CN107496426A - 含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物 - Google Patents
含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物 Download PDFInfo
- Publication number
- CN107496426A CN107496426A CN201710777309.5A CN201710777309A CN107496426A CN 107496426 A CN107496426 A CN 107496426A CN 201710777309 A CN201710777309 A CN 201710777309A CN 107496426 A CN107496426 A CN 107496426A
- Authority
- CN
- China
- Prior art keywords
- disease
- imatinib
- vascular permeability
- composition
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 79
- 201000010099 disease Diseases 0.000 title claims abstract description 70
- 230000008728 vascular permeability Effects 0.000 title claims abstract description 63
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 239000005517 L01XE01 - Imatinib Substances 0.000 title claims abstract description 47
- 229960002411 imatinib Drugs 0.000 title claims abstract description 46
- 150000003839 salts Chemical class 0.000 title claims abstract description 42
- 239000000203 mixture Substances 0.000 title claims abstract description 28
- 239000004480 active ingredient Substances 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 16
- 210000001525 retina Anatomy 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 210000003556 vascular endothelial cell Anatomy 0.000 claims description 7
- 208000017442 Retinal disease Diseases 0.000 claims description 6
- 206010038923 Retinopathy Diseases 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 208000002780 macular degeneration Diseases 0.000 claims description 6
- 201000007714 retinoschisis Diseases 0.000 claims description 6
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 201000011190 diabetic macular edema Diseases 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 3
- 208000003923 Hereditary Corneal Dystrophies Diseases 0.000 claims description 3
- 206010030113 Oedema Diseases 0.000 claims description 3
- 230000008859 change Effects 0.000 claims description 3
- 206010011005 corneal dystrophy Diseases 0.000 claims description 3
- 230000000302 ischemic effect Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 208000003807 Graves Disease Diseases 0.000 claims description 2
- 208000015023 Graves' disease Diseases 0.000 claims description 2
- 201000007737 Retinal degeneration Diseases 0.000 claims description 2
- 208000000260 Warts Diseases 0.000 claims description 2
- 210000001766 X chromosome Anatomy 0.000 claims description 2
- 230000001413 cellular effect Effects 0.000 claims description 2
- 201000010153 skin papilloma Diseases 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 244000025254 Cannabis sativa Species 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 abstract description 12
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 abstract description 7
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 abstract description 7
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 abstract description 7
