JP2022009275A - 後眼部へ薬物を送達するための眼用製剤 - Google Patents
後眼部へ薬物を送達するための眼用製剤 Download PDFInfo
- Publication number
- JP2022009275A JP2022009275A JP2021171453A JP2021171453A JP2022009275A JP 2022009275 A JP2022009275 A JP 2022009275A JP 2021171453 A JP2021171453 A JP 2021171453A JP 2021171453 A JP2021171453 A JP 2021171453A JP 2022009275 A JP2022009275 A JP 2022009275A
- Authority
- JP
- Japan
- Prior art keywords
- cyclodextrin
- compound
- topical
- eye
- ocular
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims description 211
- 238000009472 formulation Methods 0.000 title claims description 176
- 238000012377 drug delivery Methods 0.000 title description 5
- 239000000725 suspension Substances 0.000 claims abstract description 81
- 229920000858 Cyclodextrin Polymers 0.000 claims description 159
- 210000001508 eye Anatomy 0.000 claims description 144
- 230000000699 topical effect Effects 0.000 claims description 117
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 92
- 239000013543 active substance Substances 0.000 claims description 91
- -1 trimethylammonio Chemical group 0.000 claims description 79
- 150000003839 salts Chemical class 0.000 claims description 70
- 238000002360 preparation method Methods 0.000 claims description 68
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 65
- 230000002354 daily effect Effects 0.000 claims description 52
- 239000007788 liquid Substances 0.000 claims description 52
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 50
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 50
- 229960004853 betadex Drugs 0.000 claims description 46
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 43
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 43
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 38
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 33
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 31
- 229960000281 trometamol Drugs 0.000 claims description 30
- 239000001116 FEMA 4028 Substances 0.000 claims description 29
- 208000002780 macular degeneration Diseases 0.000 claims description 28
- 239000011780 sodium chloride Substances 0.000 claims description 25
- 230000001575 pathological effect Effects 0.000 claims description 21
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 17
- 230000033115 angiogenesis Effects 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 12
- 208000017442 Retinal disease Diseases 0.000 claims description 12
- 206010038923 Retinopathy Diseases 0.000 claims description 12
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 10
- 201000011190 diabetic macular edema Diseases 0.000 claims description 10
- 206010030113 Oedema Diseases 0.000 claims description 9
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 8
- 208000014674 injury Diseases 0.000 claims description 8
- 238000001356 surgical procedure Methods 0.000 claims description 8
- 230000008733 trauma Effects 0.000 claims description 8
- 208000007135 Retinal Neovascularization Diseases 0.000 claims description 7
- 208000028867 ischemia Diseases 0.000 claims description 7
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 claims description 7
- 208000011325 dry age related macular degeneration Diseases 0.000 claims description 6
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 5
- YZOUYRAONFXZSI-SBHWVFSVSA-N (1S,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-37,39,40,41,42,43,44,45,46,47,48,49-dodecamethoxy-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,38-diol Chemical compound O([C@@H]([C@H]([C@@H]1OC)OC)O[C@H]2[C@@H](O)[C@@H]([C@@H](O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3O)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O3)O[C@@H]2CO)OC)[C@H](CO)[C@H]1O[C@@H]1[C@@H](OC)[C@H](OC)[C@H]3[C@@H](CO)O1 YZOUYRAONFXZSI-SBHWVFSVSA-N 0.000 claims description 4
- CUJVBAPGYBSBHJ-YWBSARSQSA-N 2-[[(1R,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R,36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)-36,38,40,42-tetrakis(carboxymethoxy)-10,15-bis(carboxymethoxymethyl)-37,39,41,43,44,45,46,47,48,49-decahydroxy-20,25,30,35-tetrakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan-5-yl]methoxy]acetic acid Chemical compound OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCC(O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCC(O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCC(O)=O)O[C@@H]3[C@@H](CO)O[C@H](O[C@@H]4[C@@H](CO)O[C@H](O[C@@H]5[C@@H](CO)O[C@H](O[C@H]1[C@H](OCC(O)=O)[C@H]2O)[C@H](O)[C@H]5OCC(O)=O)[C@H](O)[C@H]4OCC(O)=O)[C@H](O)[C@H]3OCC(O)=O CUJVBAPGYBSBHJ-YWBSARSQSA-N 0.000 claims description 4
- 206010051151 Hyperviscosity syndrome Diseases 0.000 claims description 4
- 201000001949 Retinal Vasculitis Diseases 0.000 claims description 4
- 201000005485 Toxoplasmosis Diseases 0.000 claims description 4
- JVFGXECLSQXABC-UHFFFAOYSA-N ac1l3obq Chemical compound O1C(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(O)C2O)C(COCC(O)C)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC2C(O)C(O)C1OC2COCC(C)O JVFGXECLSQXABC-UHFFFAOYSA-N 0.000 claims description 4
- 206010003230 arteritis Diseases 0.000 claims description 4
- 201000007917 background diabetic retinopathy Diseases 0.000 claims description 4
- 206010072959 birdshot chorioretinopathy Diseases 0.000 claims description 4
- 201000007914 proliferative diabetic retinopathy Diseases 0.000 claims description 4
- 230000004263 retinal angiogenesis Effects 0.000 claims description 4
- 201000000306 sarcoidosis Diseases 0.000 claims description 4
- 210000003462 vein Anatomy 0.000 claims description 4
- PVPBHKCSQBLDEW-ZQOBQRRWSA-N (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecol 4-hydroxybutane-1-sulfonic acid Chemical compound OCCCCS(O)(=O)=O.OC[C@H]1O[C@@H]2O[C@@H]3[C@@H](CO)O[C@H](O[C@@H]4[C@@H](CO)O[C@H](O[C@@H]5[C@@H](CO)O[C@H](O[C@@H]6[C@@H](CO)O[C@H](O[C@@H]7[C@@H](CO)O[C@H](O[C@@H]8[C@@H](CO)O[C@H](O[C@H]1[C@H](O)[C@H]2O)[C@H](O)[C@H]8O)[C@H](O)[C@H]7O)[C@H](O)[C@H]6O)[C@H](O)[C@H]5O)[C@H](O)[C@H]4O)[C@H](O)[C@H]3O PVPBHKCSQBLDEW-ZQOBQRRWSA-N 0.000 claims description 3
- NOPKOJDDVCBPTP-DJSZNTTKSA-N 23739-88-0 Chemical compound CC(=O)OC[C@H]([C@H]([C@H]([C@@H]1OC(C)=O)OC(C)=O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COC(C)=O)[C@H]([C@H]([C@@H]3OC(C)=O)OC(C)=O)O[C@H]3O[C@H](COC(C)=O)[C@H]([C@H]([C@@H]3OC(C)=O)OC(C)=O)O[C@H]3O[C@H](COC(C)=O)[C@H]([C@H]([C@@H]3OC(C)=O)OC(C)=O)O[C@H]3O[C@H](COC(C)=O)[C@H]([C@H]([C@@H]3OC(C)=O)OC(C)=O)O3)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)COC(=O)C)O[C@@H]1O[C@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]3O[C@@H]1COC(C)=O NOPKOJDDVCBPTP-DJSZNTTKSA-N 0.000 claims description 3
- 208000003225 Carotid-Cavernous Sinus Fistula Diseases 0.000 claims description 3
