TW201642838A - 脂質體調配物 - Google Patents
脂質體調配物 Download PDFInfo
- Publication number
- TW201642838A TW201642838A TW105114326A TW105114326A TW201642838A TW 201642838 A TW201642838 A TW 201642838A TW 105114326 A TW105114326 A TW 105114326A TW 105114326 A TW105114326 A TW 105114326A TW 201642838 A TW201642838 A TW 201642838A
- Authority
- TW
- Taiwan
- Prior art keywords
- antibody
- formulation
- hyb
- vegf
- lipid
- Prior art date
Links
- 239000002502 liposome Substances 0.000 title claims abstract description 118
- 239000000203 mixture Substances 0.000 title claims abstract description 116
- 238000009472 formulation Methods 0.000 title claims abstract description 100
- 229960003876 ranibizumab Drugs 0.000 claims abstract description 58
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 50
- 238000011282 treatment Methods 0.000 claims abstract description 47
- 201000010099 disease Diseases 0.000 claims abstract description 46
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims abstract description 43
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims abstract description 37
- 201000011190 diabetic macular edema Diseases 0.000 claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 206010064930 age-related macular degeneration Diseases 0.000 claims abstract description 15
- 208000002780 macular degeneration Diseases 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 206010055665 Corneal neovascularisation Diseases 0.000 claims abstract description 7
- 201000000159 corneal neovascularization Diseases 0.000 claims abstract description 7
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims abstract 7
- 150000002632 lipids Chemical class 0.000 claims description 55
- 238000000034 method Methods 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 23
- 229940079593 drug Drugs 0.000 claims description 22
- 239000007864 aqueous solution Substances 0.000 claims description 21
- 230000000699 topical effect Effects 0.000 claims description 21
- 239000012049 topical pharmaceutical composition Substances 0.000 claims description 20
- 239000007924 injection Substances 0.000 claims description 19
- 238000002347 injection Methods 0.000 claims description 19
- 239000004480 active ingredient Substances 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- 229960000397 bevacizumab Drugs 0.000 claims description 16
- -1 6,7-dimethoxyquinoxalin-2-yl Chemical group 0.000 claims description 14
- 239000005557 antagonist Substances 0.000 claims description 12
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 12
- 239000012530 fluid Substances 0.000 claims description 11
- 208000022873 Ocular disease Diseases 0.000 claims description 10
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 230000033115 angiogenesis Effects 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 229960002117 triamcinolone acetonide Drugs 0.000 claims description 9
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 claims description 9
- 210000004027 cell Anatomy 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 8
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims description 7
- 150000003431 steroids Chemical class 0.000 claims description 7
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 claims description 7
- 229960001796 sunitinib Drugs 0.000 claims description 7
- 239000002525 vasculotropin inhibitor Substances 0.000 claims description 7
- 230000004304 visual acuity Effects 0.000 claims description 7
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 5
- 239000012528 membrane Substances 0.000 claims description 5
- 230000001613 neoplastic effect Effects 0.000 claims description 5
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims description 4
- 108010041308 Endothelial Growth Factors Proteins 0.000 claims description 4
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 4
- 208000001344 Macular Edema Diseases 0.000 claims description 4
- 206010025415 Macular oedema Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 230000002137 anti-vascular effect Effects 0.000 claims description 4
- 239000004599 antimicrobial Substances 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 239000003246 corticosteroid Substances 0.000 claims description 4
- 201000010230 macular retinal edema Diseases 0.000 claims description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 4
- 102000004169 proteins and genes Human genes 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 229960003787 sorafenib Drugs 0.000 claims description 4
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 3
- WLCZTRVUXYALDD-IBGZPJMESA-N 7-[[(2s)-2,6-bis(2-methoxyethoxycarbonylamino)hexanoyl]amino]heptoxy-methylphosphinic acid Chemical compound COCCOC(=O)NCCCC[C@H](NC(=O)OCCOC)C(=O)NCCCCCCCOP(C)(O)=O WLCZTRVUXYALDD-IBGZPJMESA-N 0.000 claims description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 3
- 206010038934 Retinopathy proliferative Diseases 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 claims description 3
- 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 claims description 3
- 229960002411 imatinib Drugs 0.000 claims description 3
- 229960003407 pegaptanib Drugs 0.000 claims description 3
- 230000002792 vascular Effects 0.000 claims description 3
- VLKLOAZMKOFHKA-UHFFFAOYSA-N 1,2-dimethyl-6-phenylimidazo[4,5-g]quinoxaline Chemical compound C=1N=C2C=C3N(C)C(C)=NC3=CC2=NC=1C1=CC=CC=C1 VLKLOAZMKOFHKA-UHFFFAOYSA-N 0.000 claims description 2
- KIWODJBCHRADND-UHFFFAOYSA-N 3-anilino-4-[1-[3-(1-imidazolyl)propyl]-3-indolyl]pyrrole-2,5-dione Chemical compound O=C1NC(=O)C(C=2C3=CC=CC=C3N(CCCN3C=NC=C3)C=2)=C1NC1=CC=CC=C1 KIWODJBCHRADND-UHFFFAOYSA-N 0.000 claims description 2
- RBHBOUYXUXWCNJ-UHFFFAOYSA-N 5-[(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxylic acid Chemical compound OC(=O)C1=C(C)NC(C=C2C3=CC(F)=CC=C3NC2=O)=C1C RBHBOUYXUXWCNJ-UHFFFAOYSA-N 0.000 claims description 2
- NEZONWMXZKDMKF-JTQLQIEISA-N Alkannin Chemical compound C1=CC(O)=C2C(=O)C([C@@H](O)CC=C(C)C)=CC(=O)C2=C1O NEZONWMXZKDMKF-JTQLQIEISA-N 0.000 claims description 2
- 206010003445 Ascites Diseases 0.000 claims description 2
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- WPTTVJLTNAWYAO-KPOXMGGZSA-N Bardoxolone methyl Chemical compound C([C@@]12C)=C(C#N)C(=O)C(C)(C)[C@@H]1CC[C@]1(C)C2=CC(=O)[C@@H]2[C@@H]3CC(C)(C)CC[C@]3(C(=O)OC)CC[C@]21C WPTTVJLTNAWYAO-KPOXMGGZSA-N 0.000 claims description 2
- 208000023328 Basedow disease Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 241000283707 Capra Species 0.000 claims description 2
- 201000009030 Carcinoma Diseases 0.000 claims description 2
- 208000003163 Cavernous Hemangioma Diseases 0.000 claims description 2
- 102100024649 Cell adhesion molecule 1 Human genes 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 208000006332 Choriocarcinoma Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- CUKSFECWKQBVED-INIZCTEOSA-N Decursin Chemical compound C1=CC(=O)OC2=C1C=C1C[C@H](OC(=O)C=C(C)C)C(C)(C)OC1=C2 CUKSFECWKQBVED-INIZCTEOSA-N 0.000 claims description 2
- BGXFQDFSVDZUIW-UHFFFAOYSA-N Decursinol Natural products O1C(=O)C=CC2=C1C=C1OC(C)(C)C(O)CC1=C2 BGXFQDFSVDZUIW-UHFFFAOYSA-N 0.000 claims description 2
- 206010058314 Dysplasia Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 2
- 208000010412 Glaucoma Diseases 0.000 claims description 2
- 206010018498 Goitre Diseases 0.000 claims description 2
- CUKSFECWKQBVED-UHFFFAOYSA-N Grandivittin Natural products C1=CC(=O)OC2=C1C=C1CC(OC(=O)C=C(C)C)C(C)(C)OC1=C2 CUKSFECWKQBVED-UHFFFAOYSA-N 0.000 claims description 2
- 208000015023 Graves' disease Diseases 0.000 claims description 2
- WDXRGPWQVHZTQJ-AUKWTSKRSA-N Guggulsterone Natural products C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC(=O)/C(=C/C)[C@@]1(C)CC2 WDXRGPWQVHZTQJ-AUKWTSKRSA-N 0.000 claims description 2
- WDXRGPWQVHZTQJ-NRJJLHBYSA-N Guggulsterone E Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC(=O)C(=CC)[C@@]1(C)CC2 WDXRGPWQVHZTQJ-NRJJLHBYSA-N 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 102000014150 Interferons Human genes 0.000 claims description 2
- 108010050904 Interferons Proteins 0.000 claims description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
- 239000003798 L01XE11 - Pazopanib Substances 0.000 claims description 2
- 206010023825 Laryngeal cancer Diseases 0.000 claims description 2
