JP2020172524A - 製剤 - Google Patents
製剤 Download PDFInfo
- Publication number
- JP2020172524A JP2020172524A JP2020115537A JP2020115537A JP2020172524A JP 2020172524 A JP2020172524 A JP 2020172524A JP 2020115537 A JP2020115537 A JP 2020115537A JP 2020115537 A JP2020115537 A JP 2020115537A JP 2020172524 A JP2020172524 A JP 2020172524A
- Authority
- JP
- Japan
- Prior art keywords
- volume
- weight
- ylamino
- benzyl
- amino
- 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.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 109
- 238000009472 formulation Methods 0.000 title description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 60
- OURRXQUGYQRVML-UHFFFAOYSA-N [4-[3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate Chemical compound CC1=CC(C)=CC=C1C(=O)OCC1=CC=C(C(CN)C(=O)NC=2C=C3C=CN=CC3=CC=2)C=C1 OURRXQUGYQRVML-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000006172 buffering agent Substances 0.000 claims description 14
- 239000007951 isotonicity adjuster Substances 0.000 claims description 8
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 11
- 239000012929 tonicity agent Substances 0.000 abstract description 9
- 239000000872 buffer Substances 0.000 abstract description 5
- 235000002639 sodium chloride Nutrition 0.000 description 57
- -1 4- (3-amino-1- (isoquinoline-6-ylamino) -1-oxopropan-2-yl) benzyl Chemical group 0.000 description 48
- 238000000034 method Methods 0.000 description 29
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 28
- 239000004327 boric acid Substances 0.000 description 28
- 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 27
- 229960001855 mannitol Drugs 0.000 description 27
- 229930195725 Mannitol Natural products 0.000 description 24
- 239000000594 mannitol Substances 0.000 description 24
- 235000010355 mannitol Nutrition 0.000 description 24
- 208000010412 Glaucoma Diseases 0.000 description 18
- 229960000686 benzalkonium chloride Drugs 0.000 description 17
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 17
- 150000001875 compounds Chemical class 0.000 description 16
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 16
- 229960001160 latanoprost Drugs 0.000 description 16
- ZADSZNPGFHTHPB-UHFFFAOYSA-N benzyl 2,4-dimethylbenzoate Chemical compound CC1=CC(C)=CC=C1C(=O)OCC1=CC=CC=C1 ZADSZNPGFHTHPB-UHFFFAOYSA-N 0.000 description 15
- 239000003755 preservative agent Substances 0.000 description 14
- 239000003995 emulsifying agent Substances 0.000 description 10
- 230000002335 preservative effect Effects 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 208000030533 eye disease Diseases 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 229960002645 boric acid Drugs 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- CTOHIZAYOCTKNS-UHFFFAOYSA-N 3-amino-N-isoquinolin-6-ylpropanamide Chemical compound NCCC(=O)NC=1C=C2C=CN=CC2=CC=1 CTOHIZAYOCTKNS-UHFFFAOYSA-N 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 150000003180 prostaglandins Chemical class 0.000 description 5
- 238000011200 topical administration Methods 0.000 description 5
- 229960002368 travoprost Drugs 0.000 description 5
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 229940000425 combination drug Drugs 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-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
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 239000008389 polyethoxylated castor oil Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 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 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 150000002891 organic anions Chemical class 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 229940099429 polyoxyl 40 stearate Drugs 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
