two 2-hydroxybenzyl or 2-hydroxypyridyl moieties; two acetic acid moieties; these linked by an ethylenediamine or propylenediamine bridge, optionally substituted. Such HDC are preferentially represented by substances of formula (I):
R' represents H, d-6-alkyl, or C2-is-acyl; Y represents -(CRH)0-CH2-; o = 0, 1; and R represents H, OH, or O-Ci-5-alkyl.
An exemplary substance of formula (I) is an aminophenolcarboxylate, such as the ΛζiVJ-bis(2-hydroxybenzyl)-ethylenediamine-ΛζiV"-diacetic acid (HBED):
HBED
Other substances of formula (I) have a substituted 2-hydroxybenzyl such as N,N'- bisCl^-dihydroxybenzy^-ethylenediamine-i^N'-diacetic acid (DHBED); ΛζN'-bis(2- hydroxybenzyl-5 -carboxymethyl)-ethylenediamine-iV, TV '-diacetic acid (NMCBED) ; and ΛζiV'-bis(2-hydroxybenzyl-3!,5-dimethyl)-ethylenediamine-ΛζN'-diacetic acid (H-3,5-DMBED):
Further substance of formula (I) are aminohydroxypyridylcarboxylates, e.g. from pyridoxal, such as the Λ^iV'-dipyridoxylethylenediamine-ΛζiV'-diacetic acid (PLED):
PLED
Furhter aminohydroxypyridylcarboxylates are conceived with modified pyridoxal, such as ΛζN'-bis(5-deoxypyridoxyl)ethylenediamine-iy;iV'-diacetic acid (DPLED); and its 5,5'-diphosphate ester (P5PLED):
DPLED P5PLED
The afore mendioned substances may have a propylene bridge instead of ethylene bridge, such as ΛζiV'-bis(2-hydroxyben2yl)-propylenediamine-iV,N'-diacetic acid (HBPD); ΛζiV'-bis(5-deoxypyridoxyl)propylenediamine-iV,iV'-diacetic acid (DPLPD):
HBPD DPLPD
The propylene bridge can be modified, such as in JV,Λ^-bis(2-hydroxybenzyl)-2- hydroxy- 1 ,3 -propylenediamine-Λζ N '-diacetic acid (HBHPD) :
HBHPD
Methods for preparing the compounds of formula (I) are described by Taliaferro (Inorg. Chem. 1984, 23:1183-92) and Green (Int. J. Nucl. Med. Biol, 1895, 12(5): 381-6), as well as in EP-299795, EP-436579, EP-290047, WO-99/33521 and U.S. Pat. 6,646,157. Prodrug thereof are included, such as in WO 95/16663 (Cyba Geigy).
In a conformation variant of the aforesaid HDC5 the chelating moieties thereof are assembled in different order, e.g. in ethylene-N,N'-bis-2-hydroxyρhenylglycine (EHPG):
EHPG
One or more labile hydrogen in compound of formula (I) and analogs thereof, if an increase of biotolerability or solubility is desired, may be substitute with physiological cations of inorganic and/or organic bases or amino acids, e.g Li+, K+, Na+, Ca2+, Mg2+, ammonium, substituted ammines, morpholine, glucamine, or lysine. hi a second aspect, the invention relates of HDC matching the afore mentioned criteria, being characterized by a TRENCAM or MECAM structure, or a hydroxypyridone (TREN-HOPO; ME-HOPO) analog thereof.