- 241001071917 Lithospermum Species 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- BRINSLYLKLUSSY-UHFFFAOYSA-N N-(4-chlorophenyl)-5-(pyridin-4-ylmethyl)-1H-pyridazin-2-amine Chemical compound ClC1=CC=C(NN2NC=C(C=C2)CC2=CC=NC=C2)C=C1 BRINSLYLKLUSSY-UHFFFAOYSA-N 0.000 claims description 2
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 claims description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 2
- 229930193140 Neomycin Natural products 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 206010048991 Ovarian adenoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 208000005228 Pericardial Effusion Diseases 0.000 claims description 2
- 208000002151 Pleural effusion Diseases 0.000 claims description 2
- 206010035664 Pneumonia Diseases 0.000 claims description 2
- 206010036790 Productive cough Diseases 0.000 claims description 2
- 108010007568 Protamines Proteins 0.000 claims description 2
- 102000007327 Protamines Human genes 0.000 claims description 2
- 101000739162 Rattus norvegicus Secretoglobin family 2A member 2 Proteins 0.000 claims description 2
- 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- GSNOZLZNQMLSKJ-UHFFFAOYSA-N Trapidil Chemical compound CCN(CC)C1=CC(C)=NC2=NC=NN12 GSNOZLZNQMLSKJ-UHFFFAOYSA-N 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 2
- UNNKKUDWEASWDN-UHFFFAOYSA-N alkannin Natural products CC(=CCC(O)c1cc(O)c2C(=O)C=CC(=O)c2c1O)C UNNKKUDWEASWDN-UHFFFAOYSA-N 0.000 claims description 2
- 229960003005 axitinib Drugs 0.000 claims description 2
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- PRYZSLKPMFOUNL-MHIBGBBJSA-N bevasiranib Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2CO)N2C3=NC=NC(N)=C3N=C2)O)N2C(N=C(N)C=C2)=O)O)N2C(N=C(N)C=C2)=O)O)N2C(NC(=O)C=C2)=O)O)N2C(N=C(N)C=C2)=O)O)N2C3=NC=NC(N)=C3N=C2)O)N2C(N=C(N)C=C2)=O)O)N2C(N=C(N)C=C2)=O)O)N2C3=NC=NC(N)=C3N=C2)O)N2C3=NC=NC(N)=C3N=C2)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C(N=C(N)C=C2)=O)O)N2C(N=C(N)C=C2)=O)O)N2C3=NC=NC(N)=C3N=C2)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C(N=C(N)C=C2)=O)O)N2C3=NC=NC(N)=C3N=C2)O)N2C(N=C(N)C=C2)=O)O)[C@@H](O)C1 PRYZSLKPMFOUNL-MHIBGBBJSA-N 0.000 claims description 2
- 229950006615 bevasiranib Drugs 0.000 claims description 2
- KQNZDYYTLMIZCT-KQPMLPITSA-N brefeldin A Chemical compound O[C@@H]1\C=C\C(=O)O[C@@H](C)CCC\C=C\[C@@H]2C[C@H](O)C[C@H]21 KQNZDYYTLMIZCT-KQPMLPITSA-N 0.000 claims description 2
- JUMGSHROWPPKFX-UHFFFAOYSA-N brefeldin-A Natural products CC1CCCC=CC2(C)CC(O)CC2(C)C(O)C=CC(=O)O1 JUMGSHROWPPKFX-UHFFFAOYSA-N 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 208000037976 chronic inflammation Diseases 0.000 claims description 2
- 230000006020 chronic inflammation Effects 0.000 claims description 2
- JXZWWIMXTVJNSF-UHFFFAOYSA-N decursin Natural products CC(=CC(=O)OC1Oc2cc3OC(=O)C=Cc3cc2CC1(C)C)C JXZWWIMXTVJNSF-UHFFFAOYSA-N 0.000 claims description 2
- BGXFQDFSVDZUIW-LBPRGKRZSA-N decursinol Chemical compound O1C(=O)C=CC2=C1C=C1OC(C)(C)[C@@H](O)CC1=C2 BGXFQDFSVDZUIW-LBPRGKRZSA-N 0.000 claims description 2
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 claims description 2
- 230000002357 endometrial effect Effects 0.000 claims description 2
- 201000006828 endometrial hyperplasia Diseases 0.000 claims description 2
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 229960001347 fluocinolone acetonide Drugs 0.000 claims description 2
- 108020001507 fusion proteins Proteins 0.000 claims description 2
- 102000037865 fusion proteins Human genes 0.000 claims description 2
- PFJKOHUKELZMLE-VEUXDRLPSA-N ganglioside GM3 Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@@H]([C@H](O)/C=C/CCCCCCCCCCCCC)NC(=O)CCCCCCCCCCCCC\C=C/CCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 PFJKOHUKELZMLE-VEUXDRLPSA-N 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 229950000700 guggulsterone Drugs 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 201000002222 hemangioblastoma Diseases 0.000 claims description 2
- 201000011066 hemangioma Diseases 0.000 claims description 2
- 206010020718 hyperplasia Diseases 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 229940079322 interferon Drugs 0.000 claims description 2
- 206010023841 laryngeal neoplasm Diseases 0.000 claims description 2
- IXAQOQZEOGMIQS-SSQFXEBMSA-N lipoxin A4 Chemical compound CCCCC[C@H](O)\C=C\C=C/C=C/C=C/[C@@H](O)[C@@H](O)CCCC(O)=O IXAQOQZEOGMIQS-SSQFXEBMSA-N 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 claims description 2
- 229950010895 midostaurin Drugs 0.000 claims description 2
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims description 2
- 229960004927 neomycin Drugs 0.000 claims description 2
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 claims description 2
- 229950008516 olaratumab Drugs 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 229960000639 pazopanib Drugs 0.000 claims description 2
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- YJGVMLPVUAXIQN-HAEOHBJNSA-N picropodophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-HAEOHBJNSA-N 0.000 claims description 2
- 201000011461 pre-eclampsia Diseases 0.000 claims description 2
- 229940048914 protamine Drugs 0.000 claims description 2
- 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 claims description 2
- 229950000261 ruboxistaurin Drugs 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 208000024794 sputum Diseases 0.000 claims description 2
- 210000003802 sputum Anatomy 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 229960005314 suramin Drugs 0.000 claims description 2
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 claims description 2
- 208000024891 symptom Diseases 0.000 claims description 2
- UXXQOJXBIDBUAC-UHFFFAOYSA-N tandutinib Chemical compound COC1=CC2=C(N3CCN(CC3)C(=O)NC=3C=CC(OC(C)C)=CC=3)N=CN=C2C=C1OCCCN1CCCCC1 UXXQOJXBIDBUAC-UHFFFAOYSA-N 0.000 claims description 2
- WDXRGPWQVHZTQJ-UHFFFAOYSA-N trans-guggulsterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CC(=O)C(=CC)C1(C)CC2 WDXRGPWQVHZTQJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- 229950000578 vatalanib Drugs 0.000 claims description 2
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 230000003442 weekly effect Effects 0.000 claims description 2
- 239000002997 ophthalmic solution Substances 0.000 claims 7
- 229940054534 ophthalmic solution Drugs 0.000 claims 7
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims 2
- IBXFZLDPLQETKT-UHFFFAOYSA-N (4-tert-butylphenyl)-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]methanone Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1C(=O)C1=CC=C(C(C)(C)C)C=C1 IBXFZLDPLQETKT-UHFFFAOYSA-N 0.000 claims 1
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 claims 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 1
- 239000013011 aqueous formulation Substances 0.000 claims 1
- 238000002648 combination therapy Methods 0.000 claims 1
- 210000005069 ears Anatomy 0.000 claims 1
- 210000003999 epithelial cell of bile duct Anatomy 0.000 claims 1
- 229910052697 platinum Inorganic materials 0.000 claims 1
- 150000004032 porphyrins Chemical class 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims 1
- SSGGNFYQMRDXFH-UHFFFAOYSA-N sulfanylurea Chemical compound NC(=O)NS SSGGNFYQMRDXFH-UHFFFAOYSA-N 0.000 claims 1
- 210000004291 uterus Anatomy 0.000 claims 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 abstract description 9
- 230000001772 anti-angiogenic effect Effects 0.000 abstract description 5
- 230000002491 angiogenic effect Effects 0.000 abstract description 4
- 208000035475 disorder Diseases 0.000 abstract description 4
- 229940124447 delivery agent Drugs 0.000 abstract description 3
- 239000012634 fragment Substances 0.000 abstract description 3
- 241001465754 Metazoa Species 0.000 abstract description 2
- 230000009471 action Effects 0.000 abstract description 2
- 239000011230 binding agent Substances 0.000 abstract description 2
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 description 44
- 210000001508 eye Anatomy 0.000 description 34
- 229920001223 polyethylene glycol Polymers 0.000 description 17
- 239000002202 Polyethylene glycol Substances 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 10
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 10
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 10
- 210000004087 cornea Anatomy 0.000 description 8
- 229940076783 lucentis Drugs 0.000 description 8
- 229960005294 triamcinolone Drugs 0.000 description 8
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 8