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical 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
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- BKYWPNROPGQIFZ-UHFFFAOYSA-M 2,4-dimethylbenzoate Chemical class CC1=CC=C(C([O-])=O)C(C)=C1 BKYWPNROPGQIFZ-UHFFFAOYSA-M 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-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
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-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
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- OURRXQUGYQRVML-SANMLTNESA-N [4-[(2r)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate Chemical compound CC1=CC(C)=CC=C1C(=O)OCC1=CC=C([C@H](CN)C(=O)NC=2C=C3C=CN=CC3=CC=2)C=C1 OURRXQUGYQRVML-SANMLTNESA-N 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001449 anionic compounds Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 229910001412 inorganic anion Inorganic materials 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 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
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Ophthalmology & Optometry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
活性医薬成分の安定性を維持し、そして投与時の不快感を減少させながら、活性医薬成分に十分な溶解性を提供する眼科用組成物が必要とされている。典型的には、眼科用組成物は、投与の容易さおよび投与時の不快感の低減の両方のために、生理学的pHまたはその付近で投与される。しかしながら、すべての活性医薬成分が生理学的pHで十分に可溶性であるとは限らない。それ故、活性医薬成分の十分な溶解性を可能にし、そして投与時の不快感を最小にする組成物が必要とされている。
他に定義されない限り、本明細書で使用されるすべての技術用語および科学用語は、当業者によって一般に理解されるのと同じ意味を有する。矛盾する場合、定義を含む本文書が支配する。本明細書に記載のものと類似または同等の方法および材料を本開示の実施または試験に使用することができるが、好ましい方法および材料を以下に記載する。本明細書で言及されるすべての刊行物、特許出願、特許および他の参考文献は、その全体が参照により組み込まれる。本明細書に開示された材料、方法および実施例は、例示的なものに過ぎず、限定することを意図するものではない。
一態様では、本開示は、ネタルスジルまたはその薬学的に許容される塩と、約0.01%重量/体積〜約1.0%重量/体積の緩衝剤と、約0.01%重量/体積〜約10%重量/体積の等張化剤と、を含む眼科用組成物を提供する。
眼科用組成物は緩衝剤を含み得る。緩衝剤は、組成物のpHドリフトを最小限に抑え、組成物を安定化させるのを助けるのに役立ち得る。適切な緩衝剤としては、酢酸、クエン酸、炭酸、リン酸、ホウ酸、それらの薬学的に許容される塩、トロメタミン、およびそれらの組み合わせが挙げられるが、これらに限定されない。緩衝剤は、眼科用組成物中に、約0.01%重量/体積〜約1%重量/体積、または約0.1%w/v〜約0.9%w/v、または約0.3%w/v〜約0.8%w/v、または約0.4%w/v〜約0.6%w/vの量で存在し得る。適切には、緩衝剤は少なくとも0.01%w/v、少なくとも0.05%w/v、少なくとも0.1%w/v、少なくとも0.3%w/v、または少なくとも0.5%w/vで存在し得る。適切には、緩衝剤は、1.0%w/v以下、0.8%w/v以下、または0.6%w/v以下の量で存在し得る。実施形態では、緩衝剤は、眼科用組成物中に、約0.03%w/v、約0.04%w/v、約0.05%w/v、約0.06%w/v、または約0.07%w/vの量で存在し得る。緩衝剤は適切にはホウ酸であり得る。
組成物の等張性、または浸透圧は、本技術分野で既知の従来の材料を使用することによって、正常な涙液に対して低張性、等張性、または高張性に調整され得る。等張化剤は、典型的には非イオン性化合物である。等張化剤の例は、塩化ナトリウム、塩化カリウム、マンニトール、デキストロース、グリセリン、およびプロピレングリコールを含むが、これらに限定されない。適切には、等張化剤は、眼科用組成物中に、約0.01%重量/体積〜約10%重量/体積、または約1%w/v〜約10%w/v、または約2.5%w/v〜約7.5%w/v、または約4%w/v〜約6%w/vの量で存在し得る。適切には、等張化剤は、少なくとも0.01%w/v、少なくとも0.05%w/v、少なくとも1%w/v、少なくとも2.5%w/v、少なくとも4%w/v、または少なくとも5%w/vで存在し得る。適切には、等張化剤は、10%w/v以下、7.5%w/v以下、6%w/v以下、または5%w/v以下の量で存在し得る。実施形態では、等張化剤は、眼科用組成物中に、約4.5%w/v、約4.6%w/v、約4.7%w/v、約4.8%w/v、または約4.9%w/vの量で存在し得る。等張化剤は、適切にはマンニトールであり得る。
実施形態では、組成物はまた、組成物のpHを約3.5から約5.5の間に調整するのに十分な量のpH調整剤を含み得る。適切には、眼科用組成物は、約4.5〜約5.2または約4.5〜約5.1のpHを有し得る。いくつかの実施形態では、眼科用組成物は、約4.5、4.6、4.7、4.8、4.9、5.0、5.1、5.2のpH、またはこれらの値のうちの任意の2つによって境界付けられる範囲のpHを有する。適切なpH調整剤は、水酸化ナトリウムを含むが、これに限定されない。
本開示の眼科用製剤は、溶液、懸濁液、乳濁液、およびゲルを含む、局所眼科用送達に適した様々な剤形に製剤化され得る。組成物は好適には水性である。
本開示は、以下の非限定的な例によって説明される複数の態様を有する。様々な実施例において、以下の材料および特徴付ける技術が使用されている。
表1は、4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエート製剤の組成を示す。製剤N、O、およびPは、ラベル付けされた150ミリリットル(mL)のプラスチック貯蔵容器中に、ホウ酸、d−マンニトールを添加し、0.015%の塩化ベンザルコニウムを添加してまたは添加しないことにより調製した。次いで、その溶液に、5%塩化ベンザルコニウムストック溶液を含むまたは含まない、4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートジメシレートを加え、さらに10分間撹拌することにより溶解させた。次に100ミリリットル(mL)の精製水を加えて溶液をほぼ100%にし、pHを約5.0に調整した。十分な4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートジメシレート(CAS番号:#1422144−42−0)(0.0285%w/v)を加えて、4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエート遊離塩基(CAS番号:#1254032−66−0)をを0.02%w/vで存在させた。