Such HDC are preferentially represented by substances of formulae (II) and (III):
The group (a) to (e) are generally applied in the form described herein, although a substitution on pyridinone ring can be present shall it add a therapeutic improvement
An exemplary substance of formula (II) is ΛζJV',JV"-tris-[(2,3-dihydroxybenzoyl)-2- aminoethyl]-amine (TRENCAM):
TREN-HOPOs include JV, JV', JV"-tris[(l -methyl-2κ>xo-3-hy(toxy-2,3-dihydropyridin- 4-yl)carboxamidoethyl] -amine (TREN-Me-3,2-HOPO); and JV,JV',JV"-tris[(l-hydioxy- 2-oxo- 1 ,2-dihydropyridine-6-carboxamido)ethyl] -amine (TREN- 1 ,2-HOPO):
TREN-2.1-H0P0
The substances of formula (II) may be also in "hybird form" combining one or more group (a) to (e), such as in ΛζiVJ-bis-[(253-dihydroxybenzoyl)-2-aminoethyl]-Λ''"- [(1- hydroxy-2-oxo- 1 ,2-dihydropyridine-6-carboxamido)ethyl] -amine (TRENCAM- 1 ,2- HOPO); or in the folly tris-differentiated (TRENC AM-Me-3,2-HOPO-l,2-HOPO):
The substances of formula (II) may have propylene bridge instead of ethylene, such as in iV)iV')N"-tris-[(2,3-dihydroxybenzoyl)-3-aminopropyl]-amine (TRPNCAM):
The compound of formula (II) can be prepared by know methods, e.g. those disclosed in WO9700245, as well as in Inorg. Chem., 2000, 39(16), 3624-31; Inorg.
Chem., 2002, 41(25), 6731-42; J Biol Inorg Chem. 2000 ;5(5):634-41; Inorg. Chem.,
2007, 46(2), 351-3; (all to Raymond et al.); and J. Med. Chem. 1990, 33, 1749-55
(Hider R. et al.).
A TREN-like HDC may also have a different core, the central N(CH2CH2NH)- moiety can be substituted with another triamine moiety as in CYCAM (Inorg. Chem., 2001, 40(16),3922-35). This is readily apparent in the next series of MECAM and ME-HOPOs substances described by formula (III).
Therefore, exemplary substances of formula (III) include the N,N',N"-tάs(2,3- dihydroxybenzoyl)triaminomethylbenzene (MECAM) :
MECAM
Exemplary ME-HOPO have a hydroxypiridinone group instead of catechols, as in N, N ', iV"-tris [( 1 -methyl-2-oxo-3 -hydroxy-2,3 -dihydropyridin-4-yl)carboxamido] - trimethylbenzene (ME-Me-3 ,2-HOPO); N,N',N"-tήs[(l -hydroxy-2-oxo- 1 ,2- dihydropyridin-3-yl)carboxamido]- trimethylbenzene (ME-l,2-H0P0):
ME-Me-3 ,4-HOPO ME-1 ,2-HOPO
Hydribs compounds of formula (III) with mixed groups (a), (b), (c), (d) and (e) are also included; as well as their homologues (MPCAM), and combination thereof.
The compound of formula (HI) can be prepared by know methods, e.g. found in the references cited by Raymond et al. (Inorg. Chem. 2001, 40, 3922-35), as well as in J Organomet Chem. 1999, 575(1), 149-52.
Further functionally equivalent analogs of HDC of formulae (II-III) include CacCAM and pyridinone analogs thereof linked to a CO2H functionalized triamine backbone such as disclosed by Imbert d et al. (New J. Chem., 2000, 24, 281-8).
Also in the compounds of formulae (II) and (III), on or more labile hydrogen may be substitute with physiologically compatible cations.
Pharmaceutical compositions comprising the suitable HDC as disclosed before can be prepared by know methods. The compositions can be administered orally and in a variety of dosage forms including, but not limited to, tablets, soft gelatin capsules, hard shell capsules, suspensions, solutions, and emulsions.
These compositions typically include a pharmaceutically acceptable carrier and optionally one or more pharmaceutically acceptable excipients, including diluents, binders, plasticizers, lubricants, disintegrants, colorants, stabilizers, surfactants, etc.
As generally used herein "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrators, fillers, solubilizing agents, pH modifying agents, preservatives, stabilizers, such as anti-oxidants, wetting or emulsifying agents, suspending agents and coating compositions. "Carrier" also includes all components of any coating composition, which may include plasticizers, pigments, colorants, stabilizing agents, glidants, pore formers and surfactants.
Diluents, also referred to as "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar.
Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as
acrylic acid, methacrylic acid and methyl methacrylate polymers and copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.
Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.
Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch and modified starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross-linked PVP (Polyplasdone™ XL). Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.
Pharmaceutical compositions can be also formulated as a suppository or enema or foam for rectal administration.