- 230000006872 improvement Effects 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 238000011200 topical administration Methods 0.000 description 7
- 206010025421 Macule Diseases 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 6
- 125000005647 linker group Chemical group 0.000 description 6
- 238000012014 optical coherence tomography Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 description 5
- 230000004071 biological effect Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 210000002889 endothelial cell Anatomy 0.000 description 5
- 102000058223 human VEGFA Human genes 0.000 description 5
- 230000004410 intraocular pressure Effects 0.000 description 5
- 108020004707 nucleic acids Proteins 0.000 description 5
- 150000007523 nucleic acids Chemical class 0.000 description 5
- 102000039446 nucleic acids Human genes 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000013598 vector Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 108091008605 VEGF receptors Proteins 0.000 description 4
- 150000001413 amino acids Chemical group 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical group C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 108010019674 Proto-Oncogene Proteins c-sis Proteins 0.000 description 3
- 206010057190 Respiratory tract infections Diseases 0.000 description 3
- 208000017442 Retinal disease Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 108010081667 aflibercept Proteins 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 208000030533 eye disease Diseases 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 3
- 235000019799 monosodium phosphate Nutrition 0.000 description 3
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 229940023490 ophthalmic product Drugs 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 210000001525 retina Anatomy 0.000 description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 3
- 229960001922 sodium perborate Drugs 0.000 description 3
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 3
- 239000008174 sterile solution Substances 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000004393 visual impairment Effects 0.000 description 3
- AFSHUZFNMVJNKX-UHFFFAOYSA-N 1,2-di-(9Z-octadecenoyl)glycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCC=CCCCCCCCC AFSHUZFNMVJNKX-UHFFFAOYSA-N 0.000 description 2
- AFSHUZFNMVJNKX-LLWMBOQKSA-N 1,2-dioleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](CO)OC(=O)CCCCCCC\C=C/CCCCCCCC AFSHUZFNMVJNKX-LLWMBOQKSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 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 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 108010008165 Etanercept Proteins 0.000 description 2
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 2
- 206010029113 Neovascularisation Diseases 0.000 description 2
- 108091008606 PDGF receptors Proteins 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 2
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 2
- 102100024952 Protein CBFA2T1 Human genes 0.000 description 2
- 206010038848 Retinal detachment Diseases 0.000 description 2
- 208000002847 Surgical Wound Diseases 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-UHFFFAOYSA-N 0.000 description 2
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- 229960000571 acetazolamide Drugs 0.000 description 2
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 229960002833 aflibercept Drugs 0.000 description 2
- 210000002159 anterior chamber Anatomy 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- 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 2
- 239000012153 distilled water Substances 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 206010014801 endophthalmitis Diseases 0.000 description 2
- 210000000416 exudates and transudate Anatomy 0.000 description 2
- 230000004438 eyesight Effects 0.000 description 2
- UHUSDOQQWJGJQS-UHFFFAOYSA-N glycerol 1,2-dioctadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCCCC UHUSDOQQWJGJQS-UHFFFAOYSA-N 0.000 description 2
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 2
- 239000008240 homogeneous mixture Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 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 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- DTOSIQBPPRVQHS-PDBXOOCHSA-M linolenate Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC([O-])=O DTOSIQBPPRVQHS-PDBXOOCHSA-M 0.000 description 2
- 229940040452 linolenate Drugs 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 description 2
- 229940100654 ophthalmic suspension Drugs 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000000649 photocoagulation Effects 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000004264 retinal detachment Effects 0.000 description 2
- 230000002207 retinal effect Effects 0.000 description 2
- 208000004644 retinal vein occlusion Diseases 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 229940034785 sutent Drugs 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229960004791 tropicamide Drugs 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- QZNNVYOVQUKYSC-JEDNCBNOSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid;hydron;chloride Chemical compound Cl.OC(=O)[C@@H](N)CC1=CN=CN1 QZNNVYOVQUKYSC-JEDNCBNOSA-N 0.000 description 1
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 description 1
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- JHFAEUICJHBVHB-UHFFFAOYSA-N 1h-indol-2-ol Chemical compound C1=CC=C2NC(O)=CC2=C1 JHFAEUICJHBVHB-UHFFFAOYSA-N 0.000 description 1
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 241001553178 Arachis glabrata Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- CNJYIFDPXHFZDI-UHFFFAOYSA-N C(=O)(O)C(O)C(O)C(=O)O.C1(CCC(N1)=O)=O Chemical compound C(=O)(O)C(O)C(O)C(=O)O.C1(CCC(N1)=O)=O CNJYIFDPXHFZDI-UHFFFAOYSA-N 0.000 description 1
- 206010007766 Cataract traumatic Diseases 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Natural products C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-UHFFFAOYSA-N 0.000 description 1
- WYQPLTPSGFELIB-JTQPXKBDSA-N Difluprednate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2CC[C@@](C(=O)COC(C)=O)(OC(=O)CCC)[C@@]2(C)C[C@@H]1O WYQPLTPSGFELIB-JTQPXKBDSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 208000001860 Eye Infections Diseases 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 101000851030 Homo sapiens Vascular endothelial growth factor receptor 3 Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010058031 Joint adhesion Diseases 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- GZENKSODFLBBHQ-ILSZZQPISA-N Medrysone 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@@H](C(C)=O)CC[C@H]21 GZENKSODFLBBHQ-ILSZZQPISA-N 0.000 description 1
- 206010050513 Metastatic renal cell carcinoma Diseases 0.000 description 1
- 208000003926 Myelitis Diseases 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 102000001393 Platelet-Derived Growth Factor alpha Receptor Human genes 0.000 description 1
- 108010068588 Platelet-Derived Growth Factor alpha Receptor Proteins 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 229920002675 Polyoxyl Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[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 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000012822 autophagy inhibitor Substances 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 1
- 210000003969 blast cell Anatomy 0.000 description 1
- 229960003679 brimonidine Drugs 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- PMSGJXMYHUSZEI-UHFFFAOYSA-N butanedioic acid;pyrrolidine-2,5-dione Chemical compound O=C1CCC(=O)N1.OC(=O)CCC(O)=O PMSGJXMYHUSZEI-UHFFFAOYSA-N 0.000 description 1
- 210000001043 capillary endothelial cell Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- PIQCTGMSNWUMAF-UHFFFAOYSA-N chembl522892 Chemical compound C1CN(C)CCN1C1=CC=C(NC(=N2)C=3C(NC4=CC=CC(F)=C4C=3N)=O)C2=C1 PIQCTGMSNWUMAF-UHFFFAOYSA-N 0.000 description 1
- 208000019069 chronic childhood arthritis Diseases 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000004456 color vision Effects 0.000 description 1
- 208000021921 corneal disease Diseases 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 229960002398 demeclocycline Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229960004875 difluprednate Drugs 0.000 description 1