表2は、4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートおよびラタノプロストの固定用量組み合わせの製剤を示す。製剤RおよびSは、ラベル付けされた150ミリリットル(mL)のプラスチック貯蔵容器中にホウ酸およびd−マンニトールを添加することによって調製された。次いで、その溶液に、4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートおよび塩化ベンザルコニウム/ラタノプロストストック溶液(100×)を加え、さらに10分間撹拌することにより溶解させた。次に100ミリリットル(mL)の精製水を加えて溶液をほぼ100%にし、pHを約5.0に調整した。十分な4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートジメシレート(CAS番号:#1422144−42−0)(0.0285%w/v)を加えて、4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエート遊離塩基(CAS番号:#1254032−66−0)を0.02%w/vで存在させた。
実施例1の方法に従って追加の製剤を調製し得る。表3は、防腐剤を含まない4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートおよびラタノプロストの固定用量組み合わせの製剤を示す。
表4は、そのジメシレート塩およびジHCl塩としての4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエート製剤の組成を示す。製剤N4およびO4は、ラベル付けされた150ミリリットル(mL)のプラスチック貯蔵容器中に、ホウ酸、d−マンニトールを添加し、0.015%の塩化ベンザルコニウムを添加してまたは添加しないことにより調製した。次いで、その溶液に、5%塩化ベンザルコニウムストック溶液を含むまたは含まない、4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートメシレート(CAS番号:#1422144−42−0)または4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートクロリド(CAS番号:#1253952−02−1)を加え、さらに10分間撹拌することにより溶解させた。次に100ミリリットル(mL)の精製水を加えて溶液をほぼ100%にし、pHを約5.0に調整した。
(付記1)
4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートまたはその薬学的に許容される塩と、約0.01%重量/体積〜約1.0%重量/体積の緩衝剤と、約0.01%重量/体積〜約10%重量/体積の等張化剤と、を含む、眼科用組成物。
pHは、約3.5〜約5.5である、付記1に記載の組成物。
pHは、約4.5〜約5.2である、付記1または2に記載の組成物。
防腐剤をさらに含む、付記1〜3のいずれか1つに記載の組成物。
前記防腐剤は、塩化ベンザルコニウムを含む、付記4に記載の組成物。
乳化剤をさらに含む、付記1〜5のいずれか1つに記載の組成物。
前記乳化剤は、ポリオキシル40ステアレート、ポリエトキシル化ひまし油、またはそれらの組み合わせを含む、付記6に記載の組成物。
前記等張化剤は、マンニトールを含む、付記1〜7のいずれか1つに記載の組成物。
前記緩衝剤は、ホウ酸またはその塩を含む、付記1〜8のいずれか1つに記載の組成物。
水をさらに含む、付記1〜9のいずれか1つに記載の組成物。
pH調整剤をさらに含む、付記1〜10のいずれか1つに記載の組成物。
4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートは、ジメシレート塩である、付記1〜11のいずれか1つに記載の組成物。
4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートまたはその薬学的に許容される塩は、(S)−4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートまたはその薬学的に許容される塩である、付記1〜12のいずれか1つに記載の組成物。
第2眼科用活性化合物をさらに含む、付記1〜13のいずれか1つに記載の組成物。
前記第2眼科用活性化合物は、プロスタグランジン類似体である、付記14に記載の組成物。
前記プロスタグランジン類似体は、ラタノプロストまたはトラボプロストである、付記15に記載の組成物。
約0.02%w/v〜約0.03%w/vの4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートまたはその薬学的に許容される塩を含む、付記1〜16のいずれか1つに記載の組成物。
約4.7%重量/体積のマンニトールを含む、付記1〜17のいずれか1つに記載の組成物。
約0.05%重量/体積のホウ酸を含む、付記1〜18のいずれか1つに記載の組成物。
約0.015%重量/体積の塩化ベンザルコニウムを含む、付記1〜19のいずれか1つに記載の組成物。
0.005%重量/体積のラタノプロストまたはトラボプロストをさらに含む、付記16に記載の組成物。
(S)−4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートまたはその薬学的に許容される塩と、ホウ酸と、マンニトールと、を含み、
約4.5〜約5.2のpHを有する、
眼科用組成物。
約0.02%〜約0.03%重量/体積の(S)−4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートまたはその薬学的に許容される塩と、約4.7%重量/体積のマンニトールと、約0.05%重量/体積のホウ酸と、約0.015%重量/体積の塩化ベンザルコニウムと、を含み、
約4.5〜約5.2のpHを有する、
眼科用組成物。
(S)−4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートまたはその薬学的に許容される塩と、ホウ酸と、マンニトールと、ラタノプロストと、を含む、眼科用組成物。
前記塩は、ジメシレート塩である、付記22〜24のいずれか1つに記載の組成物。
眼疾患を治療する方法であって、
該方法は、必要とする患者の眼に付記1〜24のいずれか1つに記載の組成物を局所投与することを含む、方法。
前記眼疾患は、緑内障である、付記26に記載の方法。
Claims (1)
- 4−(3−アミノ−1−(イソキノリン−6−イルアミノ)−1−オキソプロパン−2−イル)ベンジル2,4−ジメチルベンゾエートまたはその薬学的に許容される塩と、約0.01%重量/体積〜約1.0%重量/体積の緩衝剤と、約0.01%重量/体積〜約10%重量/体積の等張化剤と、を含む、眼科用組成物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662382237P | 2016-08-31 | 2016-08-31 | |
US62/382,237 | 2016-08-31 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019531599A Division JP6907319B2 (ja) | 2016-08-31 | 2017-08-30 | 眼科用組成物 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2020172524A true JP2020172524A (ja) | 2020-10-22 |