- 208000008069 Geographic Atrophy Diseases 0.000 claims description 3
- 208000000208 Wet Macular Degeneration Diseases 0.000 claims description 3
- 230000002491 angiogenic effect Effects 0.000 claims description 3
- 239000003002 pH adjusting agent Substances 0.000 claims description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 2
- 208000022873 Ocular disease Diseases 0.000 claims description 2
- 208000008709 Retinal Telangiectasis Diseases 0.000 claims description 2
- 230000003203 everyday effect Effects 0.000 claims 2
- 210000001957 retinal vein Anatomy 0.000 claims 2
- 208000021089 Coats disease Diseases 0.000 claims 1
- 208000019878 Eales disease Diseases 0.000 claims 1
- 206010015901 Exudative retinopathy Diseases 0.000 claims 1
- 208000010412 Glaucoma Diseases 0.000 claims 1
- 206010061260 Lacrimal cyst Diseases 0.000 claims 1
- 206010061876 Obstruction Diseases 0.000 claims 1
- 206010069385 Ocular ischaemic syndrome Diseases 0.000 claims 1
- 206010038933 Retinopathy of prematurity Diseases 0.000 claims 1
- 206010047115 Vasculitis Diseases 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000001568 sexual effect Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 429
- 210000001525 retina Anatomy 0.000 abstract description 52
- 210000003161 choroid Anatomy 0.000 abstract description 51
- 239000003814 drug Substances 0.000 abstract description 45
- 229940079593 drug Drugs 0.000 abstract description 36
- 206010029113 Neovascularisation Diseases 0.000 abstract description 17
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 abstract description 8
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 abstract description 8
- 230000002301 combined effect Effects 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 239000012049 topical pharmaceutical composition Substances 0.000 abstract description 4
- 230000003247 decreasing effect Effects 0.000 abstract description 3
- 235000002639 sodium chloride Nutrition 0.000 description 91
- 239000000499 gel Substances 0.000 description 83
- 239000000243 solution Substances 0.000 description 69
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 52
- 210000004087 cornea Anatomy 0.000 description 50
- 239000000825 pharmaceutical preparation Substances 0.000 description 48
- 210000001519 tissue Anatomy 0.000 description 46
- 239000012458 free base Substances 0.000 description 44
- 239000003889 eye drop Substances 0.000 description 42
- 125000003118 aryl group Chemical group 0.000 description 37
- 125000000623 heterocyclic group Chemical group 0.000 description 36
- 239000002997 ophthalmic solution Substances 0.000 description 36
- 229940127557 pharmaceutical product Drugs 0.000 description 36
- 239000007983 Tris buffer Substances 0.000 description 35
- 238000000034 method Methods 0.000 description 33
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 31
- 239000000872 buffer Substances 0.000 description 30
- 125000000217 alkyl group Chemical group 0.000 description 29
- 230000002093 peripheral effect Effects 0.000 description 27
- 235000011187 glycerol Nutrition 0.000 description 26
- 229960005150 glycerol Drugs 0.000 description 26
- 229940054534 ophthalmic solution Drugs 0.000 description 23
- 238000011282 treatment Methods 0.000 description 23
- 201000010099 disease Diseases 0.000 description 22
- 238000012384 transportation and delivery Methods 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000008363 phosphate buffer Substances 0.000 description 19
- 241000283973 Oryctolagus cuniculus Species 0.000 description 18
- 210000001742 aqueous humor Anatomy 0.000 description 18
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 18
- 239000003755 preservative agent Substances 0.000 description 17
- 239000001488 sodium phosphate Substances 0.000 description 17
- 229910000162 sodium phosphate Inorganic materials 0.000 description 17
- 235000011008 sodium phosphates Nutrition 0.000 description 17
- 239000000126 substance Substances 0.000 description 17
- 239000000375 suspending agent Substances 0.000 description 17
- 230000001225 therapeutic effect Effects 0.000 description 17
- 230000002792 vascular Effects 0.000 description 17
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 230000005764 inhibitory process Effects 0.000 description 16
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 16
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 16
- 208000005590 Choroidal Neovascularization Diseases 0.000 description 15
- 206010060823 Choroidal neovascularisation Diseases 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 229910019142 PO4 Inorganic materials 0.000 description 15
- 239000010452 phosphate Substances 0.000 description 15
- 125000001424 substituent group Chemical group 0.000 description 15
- 238000011200 topical administration Methods 0.000 description 15
- 208000001344 Macular Edema Diseases 0.000 description 14
- 206010025415 Macular oedema Diseases 0.000 description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 14
- 201000010230 macular retinal edema Diseases 0.000 description 14
- 229910052760 oxygen Inorganic materials 0.000 description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 14
- 230000008901 benefit Effects 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 13
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 13
- 229920000053 polysorbate 80 Polymers 0.000 description 13
- 229940068968 polysorbate 80 Drugs 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 239000003981 vehicle Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 125000000304 alkynyl group Chemical group 0.000 description 10
- 125000004122 cyclic group Chemical group 0.000 description 10
- 229940012356 eye drops Drugs 0.000 description 10
- 231100001274 therapeutic index Toxicity 0.000 description 10
- 108091008605 VEGF receptors Proteins 0.000 description 9
- 229940097362 cyclodextrins Drugs 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 9
- 239000006196 drop Substances 0.000 description 9
- 229940126534 drug product Drugs 0.000 description 9
- 229940088679 drug related substance Drugs 0.000 description 9
- 229940100655 ophthalmic gel Drugs 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 238000005070 sampling Methods 0.000 description 9
- 101100481408 Danio rerio tie2 gene Proteins 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 101100481410 Mus musculus Tek gene Proteins 0.000 description 8
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 8
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 8
- 210000004204 blood vessel Anatomy 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 8
- 125000004430 oxygen atom Chemical group O* 0.000 description 8