- GYZLOYUZLJXAJU-UHFFFAOYSA-N diglycidyl ether Chemical compound C1OC1COCC1CO1 GYZLOYUZLJXAJU-UHFFFAOYSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 150000002027 dodecanoic acid esters Chemical class 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 208000011323 eye infectious disease Diseases 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 229940051306 eylea Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229940043075 fluocinolone Drugs 0.000 description 1
- 229960001048 fluorometholone Drugs 0.000 description 1
- FAOZLTXFLGPHNG-KNAQIMQKSA-N fluorometholone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@]2(F)[C@@H](O)C[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FAOZLTXFLGPHNG-KNAQIMQKSA-N 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 229960003923 gatifloxacin Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- JEJLGIQLPYYGEE-UHFFFAOYSA-N glycerol dipalmitate Natural products CCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCC JEJLGIQLPYYGEE-UHFFFAOYSA-N 0.000 description 1
- 239000003316 glycosidase inhibitor Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 230000001965 increasing effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- 238000002430 laser surgery Methods 0.000 description 1
- 238000013532 laser treatment Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 229960001798 loteprednol Drugs 0.000 description 1
- YPZVAYHNBBHPTO-MXRBDKCISA-N loteprednol Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)OCCl)[C@@H]4[C@@H]3CCC2=C1 YPZVAYHNBBHPTO-MXRBDKCISA-N 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 229960001011 medrysone Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- WFJRIDQGVSJLLH-UHFFFAOYSA-N methyl n-aminocarbamate Chemical compound COC(=O)NN WFJRIDQGVSJLLH-UHFFFAOYSA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 201000003142 neovascular glaucoma Diseases 0.000 description 1
- 229960001002 nepafenac Drugs 0.000 description 1
- QEFAQIPZVLVERP-UHFFFAOYSA-N nepafenac Chemical compound NC(=O)CC1=CC=CC(C(=O)C=2C=CC=CC=2)=C1N QEFAQIPZVLVERP-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 229940086541 peg-12 glyceryl dimyristate Drugs 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- LPGZAWSMGCIBOF-UHFFFAOYSA-N pentane-1,2-diamine Chemical compound CCCC(N)CN LPGZAWSMGCIBOF-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 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
- 230000008569 process Effects 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical class NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 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
- 230000009467 reduction Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000004268 retinal thickening Effects 0.000 description 1
- 229960001487 rimexolone Drugs 0.000 description 1
- QTTRZHGPGKRAFB-OOKHYKNYSA-N rimexolone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CC)(C)[C@@]1(C)C[C@@H]2O QTTRZHGPGKRAFB-OOKHYKNYSA-N 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 230000011664 signaling Effects 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
- DZZWHBIBMUVIIW-DTORHVGOSA-N sparfloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(N)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F DZZWHBIBMUVIIW-DTORHVGOSA-N 0.000 description 1
- 229960004954 sparfloxacin Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical class CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- 229940100613 topical solution Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229940126307 triamcinolone acetate Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000002691 unilamellar liposome Substances 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/04—Drugs for disorders of the respiratory system for throat disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
-
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- 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
-
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
- A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
-
- 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
-
- 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
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Endocrinology (AREA)
- Pulmonology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Dermatology (AREA)
- Hematology (AREA)
- Dispersion Chemistry (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Otolaryngology (AREA)
- Cardiology (AREA)
- Neurology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
Abstract
本發明係關於醫藥調配物，其包含抗血管生成化合物(例如選自(例如)蘭尼單抗(ranibizumab)之單株抗體或其片段，該蘭尼單抗為抑制VEGF作用之血管內皮生長因子結合劑)，及選自醫藥上可接受之脂質體之遞送劑。該等調配物係用於治療動物及人類之各種血管生成病症及疾病，且較佳用於選自年齡相關黃斑退化、糖尿病黃斑水腫及角膜新血管生成之眼病。
Description
本申請案主張對分別於2012年8月21日；2013年3月15日；及2013年8月5日申請之美國臨時專利申請案61/691,455、61/791,693及61/862,300之優先權，該等申請案全部以引用的方式全文併入本文中。
本發明係關於包含通常藉由玻璃體內注射施加至眼睛之眼用醫藥及容許將該玻璃體內醫藥局部施加至眼睛之脂質體遞送劑的醫藥調配物。本發明亦係關於抗血管生成化合物，例如選自(例如)蘭尼單抗(ranibizumab)之單株抗體或其片段，蘭尼單抗係抑制VEGF之作用之血管內皮生長因子結合劑；及/或多重激酶VEGFR及PDGFR抑制劑，例如舒尼替尼(sunitinib)；及選自醫藥上可接受之脂質體之遞送劑。該等調配物係用於治療動物及人類之各種血管生成病症及疾病，且較佳用於選自年齡相關黃斑退化、糖尿病黃斑水腫及角膜新血管生成之眼病。
眼用疾病治療通常需要將特定藥物局部投與或玻璃體內注射至眼睛，此取決於特定疾病或病狀及關於特定藥物及疾病之投與途徑之效力。在某些眼睛疾病或病狀中，僅在該藥物係藉由玻璃體內注射投與時，可達成有效治療。藉由玻璃體內注射可有效治療多種眼睛疾病
及病狀。同時，該等注射可引起包括眼睛感染(眼內炎)、眼睛發炎、視網膜脫落及眼壓增加在內之嚴重副效應及/或與其相關。由於該等副效應或風險，眼睛之局部治療已成為治療眼睛病狀之藥物之較佳投與途徑及聖杯(Holy Grail)，此乃因在幾乎所有情形下，藥物之局部投與不能有效治療某些眼睛病狀、尤其發生在眼睛後部之彼等病狀。因此，相關技藝需要研發有效治療該等病狀並消除進行玻璃體內注射之需要之調配物。本發明者相信其已發現此一媒劑。美國專利第6,884,879號揭示各種抗VEGF抗體。此專利具體闡述並主張經批准並以商標名稱LUCENTIS®出售之單株抗體蘭尼單抗。其中所揭示之抗體係闡述為能夠預防、逆轉及/或緩和各種疾病之症狀，並闡述為具有抑制內皮細胞之VEGF誘導之增生之能力及抑制VEGF誘導之血管生成之能力。LUCENTIS®已經批准以0.5mg(0.05mL)之劑量強度藉由一個月一次玻璃體內注射用於新生血管(濕性)年齡相關黃斑退化(AMD)，且儘管有效性下降，但可以在至少四個月之一個月一次之初始方案後每三個月注射一次來投與所述經批准治療。LUCENTIS®亦在美國經批准按一個月一次玻璃體內方案使用0.5mg(0.05mL)用於視網膜靜脈阻塞(RVO)之後之黃斑水腫。另外，LUCENTIS®在歐洲及美國經批准以可注射調配物形式用於糖尿病黃斑水腫。
舒尼替尼(SU-11248，舒癌特(Sutent))係在2006年1月由FDA批准為用於治療轉移性腎細胞癌及胃腸基質瘤之單一療法。舒尼替尼抑制至少8種受體蛋白-酪胺酸激酶，該等受體蛋白-酪胺酸激酶包括血管內皮生長因子受體1至3(VEGFR1至VEGFR3)、血小板源生長因子受體(PDGFRα及PDGFRβ)。此化合物藉由減少藉助VEGFR1、VEGFR2及PDGFRβ之信號傳導來抑制血管生成。PDGFRβ係發現於圍繞毛細管內皮細胞之外周細胞中1(Roskoski，2007，附帶PDF文檔)。有證據證明，抗PDGF之組合使用在一些VEGF相關之疾病之治療中優於蘭尼
單抗單一療法。
存在多種副效應或潛在副效應，包括與玻璃體內注射抗VEGF抗體及其他眼用藥物相關之患者不適。玻璃體內注射程序需要具有一般無菌規則之專用無塵室；復蘇設施必須立即可用。此程序之併發症包括感染性眼內炎；視網膜脫落及創傷性白內障。玻璃體內注射之其他可能併發症包括眼內壓力變化，尤指眼內壓力升高。可能在注射任一種類之醫藥後立即發生與注射相關之眼內壓力升高，及可能在注射後數天或甚至數月後檢測到明確之與藥物相關之眼內壓力變化。參見Semin.Ophthamol.2009 Mar-Apr；24(2)：100-5。
相關技藝對該等抗VEGF抗體及諸如以下等其他有效眼用藥物之新局部治療方案存在迫切且未得到滿足之醫學需求：抗微生物劑、抗病毒劑、皮質類固醇及抗血管內皮生長因子藥劑，其係藉助玻璃體內注射投與之主要藥物類別。本發明包含該等脂質體與該等藥物類別內之任一該等藥物之呈局部調配物形式之組合。儘管一般而言美國專利第6,884,879號揭示包括脂質體之各種可能遞送方法或試劑及包括局部投與該等VEGF單株抗體之各種投與途徑，但蘭尼單抗之唯一經批准形式係存於液體調配物中之玻璃體內形式。相關技藝需要有效治療患有包括眼病之VEGF相關之病症之人的局部蘭尼單抗調配物。
本發明者已滿足此未得到滿足之需求，且已驚奇地發現某些包含該等VEGF單株抗體之脂質體調配物，且某些脂質體有效緩解患有糖尿病黃斑水腫之患者。可向受影響眼睛有效地局部投與該等調配物，且其較局部施加玻璃體內調配物有效。美國專利第6,958,160號揭示並主張自成型之熱力學穩定之脂質體。美國專利公開案第2010/0076209號(以引用的方式併入本文中)揭示用於脂質體及藥物遞送之PEG-脂質偶聯物。包括該等以商標名稱QsomesTM(在下文中，Qsome)出售之自成型之熱力學穩定之脂質體的各種基於脂質之產物
係由Biozone Laboratories出售用於多種治療用途並經由各種投與途徑(包括藉由向皮膚局部投與)。本發明者已發現，可將包含蘭尼單抗及該等自成型之熱力學穩定之脂質體及/或PEG-脂質偶聯物之醫藥組合物局部遞送至需要治療VEGF相關之眼用疾病及病狀之患者之眼睛。本發明進一步包含包含本文中所陳述之Qsome(自成型之熱力學穩定之脂質體)及藥物之局部調配物，其中該調配物適宜於治療眼後段疾病及/或為組合眼前段/後段疾病之疾病。所主張調配物適宜於局部投與，並特別用於治療通常經由眼周途徑或經由玻璃體內投與(眼內遞送)治療之眼用疾病及病狀。眼周投與包括結膜下、特農囊下、眼球後及球周投與。存在一些已揭示為能夠藉由局部投與遞送至眼後段之藥物-該等包括ESBA105，即抗TNF-α單鏈抗體；地塞米松(dexamethasone)；奈帕芬胺(nepafenac)；美金剛HCl(memantine HCl)；多佐胺(dorzolamide)；溴莫尼定(brimonidine)及倍他洛爾(betaxolol)。據信，該等藥物以Qsome調配物形式之局部投與將導致更有效局部遞送及更有效眼後段遞送。較佳地，然而，所主張之發明包含包括本文中所闡述之Qsome脂質體及迄今為止仍未有效地藉助局部投與遞送之藥物的局部調配物。
通常藉由玻璃體內注射給予之藥物包括抗微生物劑、抗病毒劑、皮質類固醇及抗血管內皮生長因子藥劑。本發明包含脂質體調配物，該脂質體調配物包含自成型之熱力學穩定之脂質體及選自抗微生物劑、抗病毒劑、皮質類固醇及抗血管內皮生長因子藥劑中之任一者或其組合之活性醫藥劑，其中該調配物適宜於局部遞送至患者之眼睛以治療眼部疾病或病狀。待克菲那(Diclofenac)、加替沙星(gatifloxacin)、乳酸司帕沙星(sparfloxacin lactate)、GCV、地美環素(demeclocycline)、夫比普洛芬(flurbiprofen)、多柔比星(doxorubicin)、塞來昔布(celecoxib)、布地奈德(budesonide)及順鉑
(cisplatin)已調配成膠質劑型用於經角膜或經鞏膜遞送。相對於陰離子型及中性脂質體，含有青黴素G、托平卡胺(tropicamide)及乙醯唑胺(acetazolamide)之陽離子型脂質體已用於提供跨越角膜之最大藥物運輸。參見Schaeffer等人，Liposomes in topical drug deliver.Invest.Ophthalmol.Vis Sci.1982：22(2)：220-7；Nagarsenker等人，Preparation and evaluation of liposomal formulations of tropicamide for ocular delivery.Int J Pharma.1999：190(1)：63-71及Hathout等人，Liposome as an ocular delivery system for acetazolamide：in vitro and in vivo studies.AAPS PharmaSciTech.2007；8(1)：1。
糖尿病視網膜病變(DR)係糖尿病之最常見大血管併發症2(Fong,2004)，且係工作年齡成年人中視覺喪失新個案之主要原因。糖尿病黃斑水腫(DME)係患有DR之患者之視覺喪失之最常見原因。DME之盛行率係3%最新診斷，其中每年約75,000個DME新個案(USA)。全世界患有糖尿病之患者數係令人驚愕之285,000,000。DME係由一系列生物化學及細胞變化造成，該等變化最終引起漸進洩漏及滲出，從而導致視網膜增厚及黃斑中央之1個視神經盤直徑內之硬滲出物。DME係患有糖尿病之患者之受損視覺之一最常見原因3(Bhagat,2009)。在2年之隨訪後，大約50%之患者經歷2行之BCVA之喪失4(Meyer,2007)。