The compositions can be orally or rectally administered with immediate release as well as in controlled release dosage form, i.e. a dosage form for which the HDC release accomplish the therapeutic or convenience objectives not offered by conventional immediate release dosage forms such as solutions or promptly dissolving dosage forms. Delayed release, extended release, and pulsatile release forms and their combinations are types of controlled release dosage forms. Also included are double-coated tablets and/or granules. Exemplary such controlled release formulations are, e.g., disclosed by Gazzaniga et al. (Expert Opin Drug Deliv.
2006; 3(5):583-97).
A composition of invention typically contains from 10 mg to 1000 g, more typically from 20 mg to 500 mg, preferably from 100 mg to 250 mg of a HDC. Further embodiments of the present invention further comprise one or more additional therapeutic such as, e.g., an immunosuppressive, an anti- inflammatory, a steroid, an immunomodulatory agent, a cytokine, and a TNF antagonist.
Exemplary immunosuppressives include azathioprine, methotrexate, cyclosporine,
FIL506, rapamycin, and mycophenolate mofetil. Exemplary antiinflammatories include 5-aminosalicylic acid, sulfasalazine and olsalazine. Exemplary steroids
include corticosteroids, glucocorticosteroids, prednisone, prednisolone, hydrocortisone, methylprednisolone, dexamethasone and ACTH. Exemplary immunomodulatory agents include PVAC, anti-CD40 ligand, anti-CD40, natalizumab (Antegren™), anti-VCAMI and anti-ICAMl. Exemplary cytokines include IL-IO. Exemplary TNF antagonists include infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira), and CDP870. In an other embodiment provided a pharmaceutical composition comprising a HDC in association with an effective amount of a further active ingredient(s), e.g. metronidazole, vancomycine, imipenem, vancomycin, ciprofloxacin, octreotide, corticosterois, azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, lidocaine, and carbocaine; or short-chain fatty acids (SCFA) such as sodium acetate, sodium butyrate, and sodium propionate, and combination thereof. The weight ratio of the HDC to the further active ingredient(s) may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a HDC is combined with a second active ingredient the weight ratio in range from about 1000:1 to about 10:1.
Combinations of a HDC and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active is used.
In a further embodiment is provided a method for the treatment of a subject with an inflammatory bowel disease (IBD) such as ulcerative colitis, Crohn's disease, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, infective colitis, proctitis, proctosigmoiditis, indeterminate colitis, and the so-called irritable bowel syndrome (IBS), alias spastic colitis,
In the method of this embodiment, the subject is a mammalian, typically a human. In a method of this embodiment, the HDC may be taken once, twice, three times a day. The dosages of HDC may vary from 10 mg through to 1 g per day, more typically 20 mg to 500 mg per day, still more typically 100 mg to 250 mg per day. In another embodiment, HDC administered to an iron-deficient anemic, IBD patient in conjunction with iron supplements, either from parenteral or oral routes. In this case, HDC is better administered 6 hours after or 3 hours before iron supplements.
Usually, the HDC are administered once a daily. As a general rule for long term therapy the dosage may commence at a low level, such as daily and may be elevated to a higher dosage, such as twice or three times daily if required. Administration is typically over a period of from 30 days to 60 days or more, including indefinitely for the lifetime of the patient. More typically, a method of the invention results in relief of symptoms when the HDC are administered over a period of from 60 days to 120 days. After relief or symptoms is achieved, administration of the IC may be ceased, tapered, or reduced to lower maintenance dosages for an indefinite period.
Thus, a further form of the invention provides a pack including a plurality of compositions of the first embodiment in individual dosages having different amounts of HDC packaged in such a way that dosages of the HDC are taken according to a predetermined schedule by a person to whom the dosages are administered.
It is postulated that a HDC decrease the pro-inflammatory presence OfFe3+ and Al3+ within the intestinal epithelium, hence providing a complementary therapy to IBD patients. Without to be bound to any theory, it is also postulatred that HDC may have the ancillary capacity to suppress the abnormal, pro-pathogenic microflora in gut. Chelating potency and selectivity
The affinity constant of the Fe3+-HDC interaction can be determined by a spectrophotometric competition study as described in Plant Physiology, 2000, 124, 1149-57; and Inorg. Chem. 1988, 27, 4140-9. Fe3+ complexes with HDC [Fe3+-HDC] are prepared in a 10:1 ligandaron molar ratio (total iron concentration 4.4 x 10"5 M) in 0.1 m MOPS-KOH buffer, pH 7.4. This solution is titrated against maltol resulting in the partial dissociation of Fe3+-HDC complex with formation of an orange Fe3+- maltol complex. The spectrophotometric data is inserted into the COMPTl program to evaluate the affinity constants of the complex. pFe3+ plots are calculated from pKa and KFQ3+ values using the program SPECIAZl with metal and HDC concentration,
KFGQS) values of complexes, K for Fe3+-OH interactions, and pKa values as data entry.