- 125000004434 sulfur atom Chemical group 0.000 description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 8
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 7
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 7
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 7
- 230000007246 mechanism Effects 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 230000035515 penetration Effects 0.000 description 7
- 229920001983 poloxamer Polymers 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 7
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- 206010061137 Ocular toxicity Diseases 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 206010044245 Toxic optic neuropathy Diseases 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 230000004888 barrier function Effects 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- 231100000252 nontoxic Toxicity 0.000 description 6
- 231100000327 ocular toxicity Toxicity 0.000 description 6
- 230000002335 preservative effect Effects 0.000 description 6
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 102000009465 Growth Factor Receptors Human genes 0.000 description 5
- 108010009202 Growth Factor Receptors Proteins 0.000 description 5
- 229930195725 Mannitol Natural products 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000002411 adverse Effects 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000002877 alkyl aryl group Chemical group 0.000 description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 208000030533 eye disease Diseases 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000000594 mannitol Substances 0.000 description 5
- 235000010355 mannitol Nutrition 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 230000002207 retinal effect Effects 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 4
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- 206010008790 Choroidal rupture Diseases 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- 102000001301 EGF receptor Human genes 0.000 description 4
- 108060006698 EGF receptor Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 108091008794 FGF receptors Proteins 0.000 description 4
- 201000002563 Histoplasmosis Diseases 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 208000032578 Inherited retinal disease Diseases 0.000 description 4
- 102000003746 Insulin Receptor Human genes 0.000 description 4
- 108010001127 Insulin Receptor Proteins 0.000 description 4
- 201000010183 Papilledema Diseases 0.000 description 4
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 208000032430 Retinal dystrophy Diseases 0.000 description 4
- 206010038886 Retinal oedema Diseases 0.000 description 4
- 206010038934 Retinopathy proliferative Diseases 0.000 description 4
- 241000862969 Stella Species 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 125000004442 acylamino group Chemical group 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000003732 agents acting on the eye Substances 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 125000004947 alkyl aryl amino group Chemical group 0.000 description 4
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 4
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 4
- 125000004691 alkyl thio carbonyl group Chemical group 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 210000002159 anterior chamber Anatomy 0.000 description 4
- 125000001769 aryl amino group Chemical group 0.000 description 4
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 description 4
- 125000005199 aryl carbonyloxy group Chemical group 0.000 description 4
- 125000005110 aryl thio group Chemical group 0.000 description 4
- 125000005200 aryloxy carbonyloxy group Chemical group 0.000 description 4
- 230000002146 bilateral effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 4
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
- KWEDUNSJJZVRKR-UHFFFAOYSA-N carbononitridic azide Chemical compound [N-]=[N+]=NC#N KWEDUNSJJZVRKR-UHFFFAOYSA-N 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 150000007942 carboxylates Chemical class 0.000 description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 239000008139 complexing agent Substances 0.000 description 4
- 210000000795 conjunctiva Anatomy 0.000 description 4
- 210000000695 crystalline len Anatomy 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 125000004986 diarylamino group Chemical group 0.000 description 4
- BPXYEYJNCXITEY-UHFFFAOYSA-N diazonio(trifluoromethoxy)azanide Chemical compound FC(F)(F)ON=[N+]=[N-] BPXYEYJNCXITEY-UHFFFAOYSA-N 0.000 description 4
- 210000002889 endothelial cell Anatomy 0.000 description 4
- 210000000981 epithelium Anatomy 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 201000006321 fundus dystrophy Diseases 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000000017 hydrogel Substances 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 208000017532 inherited retinal dystrophy Diseases 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- 208000001491 myopia Diseases 0.000 description 4
- 230000004379 myopia Effects 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 229940125702 ophthalmic agent Drugs 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 229960000502 poloxamer Drugs 0.000 description 4
- 229920001992 poloxamer 407 Polymers 0.000 description 4
- 229940044476 poloxamer 407 Drugs 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 201000011195 retinal edema Diseases 0.000 description 4
- 239000002356 single layer Substances 0.000 description 4
- 238000009097 single-agent therapy Methods 0.000 description 4
- 239000001509 sodium citrate Substances 0.000 description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 4
- 229940124530 sulfonamide Drugs 0.000 description 4
- 150000003456 sulfonamides Chemical class 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 230000000472 traumatic effect Effects 0.000 description 4
- 230000008728 vascular permeability Effects 0.000 description 4
- 206010003694 Atrophy Diseases 0.000 description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- 206010010741 Conjunctivitis Diseases 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 208000034038 Pathologic Neovascularization Diseases 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 3
- 239000008351 acetate buffer Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000011149 active material Substances 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000004037 angiogenesis inhibitor Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000037444 atrophy Effects 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229960004926 chlorobutanol Drugs 0.000 description 3