- 206010012689 Diabetic retinopathy Diseases 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 229960003685 imatinib mesylate Drugs 0.000 description 12
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 12
- 210000004204 blood vessel Anatomy 0.000 description 11
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 9
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 9
- 230000035699 permeability Effects 0.000 description 8
- 230000002265 prevention Effects 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 7
- 208000001344 Macular Edema Diseases 0.000 description 6
- 108091008605 VEGF receptors Proteins 0.000 description 6
- -1 alkali metal salt Chemical class 0.000 description 6
- 238000010171 animal model Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 206010025415 Macular oedema Diseases 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000006698 induction Effects 0.000 description 5
- 201000010230 macular retinal edema Diseases 0.000 description 5
- 208000005590 Choroidal Neovascularization Diseases 0.000 description 4
- 206010060823 Choroidal neovascularisation Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 4
- 206010064930 age-related macular degeneration Diseases 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 102000003923 Protein Kinase C Human genes 0.000 description 3
- 108090000315 Protein Kinase C Proteins 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 208000035719 Maculopathy Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108091008611 Protein Kinase B Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 206010047571 Visual impairment Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 201000007917 background diabetic retinopathy Diseases 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000012202 endocytosis Effects 0.000 description 2
- 208000030533 eye disease Diseases 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 229960003876 ranibizumab Drugs 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000002207 retinal effect Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 208000029257 vision disease Diseases 0.000 description 2
- 230000004393 visual impairment Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010058202 Cystoid macular oedema Diseases 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
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010066786 Diabetic keratopathy Diseases 0.000 description 1
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 description 1
- 201000001353 Doyne honeycomb retinal dystrophy Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 208000037312 Familial drusen Diseases 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 208000032578 Inherited retinal disease Diseases 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-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
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 1
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 1