JP7083005B2 JP7083005B2 (ja) | 2022-06-09 |
Family
ID=59846699
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019531599A Active JP6907319B2 (ja) | 2016-08-31 | 2017-08-30 | 眼科用組成物 |
JP2020115537A Active JP7083005B2 (ja) | 2016-08-31 | 2020-07-03 | 眼科用組成物 |
JP2021108792A Active JP7192049B2 (ja) | 2016-08-31 | 2021-06-30 | 眼科用組成物 |
JP2022195347A Pending JP2023016959A (ja) | 2016-08-31 | 2022-12-07 | 眼科用組成物 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019531599A Active JP6907319B2 (ja) | 2016-08-31 | 2017-08-30 | 眼科用組成物 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021108792A Active JP7192049B2 (ja) | 2016-08-31 | 2021-06-30 | 眼科用組成物 |
JP2022195347A Pending JP2023016959A (ja) | 2016-08-31 | 2022-12-07 | 眼科用組成物 |
Country Status (10)
Country | Link |
---|---|
US (4) | US11389441B2 (ja) |
EP (1) | EP3506890A1 (ja) |
JP (4) | JP6907319B2 (ja) |
KR (2) | KR102568079B1 (ja) |
CN (1) | CN109640966A (ja) |
AU (3) | AU2017319520A1 (ja) |
BR (1) | BR112019003945A2 (ja) |
CA (1) | CA3035566A1 (ja) |
MX (2) | MX2019002396A (ja) |
WO (1) | WO2018045091A1 (ja) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8455513B2 (en) | 2007-01-10 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-aminoisoquinoline compounds |
US8450344B2 (en) | 2008-07-25 | 2013-05-28 | Aerie Pharmaceuticals, Inc. | Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds |
JP2012525386A (ja) | 2009-05-01 | 2012-10-22 | アエリエ・ファーマシューティカルズ・インコーポレーテッド | 疾患の治療のための二重機構阻害剤 |
PT3811943T (pt) | 2013-03-15 | 2023-03-15 | Aerie Pharmaceuticals Inc | Composto para uso no tratamento de distúrbios oculares |
KR102568079B1 (ko) | 2016-08-31 | 2023-08-17 | 에어리 파마슈티컬즈, 인코포레이티드 | 안과용 조성물 |
US10442770B2 (en) | 2017-02-02 | 2019-10-15 | Assia Chemical Industries Ltd. | Solid state forms of netarsudil mesylate |
MX2019011784A (es) | 2017-03-31 | 2019-11-18 | Aerie Pharmaceuticals Inc | Compuestos de aril ciclopropil-amino-isoquinolinil amida. |
AU2019337703B2 (en) | 2018-09-14 | 2023-02-02 | Aerie Pharmaceuticals, Inc. | Aryl cyclopropyl-amino-isoquinolinyl amide compounds |
CN110437043A (zh) * | 2019-08-24 | 2019-11-12 | 黄泳华 | 由白藜芦醇与前列腺素类似物剂构成的共晶及其在制备抗肿瘤药物中的用途 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002520368A (ja) * | 1998-07-14 | 2002-07-09 | アルコン ラボラトリーズ, インコーポレイテッド | プロスタグランジン製品 |
JP2013543862A (ja) * | 2010-11-08 | 2013-12-09 | ヒールオア・リミテッド | 眼科用緩衝組成物およびその使用方法 |
JP2016515520A (ja) * | 2013-03-15 | 2016-05-30 | アエリエ・ファーマシューティカルズ・インコーポレーテッド | 併用療法 |
JP2016130268A (ja) * | 2011-02-04 | 2016-07-21 | 興和株式会社 | 緑内障予防又は治療のための薬物療法 |
JP6141385B2 (ja) * | 2009-05-01 | 2017-06-07 | アエリエ・ファーマシューティカルズ・インコーポレーテッド | 疾患の治療のための二重機構阻害剤 |
Family Cites Families (152)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2623228C3 (de) | 1976-05-24 | 1981-09-10 | Ludwig Merckle Kg Chem. Pharm. Fabrik, 7902 Blaubeuren | N-Acyl-substituierte Benzamide, Verfahren zu ihrer Herstellung und Arzneimittel, enthaltend solche Benzamide |
JPS5587771A (en) | 1978-12-27 | 1980-07-02 | Teikoku Hormone Mfg Co Ltd | 1-phenylisoquinoline derivative |
US4456757A (en) | 1981-03-20 | 1984-06-26 | Asahi Kasei Kogyo Kabushiki Kaisha | Isoquinolinesulfonyl derivatives and process for the preparation thereof |
JPS5993054A (ja) | 1982-11-18 | 1984-05-29 | Asahi Chem Ind Co Ltd | イソキノリンスルホン酸アミド誘導体 |
DK8386A (da) | 1986-01-15 | 1987-07-09 | Tpo Pharmachim | Nye n-substituerede 1-benzyl-2-carbamoyltetrahydroisoquinoliner og fremgangsmaade til fremstilling af samme |