- 239000007979 citrate buffer Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000011109 contamination Methods 0.000 description 3
- 125000004663 dialkyl amino group Chemical group 0.000 description 3
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 3
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- 229920001684 low density polyethylene Polymers 0.000 description 3
- 239000004702 low-density polyethylene Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 230000000414 obstructive effect Effects 0.000 description 3
- 229920001542 oligosaccharide Polymers 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000002028 premature Effects 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 208000004644 retinal vein occlusion Diseases 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 230000037390 scarring Effects 0.000 description 3
- 239000004334 sorbic acid Substances 0.000 description 3
- 235000010199 sorbic acid Nutrition 0.000 description 3
- 229940075582 sorbic acid Drugs 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 3
- 229940033663 thimerosal Drugs 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 206010059245 Angiopathy Diseases 0.000 description 2
- 102000009840 Angiopoietins Human genes 0.000 description 2
- 108010009906 Angiopoietins Proteins 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 101100381481 Caenorhabditis elegans baz-2 gene Proteins 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 206010010726 Conjunctival oedema Diseases 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 2
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 201000006165 Kuhnt-Junius degeneration Diseases 0.000 description 2
- 206010025421 Macule Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010067482 No adverse event Diseases 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 2
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 2
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical group C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 2
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 2
- 241000219095 Vitis Species 0.000 description 2
- 235000009754 Vitis X bourquina Nutrition 0.000 description 2
- 235000012333 Vitis X labruscana Nutrition 0.000 description 2
- 235000014787 Vitis vinifera Nutrition 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 238000009098 adjuvant therapy Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000035578 autophosphorylation Effects 0.000 description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 239000003599 detergent Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 239000010954 inorganic particle Substances 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 229940076783 lucentis Drugs 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 208000011873 mild conjunctivitis Diseases 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- WYWIFABBXFUGLM-UHFFFAOYSA-N oxymetazoline Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 WYWIFABBXFUGLM-UHFFFAOYSA-N 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229950008882 polysorbate Drugs 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000005588 protonation Effects 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 235000011083 sodium citrates Nutrition 0.000 description 2
- 238000005063 solubilization Methods 0.000 description 2
- 230000007928 solubilization Effects 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- BYJAVTDNIXVSPW-UHFFFAOYSA-N tetryzoline Chemical compound N1CCN=C1C1C2=CC=CC=C2CCC1 BYJAVTDNIXVSPW-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 239000012929 tonicity agent Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- PCWPQSDFNIFUPO-VDQKLNDWSA-N (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-37,39,41,43,45,47,49-heptakis(2-hydroxyethoxy)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,38,40,42,44,46,48-heptol Chemical compound OCCO[C@H]1[C@H](O)[C@@H]2O[C@H]3O[C@H](CO)[C@@H](O[C@H]4O[C@H](CO)[C@@H](O[C@H]5O[C@H](CO)[C@@H](O[C@H]6O[C@H](CO)[C@@H](O[C@H]7O[C@H](CO)[C@@H](O[C@H]8O[C@H](CO)[C@@H](O[C@H]1O[C@@H]2CO)[C@@H](O)[C@@H]8OCCO)[C@@H](O)[C@@H]7OCCO)[C@@H](O)[C@@H]6OCCO)[C@@H](O)[C@@H]5OCCO)[C@@H](O)[C@@H]4OCCO)[C@@H](O)[C@@H]3OCCO PCWPQSDFNIFUPO-VDQKLNDWSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- MIJDSYMOBYNHOT-UHFFFAOYSA-N 2-(ethylamino)ethanol Chemical compound CCNCCO MIJDSYMOBYNHOT-UHFFFAOYSA-N 0.000 description 1
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- BRMWTNUJHUMWMS-UHFFFAOYSA-N 3-Methylhistidine Natural products CN1C=NC(CC(N)C(O)=O)=C1 BRMWTNUJHUMWMS-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- PEPBFCOIJRULGJ-UHFFFAOYSA-N 3h-1,2,3-benzodioxazole Chemical compound C1=CC=C2NOOC2=C1 PEPBFCOIJRULGJ-UHFFFAOYSA-N 0.000 description 1
- 125000001963 4 membered heterocyclic group Chemical group 0.000 description 1
- NIOAVQYSSKOCQP-UHFFFAOYSA-N 4-hydroxynaphthalene-2-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CC(O)=C21 NIOAVQYSSKOCQP-UHFFFAOYSA-N 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 208000031295 Animal disease Diseases 0.000 description 1
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- USGUDBHKOHZUOP-UHFFFAOYSA-N Cl.N1(CCCC1)CCCCNC(NC1=NSC=C1C(=O)N)=O Chemical compound Cl.N1(CCCC1)CCCCNC(NC1=NSC=C1C(=O)N)=O USGUDBHKOHZUOP-UHFFFAOYSA-N 0.000 description 1
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 1
- 208000006069 Corneal Opacity Diseases 0.000 description 1
- 206010054760 Corneal thinning Diseases 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000006402 Endocrine-Gland-Derived Vascular Endothelial Growth Factor Human genes 0.000 description 1
- 108010044063 Endocrine-Gland-Derived Vascular Endothelial Growth Factor Proteins 0.000 description 1
- 108010041308 Endothelial Growth Factors Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000050554 Eph Family Receptors Human genes 0.000 description 1
- 108091008815 Eph receptors Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 1
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 1
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 1
- 206010016717 Fistula Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- LCWXJXMHJVIJFK-UHFFFAOYSA-N Hydroxylysine Natural products NCC(O)CC(N)CC(O)=O LCWXJXMHJVIJFK-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- UCUNFLYVYCGDHP-BYPYZUCNSA-N L-methionine sulfone Chemical compound CS(=O)(=O)CC[C@H](N)C(O)=O UCUNFLYVYCGDHP-BYPYZUCNSA-N 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000009857 Microaneurysm Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- JDHILDINMRGULE-LURJTMIESA-N N(pros)-methyl-L-histidine Chemical compound CN1C=NC=C1C[C@H](N)C(O)=O JDHILDINMRGULE-LURJTMIESA-N 0.000 description 1