To directly compare the ability of HDC to bind Fe3+, the amount of free Fe3+ in a theoretical iron-ligand system at pH 7.4 can be calculated as described by Harris et al. (J Am Chem Soc. 1979; 101, 6097-104).
Comparison of free Fe3+ concentration is thus representative of the affinity that each
HDC has for Fe3+. This required the calculation of the proton-independent solubility coefficients for each HDC using the proton-dependent solubility constants (pH 7.0) for each HDC and pK values with reference N,N-dimethyl-2,3-dihydroxybenzamide (Loomis & Raymond, Inorg Chem, 1991; 30:906-11; Reid et al. Nature, 1993;
336:455-8). A proton-dependent solubility constant at pH 7.4 for a HDC is calculated. This value is used to determine the free Fe3+ concentration expressed as pFe3+ (-log10[Fe3+]) in the model system. Thus, the larger the Fe3+ value, the lower the concentration of free Fe3+ in solution, indicating the HDC affinity for iron. The same is conceived with Al3+, and a "soft metal" such as Zn2+, with the aim to determine both activity and selectivity, since a low competition with essential metal such as Zn2+ is desired. Hence, the proposed HDC will display high affinity and specificity for Fe3+ and Al3+, with a pFe3+ higher than 20, or even higher than 25; a pAl3+ higher than 15, or even higher than 20; and with a pZn2+ lower than 12. Low systemic availability
While a generally desired property of an oral drug candidate is a good-to-excellent oral bioavailability, a HDC lead shall behave oppositely, i.e. must have a poor GI absorption in order to preserve the body iron of the IBD patient.
For example the Veber's rule (Veber et al.; J Med Chem. 2002, 45, 2615-23) which permit the provisional calculation of oral availability can be applied in inverted way
Hence, the following parameters shall apply for a HDC lead: i) 11 or higher rotatable bonds (RB); ii) Topological polar surface area (TPSA) equal to or more than 140; A2
(or 13 or higher H-bond donors and acceptors)
RB = Rotatable bonds is obtained a sum of structural values, or with the program "MarvinView - Topology Analysis " (ChemAxon Ltd., Budapest, Hungary).
TPSA, Polar surface area is obtained by the atom-based method (Ertl, Rohde & Selzer J. Med. Chem. 2000, 43, 3714-3717; or Clark J Pharm Sci 1999, 88: 815-821) or with the program "MarvinView - Polar Surface Area (PSA) Plugin" (ChemAxon). H-boundtot is the total H-acceptor and donor bounds, estimated or calculated with "MarvinView - Hydrogen Bond Donor-Acceptor (HBDA) Plugin" (ChemAxon).
Stability issue
The stability test in simulate gastric environment shall be carried out on HDC hits. In brief, a solution of 500 mg of test substance in 500 ml of 2 g/1 NaCl adjusted to pH 1.4 with HCl and added with BC Pepsin 1 :10000 (Biocatalyst Ltd, Parck Nantgarw, Wales, UK), then and kept a 37 °C for 3 hours in a rotatory shaker.
The products are isolated and analyzed by a HPLC method, e.g., according to Faller et al. (J. Med. Chem. 2000; 43 (8), 1467-75). Formulation examples
For oral administration, 150 mg of a HDC is filled in gelatine hard capsule, size 1 (Coni-Snap™, Capsugel, Bornem, Belgium) along with customary excipients.
For rectal administration, 1500 mg of a HDC is adjusted with diluted NaOH until dissolution; then water, EDTA, Na metabisulphite, parabens, and methyl cellulose are added under continuous stirring to a final volume of 1500 ml. The solution is well mixed by shaking and packaged as 100 ml doses in Wheaton enema bottles.