在DME中，受損血管將流體洩漏至導致腫脹之視網膜(黃斑)之中央部分中。黃斑與敏銳之中央視覺有涉及。中央窩係在黃斑之中央。DME可發生在患有1型或2型糖尿病之患者中。美國大約26,000,000個人患有糖尿病，且每年20歲或更大之人中診斷出1,900,000個新個案。估計每年發生多達75.000個DME新案例。DME係大部分發達國家中工作年齡之群體之失明之主要原因。DME之第一線療法係雷射外科手術，該雷射外科手術密封漏的血管以減小流體洩漏並減少視網膜中之
流體量。因此，相關技藝顯著需要產生向該等患者提供治療緩解之新調配物。
本發明係包含抗血管生成化合物或其他眼用活性成份及脂質體之醫藥調配物。較佳抗血管生成化合物係抗VEGF抗體。較佳地以局部調配物形式向需要治療之患者之眼睛投與該醫藥調配物。該醫藥調配物係用於治療VEGF相關之眼病，包括(例如)年齡相關黃斑退化及糖尿病黃斑水腫。本發明亦係關於適宜於局部投與且有效治療角膜新生血管疾病之調配物。
較佳抗VEGF抗體係選自蘭尼單抗(LUCENTIS®)，且可如美國專利第6,884,879號中所闡述製備，該專利以引用的方式併入本文中。此產物係以處方玻璃體內液體調配物之形式出售。蘭尼單抗係重組人類化IgG1 κ同型單株抗體片段。此抗體結合至VEGF-A並抑制其，且具有大約48千道耳頓(kilodalton)之分子量。該產物係於含有四環素之營養培養基中之大腸桿菌(E.coli)表現系統中產生。該處方產物係於含有0.05mL之10mg/mL蘭尼單抗之單次使用玻璃小瓶中供應。諸如貝伐珠單抗(bevacizumab)等其他抗VEGF抗體亦可用於治療某些疾病及病狀，例如角膜新生血管疾病。本文中所揭示之局部脂質體調配物有助於整個抗體(例如貝伐珠單抗)滲透至具有異常新脈管系統之眼睛中。
用於本發明之脂質體較佳包含美國專利第6,958,160號中所闡述之彼等脂質體，該專利以引用的方式全文併入本文中。如其中所闡述，脂質體係自封閉膠質顆粒，其中由一或多個脂質雙層構成之膜囊封一部分其中懸浮該等脂質體之水溶液。如'160專利中亦陳述，並非所有脂質體皆相同，且實際上，脂質體可具有包括以下之問題：膠質不穩定性及因極端條件(例如升高之壓力及溫度以及高剪切條件-其全
部皆可降解脂質組份)導致之製造問題。與脂質體相關之其他問題通常可包括雙層之大小及數量之異質分佈，其可引起或加劇放大問題。另外，滅菌條件亦可產生關於脂質體之問題。脂質體亦可具有因在懸浮液中時聚集而導致之膠質不穩定性。此導致融合問題，且對於此問題，解決方案通常係凍乾，其係昂貴之額外步驟。'160專利中所揭示之脂質體已克服該等問題，且驚奇地發現該等特定脂質體在與諸如蘭尼單抗等抗VEGF抗體組合時係有效的。
特定而言，包含自成型之熱力學穩定之脂質體及抗VEGF抗體之調配物特別適宜於在VEGF相關之眼用疾病及病狀之治療中局部施加。
用於本發明調配物之脂質體包含二醯基甘油-PEG化合物。該等化合物之熔點係低於約40℃，且醯基鏈之長度為大於或等於約14個碳。如'160專利中所陳述製備該等化合物。較佳脂質PEG偶聯物係PEG-12-GDM(聚乙二醇12-甘油二肉豆蔻酸酯)。PEG藉由在脂質體之外表面產生空間障壁來穩定脂質體，PEG鏈具有介於約300道耳頓與5000道耳頓之間之分子量。脂質體製備需要僅將脂質與水溶液混合。該等種類之脂質體以脂質可存在之最低能態存在，而在水溶液中，脂質體形成之重現性不成問題。
每次當與相同水溶液混合時，經界定之脂質、脂質混合物或脂質/化合物混合物將形成類似脂質體。在臨界濃度(約20重量對體積%)以上，非脂質體結構將開始在水溶液中形成。該等脂質體以其能態最低存在，且係熱力學穩定之自成型脂質體。PEG-12 GDM形成極小囊泡，故其可經滅菌過濾。可向脂質溶液及水溶液提供諸如振動或渦旋等動能。本發明調配物亦可使用6,958,160專利中所通常或具體闡述之其他脂質-PEG偶聯物。另外，亦可使用其他自成型之熱力學穩定之脂質PEG偶聯物，包括美國專利公開案第2010/0076209號中所闡述之
彼等化合物。下表1闡述某些PEG-12 GDM特徵。
分子量：1068g/mol
最優pH：5至7
溶解性：可溶於有機溶劑中。
在本發明之蘭尼單抗局部調配物中，使用基於溶液之最終體積1重量體積%之PEG-12 GDM，且局部溶液之pH為5.5，且脂質體在適當工作範圍中。
除抗血管生成化合物(例如，抗VEGF抗體)及熱力學穩定之自成型脂質體以外，該調配物可進一步包含其他醫藥上可接受之賦形劑。該等較佳賦形劑係選自由適宜於向眼睛局部投與之賦形劑組成之群。該等包括表面活性劑、緩衝劑、pH調整劑、鹽及其他該等成份。
該等調配物係用於治療VEGF相關之疾病及病狀及/或其他血管生成病狀。因此，本發明包括該等調配物治療年齡相關黃斑退化、包括糖尿病黃斑水腫之糖尿病視網膜疾病及角膜新血管生成之用途。在較佳實施例中，本發明包含局部調配物，並涵蓋藉由向需要治療之患者之眼睛局部投與該等調配物來治療該等VEGF相關之疾病及病狀之方法。
將在以下圖中闡述本發明。
圖1顯示來自利用脂質體蘭尼單抗調配物治療之單一患者之數
據，該患者在每天給予6滴並持續2週後在8週時期內具有經改良之使用光學同調斷層掃描術量測之中央窩厚度(OCT-CFT)。在第8週，該患者顯示CFT之增加，且在10週時以每天2滴之日劑量再起始治療。圖1顯示CFT在12週至14週時期再次出現改良。
圖2顯示利用脂質體蘭尼單抗調配物治療之相同臨床患者，其在每天給予6滴並持續2週後在8週時期內具有經改良之視覺敏銳度量測(ETDRS BCVA)。在第8週時，該患者顯示VA之降低，且在10週時以每天2滴之日劑量再起始治療。圖2顯示VA在12週至14週時期再次出現改良。
圖3顯示多層脂質體及單層脂質體之顯微鏡照片。
圖4顯示利用蘭尼單抗之脂質體調配物治療之患者之中央窩厚度隨時間之OCT結果。
圖5顯示患者對側眼睛之中央窩厚度隨時間之OCT結果。
圖6顯示三個患者之所研究眼睛之BCVA隨時間之結果。
圖7顯示對側眼睛之BCVA隨時間之結果。
本發明係關於醫藥調配物及其用途，其中該較佳調配物包含抗VEGF抗體及自成型之熱力學穩定之脂質體。本發明亦係關於包含抗VEGF抗體及自成型之熱力學穩定之脂質體之局部調配物。本發明進一步包含治療VEGF相關之疾病或病狀之方法，該方法包含向需要治療之患者投與包含抗VEGF抗體及自成型之熱力學穩定之脂質體之調配物。在較佳實施例中，該VEGF相關之疾病或病狀係選自糖尿病視網膜病變(DR)。
儘管脂質體「通常」之闡述係與各種活性成份之遞送相關，但相關技藝並未揭示或教示自成型之熱力學穩定之脂質體與抗VEGF抗體之組合。該調配物之脂質體係特別適宜於向需要治療VEGF相關之
疾病或病狀(特定而言眼部疾病或病狀)之患者遞送抗VEGF抗體。本發明之脂質體調配物係特別適於向需要治療(例如)糖尿病黃斑水腫或年齡相關黃斑退化或角膜新血管生成之患者之眼睛局部投與。本發明之脂質體具有使其尤其適於該等局部調配物之期望基本性質。該等脂質體懸浮液在調配物之溫度下熱力學穩定。構成脂質體之脂質之組合物具有若干基本性質。該等脂質具有允許形成脂質體之堆疊參數。該等脂質包括在懸浮液中空間上穩定脂質體之聚乙二醇(PEG)或具有類似性質之聚合物，作為頭基之一部分。另外，該等脂質體具有使其在與水或水溶液混合時呈液體形式之熔融溫度。
如6,610,322專利案中所述，當在水溶液中形成脂質體懸浮液時，需要添加較少能量或不需要添加能量。在本發明中，該較佳方法涉及在含有活性成份-抗VEGF抗體之水溶液之存在下形成脂質體懸浮液。因此，自組裝較佳在具有該活性成份之情況下發生，而非在將活性成份添加至該懸浮液中之前發生。脂質分子分散並自組裝至自然低能態。該等脂質體形成大或小單層囊泡(SUV)或多層囊泡(MLV)(參見圖3)，且如Biozone Laboratories網站中針對QusomesTM所闡述。
PEG鏈較佳具有介於約300道耳頓與5000道耳頓之間之分子量。適宜脂質之實例包括PEG-12 GDO(甘油二油酸酯)及PEG-12 GDM(甘油二肉豆蔻酸酯)。PEG-12 GDM在25℃下為流體，且具有分別0.853及0.889之堆疊參數Pa及Pv。該等脂質中之每一者在20℃、37℃及60℃下皆形成自發性脂質體。Pa可在介於0.84與0.88之間之範圍內，且Pv介於約0.88與0.93之間。較佳地，適宜化合物形成脂質體代替(例如)微胞。另外，脂質組合物應具有介於約0℃與100℃之間之相轉變溫度-脂質組合物具有允許該組合物在與水溶液混合時呈液體形式之熔融溫度。同樣，該組合物之彎曲彈性模數應使得脂質組合物可在水性環境中形成脂質體，而不需要任何能量輸入或任何顯著能量輸入。可將
動能施加至該溶液。較佳彎曲彈性模數係介於約0kt與15kt之間。彎曲彈性模數在很大程度上係由主鏈決定，且甘油係本發明之較佳主鏈，但亦可使用任一在彎曲彈性模數及適宜官能性方面等效之主鏈。最終溶液中之脂質之相對重量百分比可在大於0wt%(w/w)至約20wt%(w/w)之範圍內。該範圍可介於約1wt%與15wt%之間或介於約1%與10%之間或介於約1% wt/wt與5% wt/wt之間或介於大於0% wt/wt與4% wt/wt之間。
其他分子與具有長於12個之PEG鏈之脂質之混合物亦可用於本發明，限制條件係其形成脂質體。例如，PEG-45 GDS(甘油二硬脂酸酯)與膽固醇之混合物形成脂質體。如'322專利中所闡述，熟習此項技術者可改變包括PEG鏈長度及組成之變量以製備熱力學穩定之自由形成之脂質體，且該等改變在與抗VEGF抗體組合時包括於本發明之範圍內。當在脂質體形成之前添加至脂質中時膽固醇之量係高達約10% w/w。
除'322專利中所闡述之脂質以外，其他脂質亦可用於本發明。美國專利公開案第2010/0076209號闡述形成適宜於所具體闡述活性成份之藥物遞送之脂質體的某些PEG-脂質偶聯物。該參考文獻中無關於抗VEGF抗體之遞送之教示或參考文獻。特定而言，'209公開案中所闡述之二醯基甘油-聚乙二醇化合物可與抗VEGF抗體組合用於本發明調配物中。脂質化合物之一般結構係顯示於'209公開案中，且包括具有式(R2)(R1)甘油-X-PEG-R1及/或R1-PEG-X-甘油(R2)(R1)之化合物，其中R1較佳係-OH或-OCH3；R2及R3係脂肪酸，包括(但不限於)月桂酸酯、油酸酯、肉豆蔻酸酯、棕櫚酸酯、硬脂酸酯及亞麻油酸酯；且X代表在脂質與PEG之間之單一連接體或複製連接體或兩個或更多個連接體之組合。R2及R3可相同或不同。若R2係在甘油之C1位置處，則R3可定位於C2或C3處。該一般結構包括所有外消旋體及結
構異構體及/或其功能等效物。
R1亦可選自(例如)-NH2、-COOH、-OCH2CH3、-OCH2CH2CH3、-OCH2CH2OH、-COCH=CH2、-OCH2CH2NH2、-OSO2CH3、-OCH2C6H6、-OCH2COCH2CH2COONC4H4O2、-CH2CH2=CH2及-OC6H6。R1亦可係有助於將治療劑或靶向劑連接至脂質體表面之官能團。該等官能團可包括胺基烷基酯、馬來醯亞胺、縮水甘油醚、丙酸馬來醯亞胺基、胺基甲酸甲酯、對甲苯磺醯腙鹽、疊氮化物、炔丙基-胺、炔丙基醇、NHS酯、醯肼、琥珀醯亞胺基酯、酒石酸琥珀醯亞胺基酯、琥珀酸琥珀醯亞胺基酯及對甲苯磺酸酯鹽。本發明包括在脂質體組合物內具有抗VEGF抗體之脂質體調配物，且可進一步包括任一其他治療化合物，包括經由R1官能團共價結合或連接至脂質體之抗VEGF抗體。在該例子中，本發明將包括或係組合調配物或具有非共價結合之活性成份及共價結合之活性成份之調配物二者，其中該活性物可相同或不同。
可用於或適宜於此類型之脂質體調配物之連接體包括'209公開案中所闡述之彼等，且該公開案以飲用的方式併入本文中。其中表1闡述或列示該等適宜連接體，且該等連接體包括胺基、琥珀醯基胺基乙醯胺基、2-胺基戊醯胺基、2(2’)-R’-胺基乙醯基等。在每一情形中，脂質在20℃及37℃下形成自發性脂質體，如'209公開案之表4中所顯示。因此，本發明包括闡述為以下之彼等脂質：PEG-12-N1-GDO；PEG-23-N2-GDO；PEG-18-N3-GDO；PEG-23-N4-GDO；PEG-8-S1-GDO；PEG-18-S2-GDO；PEG-12-S3-GDO；PEG-18-Ac1-GDO；PEG-12-Ac2-GDO；PEG-12-N1-GDM；PEG-12-N1-GDLO；PEG-12-S3-GDM；PeG-12-S3-GDLO；PEG-12-Ac2-GDM；PEG-12-Ac2-GDLO；PEG-23-N1-GDL；PEG-12kN1-GDP；PEG-23-Ac2-GDL及PEG-12-Ac2-GDP。GDLO意指甘油二亞麻油酸酯，且GDP意指甘油二棕櫚酸
酯。該等化合物中之每一者在25℃下為流體，且具有在0.830至0.869之範圍內之堆疊參數Pa及在0.872至0.924之範圍內之Pv。
本發明進一步包括滿足其中所列舉之物理要求之已知脂質，其(例如)在25℃下為液體，且在20℃及37℃二者下自成型，且具有功能等效或等效堆疊參數，且當與水溶液組合時，在極少能量輸入或無能量輸入之情況下形成熱力學穩定之脂質體。
可用於本發明調配物之抗VEGF抗體包括任一已知抗VEGF抗體。該等抗體包括整個抗體或抗體片段，限制條件係其具有必需之抗VEGF生物學性質。在較佳實施例中，該抗體係具有必需之抗VEGF生物學及藥理學性質之抗體片段。美國專利第6,884,879號揭示可用於本發明之抗VEGF抗體。該等抗體包括具有包括以下之性質之人類化抗VEGF抗體及抗VEGF抗體變體：對VEGF之強結合親和力；抑制內皮細胞之VEGF促進之增生之能力及抑制VEGF誘導之血管生成之能力。較佳結合親和力(Kd)係不超過約5×10-9M，且具有不超過約5nM之活體外抑制內皮細胞之VEGF誘導之增生之ED50值。該等抗體包括在A673活體內腫瘤模型中以5mg/kg之抗體劑量抑制至少約50%腫瘤生長之彼等。最佳抗體係以商標名稱LUCENTIS®(蘭尼單抗)出售，且經批准以玻璃體內調配物形式用於治療年齡相關黃斑退化及各種形式之黃斑水腫。術語「抗VEGF抗體」包括整個抗體以及抗體片段。可利用抗VEGF抗體治療之疾病範圍包括與血管生成或病理血管生成病狀相關之彼等疾病或病狀。該等包括癌症以及眼內新生血管症候群，例如增生性視網膜病變或年齡相關黃斑退化(AMD)、類風濕性關節炎及牛皮癬。儘管較佳投與途徑為對眼睛之局部治療，且較佳疾病模態為糖尿病黃斑水腫，但本文中所列舉之調配物亦可用於其他遞送模式(即，可注射；靜脈內輸注)且用於治療多種VEGF相關之疾病及病狀。
抗VEGF抗體包括自編碼親代抗VEGF抗體之人類化變體之分離核酸產生之彼等，該親代抗體包含非人類可變結構域，其中該人類化變體結合人類VEGF，並具有6,884,879專利中所闡述並主張之彼等重鏈互補決定區胺基酸序列，該專利以引用的方式併入本文中。該抗VEGF抗體包括可使用具有編碼該等CDR胺基酸序列之核酸之載體及含有該等載體之分離宿主細胞產生的彼等。可培養宿主細胞以產生該等序列，且可自該等宿主細胞培養物回收人類化抗VEGF抗體。上文所列舉之分離核酸可進一步編碼具有含'879專利中所列舉之彼等序列之輕鏈互補決定區(CDR)之人類化變體。該人類化變體可包含具有顯示為'879專利中之SEQ ID NO：7之序列之重鏈可變結構域及具有顯示為SEQ ID NO：8之序列之輕鏈可變結構域。該人類化變體亦可包含'879專利中所顯示之SEQ ID NO：116之重鏈可變結構域序列及SEQ ID NO：115之輕鏈可變結構域序列。
美國專利第7,060,269號亦以引用的方式併入本文中。此專利主張並揭示蘭尼單抗。'269專利之技術方案1主張抑制受試者之VEGF誘導之血管生成之方法，該方法包含向該受試者投與有效量之人類化抗VEGF抗體，該人類化抗VEGF抗體以不超過約1×10-8之Kd值結合人類VEGF，該人類化抗VEGF抗體包含SEQ ID NO：116之重鏈可變結構域序列及SEQ ID NO：115之輕鏈可變結構域序列。蘭尼單抗係經設計用於眼內使用之重組人類化IgG1 κ同型單株抗體片段。此單株抗體結合人類血管內皮生長因子A(VEGF-A)至並抑制其。蘭尼單抗具有約48,000道耳頓之分子量，並於含有四環素之營養培養基中之大腸桿菌表現系統中產生。此產物係以商標名稱LUCENTIS®市面有售，並以於單次使用玻璃小瓶中之不含防腐劑之滅菌溶液形式供應，其可遞送0.05mL之具有10mM組胺酸HCl、10% α,α海藻糖脫水物、0.01%聚山梨醇酯20且在pH為5.5之10mg/mL蘭尼單抗水溶液。
蘭尼單抗係闡述於1999年發行之科學期刊中，於Journal of Molecular Biology(JMB)中由Chen等人以「Selection and Analysis of an Optimized Anti-VEGF Antibody：Crystal Structure of an Affinity-matured Fab in complex with Antigen」5(Chen等人，JMB,293：865-881(1999)為標題闡述。蘭尼單抗之重鏈及輕鏈序列在此文章中係命名為YO317，且係顯示於其中之圖1中。除此闡述以外，該文章亦提供關於此抗體片段與VEGF之結合親和力之數據(其中第870頁之表6)。已知蘭尼單抗結合至VEGF-A並抑制VEGF-A之生物活性，VEGF-A在眼部血管生成模型中引起新血管生成及洩漏。蘭尼單抗結合至VEGF-A並抑制其，並預防VEGF-A與內皮細胞表面上之VEGF受體相互作用，且從而減少新血管形成(血管生成)；血管洩漏及內皮細胞增生。醫藥上有效量之蘭尼單抗之投與抑制VEGF誘導之血管生成。術語抗VEGF抗體涵蓋全長抗體及抗體片段，例如Fab、Fab’、F(ab)2及Fv，限制條件係該等片段藉由結合至人類VEGF顯示期望藥理學活性。蘭尼單抗與VEGF具有不超過約1×10-8M、即約1.4×10-10之結合親和力(Kd)(參見Chen等人，第870頁)。'269專利之圖10A及10B提供蘭尼單抗之輕鏈可變及重鏈可變結構域之序列(Chen等人中所顯示之Fab Y0317)。該等序列與'269專利中之SEQ ID NO：115及SEQ ID NO：116相同。
除以上文章及專利中所闡述之蘭尼單抗及其他抗VEGF抑制劑或藥物以外，其他抗VEGF或抗血管生成藥物亦可用於本發明調配物。儘管本發明者已發現為抗體片段之抗VEGF抗體在用於疾病及病狀之治療之脂質體調配物中較佳，該治療涉及向具有健康角膜或角膜之微量新血管生成但具有一些其他眼部病狀(例如，年齡相關黃斑退化或糖尿病黃斑水腫)之患者之眼睛局部施加，但包含整個抗VEGF抗體及自成型之熱力學穩定之脂質體之調配物亦可用於治療角膜新血管生成
及該等其他眼部疾病(在具有兩種疾病之患者中)，限制條件係角膜新血管生成容許或有助於較大整個抗體及其調配物進入。完整或整個抗VEGF抗體之實例係由Genentech以商標名稱AVASTIN®(貝伐珠單抗)出售。此抗體係抑制VEGF之生物活性之重組人類化IgG1抗體。其含有人類框架區及結合至VEGF之鼠類抗體之互補決定，且具有149kD之近似分子量。此抗體係於含有慶大黴素(Gentamycin)之營養培養基中之哺乳動物細胞(中國倉鼠卵巢)表現系統中產生。美國專利第6,054,297號(以引用的方式全文併入本文中)主張並揭示貝伐珠單抗或製造貝伐珠單抗之製程(參見技術方案1、6、7、8、9、10、12、29及30)。
如經批准產物包裝插頁中所闡述，貝伐珠單抗係在活體外及活體內分析系統中結合至人類血管內皮生長因子並抑制其生物活性之重組人類化單株IgG1抗體。此抗體含有結合至VEGF之鼠類抗體之人類框架區6(參見L.G.Presta等人，(1997)Cancer Res.57：4593-99)。貝伐珠單抗之分子量係約149千道耳頓。此紙張揭示人類化F(ab)抗體片段之可變結構域「F(ab)1-12」之相互作用。貝伐珠單抗具有衍生自鼠類抗體之序列之非人類CDR以及可變結構域中於輕鏈(VL)之46位及重鏈(VH)之49位、69位、71位、73位、78位及94位處之框架取代，該等框架取代與F(ab)-12之相應位置處所顯示之取代相同，如Presta等人之圖1中所顯示。Presta等人具有關於貝伐珠單抗之分子特徵及結合特徵之資訊。