- HXHAJRMTJXHJJZ-UHFFFAOYSA-N NC(c1c(NC(NCCCCN2CCCC2)=O)[s]nc1OCc(c(F)cc(Br)c1)c1F)=O Chemical compound NC(c1c(NC(NCCCCN2CCCC2)=O)[s]nc1OCc(c(F)cc(Br)c1)c1F)=O HXHAJRMTJXHJJZ-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical group C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Chemical group C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 208000037111 Retinal Hemorrhage Diseases 0.000 description 1
- 206010038848 Retinal detachment Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 102000012753 TIE-2 Receptor Human genes 0.000 description 1
- 108010090091 TIE-2 Receptor Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000005089 alkenylaminocarbonyl group Chemical group 0.000 description 1
- 125000005090 alkenylcarbonyl group Chemical group 0.000 description 1
- 125000006193 alkinyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000005125 aryl alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960004574 azelastine Drugs 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone 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-DVTGEIKXSA-N 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000004397 blinking Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229940087373 calcium oxide Drugs 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 210000004240 ciliary body Anatomy 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 238000001246 colloidal dispersion Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 208000027744 congestion Diseases 0.000 description 1
- 231100000269 corneal opacity Toxicity 0.000 description 1
- 210000003683 corneal stroma Anatomy 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005070 decynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 1
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 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
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- PSHRANCNVXNITH-UHFFFAOYSA-N dimethylamino acetate Chemical compound CN(C)OC(C)=O PSHRANCNVXNITH-UHFFFAOYSA-N 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- 125000005411 dithiolanyl group Chemical group S1SC(CC1)* 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 238000002565 electrocardiography Methods 0.000 description 1
- 230000036040 emmetropia Effects 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 108060002566 ephrin Proteins 0.000 description 1
- 102000012803 ephrin Human genes 0.000 description 1
- 210000003560 epithelium corneal Anatomy 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- 208000019501 erythrocyte disease Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000004438 eyesight Effects 0.000 description 1
- 229960004887 ferric hydroxide Drugs 0.000 description 1
- 230000003890 fistula Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 210000004349 growth plate Anatomy 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- QJHBJHUKURJDLG-UHFFFAOYSA-N hydroxy-L-lysine Natural products NCCCCC(NO)C(O)=O QJHBJHUKURJDLG-UHFFFAOYSA-N 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000000554 iris Anatomy 0.000 description 1
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 238000001948 isotopic labelling Methods 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical group C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- 238000013532 laser treatment Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000007431 microscopic evaluation Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 229960005016 naphazoline Drugs 0.000 description 1
- 230000011234 negative regulation of signal transduction Effects 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 125000005071 nonynyl group Chemical group C(#CCCCCCCC)* 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 210000004273 ophthalmic nerve Anatomy 0.000 description 1
- 229940100654 ophthalmic suspension Drugs 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 229960001528 oxymetazoline Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 231100000191 repeated dose toxicity Toxicity 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000004264 retinal detachment Effects 0.000 description 1
- 230000004243 retinal function Effects 0.000 description 1
- 230000004281 retinal morphology Effects 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 108010038379 sargramostim Proteins 0.000 description 1
- 210000003786 sclera Anatomy 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 150000003536 tetrazoles Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960000337 tetryzoline Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 229930192474 thiophene Chemical group 0.000 description 1
- 230000009974 thixotropic effect Effects 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000002992 thymic effect Effects 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 239000008181 tonicity modifier Substances 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 230000004218 vascular function Effects 0.000 description 1
- 230000006444 vascular growth Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- 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
- 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
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- 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
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Ophthalmology & Optometry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Tropical Medicine & Parasitology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本出願は、全内容が本明細書に参照により全体として組み込まれる2013年3月14日出願の米国仮特許出願第61/784681号明細書に対する優先権および恩典を主張するものである。
本明細書および下記の特許請求の範囲では、以下の意味を有すると規定される多数の用語を参照されたい。本明細書の全てのパーセンテージ、割合および比率は、他に特に規定しない限り、重量に基づく。全ての温度は、他に特に規定しない限り、摂氏温度(℃)である。
本発明の化合物Iは、表1に示した特徴を有する。実施形態は、化合物Iもしくはこの遊離塩基である式IIの化合物の3種の製剤を提供する。
本発明は、水に類似する粘度を備える液剤として形成された化合物Iおよび/またはこの遊離塩基(式IIの化合物)の製剤を提供する。液剤には、医薬として許容される物質/賦形剤、例えば制限なく、シクロデキストリンが含まれる。こうして形成された液剤は、眼に局所投与するために適合する透明で無色の液剤である。
シクロデキストリンを含む眼用液剤は、後眼部での本発明の活性物質のバイオアベイラビリティを改善する。理論によって制限されずに、1つの実施形態では、シクロデキストリンを含む製剤は、活性物質の角膜曝露、例えば化合物Iの曝露を等モルの点眼ゲル製剤を用いた角膜曝露に比較して約5分の1から15分の1に低下させる、透明で無色の液剤を形成する。
本実施形態は、化合物および医薬として許容される賦形剤を含む化合物Iの懸濁剤を提供する。例えば、化合物I懸濁剤には、制限されずに緩衝剤、酸および塩基、例えば制限されずにHClおよびNaOHが含まれる。1つの実施形態では、化合物Iもしくはこの遊離塩基の懸濁剤には、緩衝剤、例えば、制限されずにトロメタミン(Tris)が含まれる。式IIの化合物もしくは化合物Iのトロメタミンベース懸濁剤は、眼に局所投与するために有用である。
一部の実施形態では、化合物Iもしくはこの遊離塩基の懸濁剤は、点眼ゲル形(以下で考察する。)で送達される活性物質の濃度と比較して中心脈絡膜および中心網膜で類似濃度の活性物質を提供する。
一部の実施形態では、本発明の眼科用組成物もしくは製剤は、点眼ゲルとして調製される。点眼ゲル製剤には、界面活性剤添加物を必要とせずに約0.005%から約2.0%の化合物Iで必要とされる緩衝能力および自由流動性のろ過可能な製剤を提供するために約0.05%以下の一塩基性ナトリウムホスフェート一水和物が含まれる。
本明細書で開示されるのは、患者にとって医薬として許容され、便宜的で安全で数分間で作用が開始される薬物送達の形態である、点眼薬として開示された化合物を含む製剤である。米国連邦政府規制に従って療法に使用される標準点眼薬は、無菌であり、約6.0から7.4のpHを有し、2回以上使用しなければならない場合は保存料を含有するが、開封後には通常は1カ月間の限定された保管寿命を有する。点眼薬が無菌の単回使用専用単位用量ディスペンサーに包装される場合は、保存料を除外することができる。