- 206010025421 Macule Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000005765 Proto-Oncogene Proteins c-akt Human genes 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 208000032430 Retinal dystrophy Diseases 0.000 description 1
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 1
- 208000027073 Stargardt disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 201000001408 X-linked juvenile retinoschisis 1 Diseases 0.000 description 1
- 208000017441 X-linked retinoschisis Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000002137 anti-vascular effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 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 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003161 choroid Anatomy 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 201000010206 cystoid macular edema Diseases 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 201000006321 fundus dystrophy Diseases 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 150000005204 hydroxybenzenes Chemical class 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 208000017532 inherited retinal dystrophy Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 201000007914 proliferative diabetic retinopathy Diseases 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000001210 retinal vessel Anatomy 0.000 description 1
- ZCBUQCWBWNUWSU-SFHVURJKSA-N ruboxistaurin Chemical compound O=C1NC(=O)C2=C1C(C1=CC=CC=C11)=CN1CCO[C@H](CN(C)C)CCN1C3=CC=CC=C3C2=C1 ZCBUQCWBWNUWSU-SFHVURJKSA-N 0.000 description 1
- 229950000261 ruboxistaurin Drugs 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Ophthalmology & Optometry (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Endocrinology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本申请涉及含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物。本发明涉及含有以往作为慢性髓性白血病的治疗剂使用的伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的药物组合物及利用上述组合物来治疗血管渗透性疾病的方法。本发明的用于治疗或预防血管渗透性疾病的药物组合物含有以往作为慢性髓性白血病的治疗剂使用的伊马替尼作为有效成分，提供了伊马替尼的新用途的同时，能够有效地治疗或预防血管渗透性疾病，因此，能够广泛应用于新的血管渗透性疾病的治疗剂的开发。
Description
本申请是申请日为2013年6月10日的申请号为201380032289.9(PCT申请号：PCT/KR2013/005068)、发明名称为“含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物”的分案申请。
技术领域
本发明涉及含有伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物，更具体地，本发明涉及含有以往作为慢性髓性白血病的治疗剂使用的伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的药物组合物及利用上述组合物来治疗血管渗透性疾病的方法。
背景技术
血管是构成人体的所有细胞的生存及正常功能的维持所必需的器官，特别是，构成血管的最内侧的血管内皮细胞由单层构成，形成用于调节血液内的蛋白质、流体及电解质渗漏到周边组织的细胞性屏障。这种血管内皮细胞之间的间隔在正常血管中很窄而血管的渗透性低，但当血管中浸润炎症细胞或因血管损伤导致低氧状态时，各种细胞因子及血管内皮细胞生长因子(vascular endothelial growth factor，VEGF)之类的生长因子的分泌会显著地增加。特别是，VEGF促进血管内皮细胞的增殖、生存及移动，以促进新生血管的生成，同时使血管内皮细胞间的间隔变得不稳定，以显著地提升血管渗透性。因此，通过VEGF过表达而形成的血管具有体液朝向周边组织的渗漏增加的特征。