Claims
1. Use of a hexadentate chelator (HDC) for the manufacturing of a medicine to treat patients with an inflammatory bowel disease, wherein said HDC is characterized in that: - it possesses high affinity and specificity for Fe3+ and Al3+, with an overall a ρFe3+ value > 20, preferably > 25; and ρAl3+ value > 15, preferably > 20.
- it forms a 1 : 1 HDC-Fe and HDC-Al complex, in order to avoid Fe3+ and Al3+ redistribution or the formation of partially chelated, reactive complexes;
- it is highly hydrophilic and/or has a high molecular weight, so to provide a low, if any, systemic availability;
- his structure is non-acid labile, meaning that its hexadentate structure shall resist to the acidic and enzymatic hydrolysis from the gastric secretion.
2. Use according to claim 1 wherein said HDC is a substance of formula (I):
3. Use according to claim 3 wherein said substance is HBED or an alkaline or an earth-alkaline salt thereof.
4. Use according to claim 3 wherein said substance is PLED or an alkaline or an earth-alkaline salt thereof.
5. Use according to claim 1 wherein said HDC is a substance of formulae (II)-(III):
6. Use according to claim 6 wherein said HDC is TRENCAM or a TREN-HOPO, i.e. wherein (a) is partially or fully substituted with one or more (b) to (e) group.
7. Use according to claim 6 wherein said HDC is MECAM or a ME-HOPO, i.e. wherein (a) is partially or fully substituted with one or more (b) to (e) group.
8. Use according to claim 7 or 8 wherein said HDC is an alkaline salt thereof.
9. A pharmaceutical composition for the treatment of an inflammatory bowel disease (IBD) comprising a HDC according to one or more of claims 1 to 8.
10. The pharmaceutical composition of claim 9 wherein said IBD is ulcerative colitis or Crohn' s disease.
11. The pharmaceutical composition of claim 9 wherein said IBD is selected from the group consisting of collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, infective colitis, proctitis, proctosigmoiditis, and indeterminate colitis.
12. The pharmaceutical composition of claim 9 wherein said IBD is irritable bowel syndrome.
13. The pharmaceutical composition according to claim 9 for oral administration comprising pharmacologically acceptable excipients in the form of tablet, granules, capsule, micropellets, or sachet.
14. The pharmaceutical composition according to claim 9 for rectal administration in the form of suppository, enema, foam, cream, ointment, or gel.
15. A method for the treatment of IBD including administering to said mammal a pharmaceutical composition comprising an effective amount of an HDC of formula (I) according to claim 2.
16. A method for the treatment of a IBD including administering to said mammal a pharmaceutical composition comprising an effective amount of an HDC of formulae (II) and (III) according to claim 5.
17. The method of claim 15 or 16 wherein said mammal is a human.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2009/005637 WO2010133907A1 (en) | 2009-05-18 | 2009-05-18 | Hexadentate chelators in inflammatory bowel disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2009/005637 WO2010133907A1 (en) | 2009-05-18 | 2009-05-18 | Hexadentate chelators in inflammatory bowel disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2010133907A1 true WO2010133907A1 (en) | 2010-11-25 |
Family
ID=43125794
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2009/005637 WO2010133907A1 (en) | 2009-05-18 | 2009-05-18 | Hexadentate chelators in inflammatory bowel disease |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2010133907A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT201700057247A1 (en) * | 2017-05-26 | 2018-11-26 | Valagro Spa | KELANIC AGENTS FOR THE TREATMENT OF NUTRITIONAL DISORDERS OF PLANTS |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4935518A (en) * | 1987-05-08 | 1990-06-19 | Salutar, Inc. | Manganese(II), chelate contrast agents derived from N,N'-bis-(pyridoxal ethylene diamine-N,N')-diacetic acid and derivatives thereof |