本発明の製剤は、眼科用に適合する可能性がある。1つの実施形態では、製剤は液剤である。本発明の液剤は、透明、無色、無菌、等張性、緩衝自由流動水性液体製剤であってよい。薬物製品はおよそ6.0のpHを有し、+5℃で保存されてよい。薬物製品は、ドロッパーのチップおよびキャップを備える半透明の眼科用ディスペンサーボトルからなる容器栓システム内で提供されてよい。
薬物製品:臨床試験用の化合物I眼科用製剤は、0.05%から1.0%の用量強度で(化合物Iとして)製造される。一部の実施形態では、製剤中の化合物Iの用量は、0.05%、0.1%、0.2%、0.3%、0.4%、0.6%、0.8%もしくは1.0%である。化合物I眼科用製剤(液剤もしくは懸濁剤)は、臨床設定における眼への連日投与、単回使用、局所投与のためである。有効成分に加えて、一部の実施形態では、薬物製品は保存料としての約0.005%のBAK、ビヒクルとしての精製水を含有し、ナトリウムヒドロキシドを用いてpH6.0へpH調整される。
ナトリウムホスフェートベース製剤(表6に列挙されている。)中の化合物Iの眼科的利点は、例えばナトリウムホスフェートなどのバッファー中でのAPIの自己ゲル化特性の結果として生じる。透明溶液からの化合物Iの自己形成性チキソトロープゲルの自然形成は、ナトリウムホスフェート中の活性物質濃度を増加させることによって形成される。ホスフェートバッファー中の活性物質濃度が超飽和状態に達すると、化合物Iの不溶性粒子がゲル内で観察される。
本開示は、トロメタミンベース製剤中の化合物Iの懸濁剤を提供する。一部の実施形態では、トロメタミンベース製剤中の化合物Iの懸濁剤は、不溶形にある95%以上の活性薬剤物質を有する。この特徴は、点眼ゲル(活性物質の濃度が増加するため完全には溶解状態ではない点眼ゲル(ゲル))中またはシクロデキストリンベース製剤中において可溶性もしくは半溶解性状態の化合物Iから識別可能である。化合物Iのトロメタミンベース製剤は、活性物質濃度が増加するにつれて増加した濁度を示す。可溶性および不溶性活性物質成分の組み合わせである化合物I懸濁剤の局所用滴剤の眼への投与は、安全性/忍容性および有効性の両方に関して有益である。
1から4つの結合を通して結合された6から8デキストロース単位から製造された環状オリゴ糖であるシクロデキストリン(α-、β-およびγ-CD)は、これらが相対的不溶性薬物のための可溶化剤として機能する能力のために周知である。Stella & He,Cyclodextrins,Toxicol.Pathol.,36:30-42(2008)を参照されたい。
本開示は、化合物Iの様々な製剤および用法/用量の局所的眼用量投与後の眼薬物動態を提供する。化合物Iの9種の局所眼製剤中での3種の用量強度は、1、2、3、4もしくは5連続日中の1日1回(QD)または1日2回(BID)いずれかの投与のために使用される。被験者は各々、容積移送式ピペットを使用して、3種の化合物I製剤またはビヒクル製剤の内の1つの30μLの両側の局所眼投与を受ける。
本開示は、眼投与後のヒドロキシプロピル-β-シクロデキストリン(「HDβCD」)を含有する化合物Iの様々な用法・用量の局所的眼液剤の眼薬物動態を提供する。化合物Iの様々な局所的眼液剤は、4もしくは5連続日いずれかにわたる1日1回(QD)または1日2回(BID)いずれかで投与される。被験者は各々、1から4種の化合物I用量強度の30μLの両側性局所眼投与を受ける。
一部の実施形態では、眼の様々な組織中および眼液中の活性物質の濃度は、約0.4%(約4mg/mL)の化合物Iおよびシクロデキストリンの液剤の局所眼投与後に測定する。化合物Iの平均濃度は、中心脈絡膜、中心網膜、眼房水および角膜中で測定する。化合物Iは、8.41%のKLEPTOSE(R)および0.142%のホスフェートバッファー;8.9%のKLEPTOSE(R)HPBおよび0.142%のホスフェートバッファー;4.88%のCAPTISOL(R)および0.142%ホスフェートバッファー;または4.88%のCAPTISOL(R)および0.122%のホスフェートバッファーを含む液剤(0.4%もしくは4mg/mL)中にある。表10AからBを参照されたい。
本開示は、新生血管加齢性黄斑変性症(AMD)を有する患者における化合物Iの局所眼投与後の安全性、忍容性および薬物動態を評価するための12週間オープンラベル用量漸増多施設共同臨床試験を含む第I相試験を提供する。計60例までの患者が1日1から2回、3カ月間にわたり化合物I眼科用液剤の局所眼投与により治療されるが、このとき3群の用量漸増単剤療法群およびLUCENTIS(R)+最大忍容単剤療法用量の単回硝子体内注射を使用する1群の補助療法群が計画される(1治療群当たり患者15例)。独立読影センターによって確証された、事前に規定された視覚およびCNV病変基準を満たす患者は、同時に局所眼投与を中止して標準的ケアを行う治療を受けさせられる。
本開示の製剤の非限定的例は、表12に略述されている。
本発明の製剤は、哺乳動物被験者の眼における脈絡膜および網膜血管新生(NV)を治療もしくは予防する(即ち、退行させる)ことに有効である。本発明の化合物Iは、規定用量で受容体チロシンキナーゼを阻害する。一部の実施形態では、化合物I製剤は、規定用量でVEGFR、FGFR、Tie2およびEphB-4を含む受容体チロシンキナーゼを阻害する。本発明の製剤による数種のRTKの規定用量での同時の阻害は相乗作用を有し、後眼部におけるNVの治療および退行において効果的である。
眼の疾患もしくは状態を治療するための方法が開示される。本明細書に開示した方法は、被験者に本明細書に開示した化合物およびこれらの製剤の1つ以上を投与する工程によって、眼血管新生(NV)を治療する、予防するもしくは管理する工程、またはNVの発現に関連する疾患もしくは状態を治療することに関する。
さらに開示されるのは、ヒト、哺乳動物または細胞へ薬物送達するための本明細書に開示した化合物および組成物のキットである。キットは、ヒト、哺乳動物または細胞へ送達するべき1つ以上の化合物を含む組成物の1つ以上の包装単位用量を含むことができる。送達されなければならない化合物が使用前にこの中に包装される単位用量アンプルもしくは多用量容器は、医薬的に有効な投与量または有効な投与量の倍数に適合するある量の活性物質もしくは医薬として許容される塩またはこの製剤を同封している気密密閉容器を含むことができる。これらの化合物は無菌製剤として包装できる、および気密密閉容器は製剤を使用時まで無菌性を保存するように設計されている。
主要薬物動態
化合物Iのインビトロ有効性薬理学
化合物Iは、様々なインビトロアッセイ中に、血管内皮成長因子受容体2(VEGF-2)のチロシンキナーゼ活性ならびに選択的サブセットの他の血管新生促進性RTKを強力に阻害する。詳細には、化合物I化合物は、培養内皮細胞の増殖とともに細胞全体でのVEGF誘発性VEGFR-2リン酸化を遮断した。化合物Iは、VEGFR-2およびFGFR-2の組み換えチロシンキナーゼ活性を各々10.55nM(6ng/mL)および8.79nM(5ng/mL)の50%阻害濃度(IC50)で阻害した;および無傷細胞内でのVEGFR-2自己リン酸化をIC50=5.27nM(3ng/mL)で阻害した。この阻害は他の多くのチロシンキナーゼに対して選択的であり、例えばVEGFR-2のIC50は、内皮成長因子(EGFR)およびインスリン受容体(IR)チロシンキナーゼに対して各々およそ500分の1および1000分の1低かった(表2を参照)。
薬剤物質:
医薬品有効成分(API)である式IIのヒドロクロリド(化合物I、CP-547632-01)は、単一多形の低分子である。API物質は、99.7%を超える純度で一貫して製造される。薬剤物質中の≧0.15%の何らかの不純物は、毒物学試験において適格であると認められ、新規の不明な個別不純物についての本仕様はNMT 0.2%に設定されている。最終の薬剤物質および薬物製品は、標準方法を使用して分析される。
臨床試験のための化合物I眼科用製剤は、0.05%から1.0%の用量強度で(化合物Iとして)製造された。GLPバッチのために使用される強度は、化合物Iの0%(プラセボ)、0.05%、0.1%、0.2%、0.3%、0.4%、0.6%、0.8%および1.0%である。化合物I眼科用製剤(液剤もしくは懸濁剤)は、臨床試験における眼への連日投与、単回使用、局所投与のために使用される。有効成分に加えて、薬物製品は保存料としての約0.005%のBAK、ビヒクルとしての精製水を含有し、ナトリウムヒドロキシドを用いてpH6.0へpH調整される。
ナトリウムホスフェートベースの点眼ゲル
ナトリウムホスフェートベース製剤(表6に列挙されている。)中の化合物Iの眼科的利点は、例えばナトリウムホスフェートなどのバッファー中でのAPIの自己ゲル化特性の結果として生じる。透明溶液からの化合物Iの自己形成性チキソトロープゲルの自然形成は、ナトリウムホスフェート中のAPI濃度を増加させることによって形成された。このゲルは、最初は透明に見えたが、この後API濃度が高くなると厚さ/粘度の増加を示し、ならびにますます不透明になり、即ち混濁した。ホスフェートバッファー中のAPI濃度が超飽和状態に達すると、ゲル内で化合物Iの不溶性粒子が観察された。
トロメタミンベース懸濁剤
トロメタミンベース製剤中の化合物I(約1mg/mLから約10mg/mL)は懸濁剤を形成した。トロメタミンベース製剤中の化合物Iの懸濁剤は、不溶形にある>95%の活性薬剤物質を有した。この特徴は、点眼ゲル(点眼ゲル(ゲル)は活性物質の濃度が増加するため完全には溶解状態ではない。)中またはシクロデキストリンベース製剤中において可溶性もしくは半溶解性状態の化合物Iから識別可能である。化合物Iのトロメタミンベース製剤は、活性物質濃度が増加するにつれて増加した濁度を示した。化合物I懸濁剤の局所用滴剤(可溶性および不溶性活性物質成分の組み合わせである。)の眼への投与は、安全性/忍容性および有効性の両方に関連する固有の利点を提供すると予想された。
シクロデキストリンベース液剤
1から4つの結合を通して結合された6から8デキストロース単位から作られた環状オリゴ糖であるシクロデキストリン(α-、β-およびγ-CD)は、相対的不溶性薬物のための可溶化剤として機能するこれらの能力のために周知である。Stella & He,Cyclodextrins,Toxicol.Pathol.,36:30-42(2008)を参照されたい。
シクロデキストリンベース液剤中の局所的眼化合物Iを用いた1から5日間のPK結果
ダッチベルテッド種のウサギにおける化合物Iの様々な製剤および用法・用量の局所眼投与後に、眼薬物動態を調査した。化合物Iの3種の用量を有する9種の局所眼製剤は、4もしくは5連続日いずれかにわたり1日1回(QD)または1日2回(BID)いずれかで投与された。試験デザイン(表10AからCを参照)は、各々、容積移送式ピペットを使用して、3種の化合物I製剤またはビヒクル製剤の内の1つの30μLの両側の局所眼投与を受ける72匹のウサギから構成した。
シクロデキストリンベース液剤中の局所的眼化合物Iを用いた5日間のPK結果
様々な用法・用量のダッチベルテッド種のウサギにおけるヒドロキシプロピル-β-シクロデキストリン(「HDβCD」)を含有する化合物Iの局所眼液剤の眼投与後に、眼薬物動態を計算した。化合物Iの4種の用量を有する9種の局所的眼液剤は、4もしくは5連続日いずれかにわたり1日1回(QD)または1日2回(BID)いずれかで投与された。試験デザインは、各々が容積移送式ピペットを使用して、4種の化合物I製剤強度の1つの30μLの両側の局所眼投与を受ける40匹のウサギから構成した。
様々な眼液および組織中の化合物Iの濃度(単位:μM)
シクロデキストリンを含む化合物Iの眼科用液剤を調製し、様々な動物群において試験した。0.4%(4mg/mL)の化合物Iおよびシクロデキストリンの液剤の局所眼投与後、活性物質の濃度を眼の様々な組織中および眼液中で測定した。化合物Iの平均濃度は、中心脈絡膜、中心網膜、眼房水および角膜中で測定した。化合物Iは、8.41%のKLEPTOSE(R)および0.142%のホスフェートバッファー;8.9%のKLEPTOSE(R)HPBおよび0.142%のホスフェートバッファー;4.88%のCAPTISOL(R)および0.142%ホスフェートバッファー;または4.88%のCAPTISOL(R)および0.122%のホスフェートバッファーを含む液剤(0.4%もしくは4mg/mL)中にあった。表10AからBを参照されたい。
眼毒性試験
用量限定性眼毒性は、ダッチベルテッド種ウサギおよびビーグル犬における角膜および結膜所見によって特徴付けた。化合物I眼科用点眼ゲルを用いた反復投与毒性試験からのこれらの眼所見は、臨床的眼科学的および組織病理学的評価に基づいており、結膜充血、結膜浮腫、うっ血および分泌、角膜混濁および上皮びらんならびに角膜結膜炎に限定された。眼のより深部の構造(虹彩、水晶体、毛様体、網膜、脈絡膜、強膜)または視神経に関係する不都合ではない変化が観察された。網膜機能は、ウサギにおいて実施された全視野網膜電図検査中の全試験製品群およびビヒクル治療群において正常であった。
新生血管AMDを有する患者における用量漸増試験のための第1相プロトコル
第1相試験は、新生血管加齢性黄斑変性症(AMD)を有する患者における化合物Iの局所眼投与後の安全性、忍容性および薬物動態を評価するために設計された12週間オープンラベル用量漸増多施設共同臨床試験である。計60例までの患者が1日1から2回、3カ月間にわたり化合物I眼科用液剤の局所眼投与により治療されるが、このとき3群の用量漸増単剤療法群、およびLUCENTIS(R)+最大忍容単剤療法用量の単回硝子体内注射を使用する1群の補助療法群を計画する(1治療群当たり患者15例)。独立読影センターによって確証された、事前に規定された視覚およびCNV病変基準を満たす患者は、同時に局所眼投与を中止して標準的ケアを行う治療を受ける。
0.1から1.0%(1から10mg/mL)の薬物強度にわたって物理的および化学的の両方で安定性である「非ゲル」、「非粘性」の均質な眼科用液剤局所製剤を、化合物Iの溶解度および安定性に関して化合物Iの濃度、シクロデキストリン錯化剤濃度、pHおよび張性を測定することによって調製した。適切な緩衝系は、1mg/mL未満の濃度での安定性に関するpHドリフトを防止する。ホスフェートおよびトロメタモール(Tris)はどちらも緩衝剤であると評価された。ナトリウムクロリドは、張性を調整するために使用された。
表12および13に略記した製剤は、列挙した一般方法を用いて調製した。
本明細書で言及した特許文献および科学論文の各々の全開示は、あらゆる目的で参照により本明細書に組み込まれる。本開示では、多数の文献は十分な特殊性および本開示が参考文献の状況に基づいて重要であると見なされる材料を用いて同定されている。刊行物および特許文献の言及は、いずれかが適切な先行技術であると承認することは意図しておらず、同一物の内容および日付に関して何らかの承認を構成するものではない。ここまで本発明を文書による説明によって記載してきたが、当業者であれば、本発明は様々な実施形態で実施できること、および上記の説明および実施例は例示するためであって下記の特許請求の範囲を限定するものでないことを認識できる。