过度的血管渗透性的增加会成为多种疾病的原因，特别是，视网膜(retina)或脉络膜(choroid)中的过度的血管渗透性增加会促进出血和黄斑水肿(macular edema)，从而作用为致命性的失明的最为常见的原因。作为具有这种发病机理的代表性的疾病有糖尿病性视网膜症(diabetic retinopathy，DR)、糖尿病性黄斑水肿(diabetic macular edema，DME)、老年性黄斑变性(age-related macular degeneration，AMD)、脉络膜新生血管(choroidal neovascularization)、早产儿视网膜病变(ROP：retinopathy ofprematurity)等。黄斑水肿在糖尿病患者中的轻微的糖尿病性视网膜症中以2～6％的频度、在中度糖尿病性视网膜症中以20～63％的频度及在严重的糖尿病性视网膜症中以70％以上的频度发生，一旦在黄斑部位上发生水肿，其中约50％的患者上会出现视力下降。为了预防这种基于糖尿病的严重的视力下降及损失，尝试有通过减少毛细管泄漏来治疗及抑制黄斑水肿的方法，报告了在抑制了用于增加血管渗透性的VEGF的活性的情况下，显示出抑制血管水肿的效果。这种抑制VEGF的活性的方法有：通过使用与VEGF直接结合的抗体(贝伐单抗(Bevacizumab)、兰尼单抗(Ranibizumab)等)来抑制VEGF受体的活性以减少血管渗透性的方法，通过使用用于诱导血管内皮细胞的紧密结合(tight juction)分子的向细胞内的内吞(endocytosis)的PKC(蛋白激酶C(protein kinase C))的抑制剂(鲁伯斯塔(ruboxistaurin)等)来抑制黄斑水肿的方法，同时抑制用于参与VEGF和VEGF受体的信号传递途径并增加视网膜血管渗透性的Src(可溶性酪氨酸激酶(soluble tyrosine kinase))和VEGF受体的方法等。但是，目前为止的大部分的关于血管新生及血管渗透性调节的研究仍局限于VEGF或VEGF受体，大部分集中于上述基因的抑制剂的开发，因此，关于血管新生及血管渗透性调节的研究处于欠缺的状况。
发明内容
本发明的发明人为了找到眼部疾病中的血管渗透性疾病的治疗物质而不断努力的结果，确认了以往作为慢性髓性白血病的治疗剂使用的伊马替尼(imatinib)或其药学上可接受的盐能够减少血管渗透性，从而可将伊马替尼或其药学上可接受的盐作为血管渗透性疾病的治疗剂使用，从而完成了本发明。
本发明的一个目的在于提供一种用于治疗或预防血管渗透性疾病的组合物，其中，含有伊马替尼或其药学上可接受的盐作为有效成分。
本发明的另一目的在于提供一种利用上述组合物来治疗血管渗透性疾病的方法。
本发明的用于治疗或预防血管渗透性疾病的药物组合物含有以往作为慢性髓性白血病的治疗剂使用的伊马替尼作为有效成分，提供了伊马替尼的新用途的同时，能够有效地治疗或预防血管渗透性疾病，因此，能够广泛应用于新的血管渗透性疾病的治疗剂的开发。
附图说明
图1是表示以诱导了作为血管渗透性增加疾病模型的糖尿病性视网膜症的大鼠为对象，确认了甲磺酸伊马替尼的治疗效果的结果的照片及图表，(A)是表示与甲磺酸伊马替尼的处理浓度对应的血管渗透性改善效果的照片，(B)是表示与甲磺酸伊马替尼的处理浓度对应的血管渗透性改善效果的图表。
具体实施方式
作为用于实现上述目的的一个实施方式，本发明提供一种含有伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的药物组合物。
本发明的发明人为了在眼部疾病中找到血管渗透性相关疾病的治疗物质而进行多种研究的过程中，注意到作为慢性髓性白血病的治疗剂使用的伊马替尼(imatinib)的新用途。根据目前所知的情况来说，上述伊马替尼对于血管渗透性相关疾病的治疗效果尚未被人所知，但是报告有其除了通常所知的慢性髓性白血病以外，对于类风湿性关节炎、病毒性肝炎等多种疾病显示出治疗效果，因此，预测出其对于上述血管渗透性相关疾病也会具有显示出一定水平的治疗效果的可能性。鉴于此，对通过注射STZ而诱导了作为血管渗透性增加疾病模型的糖尿病性视网膜症的大鼠，将伊马替尼进行给药，并确认其效果的结果，确认了通过注射STZ而显示出的血管渗透性随着伊马替尼的给药而显著地减少，从而证实了上述伊马替尼显示出治疗或预防糖尿病性视网膜症等血管渗透性疾病的效果。因此，本发明中提供的伊马替尼或其药学上可接受的盐能够作为用于预防或治疗血管渗透性相关疾病的药物组合物的有效成分而使用。
本发明的用语“伊马替尼(imatinib)”指的是化学上由4-[(4-甲基-1-哌嗪基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯基]-苯甲酰胺(4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-((4-pyridin-3-yl)pyrimi din-2-yl-amino)phenyl]-benzamide)表示的化合物。上述伊马替尼结合于由Bcr-Abl基因诱导表达的酪氨酸激酶的ATP结合部位，特异性地抑制酪氨酸激酶的活性，从而被认知为治疗慢性髓性白血病的治疗剂，作为其药学上可接受的盐的一种的甲磺酸伊马替尼以称为格列卫(GleevecTM，Novartis Pharmaceuticals，美国)的商品名进行有销售。并且，已知对于来自血小板的生长因子受体β(PDGF-β)、Akt(蛋白质激酶B)、细胞外调节激酶1和2(ERK1和ERK2)、c-kit等其它种类的酪氨酸激酶也显示出抑制效果。已知上述伊马替尼除了慢性髓性白血病以外，对于类风湿性关节炎(WO 03/063844)、病毒性肝炎(WO 2005/117885)等疾病的预防或治疗显示出效果，而对于血管渗透性疾病的效果则从未被所知。本发明的发明人首次确定了以往作为慢性髓性白血病的治疗剂所知的伊马替尼，其能够显著地减少由血管渗透性疾病而增加的血管渗透性。
本发明的用语“药学上可接受的盐”指的是在作为阳离子和阴离子通过静电引力结合的物质的盐中也能够在药剂学上使用的形态的盐，在本发明的目的上，上述药学上可接受的盐可被解释为是，适合于预计血管渗透性疾病的发病或上述疾病已发病的患者的治疗的伊马替尼的酸加成盐或碱加成盐。
在本发明中，只要能够适合使用于预计血管渗透性疾病的发病或上述疾病已发病的患者的治疗，对于上述伊马替尼的药学上可接受的盐没有特别的限定，但是优选为是伊马替尼的金属盐、与有机碱的盐、与无机酸的盐、与有机酸的盐、与碱性或酸性氨基酸的盐等，更优选为是碱金属盐(钠盐、钾盐等)、碱土金属盐(钙盐、镁盐、钡盐等)、铝盐等金属盐；与三乙胺、吡啶、甲基吡啶、2，6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己胺、N，N-二苄基乙二胺等有机碱的盐；与盐酸、氢溴酸、硝酸、硫酸、磷酸等无机酸的盐；与甲酸、乙酸、三氟乙酸、邻苯二甲酸、富马酸、草酸、酒石酸、马来酸、柠檬酸、琥珀酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸的盐；与精氨酸、赖氨酸、鸟氨酸等碱性氨基酸的盐；与天门冬氨酸、谷氨酸等酸性氨基酸的盐，最优选为是甲磺酸伊马替尼。