EP0266949B1 (en) | 1986-10-28 | 1990-11-28 | Smith Kline & French Laboratories Limited | Tetrahydroisoquinolin-2-yl derivatives of carboxylic acids as thromboxane a2 antagonists |
US4911928A (en) | 1987-03-13 | 1990-03-27 | Micro-Pak, Inc. | Paucilamellar lipid vesicles |
US5591887A (en) | 1987-04-30 | 1997-01-07 | R-Tech Ueno, Ltd. | Prostaglandins of the F series |
JPH01139528A (ja) | 1987-11-24 | 1989-06-01 | Showa Denko Kk | 抗潰瘍剤 |
ES2186670T3 (es) | 1988-09-06 | 2003-05-16 | Pharmacia Ab | Derivados de prostaglandina para el tratamiento del glaucoma o la hipertension ocular. |
EP0389995B1 (en) | 1989-03-28 | 1995-05-31 | Nisshin Flour Milling Co., Ltd. | Isoquinoline derivatives for the treatment of glaucoma or ocular hypertension |
KR920008026A (ko) | 1990-10-24 | 1992-05-27 | 오노 화아마슈티칼 캄파니 리미팃드 | 이소퀴놀리논 유도체 또는 이의 무독성 산부가염 또는 이의 수화물, 이의 제조방법 및 이를 포함하는 약제 조성물 |
EP0630373A1 (en) | 1992-03-12 | 1994-12-28 | Smithkline Beecham Plc | Indole derivatives as 5ht1c antagonists |
US5972991A (en) | 1992-09-21 | 1999-10-26 | Allergan | Cyclopentane heptan(ene) oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
DE4332168A1 (de) | 1993-02-22 | 1995-03-23 | Thomae Gmbh Dr K | Cyclische Derivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
US5510383A (en) | 1993-08-03 | 1996-04-23 | Alcon Laboratories, Inc. | Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension |
US6124344A (en) | 1993-12-28 | 2000-09-26 | Allergan Sales, Inc. | Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
US5462968A (en) | 1994-01-19 | 1995-10-31 | Allergan, Inc. | EP2 -receptor agonists as agents for lowering intraocular pressure |
US5698733A (en) | 1994-09-30 | 1997-12-16 | Alcon Laboratories, Inc. | Use of 9-deoxy prostaglandin derivatives to treat glaucoma |
AU7672096A (en) | 1995-06-07 | 1998-06-03 | Alcon Laboratories, Inc. | Conformationally rigid aryl- or heteroaryl prostaglandins for use in glaucoma therapy |
US5814660A (en) | 1995-12-22 | 1998-09-29 | Alcon Laboratories, Inc. | 9-oxa prostaglandin analogs as ocular hypotensives |
ES2225897T3 (es) | 1995-12-22 | 2005-03-16 | Alcon Laboratories, Inc. | Analogos de tetrahidrofurano sustituido de prostaglandinas como hipotensores oculares. |
US5866602A (en) | 1995-12-22 | 1999-02-02 | Alcon Laboratories, Inc. | Keto-substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives |
US6586425B2 (en) | 1996-02-21 | 2003-07-01 | Wisconsin Alumni Research Foundation | Cytoskeletal active agents for glaucoma therapy |
US5798380A (en) | 1996-02-21 | 1998-08-25 | Wisconsin Alumni Research Foundation | Cytoskeletal active agents for glaucoma therapy |
DE69714274T3 (de) | 1996-09-17 | 2006-06-01 | Asahi Glass Co., Ltd. | Fluorierte prostaglandinderivate und medikamente |
WO1998020880A2 (en) | 1996-11-12 | 1998-05-22 | Alcon Laboratories, Inc. | 11-halo prostaglandins for the treatment of glaucoma or ocular hypertension |
WO1998020881A1 (en) | 1996-11-12 | 1998-05-22 | Alcon Laboratories, Inc | 15-ketal prostaglandins for the treatment of glaucoma or ocular hypertension |
EP0944593A2 (en) | 1996-11-12 | 1999-09-29 | Alcon Laboratories, Inc. | $i(CIS)-$g(D)?4 ANALOGS OF PROSTAGLANDINS AS OCULAR HYPOTENSIVES |
AU5355498A (en) | 1996-11-12 | 1998-06-03 | Alcon Laboratories, Inc. | 15-fluoro prostaglandins as ocular hypotensives |
CA2276666A1 (en) | 1997-03-07 | 1998-09-11 | Alcon Laboratories, Inc. | 13-thia prostaglandins for use in glaucoma therapy |
WO1998050024A1 (en) | 1997-05-09 | 1998-11-12 | The Mount Sinai School Of Medicine Of The City University Of New York | 8-iso-prostaglandins for glaucoma therapy |
US5891646A (en) | 1997-06-05 | 1999-04-06 | Duke University | Methods of assaying receptor activity and constructs useful in such methods |