本発明は、本発明の精神または本質的な特徴から逸脱せずに他の特定形態で実施することができる。このため上記の実施形態は、本明細書に記載した本発明を限定するのではなくむしろあらゆる面で例示と見なすべきである。従って本発明の範囲は、上記の説明によってではなくむしろ添付の特許請求の範囲によって指示され、特許請求項の同等性の意味および範囲に含まれる全ての変更点はこの中に包含されることが意図されている。
Claims (27)
- 可溶化剤を含む、請求項1に記載の局所眼製剤。
- 可溶化剤は、2-ヒドロキシプロピル-β-シクロデキストリン、メチル-β-シクロデキストリン、ランダムメチル化-β-シクロデキストリン、エチル化-β-シクロデキストリン、トリアセチル-β-シクロデキストリン、パーアセチル化-β-シクロデキストリン、カルボキシメチル-β-シクロデキストリン、ヒドロキシメチル-β-シクロデキストリン、2-ヒドロキシ-3-(トリメチルアンモニオ)プロピル-β-シクロデキストリン、グルコシル-β-シクロデキストリン、マルトシル-β-シクロデキストリン、スルホブチルエーテル-β-シクロデキストリン、分岐β-シクロデキストリン、ヒドロキシプロピル-γ-シクロデキストリン、ランダムメチル化-γ-シクロデキストリン、トリメチル-γ-シクロデキストリンおよびこれらの組み合わせからなる群より選択されるシクロデキストリンである、請求項2に記載の局所眼製剤。
- 可溶化剤は、2-ヒドロキシプロピル-β-シクロデキストリンもしくはβ-シクロデキストリンスルホブチルエーテルである、請求項3に記載の局所眼製剤。
- 約0.005%、約0.05%、約0.1%、約0.2%、約0.3%、約0.4%、約0.5%、約0.6%、約0.7%、約0.8%、約0.9%、約1.0%、約2.0%、約3.0%、約4.0%もしくは約5.0%(w/v)の活性物質もしくはこの医薬として許容される塩を含む、請求項3に記載の局所眼製剤。
- ベンザルコニウムクロリド(BAK)、ナトリウムクロリドおよびpH調整剤の内の1つ以上を含む、請求項3に記載の局所眼製剤。
- 約0.005%、約0.05%、約0.1%、約0.2%、約0.3%、約0.4%、約0.5%、約0.6%、約0.7%、約0.8%、約0.9%、約1.0%、約2.0%、約3.0%、約4.0%もしくは約5.0%(w/v)の活性物質もしくはこの医薬として許容される塩および約0.3%から約1%(w/v)のトロメタミンを含む、請求項1に記載の局所眼製剤。
- 約0.005%、約0.05%、約0.1%、約0.2%、約0.3%、約0.4%、約0.5%、約0.6%、約0.7%、約0.8%、約0.9%、約1.0%、約2.0%、約3.0%、約4.0%もしくは約5.0%(w/v)の活性物質もしくはこの医薬として許容される塩、約0.3%から約1%(w/v)のトロメタミンおよび約0.005%(w/v)のベンザルコニウムクロリド(BAK)を含む、請求項1に記載の局所眼製剤。
- 約40℃以下で約4.5から約7.5のpH値を有する、請求項1に記載の局所眼製剤。
- 約40℃以下で約6.0のpH値を有する、請求項1に記載の局所眼製剤。
- 約40℃以下で約5.0から約7.0のpH値を有する、請求項1に記載の局所眼製剤。
- 後眼部にアクセスするため、および/または眼血管新生を治療および/または緩和するために適合する、請求項1に記載の局所眼製剤。
- 後眼部にアクセスするため、および/または糖尿病性網膜症、加齢性黄斑変性症(AMD)、病理的脈絡膜血管新生(CNV)、病理的網膜血管新生、ブドウ膜炎、網膜静脈閉鎖、眼外傷、手術誘導性浮腫、手術誘導性血管新生、涙嚢胞黄斑浮腫、眼虚血、未熟児網膜症、コーツ病(Coat’s disease)、鎌状赤血球網膜症および血管新生緑内障からなる群より選択される後眼部疾患を治療および/または緩和するために適切な医薬品の製造における請求項1に記載の局所眼製剤の使用。
- 糖尿病性網膜症は、背景糖尿病性網膜症、増殖性糖尿病性網膜症または糖尿病性黄斑浮腫である、請求項14に記載の局所眼製剤の使用。
- AMDは、新生血管AMD、乾性AMDまたは地図状萎縮症である、請求項14に記載の局所眼製剤の使用。
- 新生血管AMDは、湿性AMDまたは滲出性AMDである、請求項16に記載の局所眼製剤の使用。
- CNVは、強度近視、外傷、鎌状赤血球網膜症、眼ヒストプラスマ症、色素線条、外傷性脈絡膜破裂、眼神経のドルーゼまたは数種の網膜ジストロフィーに関連する、請求項14に記載の局所眼製剤の使用。
- 病理的網膜血管新生は、鎌状赤血球網膜症、イールズ病(Eales disease)、眼虚血症候群、頚動脈-海綿静脈洞フィステル、家族性滲出性硝子体網膜症、過粘稠度症候群、特発性閉塞性細動脈炎、バードショット脈絡網膜症、網膜血管炎、サルコイドーシスもしくはトキソプラズマ症に関連する、請求項14に記載の局所眼製剤の使用。
- 網膜静脈閉鎖は、中心静脈もしくは分枝静脈閉鎖である、請求項14に記載の局所眼製剤の使用。
- 製剤を連日または隔日に1日1回、2回、3回もしくは4回投与する工程を含む、請求項14に記載の局所眼製剤の使用。
- 製剤を連日または隔日に1日2回もしくは3回投与する工程を含む、請求項14に記載の局所眼製剤の使用。
- 約0.005%、約0.05%、約0.1%、約0.2%、約0.3%、約0.4%、約0.5%、約0.6%、約0.7%、約0.8%、約0.9%、約1.0%、約2.0%、約3.0%、約4.0%もしくは約5.0%(w/v)の活性物質を含む製剤を連日または隔日に1日2回投与する工程を含む、請求項14に記載の局所眼製剤の使用。
- 製剤は、片眼または両眼に投与される、請求項23に記載の局所眼製剤の使用。
- 製剤は、可溶化剤を含む、請求項23に記載の局所眼製剤の使用。
- 可溶化剤は、2-ヒドロキシプロピル-β-シクロデキストリン、メチル-β-シクロデキストリン、ランダムメチル化-β-シクロデキストリン、エチル化-β-シクロデキストリン、トリアセチル-β-シクロデキストリン、パーアセチル化-β-シクロデキストリン、カルボキシメチル-β-シクロデキストリン、ヒドロキシメチル-β-シクロデキストリン、2-ヒドロキシ-3-(トリメチルアンモニオ)プロピル-β-シクロデキストリン、グルコシル-β-シクロデキストリン、マルトシル-β-シクロデキストリン、スルホブチルエーテル-β-シクロデキストリン、分岐β-シクロデキストリン、ヒドロキシプロピル-γ-シクロデキストリン、ランダムメチル化-γ-シクロデキストリン、トリメチル-γ-シクロデキストリンおよびこれらの組み合わせからなる群より選択されるシクロデキストリンである、請求項25に記載の局所眼製剤の使用。
- 可溶化剤は、2-ヒドロキシプロピル-β-シクロデキストリンもしくはβ-シクロデキストリンスルホブチルエーテルである、請求項26に記載の局所眼製剤の使用。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361784681P | 2013-03-14 | 2013-03-14 | |
US61/784,681 | 2013-03-14 | ||
JP2016502486A JP6542193B2 (ja) | 2013-03-14 | 2014-03-14 | 後眼部へ薬物を送達するための眼用製剤 |
JP2019108399A JP6965308B2 (ja) | 2013-03-14 | 2019-06-11 | 後眼部へ薬物を送達するための眼用製剤 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019108399A Division JP6965308B2 (ja) | 2013-03-14 | 2019-06-11 | 後眼部へ薬物を送達するための眼用製剤 |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2022009275A true JP2022009275A (ja) | 2022-01-14 |
Family
ID=50625096
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016502486A Active JP6542193B2 (ja) | 2013-03-14 | 2014-03-14 | 後眼部へ薬物を送達するための眼用製剤 |
JP2019108399A Active JP6965308B2 (ja) | 2013-03-14 | 2019-06-11 | 後眼部へ薬物を送達するための眼用製剤 |
JP2021171453A Pending JP2022009275A (ja) | 2013-03-14 | 2021-10-20 | 後眼部へ薬物を送達するための眼用製剤 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016502486A Active JP6542193B2 (ja) | 2013-03-14 | 2014-03-14 | 後眼部へ薬物を送達するための眼用製剤 |
JP2019108399A Active JP6965308B2 (ja) | 2013-03-14 | 2019-06-11 | 後眼部へ薬物を送達するための眼用製剤 |
Country Status (23)
Country | Link |
---|---|
US (7) | US9446026B2 (ja) |
EP (2) | EP3520773A1 (ja) |
JP (3) | JP6542193B2 (ja) |
KR (2) | KR102433489B1 (ja) |
CN (2) | CN105142686B (ja) |
AU (3) | AU2014239252B2 (ja) |
BR (1) | BR112015021334B1 (ja) |
CA (1) | CA2900840C (ja) |
DK (1) | DK2968650T3 (ja) |
ES (1) | ES2710152T3 (ja) |
HK (1) | HK1216236A1 (ja) |
HU (1) | HUE042528T2 (ja) |
IL (2) | IL240510B (ja) |
MX (1) | MX360888B (ja) |
PH (2) | PH12015501938B1 (ja) |
PL (1) | PL2968650T3 (ja) |
PT (1) | PT2968650T (ja) |
RU (2) | RU2665953C2 (ja) |
SA (1) | SA516380321B1 (ja) |
SG (2) | SG10201710928PA (ja) |
TR (1) | TR201901462T4 (ja) |
WO (1) | WO2014152661A1 (ja) |
ZA (2) | ZA201505447B (ja) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2013314303B2 (en) | 2012-09-12 | 2018-01-18 | Novaliq Gmbh | Semifluorinated alkane compositions |
KR101874219B1 (ko) | 2012-09-12 | 2018-07-03 | 노바리크 게엠베하 | 부분불소화 알칸의 혼합물을 포함하는 조성물 |
JP6657193B2 (ja) * | 2014-09-17 | 2020-03-04 | パンオプティカ,インコーポレイテッド | 薬物送達および前眼部保護のための眼用製剤 |
US20170087100A1 (en) | 2015-09-30 | 2017-03-30 | Novaliq Gmbh | Semifluorinated compounds and their compositions |
CA3016602A1 (en) | 2016-03-11 | 2017-09-14 | Georgia-Pacific Gypsum Llc | Gypsum panels, systems, and methods |
KR102351816B1 (ko) * | 2017-04-21 | 2022-01-17 | 노바리크 게엠베하 | 요오드 조성물 |
EP3621601A1 (en) | 2017-05-12 | 2020-03-18 | Novaliq GmbH | Pharmaceutical compositions comprosing semifluorinated alkanes for the treatment of contact lense-related conditions |
RU2652342C1 (ru) * | 2017-07-13 | 2018-04-25 | Наталья Александровна Гаврилова | Композиция для лечения ретинальной неоваскуляризации в эксперименте и способ лечения с ее использованием |
CA3076776A1 (en) | 2017-09-27 | 2019-04-04 | Novaliq Gmbh | Ophthalmic compositions comprising latanoprost for use in the treatment of ocular diseases |
US11896559B2 (en) | 2017-10-04 | 2024-02-13 | Novaliq Gmbh | Opthalmic compositions comprising F6H8 |
AT522609B1 (de) | 2019-05-28 | 2022-06-15 | Miba Frictec Gmbh | Reibvorrichtung |
TW202308703A (zh) | 2021-05-03 | 2023-03-01 | 美商亞維拉治療公司 | 用於降解免疫球蛋白及其他蛋白質之有效asgpr結合化合物 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050074497A1 (en) * | 2003-04-09 | 2005-04-07 | Schultz Clyde L. | Hydrogels used to deliver medicaments to the eye for the treatment of posterior segment diseases |
WO2009020145A1 (ja) * | 2007-08-09 | 2009-02-12 | Senju Pharmaceutical Co., Ltd. | ピレノキシン含有二液性点眼剤 |
JP2009525965A (ja) * | 2006-01-27 | 2009-07-16 | アムジエン・インコーポレーテツド | Ang2とVEGF阻害剤の組合せ |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2201134A1 (en) | 1994-10-10 | 1996-04-18 | Alfred Sallmann | Ophthalmic and aural compositions containing diclofenac potassium |