本发明的用语“血管渗透性疾病”指的是血管渗透性的正常调节崩溃引起的疾病，一般指的是血管发生变化而渗透性增加引起出血的疾病。只要能够通过本发明提供的药物组合物来治疗预计发病或已发病的疾病，对于上述血管渗透性疾病没有特别的限定，但是可以是脉络膜新生血管(choroidal neovascularization)、青光眼性视网膜色素变性(glaucoma retinitis pigmentosa)、早产儿视网膜病变(ROP：retinopathy ofprematurity)、增殖性糖尿病性视网膜症(proliferative diabetic retinopathy)、老年性黄斑变性(age-related macular degeneration)、青光眼、角膜营养不良症(cornealdystrophy)、视网膜劈裂症(retinoschises)、斯特格氏病(Stargardt's disease)、常染色体显性玻璃膜疣(autosomal dominant druzen)、贝斯特氏黄斑营养不良症(Best'smacular dystrophy)、非增殖性糖尿病性视网膜症(non-proliferative diabeticretinopathy)、黄斑囊样水肿(cystoid macular edema)、缺血性视网膜病变(ischemicretinopathy)、炎症诱导视网膜退行性疾病(inflammation-induced retinaldegenerative disease)、糖尿病性黄斑水肿(diabetic macular edema，DME)、与X染色体相关的青少年性视网膜劈裂症(X-linked juvenile retinoschisis)、莫拉蒂致拉分提那斯(Malattia Leventinese；ML)、多恩蜂窝状视网膜营养不良症(Doyne honeycombretinal dystrophy)、血管内皮细胞相关炎症疾病等。
本发明的用语“治疗”指的是为了改变所要治疗的个体或细胞的天然过程而临床上介入的所有行为，可在临床病理状态进行期间或为了预防其而执行。作为目标的治疗效果包括：预防疾病的发生或复发、缓解症状、阻碍伴随疾病的所有直接或间接的病理学结果、预防转移、减小疾病进行速度、减轻或暂时缓解疾病状态、病情好转或改善预后。
在本发明中，上述治疗优选地被解释为是利用伊马替尼或其药学上可接受的盐的血管渗透性疾病的治疗。
本发明的用语“预防”指的是向预计血管渗透性疾病发病的个体将本发明提供的包含伊马替尼或其药学上可接受的盐作为有效成分的药物组合物进行给药，从而抑制或延迟上述疾病的发病的所有行为。
根据本发明的一实施例，通过向大鼠将STZ进行给药来诱导作为血管渗透性相关疾病的糖尿病性视网膜症的发病，在向其将甲磺酸伊马替尼进行给药的结果，确认了血管渗透性显著地减少(图1)，从而可知伊马替尼或其药学上可接受的盐显示出血管渗透性相关疾病的治疗效果。
另外，本发明的药物组合物可进一步包含通常使用于药物组合物的制造的适合的载体、赋型剂或稀释剂。具体地，上述药物组合物可分别根据通常的方法以散剂、颗粒剂、片剂、胶囊剂、悬浊液、乳剂、糖浆、气雾剂等口服型剂型、外用剂、栓剂及灭菌注射溶液的形态进行剂型化而使用。在本发明中，上述药物组合物中可包括的载体、赋型剂及稀释剂可举出乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯橡胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油。在制剂化的情况下，通过使用通常使用的填充剂、增量剂、结合剂、湿润剂、崩解剂、表面活性剂等稀释剂或赋型剂进行调剂。用于口服给药的固体制剂中包含片剂、丸剂、散剂、颗粒剂、胶囊剂等，这种固体制剂是通过在伊马替尼或其药学上可接受的盐中混合至少一种以上的赋型剂，例如淀粉、碳酸钙(calciumcarbonate)、蔗糖(sucrose)或乳糖(lactose)、明胶等进行调剂。并且，除了单纯的赋型剂以外，还使用硬脂酸镁、滑石之类的润滑剂。用于口服的液状制剂有悬浊剂、内用液剂、乳剂、糖浆剂等，除了作为经常使用的单纯稀释剂的水、液体石蜡以外，还可包含多种赋型剂，例如湿润剂、甘味剂、芳香剂、保存剂等。用于非口服给药的制剂包括灭菌的水溶液、非水性溶剂、悬浊剂、乳剂、冻干制剂、栓剂。作为非水性溶剂、悬浊剂可使用丙二醇(propyleneglycol)、聚乙二醇、橄榄油等植物油、油酸乙酯等可注射的酯等。作为栓剂的基剂可使用威铁普首(witepsol)、聚乙二醇、吐温(tween)61、可可脂、月桂酸酯、甘油明胶等。
虽然本发明的一实施例的药物组合物中含有的上述伊马替尼或其药学上可接受的盐的含量没有特别的限定，但是以最终组合物总重量为基准，可以含有0.0001至50重量％的含量，更优选地含有0.01至10重量％的含量。
上述本发明的药物组合物可以按药剂学上有效的量进行给药，本发明的用语“药剂学上有效的量”指的是以可适用于医学治疗或预防的合理的受惠/危险比率足以治疗或预防疾病的量，可根据包括疾病的严重程度、药物的活性、患者的年龄、体重、健康、性别、患者对药物的敏感度、所使用的本发明组合物的给药时间、给药途径及排出比率、治疗时间、与所使用的本发明的组合物配合或同时使用的药物的要素及其它医学领域中公知的要素来决定有效用量水平。本发明的药物组合物可作为单独的治疗剂进行给药，或是与其它治疗剂并用地进行给药，可以与以往的治疗剂依次地或同时地进行给药。此外，可单次或多次地进行给药。重要的是，需要对上述要素均加以考虑，并且以无副作用的最少的量可取得最大效果的量进行给药。
本领域的技术人员可考虑使用目的、疾病的严重程度、患者的年龄、体重、性别、既往病历，或是作为有效成分使用的物质的种类等来决定本发明的药物组合物的给药量。例如，含有上述伊马替尼或其药学上可接受的盐的本发明的药物组合物，其优选地向包括人的哺乳动物一天给药1至20mg/kg，更优选地给药1至10mg/kg，本发明的组合物的给药频度没有特别的限定，但是可一天给药一次或是分用量给药多次。
作为用于实现上述目的的另一实施方式，本发明提供一种用于预防或治疗血管渗透性疾病的方法，其中，包括将包含上述伊马替尼或其药学上可接受的盐作为有效成分的药物组合物以药剂学上有效的量给药至有血管渗透性疾病的发病可能性或已发病的个体的步骤。
如上所述，本发明提供的伊马替尼或其药学上可接受的盐可作为用于预防或治疗血管渗透性疾病的药物组合物的有效成分来使用，因此，上述组合物可使用于血管渗透性疾病的预防或治疗。
本发明的用语“个体”指的是有上述血管渗透性疾病的发病可能性或已发病的包括人的所有动物，无任何限制。通过将本发明的组合物给药至个体，能够缓解或治疗血管渗透性疾病。
本发明的用语“缓解”指的是通过将本发明的组合物进行给药来使血管渗透性疾病好转或有利的所有行为。
本发明的用语“给药”指的是通过某种适当的方法向对象导入本发明的药物组合物，对于给药途径而言，只要能够到达目标组织，其可通过口服或非口服的多种途径进行给药。
在本发明的治疗血管渗透性疾病的方法中，对于上述药物组合物的给药途径而言，只要能够到达目标组织，其可通过任何的一般途径都能够进行给药。本发明的药物组合物对此没有特别的限定，但是可根据所目的而进行腹腔内给药、静脉内给药、肌内给药、皮下给药、皮内给药、口服给药、鼻内给药、肺内给药、直肠内给药。并且，上述组合物可通过可使活性物质移动至靶细胞的任何装置进行给药。
实施例
以下，通过实施例对本发明进行更加详细的说明。但是这些实施例仅是为了例示性地说明本发明，本发明的范围并不限定于这些实施例。