SE9702706D0 (sv) | 1997-07-11 | 1997-07-11 | Pharmacia & Upjohn Ab | Prostaglandin derivatives devoid of side-effects for the treatment of glaucoma |
DE69809268T2 (de) | 1997-09-09 | 2003-08-28 | Procter & Gamble | Aromatische c16-c20-substituierte tetrahydro-prostaglandine und ihre verwendung als prostaglandin f agonisten |
SK3362000A3 (en) | 1997-09-09 | 2000-10-09 | Procter & Gamble | A compound analogous to prostaglandin f and use thereof |
ES2223141T3 (es) | 1997-09-09 | 2005-02-16 | Duke University | Prostaglandinas aromaticas tetrahidro sustituidas por c16?-c20? utilizadas como agonistas fp. |
US5877211A (en) | 1997-11-21 | 1999-03-02 | Allergan | EP2 receptor agonists as neuroprotective agents for the eye |
AU1709699A (en) | 1997-12-22 | 1999-07-12 | Alcon Laboratories, Inc. | 13-oxa prostaglandins for the treatment of glaucoma and ocular hypertension |
TWI249520B (en) | 1998-07-15 | 2006-02-21 | Ono Pharmaceutical Co | 5-Thia-omega-substituted phenyl prostaglandin E derivatives, method for producing the same and medicines containing the same as the active ingredient |
US6720175B1 (en) | 1998-08-18 | 2004-04-13 | The Johns Hopkins University School Of Medicine | Nucleic acid molecule encoding homer 1B protein |
US20020065296A1 (en) | 1999-01-13 | 2002-05-30 | Bayer Corporation | Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors |
CA2374793A1 (en) | 1999-05-24 | 2000-11-30 | Penglie Zhang | Inhibitors of factor xa |
EP1192135A2 (en) | 1999-06-14 | 2002-04-03 | Eli Lilly And Company | Serine protease inhibitors |
AU780790B2 (en) | 1999-11-26 | 2005-04-14 | Shionogi & Co., Ltd. | NPY Y5 antagonists |
CN1217936C (zh) | 1999-12-28 | 2005-09-07 | 卫材株式会社 | 含有磺酰胺的杂环化合物 |
YU54202A (sh) | 2000-01-18 | 2006-01-16 | Agouron Pharmaceuticals Inc. | Jedinjenja indazola, farmaceutske smeše i postupci za stimulisanje i inhibiranje ćelijske proliferacije |
HN2001000008A (es) | 2000-01-21 | 2003-12-11 | Inc Agouron Pharmaceuticals | Compuesto de amida y composiciones farmaceuticas para inhibir proteinquinasas, y su modo de empleo |
AU781506B2 (en) | 2000-02-03 | 2005-05-26 | Eisai R&D Management Co., Ltd. | Integrin expression inhibitors |
US6410566B1 (en) | 2000-05-16 | 2002-06-25 | Teijin Limited | Cyclic amine derivatives and their use as drugs |
US6908741B1 (en) | 2000-05-30 | 2005-06-21 | Transtech Pharma, Inc. | Methods to identify compounds that modulate RAGE |
US6855690B2 (en) | 2000-06-01 | 2005-02-15 | Children's Medical Center Corporation | Methods and compositions for treating ocular disorders |
US6323228B1 (en) | 2000-09-15 | 2001-11-27 | Abbott Laboratories | 3-substituted indole angiogenesis inhibitors |
JP4080868B2 (ja) | 2000-10-17 | 2008-04-23 | アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ | 医薬として活性なスルファニリド誘導体 |
US7163800B2 (en) | 2000-11-03 | 2007-01-16 | Molecular Devices Corporation | Methods of screening compositions for G protein-coupled receptor desensitization inhibitory activity |
WO2002069965A1 (en) | 2001-03-05 | 2002-09-12 | Transtech Pharma, Inc. | Benzimidazole derivatives as therapeutic agents |
DE60218445T2 (de) | 2001-04-20 | 2007-11-29 | Bayer Pharmaceuticals Corp., West Haven | Inhibierung der raf-kinase durch chinolin-, isochinolin- oder pyridin-harnstoffe |
US6956035B2 (en) | 2001-08-31 | 2005-10-18 | Inotek Pharmaceuticals Corporation | Isoquinoline derivatives and methods of use thereof |
ES2305435T3 (es) | 2002-01-10 | 2008-11-01 | Bayer Healthcare Ag | Inhibidores de la rho-quinasa. |
TW200306819A (en) | 2002-01-25 | 2003-12-01 | Vertex Pharma | Indazole compounds useful as protein kinase inhibitors |