JPH10203960A (ja) | 1997-01-24 | 1998-08-04 | Ofutekusu:Kk | 点眼液組成物 |
UA60365C2 (uk) | 1998-06-04 | 2003-10-15 | Пфайзер Продактс Інк. | Похідні ізотіазолу, спосіб їх одержання, фармацевтична композиція та спосіб лікування гіперпроліферативного захворювання у ссавця |
US6239113B1 (en) * | 1999-03-31 | 2001-05-29 | Insite Vision, Incorporated | Topical treatment or prevention of ocular infections |
US6254860B1 (en) | 1999-04-13 | 2001-07-03 | Allergan Sales, Inc. | Ocular treatment using cyclosporin-A derivatives |
MXPA02002452A (es) | 1999-09-06 | 2004-09-10 | Ono Pharmaceutical Co | Agentes preventivos y terapeuticos para enfermedades de oftalmicas. |
SK5862003A3 (en) * | 2000-11-28 | 2004-05-04 | Pfizer Prod Inc | Salts of a isothiazole-4-carboxamide and their use as anti-hyperproliferation agents |
WO2004011461A1 (en) * | 2002-07-25 | 2004-02-05 | Pfizer Products Inc. | Isothiazole derivatives useful as anticancer agents |
EP1542164A1 (en) * | 2002-08-29 | 2005-06-15 | Kistem Co. Ltd. | Vision aid network server, vision aid network system, vision aid method, vision aid system, color sense function reporting system, program for reporting color sense function, method for reporting color sense function, color sense aid system, color sense aid program, and color sense aid method |
US20050234018A1 (en) * | 2004-04-15 | 2005-10-20 | Allergan, Inc. | Drug delivery to the back of the eye |
WO2005102327A1 (en) * | 2004-04-20 | 2005-11-03 | Pfizer Products Inc. | Dosage forms and methods of treatment using vegfr inhibitors |
US7483533B2 (en) * | 2004-08-05 | 2009-01-27 | King Fahd University Of Petroleum | Elliptic polynomial cryptography with multi x-coordinates embedding |
JP2006111621A (ja) | 2004-09-15 | 2006-04-27 | Santen Pharmaceut Co Ltd | ピレノキシン懸濁型点眼剤 |
CA2578176C (en) * | 2004-11-09 | 2013-09-24 | Novagali Pharma Sa | Ophthalmic emulsions containing an immunosuppressive agent |
WO2006133411A1 (en) * | 2005-06-08 | 2006-12-14 | Targegen, Inc. | Methods and compositions for the treatment of ocular disorders |
JP2007012937A (ja) * | 2005-06-30 | 2007-01-18 | Seiko Epson Corp | 表示ドライバ |
JP2007011785A (ja) * | 2005-06-30 | 2007-01-18 | Toshiba Corp | 情報処理装置、およびタッチパネルの振動制御方法 |
US7893040B2 (en) * | 2005-07-22 | 2011-02-22 | Oculis Ehf | Cyclodextrin nanotechnology for ophthalmic drug delivery |
CN101282714B (zh) * | 2005-10-10 | 2012-12-12 | 诺瓦加利制药公司 | 包含前列腺素的眼用乳剂 |
DE102006051512A1 (de) * | 2005-12-06 | 2007-06-14 | Pari GmbH Spezialisten für effektive Inhalation | Pharmazeutische Medikamentenzusammensetzungen mit Cyclosporin |
CN101687786B (zh) * | 2007-02-22 | 2013-05-22 | 奥特拉控股公司 | 羟胺化合物及其用法 |
WO2010119942A1 (ja) | 2009-04-17 | 2010-10-21 | 参天製薬株式会社 | レボカバスチン懸濁型点眼剤 |
JP2012250918A (ja) | 2011-05-31 | 2012-12-20 | Rohto Pharmaceutical Co Ltd | ニューキノロン剤含有水性組成物 |
EP2817031A4 (en) | 2012-02-22 | 2015-08-05 | Tufts College | COMPOSITIONS AND METHODS FOR OCULAR DELIVERY OF A THERAPEUTIC AGENT |
-
2014
- 2014-03-14 KR KR1020157028846A patent/KR102433489B1/ko active IP Right Grant
- 2014-03-14 TR TR2019/01462T patent/TR201901462T4/tr unknown
- 2014-03-14 PT PT14724204T patent/PT2968650T/pt unknown
- 2014-03-14 US US14/211,427 patent/US9446026B2/en active Active
- 2014-03-14 EP EP18210412.5A patent/EP3520773A1/en active Pending
- 2014-03-14 CN CN201480014617.7A patent/CN105142686B/zh active Active
- 2014-03-14 CN CN202010184735.XA patent/CN111789814B/zh active Active
- 2014-03-14 SG SG10201710928PA patent/SG10201710928PA/en unknown
- 2014-03-14 MX MX2015012653A patent/MX360888B/es active IP Right Grant
- 2014-03-14 DK DK14724204.4T patent/DK2968650T3/en active
- 2014-03-14 PL PL14724204T patent/PL2968650T3/pl unknown
- 2014-03-14 JP JP2016502486A patent/JP6542193B2/ja active Active
- 2014-03-14 US US14/775,357 patent/US10092549B2/en active Active
- 2014-03-14 EP EP14724204.4A patent/EP2968650B1/en active Active
- 2014-03-14 AU AU2014239252A patent/AU2014239252B2/en active Active
- 2014-03-14 ES ES14724204T patent/ES2710152T3/es active Active
- 2014-03-14 SG SG11201507316UA patent/SG11201507316UA/en unknown
- 2014-03-14 HU HUE14724204A patent/HUE042528T2/hu unknown
- 2014-03-14 BR BR112015021334A patent/BR112015021334B1/pt active IP Right Grant
- 2014-03-14 KR KR1020217033904A patent/KR20210132205A/ko not_active Application Discontinuation
- 2014-03-14 CA CA2900840A patent/CA2900840C/en active Active
- 2014-03-14 RU RU2015143898A patent/RU2665953C2/ru active
- 2014-03-14 WO PCT/US2014/027589 patent/WO2014152661A1/en active Application Filing
- 2014-03-14 RU RU2018128980A patent/RU2768489C2/ru active
-
2015
- 2015-07-29 ZA ZA2015/05447A patent/ZA201505447B/en unknown
- 2015-08-12 IL IL240510A patent/IL240510B/en active IP Right Grant
- 2015-09-02 PH PH12015501938A patent/PH12015501938B1/en unknown
- 2015-09-14 SA SA516380321A patent/SA516380321B1/ar unknown
-
2016
- 2016-04-11 HK HK16104118.1A patent/HK1216236A1/zh unknown
- 2016-08-19 US US15/241,545 patent/US20160354349A1/en not_active Abandoned
-
2017
- 2017-08-02 AU AU2017210543A patent/AU2017210543B2/en active Active
-
2018
- 2018-07-23 US US16/042,003 patent/US10307404B1/en active Active
-
2019
- 2019-04-16 US US16/385,711 patent/US20190240201A1/en not_active Abandoned
- 2019-04-23 US US16/391,425 patent/US20190247368A1/en not_active Abandoned
- 2019-04-24 AU AU2019202857A patent/AU2019202857B2/en active Active
- 2019-06-11 JP JP2019108399A patent/JP6965308B2/ja active Active
- 2019-08-15 PH PH12019501902A patent/PH12019501902A1/en unknown
- 2019-10-30 ZA ZA2019/07176A patent/ZA201907176B/en unknown
-
2020
- 2020-07-13 IL IL276016A patent/IL276016B/en unknown
-
2021
- 2021-03-12 US US17/199,506 patent/US20210196690A1/en active Pending
- 2021-10-20 JP JP2021171453A patent/JP2022009275A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050074497A1 (en) * | 2003-04-09 | 2005-04-07 | Schultz Clyde L. | Hydrogels used to deliver medicaments to the eye for the treatment of posterior segment diseases |
JP2009525965A (ja) * | 2006-01-27 | 2009-07-16 | アムジエン・インコーポレーテツド | Ang2とVEGF阻害剤の組合せ |
WO2009020145A1 (ja) * | 2007-08-09 | 2009-02-12 | Senju Pharmaceutical Co., Ltd. | ピレノキシン含有二液性点眼剤 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6965308B2 (ja) | 後眼部へ薬物を送達するための眼用製剤 | |
JP6890692B2 (ja) | 薬物送達および前眼部保護のための眼用製剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20211118 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20211118 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20221018 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230117 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230425 |