如先前所陳述，除蘭尼單抗及貝伐珠單抗以外，其他已知抗VEGF抗體或抗血管生成藥物亦可用於本發明。本發明之抗VEGF抗體係如上文關於其所引用之專利參考文獻中所闡述製備。通常，將編碼該抗體之分離核酸；包含該核酸之載體可操作連接至由經該載體轉化之宿主細胞識別之對照序列；具有該載體之宿主細胞全部共同用於在
培養該等細胞並收集並純化該抗體後產生所關注抗體之製程。可將任一適宜醫藥賦形劑添加至該抗體中，且亦可根據需要使該抗體凍乾。「抗VEGF抗體」包括各種形式，且可為具有完整人類Fc區之全長抗體或抗體片段(例如，Fab、Fab’或F(ab’)2)。適於與本文中所揭示之脂質組合形成脂質體調配物之其他抗血管生成藥物包括哌加他尼(pegaptanib)或依那西普(etanercept)(TNF抑制劑)。在後一情形中，此調配物可用於治療各種自體免疫疾病或病狀。依那西普係以商標名稱Enbrel®出售，其係用於治療類風濕性、幼年型類風濕性及牛皮癬關節炎、斑塊狀牛皮癬及關節黏連性脊髓炎。其他適宜藥物包括舒尼替尼，即VEGF及PDGF受體蛋白激酶及血管生成抑制劑(以名稱舒癌特(SUTENT®)出售之2-羥吲哚)，且其係闡述並主張於美國專利第6,573,293號中(該專利案之內容已以引用的方式併入本文中)；或FOVISTATM(以前稱為E10030)，即血小板源生長因子B(PDGF-B)之調節劑(1.5mg/.5mg蘭尼單抗)。組合使用之其他適宜藥物包括干擾素-α-2a或替西羅莫司(Temsirolimus)或其他mTOR抑制劑(例如)雷帕黴素(rapamycin)。可組合使用之用於眼部疾病之藥物類別亦包括蛋白酶體抑制劑、自體吞噬抑制劑、類視色素、溶酶體抑制劑、熱休克反應激活劑、Hsp90伴隨蛋白抑制劑、蛋白運輸抑制劑、糖苷酶抑制劑、酪胺酸激酶抑制劑及組蛋白去乙醯酶抑制劑。該等藥物可單獨用於脂質體調配物，或可以與抗VEGF化合物或抗體之組合成調配物形式使用，或可以依序組合形式且較佳以局部調配物形式使用。當組合FOVISTATM(0.03-3.0mg/眼睛，與0.5mg蘭尼單抗或其他抗VEGF化合物組合)(及/或具有PDGF抑制活性之其他藥物)與蘭尼單抗時，較佳適應症係治療年齡相關黃斑退化。阿柏西普(Aflibercept)(2.0mg/0.05mL)(EyleaTM)亦可單獨或與蘭尼單抗或其他活性成份組合用於脂質體調配物。本發明進一步包括本文中所列舉包含FOVISTA及阿
柏西普及/或任一其他抗血管生成藥物之局部脂質體調配物，限制條件係至少一種活性成份係與本發明之熱力學穩定之自成型脂質體摻和/組合。FOVISTA(針對PDGF-B之適配體)亦已知且在美國專利公開案第2012/0100136號中闡述為「拮抗劑A」，該專利公開案之內容已以引用的方式全文併入本文中。拮抗劑A之合成係闡述於'136公開案中之實例4中(亦參見其中之圖7)。當所闡述之個別VEGF拮抗劑及PDGF拮抗劑中至少一種藥劑與本文中所闡述形成熱力學穩定之自成型脂質體之脂質調配在一起時，其中每一者亦包括於本發明之範圍內。具有本文中所列舉之活性成份中之任一者或任一組合之局部調配物優於藉由玻璃體內注射投與之藥物或其組合。另外，向眼睛局部施加用於眼部疾病相對於全身性經口投與較佳。可用於本發明之組合物包括(以脂質體調配物或脂質體調配物及/或任一組合形式之其他調配物之形式)(a)(PDGF抑制劑)ARC-127、拮抗劑A、拮抗劑B、拮抗劑C、拮抗劑D、1B3抗體、CDP860、IMC-3G3、伊馬替尼(imatinib)、162.62抗體、163.31抗體、169.14抗體、169.31抗體、αR1抗體、2A1E2抗體、M4TS.11抗體、M4TS.22抗體、A10、佈雷菲德菌素A(brefeldin A)、舒尼替尼、Hyb 120.1.2.1.2抗體、Hyb 121.6.1.1.1抗體、Hyb 127.5.7.3.1抗體、Hyb 127.8.2.2.2抗體、Hyb 1.6.1抗體、Hyb 1.11.1抗體、Hyb 1.17.1抗體、Hyb 1.18.1抗體、Hyb 1.19.1抗體、Hyb 1.23.1抗體、Hyb 1.24抗體、Hyb 1.25抗體、Hyb 1.29抗體、Hyb 1.33抗體、Hyb 1.38抗體、Hyb 1.39抗體、Hyb 1.40抗體、Hyb 1.45抗體、Hyb 1.46抗體、Hyb 1.48抗體、Hyb 1.49抗體、Hyb 1.51抗體、Hyb 6.4.1抗體、F3抗體、人類化F3抗體、C1抗體、人類化C1抗體、6.4抗體、抗mPGDF-C山羊IgG抗體、C3.1抗體、5-甲基-7-二乙基胺基-s-三唑并(1,5-a)嘧啶、干擾素、魚精蛋白、PDGFR-B1單株抗體、PDGFR-B2單株抗體、6D11單株抗體、Sis單株抗體、PR7212單株抗體、PR292單
株抗體、HYB9610單株抗體、HYB 9611單株抗體、HYB 9612單株抗體、HYB 9613單株抗體、苯磺酸4-(2-(N-(2-甲醯胺基-吲哚)胺基乙基)酯、4-(2-(N-(-2-甲醯胺吲哚)胺基乙基)-磺醯基脲、CGP 53716、人類抗體g162、吡唑并[3,4-g]喹喏啉、6-[2-(甲基胺甲醯基)苯基硫烷基]-3-E-[2-(吡啶-2-基)乙烯基]-吲唑、1-{2-[5-(2-甲氧基-乙氧基)-苯并咪唑-1-基]-喹啉-8-基}-六氫吡啶-4-基胺、4-{4-[N-(4-硝基苯基)胺甲醯基]-1-六氫吡嗪基]-6,7-二甲氧基喹唑啉、4-胺基-5-氟-3-(6-(4-甲基-六氫吡嗪-1-基)-1H-苯并咪唑-2-基)1H-喹啉-2-酮、(4-第三丁基苯基){4-[(6,7-二甲氧基-4-喹啉基)氧基]苯基}甲酮、5-甲基-N-[4-(三氟甲基)苯基]-4-異噁唑甲醯胺、反式-4-[(6,7-二甲氧基喹喏啉-2-基)胺基]環己醇、(Z)-3-[(2,4-二甲基-5-(2-側氧基-1,2-二氫吲哚-3-亞基甲基)-1H-吡咯-3-基)-丙酸、5-(5-氟-2-側氧基-1,2-二氫吲哚-3-亞基甲基)-2,4-二甲基-1H-吡咯-3-甲酸、1-(4-氯苯胺基)-4-(4-吡啶基甲基)酞嗪、N-{4-(3-胺基-1H-吲唑-4-基)苯基-N”-(2-氟-5-甲基苯基)脲、1,2-二甲基-7-(2-噻吩)咪唑并[5,4-g]喹喏啉、1,2-二甲基-6-苯基-咪唑并[5,4-g]喹喏啉、1,2-二甲基-6-(2-噻吩)咪唑并[5,4-g]喹喏啉、AG1295、AG1296、3-芳基喹啉、4-吡啶基-2-芳基嘧啶、索拉菲尼(sorafenib)、MLN518、PKC412、AMN107、蘇拉明(suramin)、新黴素或其醫藥上可接受之鹽；及(b)(VEGF抑制劑)蘭尼單抗、貝伐珠單抗、阿柏西普、KH902VEGF受體-Fe融合蛋白、2C3抗體、ORA102、哌加他尼、貝伐西尼(bevasiranib)、鈍端貝伐西尼、SIRNA-027、紫花前胡素(decursin)、紫花前胡醇(decursinol)、鬼臼苦素(picropodophyllin)、香膠樹脂酮(guggulsterone)、PLG101、類花生酸LXA4、PTK787、帕唑帕尼(Pazopanib)、阿西替尼(axitinib)、CDDO-Me、CDDO-Imm、紫草素、β羥基異戊醯基紫草素、神經節苷脂GM3、DC101抗體、Mab 25抗體、Mab73抗體、4A5抗體、4E10抗體、5F12抗體、VA01抗體、BL2
抗體、BECG相關蛋白、sFLT01、sFLT02、肽B3、TG100801、索拉菲尼、G6-31抗體或抑制VEGF相關之血管生成之其他化合物。除抗體以外，適宜於治療眼部疾病或病狀(包括眼睛前部之疾病，例如角膜疾病)或因手術切口、創傷或潰瘍而必需之癒合的其他基於蛋白質之活性成份包括(例如)人類生長激素或其他已知激素肽或其變體。
脂質體調配物係藉由以任一順序遵循以下一般步驟來製備：(1)提供含有抗VEGF抗體及/或上文所闡述之其他活性物之水溶液；(2)將能夠形成脂質體之熱力學穩定之自成型脂質添加至步驟(1)之該水溶液中；及(3)視情況添加醫藥上可接受之賦形劑。可利用製備脂質體懸浮液調配物之製程之任一變化形式，包括組合抗VEGF抗體(或VEGF抑制劑或PDGF抑制劑)與脂質且然後添加水溶液或將每一成份分開添加至水溶液中。基於預期遞送途徑(例如，局部等)製備該懸浮液，且亦基於該途徑選擇其他賦形劑。載劑、穩定劑及/或賦形劑包括緩衝液，例如磷酸鹽、檸檬酸鹽或其他無機酸；抗氧化劑，例如抗壞血酸及/或甲硫胺酸；防腐劑；低分子量多肽；蛋白質，例如明膠、血清白蛋白或免疫球蛋白；親水聚合物，例如PVP；胺基酸；單糖或二糖或其他碳水化合物；螯合劑；糖；鹽形成抗衡離子；非離子型表面活性劑及諸如此類。該脂質體調配物亦可呈溶液之形式。
該等調配物可用於治療VEGF相關之疾病及病症。欲利用本文所闡述之調配物治療之較佳疾病或病狀係眼部疾病。如上文所闡述，本發明之較佳疾病或病狀係治療糖尿病黃斑水腫。如上文所參考，DME係由一系列生物化學及細胞事件造成，該等事件最終引起漸進洩漏及滲出，從而導致視網膜增厚及黃斑中央之一個視神經盤直徑內形成硬滲出物。雷射光凝係主要治療，且可有效以約505預防中度視覺喪失之風險[ETDRSRG,1985]。雷射光凝改良閱讀線得分，但具有相關併發症，例如瘢痕漸進增大、中央盲點、對比敏感度降低及色覺
受損。
脂質體調配物可廣泛地治療與VEGF及/或PDGF相關之腫瘤或視網膜病症或任一其他眼部疾病或病狀，此取決於特定活性成份。抗VEGF抗體抑制一或多種由VEGF引起之生物學活性。治療應用涉及向需要特定疾病或病狀治療之患者投與之醫藥上可接受之劑型。適宜劑型儘管較佳為局部，但亦可包括藉由呈濃注形式之靜脈內方式或藉由連續輸注；肌內、腹膜內、腦脊髓內、皮下、關節內、滑膜內、鞘內、經口或藉由吸入之投與。另外，該等抗體調配物亦可藉由腫瘤內、瘤周、病灶內或灶周途徑來投與。適於利用抗體調配物治療之腫瘤性疾病包括各種癌，包括乳癌、肺癌、胃癌、食管癌、結腸直腸癌、肝癌、卵巢癌、含睪丸細胞之卵巢腺瘤、子宮頸癌、子宮內膜癌、子宮內膜增生、子宮內膜組織異位症、纖維肉瘤、絨毛膜癌、頭頸癌、鼻咽癌、喉癌、肝胚細胞癌、卡波西氏肉瘤(Kaposi’s sarcoma)、黑色素瘤、皮膚癌、血管瘤、海綿狀血管瘤、血管母細胞瘤、胰臟癌及其他類型之癌症。VEGF相關之非腫瘤性病狀包括類風濕性關節炎、牛皮癬、動脈粥樣硬化、糖尿病及其他增生性視網膜病變(包括早產兒視網膜病變)、晶狀體後纖維組織增生、新生血管性青光眼、年齡相關黃斑退化、糖尿病黃斑水腫及其他形式之黃斑水腫、甲狀腺增生(包括格雷氏病(Graves’ disease))、角膜及其他組織移植、慢性發炎、肺發炎、腎炎症候群、子癇前症、腹水、心包積液及肋膜積液。利用較佳局部調配物治療之較佳病狀或疾病係糖尿病黃斑水腫。所投與之劑量及投與頻率將取決於疾病之類型及嚴重性及特定患者之狀態。例如，抗VEGF抗體可以1μg/kg至約50mg/kg或約0.1mg/kg至20mg/kg之劑量範圍向需要治療之患者投與。用於治療DME且關於蘭尼單抗之局部調配物之較佳劑量方案係闡述於本文實例3中。活性成份之濃度及量可視特定患者及治療天數而變，且每天或週
或月所提供之量亦可視患者之反應以及視覺敏銳度及視網膜增厚之改良之體徵而變。
出於治療DME或其他VEGF相關之眼部病狀之目的之理想治療模態可係導致迅速且持久之視覺改良者。目前用於治療DME之其他治療形態包括選擇性PKCβ抑制劑(魯伯斯塔(ruboxistaurin))；類固醇(曲安奈德(triamcinolone acetonide)、丙酮氟洛皮質醇(fluocinolone acetonide))；VEGF抑制劑(貝伐珠單抗；蘭尼單抗及哌加他尼-可注射劑)及玻璃體切除術。本發明脂質體調配物提供較(例如)目前市售玻璃體內調配物顯著改良之局部治療方案。本發明調配物可與其他已知治療組合用於本文中所列舉及/或上文所闡述之眼部或VEGF相關之疾病或病狀，且限制條件係不存在任何禁忌。該等治療方案或治療方法包括(例如)siRNA分子(例如貝伐西尼)以及包括本發明所利用之熱力學穩定之自成型脂質體之適當遞送媒劑。
可單獨或與任一其他活性成份組合用於脂質體調配物之眼用類固醇包括地塞米松、膚輕鬆(fluocinolone)、氯替潑諾(loteprednol)、二氟潑尼酯(difluprednate)、氟米龍(fluorometholone)、去氫皮質醇(prednisolone)、甲羥松(medrysone)、曲安奈德、利美索龍(rimexolone)及其各種鹽形式。其他眼用抗炎劑(例如NSAID)亦可用於脂質體調配物。視活性成份而定，可利用除熱力學穩定之自成型脂質體以外或作為其之替代方案之其他脂質體。
以下實例意欲進一步闡釋本發明之某些實施例，且並非限制性：
實例1
-A 脂質體及蘭尼單抗之溶液
獲得含有0.5mg濃度為10mg/mL之蘭尼單抗(0.05mL)之小瓶。將0.015克PEG-12甘油二肉豆蔻酸酯(PEG-12 GDM)QsomesTM添加至
此溶液中(PEG後面之數字指示PEG鏈中之C2H4O亞單位之數量)。使用1.45mL由磷酸鹽、氯化鈉及硬脂酸聚羥氧40酯組成之緩衝溶液將此脂質體懸浮液之體積稀釋至1.5mL之最終體積，以提供於脂質體懸浮液中0.333mg/mL之蘭尼單抗濃度及約1%(10mg/mL)之脂質百分比。添加過硼酸鈉(0.28mg/mL)作為防腐劑。1mL之此懸浮液相當於20滴。每一滴含有大約17μg蘭尼單抗。
藉由組合15mL硬脂酸聚羥氧40酯、氯化鈉、磷酸二氫鈉及磷酸氫二鈉溶液與5mL過硼酸鈉溶液來製備該緩衝溶液(V=20mL,pH 5.5)。然後如上文所直接闡述利用1.45mL之此溶液。眼用脂質體懸浮液調配物中之每一賦形劑之濃度為0.142mg/mL(磷酸氫二鈉)；6.7mg/mL(磷酸二氫鈉)；50mg/mL(硬脂酸聚羥氧40酯)；5.1mg/mL(氯化鈉)；0.333mg/mL(蘭尼單抗)；10mg/mL(PEG-12 GDM)及2.8mg/mL(過硼酸鈉)。可利用HCl或NaOH調整pH，且亦可利用低分子量胺基酸或有機酸。圖3顯示至少兩種類型之脂質體(Qusomes®)，該等脂質體係在將脂質與水溶液混合時形成(來自Biozone Laboratories網站)。
實例2
-兔角膜中之擴散室研究
使用下文所闡述之方法生成施加至兔角膜之脂質體調配物之擴散室數據。概言之，在10分鐘、20分鐘及30分鐘及1小時、2小時、3小時、4小時、5小時、6小時及24小時處獲取樣品。該等數據顯示局部施加之脂質體蘭尼單抗調配物在34℃下進入兔角膜之眼前房液中之顯著滲透速率。在脂質體調配物中，在3小時處開始鑑別蘭尼單抗，且其在投與後保持存在長達24小時，與先前針對非脂質體調配物在兔中所報導之7天及14天相對(數據未顯示，參見Chen等人，Eye London 2011 Nov；25(11)：1504-11)。在具有水平流之玻璃Valia-Chen室中實施研究。水以34℃之溫度再循環。將膜置於室之接面之間，且在此實例
中，使用兔角膜作為該膜。用3.2mL之鹽水溶液填充受體室，以模擬眼睛之前面部分中之眼前房液之內容物。供體室係提供有3mL包含蘭尼單抗及熱力學穩定之自成型脂質之眼用調配物。不斷攪動擴散室。在各種時間點處自受體室收集樣品-獲取400μL樣品並每次用400μL之鹽水溶液替代。在以下時間點處獲取樣品：10min；20min；30min；1hr；2hr；3hr；4hr；5hr；6hr及24hr。早在第3個小時時藉由HPLC檢測蘭尼單抗。使用Lucentis®作為HPLC標準之對照溶液。亦使用電泳評價脂質體調配物穿過兔角膜膜，且結果與HPLC數據一致。
實例3
-對患有DME之患者之先導性臨床研究
每天利用每3小時1滴之調配物將患有DME之患者治療6次/天(6×/天)，並持續2週。蘭尼單抗之總劑量/天係6×17ug或102ug。在此2週時期後整個6週內見到平均中央窩厚度(CFT)之損失之改良及視覺敏銳度之增加(參見圖1及圖2)。在第8週，發生視網膜厚度之增加及視覺敏銳度之降低，且在第10週，以2滴/天(34ug/天)再起始治療。在第14週，觀測到OCT及BCVA改良之清晰趨勢(參見圖1及2)。亦使用相同方案治療2個其他患者。所有三個患者之結果係呈現於圖4至7中，並顯示CFT及VA相對於對照之改良。
實例4
-使用曲安奈德對患有DME之患者進行之先導性臨床研究
在單一中心、開放標籤之先導性研究中，患有DME之合格患者接受包含去炎松(triamcinolone，TA)之局部調配物。3位患有涉及黃斑中央之DME之患者(平均年齡58歲，在53歲至64歲範圍內)之總共3隻眼睛在研究眼睛之最佳矯正視力(BCVA)使用ETDRS測試65個至40個字母。在十二(12)週之控制治療時期期間在患者醒著時，引導其每2小時將含有133ug(微克)之TA之1滴施加於研究眼睛中(6次)。主要結果量度包括3個月時之主要端點，例如眼部及全身性不良事件之頻率
及嚴重性以及中央窩厚度(CFT)相對於基線之變化，如藉由光學同調斷層掃描術(OCT)隨時間來量測。次要結果係相對於基線BCVA得分隨時間之變化、根據眼底照相(FP)之ETDRS視網膜病變嚴重性相對於基線具有>3步進展之患者之比例、根據螢光血管攝影(FA)解決洩漏之患者之比例及黃斑雷射治療隨時間之需求。以與蘭尼單抗調配物類似之方式自市售起始材料製備該TA調配物。
去炎松+1%脂質體眼用懸浮液
最終調配物係滅菌水性懸浮液。其含量係如以下：
PEG-12-GDM：脂質體；二醯基甘油-聚乙二醇(PEG 12)、甘油二肉豆蔻酸酯(GDM)。
* TA係最終產物。其係微粉化TA(大約12mm)且不含防腐劑。
去炎松+1%脂質體眼用懸浮液之製備方案
1.將蒸餾水之最終體積之40%置於燒杯中，且將其加熱至70℃
至80℃。
2.添加羥丙基甲基纖維素，並停止混合，直至達到室溫且其變成澄清且均質之混合物為止。
3.對其進行高壓處理，且在滅菌後使其達到室溫，同時攪拌。
4.將蒸餾水之最終體積之40%置於另一燒杯中。添加並混合，直至逐個完全溶解以下試劑為止：
a)磷酸二氫鈉
b)磷酸氫二鈉
c)EDTA
d)氯化鈉
e)聚山梨醇酯80
5.在10%之剩餘體積之水中，以50%添加苯紮氯銨並混合，直至完全納入為止。在溶解後，將此新溶液添加至含有磷酸鹽、EDTA、氯化鈉及聚山梨醇酯80之上文溶液中。為滅菌，藉由0.22μm膜過濾。
6.混合羥丙基甲基纖維素之滅菌溶液與含有該等鹽及防腐劑苯紮氯銨之另一滅菌溶液，並混合直至得到澄清均質混合物為止。
7.將乙酸去炎松添加至具有緩衝液及苯紮氯銨之溶液中，並攪拌直至完全納入為止。
8.將脂質體添加至此混合物中，並在15分鐘期間利用磁性攪拌器攪拌，以獲得最終懸浮液。
9.將該懸浮液封裝於專用眼睛滴管中。每一滴管瓶含有1.5mL之此去炎松眼用懸浮液。
結果： 在脂質體調配物中包含TA之局部調配物在患有涉及中央之臨床顯著之DME之患者中的使用具有良好耐受性。未報導眼部或全身性不良事件。在第2個月，所有三個患者之CFT相對於基線而降
低。三個患者中之兩者具有至少100um之CFT降低。在第3個月，所有三個患者顯示視覺敏銳度改良。患者中之一者得到>15個字母。
儘管已詳細並參照其具體實施例闡述所主張發明，但熟習此項技術者將顯而易見，可對所主張發明進行各種變化及修改，而不背離其精神及範圍。因此，例如，熟習此項技術者僅使用常規實驗即可認識到或能夠確定所主張發明之許多可尚未明確闡述之實施例。該等實施例屬於本發明之範圍。