DE60325025D1 (de) | 2002-02-15 | 2009-01-15 | Glaxo Group Ltd | Modulatoren des vanilloidrezeptors |
US20040180889A1 (en) | 2002-03-01 | 2004-09-16 | Pintex Pharmaceuticals, Inc. | Pin1-modulating compounds and methods of use thereof |
CN100525763C (zh) | 2002-03-05 | 2009-08-12 | 特兰斯泰克制药公司 | 抑制配体与高级糖化终产物受体相互作用的单和双环吡咯衍生物 |
GB0206876D0 (en) | 2002-03-22 | 2002-05-01 | Merck Sharp & Dohme | Therapeutic agents |
US7645878B2 (en) | 2002-03-22 | 2010-01-12 | Bayer Healthcare Llc | Process for preparing quinazoline Rho-kinase inhibitors and intermediates thereof |
JP2005525814A (ja) | 2002-05-13 | 2005-09-02 | ノラック バイオサイエンシズ インコーポレイテッド | 構成的に転位する細胞系 |
ES2382733T3 (es) | 2002-08-29 | 2012-06-13 | Santen Pharmaceutical Co., Ltd. | Remedio para el glaucoma que comprende un inhibidor de la Rho quinasa y prostaglandinas |
WO2004022753A1 (ja) | 2002-08-30 | 2004-03-18 | Anges Mg, Inc. | アクチン関連新規細胞骨格タンパク質lacs |
CA2502583A1 (en) | 2002-09-12 | 2004-03-25 | Kirin Beer Kabushiki Kaisha | Isoquinoline derivatives having kinase inhibitory activity and medicament containing the same |
US7495016B2 (en) | 2002-10-21 | 2009-02-24 | Irm Llc | Pyrrolidones with anti-HIV activity |
US7557129B2 (en) | 2003-02-28 | 2009-07-07 | Bayer Healthcare Llc | Cyanopyridine derivatives useful in the treatment of cancer and other disorders |
PL1632477T3 (pl) | 2003-06-12 | 2017-07-31 | Astellas Pharma Inc. | Pochodna benzamidu lub jej sól |
CA2536954C (en) | 2003-08-29 | 2012-11-27 | Exelixis, Inc. | C-kit modulators and methods of use |
US20070123561A1 (en) | 2003-10-06 | 2007-05-31 | Dennis Lee | Preparation of 1,7-disubstituted azabensimidazoles as kinase inhibitors |
JP2007008816A (ja) | 2003-10-15 | 2007-01-18 | Ube Ind Ltd | 新規イソキノリン誘導体 |
DE10348023A1 (de) | 2003-10-15 | 2005-05-19 | Imtm Gmbh | Neue Alanyl-Aminopeptidasen-Inhibitoren zur funktionellen Beeinflussung unterschiedlicher Zellen und zur Behandlung immunologischer, entzündlicher, neuronaler und anderer Erkrankungen |
JP4110324B2 (ja) | 2003-10-15 | 2008-07-02 | 宇部興産株式会社 | 新規インダゾール誘導体 |
SE0400284D0 (sv) | 2004-02-10 | 2004-02-10 | Astrazeneca Ab | Novel compounds |
JP2005227441A (ja) | 2004-02-12 | 2005-08-25 | Konica Minolta Medical & Graphic Inc | 光熱写真画像形成材料 |
JP4857128B2 (ja) | 2004-02-20 | 2012-01-18 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | 新規な化合物 |
US20080096238A1 (en) | 2004-03-30 | 2008-04-24 | Alcon, Inc. | High throughput assay for human rho kinase activity with enhanced signal-to-noise ratio |
DE102004017438A1 (de) | 2004-04-08 | 2005-11-03 | Bayer Healthcare Ag | Hetaryloxy-substituierte Phenylaminopyrimidine |
US7453002B2 (en) | 2004-06-15 | 2008-11-18 | Bristol-Myers Squibb Company | Five-membered heterocycles useful as serine protease inhibitors |
JP2008503492A (ja) | 2004-06-17 | 2008-02-07 | スミスクライン・ビーチャム・コーポレイション | Rho−キナーゼの新規阻害剤 |
DK1607840T3 (da) | 2004-06-18 | 2015-02-16 | Tobii Technology Ab | Øjenstyring af et computerapparat |
ES2341351T3 (es) | 2004-08-26 | 2010-06-18 | Pfizer, Inc. | Compuestos de aminoheteroarilo enantiomericamente puros como inhibidores de proteina cinasas. |
EP1810965A4 (en) | 2004-10-13 | 2009-10-28 | Eisai R&D Man Co Ltd | HYDRAZIDE DERIVATIVES |
UY29198A1 (es) | 2004-11-09 | 2006-05-31 | Cancer Rec Tech Ltd | Derivados sustituidos de quinazolinona y derivados sustituidos de quinazolina-2, 4-diona, composiciones conteniéndolos, procedimientos de preparación y aplicaciones |
GB0425026D0 (en) | 2004-11-12 | 2004-12-15 | Biofocus Discovery Ltd | Compounds which bind to the active site of protein kinase enzymes |