实施例1：动物模型中的甲磺酸伊马替尼的效果
向斯普拉-道来大鼠(Sprague Dawley rat，SD rat)的腹腔以200mg/kg的用量将STZ(链脲霉素(streptozotocin)，Sigma)进行给药(对照组)，或是在与STZ注射同时在动物模型的视网膜以50、100或250μg的用量处理了甲磺酸伊马替尼(Imatinib mesylate，Novatis.瑞士)(实验组)。将上述对照组作为对象，在一周后测定血糖水平的结果，显示出300mg/dL的血糖数值。
另外，将上述动物模型(对照组及实验组)饲养两周后，麻醉上述动物模型，将FITC标记葡聚糖(Fluorescein isothiocyanate-dextran)注射至上述动物模型的心脏(intracardiac FITC-Dextran iniection)，以使荧光物质沿着血液流动。30分钟后，将上述动物模型的视网膜摘出分离，执行平板安装(flat mounting)后，通过荧光显微镜观察了视网膜中存在的荧光物质的分布程度(图1)。图1是表示确认了对于作为血管渗透性增加疾病模型的糖尿病性视网膜症的诱导的甲磺酸伊马替尼的预防效果的照片及图表，图1的(A)是表示与甲磺酸伊马替尼的处理浓度对应的血管渗透性改善效果的照片，图1的(B)是表示与甲磺酸伊马替尼的处理浓度对应的血管渗透性疾病预防效果的图表。如图1所示，在注射STZ的动物模型(对照组)的视网膜中，视网膜血管的渗透性增加，荧光物质向血管周边组织泄漏，从而可以确认诱发了糖尿病性视网膜症，而在与上述STZ的注射同时处理了甲磺酸伊马替尼的情况下，荧光物质的泄漏程度显著地减少，从而可以确认能够预防或缓解所诱发的糖尿病性视网膜症的诱发。
由上述结果可知，甲磺酸伊马替尼能够治疗或预防血管渗透性增加的糖尿病性视网膜症。
Claims (6)
1.一种用于治疗或预防血管渗透性疾病的组合物，其中，包含伊马替尼或其药学上可接受的盐作为有效成分，所述伊马替尼为4-[(4-甲基-1-哌嗪基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯基]-苯甲酰胺。
2.根据权利要求1所述的组合物，其中，伊马替尼的药学上可接受的盐为甲磺酸伊马替尼。
3.根据权利要求1所述的组合物，其中，所述血管渗透性疾病选自脉络膜新生血管、青光眼性视网膜色素变性、早产儿视网膜病变即ROP、糖尿病性黄斑水肿即DME、老年性黄斑变性、青光眼、角膜营养不良症、视网膜劈裂症、斯特格氏病、常染色体显性玻璃膜疣、糖尿病性视网膜症、贝斯特氏黄斑营养不良症、黄斑囊样水肿、缺血性视网膜病变、炎症诱导视网膜退行性疾病、与X染色体相关的青少年性视网膜劈裂症、莫拉蒂致拉分提那斯即ML、多恩蜂窝状视网膜营养不良症及血管内皮细胞相关炎症疾病。
4.根据权利要求1所述的组合物，其中，进一步包含药学上可接受的载体、赋型剂或稀释剂。
5.根据权利要求1所述的组合物，其中，以组合物总重量为基准，所述伊马替尼或其药学上可接受的盐的含量为0.0001～50重量％。
6.一种预防或治疗血管渗透性疾病的方法，其中，包括将包含伊马替尼或其药学上可接受的盐作为有效成分的药物组合物以药剂学上有效的量给药至有血管渗透性疾病的发病可能性或已发病的个体的步骤，所述伊马替尼为4-[(4-甲基-1-哌嗪基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯基]-苯甲酰胺。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020120065193A KR101386697B1 (ko) | 2012-06-18 | 2012-06-18 | 이매티닙 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 혈관 투과성 관련 질환의 치료 또는 예방용 조성물 |
| KR10-2012-0065193 | 2012-06-18 | ||
| CN201380032289.9A CN104582704A (zh) | 2012-06-18 | 2013-06-10 | 含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380032289.9A Division CN104582704A (zh) | 2012-06-18 | 2013-06-10 | 含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107496426A true CN107496426A (zh) | 2017-12-22 |
Family
ID=49768959
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710777309.5A Pending CN107496426A (zh) | 2012-06-18 | 2013-06-10 | 含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物 |
| CN201380032289.9A Pending CN104582704A (zh) | 2012-06-18 | 2013-06-10 | 含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380032289.9A Pending CN104582704A (zh) | 2012-06-18 | 2013-06-10 | 含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物 |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US9511068B2 (zh) |
| EP (1) | EP2862573B1 (zh) |
| JP (1) | JP6030234B2 (zh) |
| KR (1) | KR101386697B1 (zh) |
| CN (2) | CN107496426A (zh) |
| BR (1) | BR112014032264A8 (zh) |
| CA (1) | CA2876926C (zh) |
| ES (1) | ES2668908T3 (zh) |
| MX (1) | MX365021B (zh) |
| RU (2) | RU2014151382A (zh) |
| WO (1) | WO2013191401A1 (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101498973B1 (ko) | 2013-11-21 | 2015-03-05 | 현대모비스(주) | 차량용 주차 지원 시스템 및 방법 |