1. Roskoski Jr, Sunitinib: A VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. BBRC, 2007.
2. Fong D, Diabetic Retinopathy. Diabetes Care, 2004.
3. Bhagat N, Diabetic Macular Edema: Pathogenesis and Treatment. Survey of Ophthalmology 2009.
4. Meyer C, Current Treatment Approaches in Diabetic Macular Edema, Ophthalmologica, 2007.
5. Chen Y, Selection and analysis of an optimized Anti-VEGF antibody: Crystal structure of an affinity-matured Fab in complex with antigen, JMB, 1999.
6. Presta L, Humanization of an Anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders.
7. ETDRSR, Photocoagulation for macular Edema, Report 1, 1985.
Claims (50)
- 一種水性調配物，其包含抗血管生成藥物及自基於PEG之脂質形成之熱力學穩定之自成型脂質體，其中該脂質之重量百分比係小於約20% wt/wt。
- 如請求項1之調配物，其中該抗血管生成藥物係選自蘭尼單抗(ranibizumab)或貝伐珠單抗(bevacizumab)之抗VEGF抗體。
- 如請求項1之調配物，其中該熱力學穩定之自成型脂質體包含具有介於約300道耳頓(Dalton)至約5,000道耳頓之間之分子量之PEG鏈，且係由在25℃下為流體且在20℃及37℃二者下於水溶液中自成型之脂質形成。
- 如請求項1之調配物，其中該調配物係局部調配物。
- 如請求項4之調配物，其中該抗VEGF抗體係蘭尼單抗。
- 如請求項5之調配物，其中形成該熱力學穩定之自成型脂質體之該脂質係選自如下之脂質：在25℃下為流體，且包含具有介於約300道耳頓至約5,000道耳頓之間之分子量之PEG鏈，且在20℃及37℃二者下於水溶液中自成型。
- 如請求項6之調配物，其中該脂質係選自PEG-12 GDM或PEG-12 GDO。
- 一種如請求項1之醫藥調配物之用途，其用於治療需要該治療之患者之VEGF相關之疾病或病狀。
- 如請求項8之用途，其中向該患者投與之該抗VEGF抗體之日劑量或週劑量範圍係在約1μg/kg至約50mg/kg之範圍內。
- 一種治療VEGF相關之疾病或病狀之方法，其包含向需要治療之患者投與醫藥上有效量之包含抗VEGF抗體及熱力學穩定之自成型脂質體之醫藥調配物。
- 如請求項10之方法，其中該抗VEGF抗體係選自蘭尼單抗或貝伐珠單抗。
- 如請求項10之方法，其中形成該熱力學穩定之自成型脂質體之脂質在25℃下為流體，且包含具有介於約300道耳頓至約5,000道耳頓之間之分子量之PEG鏈，且在20℃及37℃二者下於水溶液中自成型。
- 如請求項12之方法，其中該調配物係局部調配物。
- 如請求項12之方法，其中該脂質係選自由PEG-12 GDM或PEG-12 GDO組成之群。
- 如請求項10之方法，其中該VEGF相關之疾病或病狀係選自腫瘤性或非腫瘤性疾病或病狀。
- 如請求項15之方法，其中該腫瘤性疾病或病狀係選自由乳癌、肺癌、胃癌、食管癌、結腸直腸癌、肝癌、卵巢癌、含睪丸細胞之卵巢腺瘤、子宮頸癌、子宮內膜癌、子宮內膜增生、子宮內膜組織異位症、纖維肉瘤、絨毛膜癌、頭頸癌、鼻咽癌、喉癌、肝胚細胞癌、卡波西氏肉瘤(Kaposi’s sarcoma)、黑色素瘤、皮膚癌、血管瘤、海綿狀血管瘤、血管母細胞瘤、胰臟癌及其他類型之癌症組成之群。
- 如請求項15之方法，其中該非腫瘤性疾病係選自由類風濕性關節炎、牛皮癬、動脈粥樣硬化、糖尿病及其他增生性視網膜病變(包括早產兒視網膜病變)、晶狀體後纖維組織增生、新生血管性青光眼、年齡相關黃斑退化、糖尿病黃斑水腫及其他形式之黃斑水腫、甲狀腺增生(包括格雷氏病(Graves’ disease))、角膜及其他組織移植、慢性發炎、肺發炎、腎炎症候群、子癇前症、腹水、心包積液及肋膜積液組成之群。
- 如請求項17之方法，其中該疾病或病狀係選自年齡相關黃斑退 化、糖尿病黃斑水腫或角膜新血管生成。
- 一種局部眼用調配物，其適宜於向需要治療之患者之眼睛投與，其包含抗VEGF抗體及熱力學穩定之自成型脂質體。
- 如請求項19之調配物，其中該抗VEGF抗體係選自蘭尼單抗或貝伐珠單抗。
- 如請求項20之調配物，其中該熱力學穩定之自成型脂質體係由在25℃下為流體且包含具有介於約300道耳頓至約5,000道耳頓之間之分子量之PEG鏈，且在20℃及37℃下於水溶液中自成型之脂質形成。
- 如請求項21之調配物，其中該脂質係PEG-12 GDM或PEG-12 GDO。
- 一種眼用溶液，其包含(a)蘭尼單抗及(b)熱力學穩定之自成型脂質體，其係自基於PEG之脂質形成且重量百分比小於約20% wt/wt。
- 如請求項23之眼用溶液，其中該蘭尼單抗係以約0.01mg/mL至1.0mg/mL之濃度範圍存在。
- 如請求項24之眼用溶液，其進一步包含醫藥上可接受之賦形劑及/或試劑。
- 如請求項25之眼用溶液，其中該溶液之pH為約4.5至約7.5。
- 如請求項23之眼用溶液，其中該脂質係以約5mg/mL至約25mg/mL之濃度範圍存在。
- 如請求項27之眼用溶液，其中脂質之濃度為約10mg/mL。
- 一種治療患有糖尿病黃斑水腫之患者之方法，其包含向該患者之受影響眼睛局部投與醫藥上有效量之如請求項23至28之眼用溶液。
- 如請求項29之方法，其中向該患者投與之蘭尼單抗之日劑量為約10μg/天至約125μg/天。
- 如請求項30之方法，其中該劑量係每3小時以約15μg/劑量至20μg/劑量之蘭尼單抗之劑量量投與，6×/天。
- 如請求項31之方法，其中該6×/天投與約15μg至20μg之劑量係投與2週時期，且然後根據需要每天一次或每天兩次投與小於約50μg之總日劑量。
- 一種局部調配物，其包含：(a)VEGF抑制劑；(b)PDGF抑制劑；及(c)熱力學穩定之自成型脂質體。
- 如請求項33之調配物，其中該PDGR抑制劑(a)及該VEGF抑制劑(b)係選自包含以下之群：(a)ARC-127、拮抗劑A、拮抗劑B、拮抗劑C、拮抗劑D、1B3抗體、CDP860、IMC-3G3、伊馬替尼、162.62抗體、163.31抗體、169.14抗體、169.31抗體、αR1抗體、2A1E2抗體、M4TS.11抗體、M4TS.22抗體、A10、佈雷菲德菌素A(brefeldin A)、舒尼替尼(sunitinib)、Hyb 120.1.2.1.2抗體、Hyb 121.6.1.1.1抗體、Hyb 127.5.7.3.1抗體、Hyb 127.8.2.2.2抗體、Hyb 1.6.1抗體、Hyb 1.11.1抗體、Hyb 1.17.1抗體、Hyb 1.18.1抗體、Hyb 1.19.1抗體、Hyb 1.23.1抗體、Hyb 1.24抗體、Hyb 1.25抗體、Hyb 1.29抗體、Hyb 1.33抗體、Hyb 1.38抗體、Hyb 1.39抗體、Hyb 1.40抗體、Hyb 1.45抗體、Hyb 1.46抗體、Hyb 1.48抗體、Hyb 1.49抗體、Hyb 1.51抗體、Hyb 6.4.1抗體、F3抗體、人類化F3抗體、C1抗體、人類化C1抗體、6.4抗體、抗mPGDF-C山羊IgG抗體、C3.1抗體、5-甲基-7-二乙基胺基-s-三唑并(1,5-a)嘧啶、干擾素、魚精蛋白、PDGFR-B1單株抗體、PDGFR-B2單 株抗體、6D11單株抗體、Sis單株抗體、PR7212單株抗體、PR292單株抗體、HYB9610單株抗體、HYB 9611單株抗體、HYB 9612單株抗體、HYB 9613單株抗體、苯磺酸4-(2-(N-(2-甲醯胺基-吲哚)胺基乙基)酯、4-(2-(N-(-2-甲醯胺吲哚)胺基乙基)-磺醯基脲、CGP 53716、人類抗體g162、吡唑并[3,4-g]喹喏啉、6-[2-(甲基胺甲醯基)苯基硫烷基]-3-E-[2-(吡啶-2-基)乙烯基]-吲唑、1-{2-[5-(2-甲氧基-乙氧基)-苯并咪唑-1-基]-喹啉-8-基}-六氫吡啶-4-基胺、4-{4-[N-(4-硝基苯基)胺甲醯基]-1-六氫吡嗪基]-6,7-二甲氧基喹唑啉、4-胺基-5-氟-3-(6-(4-甲基-六氫吡嗪-1-基)-1H-苯并咪唑-2-基)1H-喹啉-2-酮、(4-第三丁基苯基){4-[(6,7-二甲氧基-4-喹啉基)氧基]苯基}甲酮、5-甲基-N-[4-(三氟甲基)苯基]-4-異噁唑甲醯胺、反式-4-[(6,7-二甲氧基喹喏啉-2-基)胺基]環己醇、(Z)-3-[(2,4-二甲基-5-(2-側氧基-1,2-二氫吲哚-3-亞基甲基)-1H-吡咯-3-基)-丙酸、5-(5-氟-2-側氧基-1,2-二氫吲哚-3-亞基甲基)-2,4-二甲基-1H-吡咯-3-甲酸、1-(4-氯苯胺基)-4-(4-吡啶基甲基)酞嗪、N-{4-(3-胺基-1H-吲唑-4-基)苯基-N”-(2-氟-5-甲基苯基)脲、1,2-二甲基-7-(2-噻吩)咪唑并[5,4-g]喹喏啉、1,2-二甲基-6-苯基-咪唑并[5,4-g]喹喏啉、1,2-二甲基-6-(2-噻吩)咪唑并[5,4-g]喹喏啉、AG1295、AG1296、3-芳基喹啉、4-吡啶基-2-芳基嘧啶、索拉菲尼(sorafenib)、MLN518、PKC412、AMN107、蘇拉明(suramin)、新黴素或其醫藥上可接受之鹽；及(b)蘭尼單抗、貝伐珠單抗、阿柏西普(aflibercept)、KH902 VEGF受體-Fe融合蛋白、2C3抗體、ORA102、哌加他尼(pegaptanib)、貝伐西尼(bevasiranib)、鈍端貝伐西尼、SIRNA-027、紫花前胡素(decursin)、紫花前胡醇(decursinol)、鬼臼苦素(picropodophyllin)、香膠樹脂酮(guggulsterone)、PLG101、類花 生酸LXA4、PTK787、帕唑帕尼(Pazopanib)、阿西替尼(axitinib)、CDDO-Me、CDDO-Imm、紫草素、β羥基異戊醯基紫草素、神經節苷脂GM3、DC101抗體、Mab 25抗體、Mab73抗體、4A5抗體、4E10抗體、5F12抗體、VA01抗體、BL2抗體、BECG相關蛋白、sFLT01、sFLT02、肽B3、TG100801、索拉菲尼(sorafenib)、G6-31抗體或抑制VEGF相關之血管生成之其他化合物。
- 如請求項34之局部調配物，其中該PDGF抑制劑係選自拮抗劑A或舒尼替尼，且該VEGF抑制劑係選自蘭尼單抗。
- 如請求項1之調配物，在組合療法中其進一步包含曲安奈德(triamcinolone acetonide)之局部用或玻璃體內用調配物。
- 一種局部調配物，其包含醫藥活性量之通常藉由玻璃體內注射遞送以治療眼後段疾病或病狀之活性成份及自基於PEG之脂質形成之熱力學穩定之自成型脂質體，其中該脂質之重量百分比係小於約20% wt/wt。
- 如請求項37之調配物，其中該眼後段疾病或病狀係選自年齡相關黃斑退化或糖尿病視網膜病變。
- 如請求項37之調配物，其中該活性成份係選自蘭尼單抗、曲安奈德或其組合。
- 如請求項37之調配物，其中蘭尼單抗係該活性成份，且與選擇性PKCβ抑制劑(魯伯斯塔(ruboxistaurin))；類固醇(曲安奈德、丙酮氟洛皮質醇(fluocinolone acetonide))；及視情況選用之玻璃體切除術組合使用。
- 一種眼用調配物，其用於局部遞送以治療眼後段疾病，其包含脂質體及類固醇。
- 如請求項41之調配物，其中該脂質體係熱力學穩定之自成型脂 質體。
- 如請求項41之調配物，其中該類固醇係選自曲安奈德。
- 一種為需要治療之患者治療眼後段疾病之方法，其包含投與醫藥上有效量之局部調配物，該局部調配物包含脂質體及類固醇或通常藉由玻璃體內注射遞送之其他藥物。
- 如請求項44之方法，其中該眼後段疾病係糖尿病黃斑水腫。
- 如請求項44之方法，其中該脂質體係自成型之熱力學穩定之脂質體。
- 如請求項44之方法，其中該類固醇係選自曲安奈德。
- 如請求項47之方法，其中曲安奈德係以50ug/每滴調配物至150ug/每滴之劑量範圍投與，並每2小時向眼睛局部施加1滴，4×/天至6×/天。
- 如請求項44之方法，其中該患者顯示改善之中央窩厚度及視覺敏銳度。
- 一種脂質體調配物，其包含自成型之熱力學穩定之脂質體及活性醫藥劑，該活性醫藥劑選自抗微生物劑、抗病毒劑、皮質類固醇及抗血管內皮生長因子藥劑中之任一者或組合，其中該調配物適宜於向患者之眼睛局部遞送以治療眼部疾病或病狀。
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261691455P | 2012-08-21 | 2012-08-21 | |
| US61/691,455 | 2012-08-21 | ||
| US201361791693P | 2013-03-15 | 2013-03-15 | |
| US61/791,693 | 2013-03-15 | ||
| US201361862300P | 2013-08-05 | 2013-08-05 | |
| US61/862,300 | 2013-08-05 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201642838A true TW201642838A (zh) | 2016-12-16 |
| TWI683675B TWI683675B (zh) | 2020-02-01 |
Family
ID=50150466
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW105114326A TWI683675B (zh) | 2012-08-21 | 2013-08-22 | 脂質體調配物 |
| TW102130093A TWI608848B (zh) | 2012-08-21 | 2013-08-22 | 脂質體調配物 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW102130093A TWI608848B (zh) | 2012-08-21 | 2013-08-22 | 脂質體調配物 |