| WO1999039706A1 (en) * | 1998-02-04 | 1999-08-12 | University Of Florida Research Foundation, Inc. | Pharmaceuticals comprising n,n'-bis(2- hydroxybenzyl) ethylenediamine-n, n'-diacetic acid for iron chelating therapy |
-
2009
- 2009-05-18 WO PCT/IB2009/005637 patent/WO2010133907A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4935518A (en) * | 1987-05-08 | 1990-06-19 | Salutar, Inc. | Manganese(II), chelate contrast agents derived from N,N'-bis-(pyridoxal ethylene diamine-N,N')-diacetic acid and derivatives thereof |
| WO1999039706A1 (en) * | 1998-02-04 | 1999-08-12 | University Of Florida Research Foundation, Inc. | Pharmaceuticals comprising n,n'-bis(2- hydroxybenzyl) ethylenediamine-n, n'-diacetic acid for iron chelating therapy |
Non-Patent Citations (2)
| Title |
|---|
| MARTELL ET AL.: "New chelating agents suitable for the treatment of iron overload", INORGANICA CHIMICA ACTA, vol. 291, 2 February 1999 (1999-02-02), pages 238 - 246, XP027217524 * |
| MILLAR ET AL.: "Effects of iron and iron chelation in vitro on muscosal oxidant activity", ALIMENT PHARMACOL THER, vol. 14, 1 May 2000 (2000-05-01), pages 1163 - 1168, XP002964704, DOI: doi:10.1046/j.1365-2036.2000.00828.x * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT201700057247A1 (en) * | 2017-05-26 | 2018-11-26 | Valagro Spa | KELANIC AGENTS FOR THE TREATMENT OF NUTRITIONAL DISORDERS OF PLANTS |
| EP3406590A1 (en) * | 2017-05-26 | 2018-11-28 | Valagro S.p.A. | Chelating agents for treating nutritional disorders of plants |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4632204B2 (en) | Antidiarrheal irritable bowel syndrome treatment | |
| KR101447909B1 (en) | Compositions and methods for inhibiting gastric acid secretion | |
| KR102024955B1 (en) | Choline salt of an anti-inflammatory substituted cyclobutenedione compound | |
| US9498445B2 (en) | Pharmaceutical compositions for the treatment of Helicobacter pylori | |
| ZA200304878B (en) | Medicinal compositions containing aspirin. | |
| US4452800A (en) | Salts of 3(n-butyl)-4-hydroxy-1-phenyl-1,8-naphthyridine-2(1H)-one and their use in treating chronic obstructive lung diseases | |
| WO2020072645A1 (en) | Benzimidazole derivative for use in the treatment of inflammatory disorders | |
| HUT76542A (en) | Use of valsartan for the preparation of pharmaceutical composition serving for the treatment of diabetic nephropathy | |
| EP1559446B1 (en) | Treating agent for diarrhea-predominant irritable bowel syndrome | |
| TWI606826B (en) | Use of iguratimod or a salt thereof | |
| WO2010133907A1 (en) | Hexadentate chelators in inflammatory bowel disease | |
| SG190326A1 (en) | Complex formulation comprising lercanidipine hydrochloride and valsartan and method for the preparation thereof | |
| JP2002255814A (en) | Pharmaceutical composition comprising aspirin | |
| CA2215160A1 (en) | Low dose ridogrel formulations and their use for the treatment of inflammatory bowel diseases | |
| US20040068014A1 (en) | Medicinal compositions comprising diclofenac and ornoprostil | |
| EP2123277B1 (en) | Preventive or therapeutic agent for inflammatory bowel disease | |
| WO2010143006A1 (en) | Orally bioavailable iron chelators in the treatment of an inflammatory bowel disease | |
| JP2621382B2 (en) | Uric acid excretion agent | |
| WO2022154687A1 (en) | Pharmaceutical composition containing esomeprazole | |
| WO2022090482A1 (en) | Pharmaceutical compositions comprising 15-hetre and methods of use thereof | |
| US20220387443A1 (en) | Respiratory syncytial virus fusion protein inhibitor compositions and methods for the treatment and prophylaxis of rsv diseases using the same | |
| JP2000290198A (en) | Depressant against nasal cavity resistant increase or the like | |
| JP3685508B2 (en) | Anti-urease agent | |
| WO2011052499A1 (en) | Pharmaceutical composition having improved storage stability | |
| AU2017251803A1 (en) | Choline salt of an anti-inflammatory substituted cyclobutenedione compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09844842 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 09844842 Country of ref document: EP Kind code of ref document: A1 |