| GB201401005D0 (en) * | 2014-01-21 | 2014-03-05 | Ucl Business Plc | Inhibitor |
| KR101778004B1 (ko) | 2015-06-22 | 2017-09-15 | (주) 에빅스젠 | 이마티닙을 유효성분으로 포함하는 안구 건조 질환 예방 및 치료용 약학 조성물 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1780627A (zh) * | 2003-04-29 | 2006-05-31 | 贝林格尔.英格海姆国际有限公司 | 用于治疗涉及细胞增殖、骨髓瘤细胞迁移或凋亡或者血管增殖疾病的联用药物 |
| CN1856469A (zh) * | 2003-07-23 | 2006-11-01 | 拜尔医药品股份有限公司 | 用于治疗和预防疾病和疾病症状的氟代ω－羧芳基二苯基脲 |
| CN101035536A (zh) * | 2004-10-08 | 2007-09-12 | 诺瓦提斯公司 | 有机化合物的组合 |
| CN101594851A (zh) * | 2006-11-09 | 2009-12-02 | 阿伯特有限及两合公司 | 用于口服给药的酪氨酸激酶抑制剂的药物剂型 |
| WO2010141427A1 (en) * | 2009-06-02 | 2010-12-09 | Novartis Ag | Treatment of ophthalmologic disorders mediated by albha-carbonic anhydrase isoforms |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5521184A (en) * | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
| GB0201882D0 (en) | 2002-01-28 | 2002-03-13 | Novartis Ag | Organic compounds |
| EP1494699A4 (en) | 2002-04-11 | 2009-07-22 | Childrens Medical Center | METHOD FOR INHIBITING VASCULAR HYPERPERMEABILITY |
| KR101471732B1 (ko) | 2003-08-27 | 2014-12-16 | 옵쏘테크 코포레이션 | 안구의 혈관신생성 장애를 치료하기 위한 조합 치료법 |
| GB0421438D0 (en) | 2004-09-27 | 2004-10-27 | Astrazeneca Ab | Combination therapy |
| PL1750713T3 (pl) | 2004-06-04 | 2013-04-30 | Bioniche Life Sciences Inc | Zastosowanie imatinibu do leczenia zaburzeń czynności wątroby i infekcji wirusowych |
| CA2579067A1 (en) | 2004-09-27 | 2006-04-06 | Astrazeneca Ab | Cancer combination therapy comprising azd2171 and imatinib |
| KR20070072543A (ko) * | 2004-09-27 | 2007-07-04 | 아스트라제네카 아베 | Ｚｄ6474 및 이마티닙을 포함하는 병합법 |
| CN101180060B (zh) | 2005-06-03 | 2011-12-28 | 诺瓦提斯公司 | 治疗或预防增殖性疾病的嘧啶基氨基苯甲酰胺化合物和伊马替尼的组合 |
| US20080003219A1 (en) * | 2005-09-26 | 2008-01-03 | Minu, L.L.C. | Delivery of an ocular agent |
| AU2007316558A1 (en) | 2006-11-09 | 2008-05-15 | Abbott Gmbh & Co. Kg | Pharmaceutical dosage form for oral administration of tyrosine kinase inhibitor |
| EP2305263B1 (en) | 2007-06-07 | 2012-09-19 | Novartis AG | Stabilized amorphous forms of imatinib mesylate |
| KR101138840B1 (ko) | 2009-12-28 | 2012-05-10 | 주식회사 셀트리온화학연구소 | 이마티닙 다이클로로아세트산염 및 이를 포함하는 항암제 조성물 |
-
2012
- 2012-06-18 KR KR1020120065193A patent/KR101386697B1/ko active IP Right Grant
-
2013
- 2013-06-10 CA CA2876926A patent/CA2876926C/en active Active
- 2013-06-10 CN CN201710777309.5A patent/CN107496426A/zh active Pending
- 2013-06-10 MX MX2014015785A patent/MX365021B/es active IP Right Grant
- 2013-06-10 US US14/409,441 patent/US9511068B2/en active Active
- 2013-06-10 JP JP2015518325A patent/JP6030234B2/ja active Active
- 2013-06-10 CN CN201380032289.9A patent/CN104582704A/zh active Pending
- 2013-06-10 WO PCT/KR2013/005068 patent/WO2013191401A1/ko active Application Filing
- 2013-06-10 RU RU2014151382A patent/RU2014151382A/ru unknown
- 2013-06-10 ES ES13807815.9T patent/ES2668908T3/es active Active
- 2013-06-10 EP EP13807815.9A patent/EP2862573B1/en active Active
- 2013-06-10 RU RU2018128737A patent/RU2018128737A/ru unknown