Country Status (16)
| Country | Link |
|---|---|
| US (2) | US10548841B2 (zh) |
| EP (1) | EP2887958B1 (zh) |
| JP (3) | JP6336448B2 (zh) |
| KR (2) | KR102083700B1 (zh) |
| CN (1) | CN104582728A (zh) |
| AR (1) | AR092372A1 (zh) |
| BR (1) | BR112015003658B1 (zh) |
| CA (2) | CA3098856C (zh) |
| CL (1) | CL2015000418A1 (zh) |
| ES (1) | ES2881671T3 (zh) |
| HU (1) | HUE058912T2 (zh) |
| MX (2) | MX363822B (zh) |
| PL (1) | PL2887958T3 (zh) |
| RU (1) | RU2680096C2 (zh) |
| TW (2) | TWI683675B (zh) |
| WO (1) | WO2014031429A2 (zh) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2016523956A (ja) * | 2013-07-11 | 2016-08-12 | ノバルティス アーゲー | 未熟児網膜症の治療におけるｖｅｇｆアンタゴニストの使用 |
| CA2924401A1 (en) * | 2013-12-19 | 2015-06-25 | F. Hoffmann-La Roche Ag | Cetp modulator for use in the treatment of eye disease |
| EP3145532A4 (en) * | 2014-05-02 | 2018-02-21 | Mayo Foundation for Medical Education and Research | Individualized treatment of eye disease |
| KR101778004B1 (ko) | 2015-06-22 | 2017-09-15 | (주) 에빅스젠 | 이마티닙을 유효성분으로 포함하는 안구 건조 질환 예방 및 치료용 약학 조성물 |
| WO2017083800A1 (en) * | 2015-11-13 | 2017-05-18 | Ohr Pharmaceutical, Inc. | Occult cnv size as a predictor for treatment with squalamine |
| SG11202006712XA (en) * | 2018-02-06 | 2020-08-28 | Hoffmann La Roche | Treatment of ophthalmologic diseases |
| CN113286579A (zh) * | 2018-08-23 | 2021-08-20 | 埃里克·F·伯恩斯坦 | 应用抗vegf化合物和使用这类化合物治疗皮肤病的系统、装置和方法 |
| CN109180798B (zh) * | 2018-09-04 | 2020-10-27 | 武汉原生药谷生物医药科技有限公司 | 一种增强型治疗性抗体及其应用 |
| CN113966237A (zh) * | 2019-03-15 | 2022-01-21 | 罗德岛大学理事会 | pHLIP®介导的皮质类固醇靶向病变组织 |
| EP3968949A1 (en) | 2019-05-16 | 2022-03-23 | OPKO Pharmaceuticals, LLC | Triamcinolone acetonide-loaded liposomes topical ophthalmic formulations for prevention of macular thickening and its associated visual outcomes after lens surgery |
| CN113546172A (zh) * | 2020-04-24 | 2021-10-26 | 山东大学齐鲁医院 | Vegf抑制剂在制备治疗缺氧相关疾病药物中的应用 |
| WO2021257193A1 (en) * | 2020-06-15 | 2021-12-23 | Opko Pharmaceuticals, Llc | Triamcinolone acetonide-loaded liposomes topical ophthalmic formulations as primary therapy for macular edema secondary to branch retinal vein occlusion |
| CN116585304B (zh) * | 2023-04-25 | 2024-04-05 | 四川大学华西医院 | 一种急性肝损伤保护药物及其制备方法 |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6565861B1 (en) * | 2000-02-11 | 2003-05-20 | Isis Innovation Limited | Artificial tear formulation |
| US6610322B1 (en) | 2000-12-20 | 2003-08-26 | Brian Charles Keller | Self forming, thermodynamically stable liposomes and their applications |
| US7785578B2 (en) | 2002-10-11 | 2010-08-31 | Aciont, Inc. | Non-invasive ocular drug delivery |
| US20060165744A1 (en) * | 2003-05-22 | 2006-07-27 | Neopharm, Inc | Combination liposomal formulations |
| WO2007076274A2 (en) | 2005-12-22 | 2007-07-05 | Bausch & Lomb Incorporated | Artificial tear solution containing poly (ethylene glycol) peg lipids |
| EP1965762A1 (en) | 2005-12-23 | 2008-09-10 | Alcon, Inc. | Pharmaceutical formulation for delivery of receptor tyrosine kinase inhibiting (rtki) compounds to the eye |
| US20100111963A1 (en) * | 2006-11-10 | 2010-05-06 | Genentech, Inc. | Method for treating age-related macular degeneration |
| MY180595A (en) | 2006-12-07 | 2020-12-03 | Genentech Inc | Phosphoinositide 3-kinase inhibitor compounds and methods of use |
| CN101918579A (zh) * | 2007-10-22 | 2010-12-15 | 先灵公司 | 完全人抗-vegf抗体和使用方法 |
| US8887944B2 (en) * | 2007-12-11 | 2014-11-18 | Tokitae Llc | Temperature-stabilized storage systems configured for storage and stabilization of modular units |
| US8470792B2 (en) * | 2008-12-04 | 2013-06-25 | Opko Pharmaceuticals, Llc. | Compositions and methods for selective inhibition of VEGF |
| US20110040113A1 (en) * | 2009-06-02 | 2011-02-17 | Nian Wu | Pure PEG-lipid conjugates |
| US20110033527A1 (en) * | 2009-06-02 | 2011-02-10 | Nian Wu | Opthalmic compositions of cyclosporin |
| US8956600B2 (en) * | 2009-08-10 | 2015-02-17 | Taiwan Liposome Co. Ltd. | Ophthalmic drug delivery system containing phospholipid and cholesterol |
| NZ598808A (en) * | 2009-09-09 | 2014-07-25 | Celgene Avilomics Res Inc | Pi3 kinase inhibitors and uses thereof |
-
2013
- 2013-08-15 CN CN201380044348.4A patent/CN104582728A/zh active Pending
- 2013-08-15 PL PL13830622T patent/PL2887958T3/pl unknown
- 2013-08-15 CA CA3098856A patent/CA3098856C/en active Active
- 2013-08-15 HU HUE13830622A patent/HUE058912T2/hu unknown
- 2013-08-15 JP JP2015528536A patent/JP6336448B2/ja active Active
- 2013-08-15 WO PCT/US2013/055084 patent/WO2014031429A2/en active Application Filing
- 2013-08-15 KR KR1020157004549A patent/KR102083700B1/ko active IP Right Grant
- 2013-08-15 KR KR1020207005268A patent/KR102177437B1/ko active IP Right Grant
- 2013-08-15 RU RU2015107317A patent/RU2680096C2/ru active
- 2013-08-15 EP EP13830622.0A patent/EP2887958B1/en active Active
- 2013-08-15 MX MX2015002233A patent/MX363822B/es active IP Right Grant
- 2013-08-15 CA CA2879597A patent/CA2879597C/en active Active
- 2013-08-15 BR BR112015003658-9A patent/BR112015003658B1/pt active IP Right Grant
- 2013-08-15 US US14/422,587 patent/US10548841B2/en active Active
- 2013-08-15 ES ES13830622T patent/ES2881671T3/es active Active
- 2013-08-21 AR ARP130102960A patent/AR092372A1/es not_active Application Discontinuation
- 2013-08-22 TW TW105114326A patent/TWI683675B/zh active
- 2013-08-22 TW TW102130093A patent/TWI608848B/zh active
-
2015
- 2015-02-19 MX MX2019001021A patent/MX2019001021A/es unknown
- 2015-02-20 CL CL2015000418A patent/CL2015000418A1/es unknown
-
2018
- 2018-05-02 JP JP2018088574A patent/JP6680827B2/ja active Active
-
2019
- 2019-12-12 US US16/712,261 patent/US11712419B2/en active Active
-
2020
- 2020-03-17 JP JP2020046303A patent/JP7098674B2/ja active Active
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11712419B2 (en) | Liposome formulations | |
| US11707506B2 (en) | Use of a VEGF antagonist to treat angiogenic eye disorders | |
| JP7080263B2 (ja) | 高濃度の抗ｖｅｇｆ抗体を含有する安定状態のタンパク質溶液製剤 | |
| US11458199B2 (en) | Liposome formulations | |
| US11944663B2 (en) | Method for treating angiogenic eye disorders using VEGF antagonists | |
| JP7497854B2 (ja) | 薬物デリバリーキャリアおよびこれを用いる医薬組成物 | |
| RU2817350C2 (ru) | Липосомальные препараты |