- 2013-06-10 BR BR112014032264A patent/BR112014032264A8/pt not_active Application Discontinuation
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1780627A (zh) * | 2003-04-29 | 2006-05-31 | 贝林格尔.英格海姆国际有限公司 | 用于治疗涉及细胞增殖、骨髓瘤细胞迁移或凋亡或者血管增殖疾病的联用药物 |
| CN1856469A (zh) * | 2003-07-23 | 2006-11-01 | 拜尔医药品股份有限公司 | 用于治疗和预防疾病和疾病症状的氟代ω－羧芳基二苯基脲 |
| CN101035536A (zh) * | 2004-10-08 | 2007-09-12 | 诺瓦提斯公司 | 有机化合物的组合 |
| CN101594851A (zh) * | 2006-11-09 | 2009-12-02 | 阿伯特有限及两合公司 | 用于口服给药的酪氨酸激酶抑制剂的药物剂型 |
| WO2010141427A1 (en) * | 2009-06-02 | 2010-12-09 | Novartis Ag | Treatment of ophthalmologic disorders mediated by albha-carbonic anhydrase isoforms |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104582704A (zh) | 2015-04-29 |
| KR20130141998A (ko) | 2013-12-27 |
| ES2668908T3 (es) | 2018-05-23 |
| BR112014032264A8 (pt) | 2022-03-03 |
| EP2862573A1 (en) | 2015-04-22 |
| BR112014032264A2 (pt) | 2017-06-27 |
| MX365021B (es) | 2019-05-20 |
| RU2014151382A (ru) | 2016-08-10 |
| CA2876926C (en) | 2017-04-04 |
| JP6030234B2 (ja) | 2016-11-24 |
| US9511068B2 (en) | 2016-12-06 |
| MX2014015785A (es) | 2015-06-10 |
| US20150320750A1 (en) | 2015-11-12 |
| JP2015520226A (ja) | 2015-07-16 |
| EP2862573B1 (en) | 2018-03-07 |
| CA2876926A1 (en) | 2013-12-27 |
| RU2018128737A3 (zh) | 2019-03-14 |
| WO2013191401A1 (ko) | 2013-12-27 |
| KR101386697B1 (ko) | 2014-04-18 |
| RU2018128737A (ru) | 2019-03-14 |
| EP2862573A4 (en) | 2016-01-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103917231B (zh) | 组蛋白脱乙酰酶抑制剂与苯达莫司汀的联合制剂及其用途 | |
| JP6887462B2 (ja) | ２，４，６−トリフルオロ−ｎ−［６−（１−メチル−ピペリジン−４−カルボニル）−ピリジン−２−イル］−ベンズアミドの組成物 | |
| US20160361298A1 (en) | Methods and compositions for treating cancer | |
| CN104220053B (zh) | cAMP直接活化交换蛋白(EPAC)的调节剂 | |
| JP2008505173A (ja) | 痛みおよび他のα２アドレナリン作動性仲介状態を処置するための方法および組成物 | |
| CN102724962B (zh) | 包衣药物球状体及其用于消除或减少病症比如呕吐和腹泻的用途 | |
| EP2319539A1 (en) | Prophylactic or therapeutic agent for axial myopia | |
| CN107530304A (zh) | Olig2活性的抑制 | |
| CN105636590A (zh) | 眼病的治疗剂或预防剂 | |
| CN108503650A (zh) | 二噁烷并喹唑啉类化合物或其药用盐或其水合物及其作为酪氨酸激酶抑制剂的应用 | |
| CN109069511A (zh) | Braf抑制剂用于治疗皮肤反应的用途 | |
| CN107683137A (zh) | 用于使用stat3途径抑制剂和激酶抑制剂治疗癌症的方法 | |
| CN107496426A (zh) | 含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物 | |
| CN101686970A (zh) | 邻氨基苯甲酰胺吡啶脲及苯甲酰胺衍生物的协同组合 | |
| CN108430978A (zh) | 3-羟基-喹唑啉-2,4-二酮衍生物及其作为核酸酶调节剂的用途 | |
| CN102227227B (zh) | 包含吡啶并[4，3-d]嘧啶衍生的HSP90抑制剂和HER2抑制剂的药物组合 | |
| CN106255500B (zh) | 用于治疗癌症的新的头孢菌素衍生物 | |
| KR102063398B1 (ko) | Pfi-3를 포함하는 신장암의 예방 또는 치료용 조성물 | |
| CN112851695A (zh) | 甲酰胺类化合物在制备抗脊索肿瘤药物中的应用及试剂盒 | |
| US20210061800A1 (en) | Compounds for treating eye diseases and methods thereof | |
| JP6243850B2 (ja) | 抗がん剤による末梢神経障害の予防、治療、または軽減剤 | |
| CN105934245B (zh) | 多发性硬化症的治疗剂或预防剂 | |
| KR102410696B1 (ko) | 암 치료법의 조합 | |
| KR101674457B1 (ko) | 다사티닙 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물 | |
| CN103570616B (zh) | N′‑直链烷酰基邻吡啶酰肼衍生物及其制法和药物组合物与用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20171222 |