CA2589271A1 (en) | 2004-12-07 | 2006-06-15 | Locus Pharmaceuticals, Inc. | Urea inhibitors of map kinases |
WO2007060028A1 (en) | 2004-12-31 | 2007-05-31 | Gpc Biotech Ag | Napthyridine compounds as rock inhibitors |
EP1856053A1 (en) | 2005-01-14 | 2007-11-21 | Millennium Pharmaceuticals, Inc. | Cinnamide and hydrocinnamide derivatives with raf-kinase inhibitory activity |
RU2371433C2 (ru) | 2005-01-28 | 2009-10-27 | Айрм Ллк | Фенилзамещенные пирролидоны |
EP1851197A2 (en) | 2005-02-09 | 2007-11-07 | Microbia, Inc. | Phenylazetidinone derivatives |
WO2006127203A2 (en) | 2005-05-25 | 2006-11-30 | Wyeth | Methods of synthesizing 6-alkylaminoquinoline derivatives |
ES2580108T3 (es) | 2005-07-11 | 2016-08-19 | Aerie Pharmaceuticals, Inc | Compuestos de isoquinolina |
WO2007008942A2 (en) | 2005-07-11 | 2007-01-18 | Aerie Pharmaceuticals, Inc. | Phenylamino-acetic acid [1-(pyridin-4-yl)-methylidene]-hydrazide derivatives and related compounds as modulators of g protein-coupled receptor kinases for the treatment of eye diseases |
EP1951253A2 (en) | 2005-10-26 | 2008-08-06 | Cotherix, Inc. | Fasudil in combination therapies for the treatment of pulmonary arterial hypertension |
TW200738682A (en) | 2005-12-08 | 2007-10-16 | Organon Nv | Isoquinoline derivatives |
EP1962853A1 (en) | 2005-12-22 | 2008-09-03 | Alcon Research, Ltd. | (indazol-5-yl)-pyrazines and (1,3-dihydro-indol-2-one)- pyrazines for treating rho kinase-mediated diseases and conditions |
AR057252A1 (es) | 2005-12-27 | 2007-11-21 | Alcon Mfg Ltd | Inhibicion de rho quinasa mediada por arni para el tratamiento de trastornos oculares |
US8129411B2 (en) | 2005-12-30 | 2012-03-06 | Novartis Ag | Organic compounds |
CA2636701C (en) | 2006-01-27 | 2014-08-05 | Shanghai Hengrui Pharmaceutical Co. Ltd. | Pyrrolo [3,2-c] pyridine-4-one 2-indolinone protein kinase inhibitors |
JP5476559B2 (ja) | 2006-02-10 | 2014-04-23 | 国立大学法人九州大学 | リン酸化酵素の新規基質ポリペプチド |
WO2007101204A1 (en) | 2006-02-27 | 2007-09-07 | Alcon Research, Ltd. | Method of treating glaucoma |
JP2009528365A (ja) | 2006-02-28 | 2009-08-06 | アムゲン インコーポレイティッド | ホスホジエステラーゼ10阻害剤としてのシンノリン及びキナゾリン誘導体 |
JP2007246466A (ja) | 2006-03-17 | 2007-09-27 | Osaka Univ | 中枢神経損傷に対する嗅粘膜移植にRhoキナーゼ阻害剤を用いた神経機能再建法 |
TW200815398A (en) | 2006-06-08 | 2008-04-01 | Ube Industries | A novel indazole derivative having spirocyclic structure in the side chain |
CA2658764A1 (en) | 2006-07-20 | 2008-01-24 | Mehmet Kahraman | Benzothiophene inhibitors of rho kinase |
WO2008036459A2 (en) | 2006-07-20 | 2008-03-27 | Borchardt Allen J | Inhibitors of rho kinase |
US20090247552A1 (en) | 2006-07-31 | 2009-10-01 | Shirou Sawa | Aqueous liquid preparation containing amide compound |
WO2008036540A2 (en) | 2006-09-20 | 2008-03-27 | Boehringer Ingelheim International Gmbh | Rho kinase inhibitors |
US20110039893A1 (en) | 2006-10-11 | 2011-02-17 | Takeda Pharmaceutical Company Limited | Gsk-3beta inhibitor |
US8949825B1 (en) | 2006-10-17 | 2015-02-03 | Manageiq, Inc. | Enforcement of compliance policies in managed virtual systems |
WO2008049000A2 (en) | 2006-10-18 | 2008-04-24 | United Therapeutics Corporation | Combination therapy for pulmonary arterial hypertension |
WO2008049919A2 (en) | 2006-10-26 | 2008-05-02 | Devgen N.V. | Rho kinase inhibitors |
US8071779B2 (en) | 2006-12-18 | 2011-12-06 | Inspire Pharmaceuticals, Inc. | Cytoskeletal active rho kinase inhibitor compounds, composition and use |
WO2008079945A2 (en) | 2006-12-20 | 2008-07-03 | University Of South Florida | Rock inhibitors and uses thereof |
AR064420A1 (es) | 2006-12-21 | 2009-04-01 | Alcon Mfg Ltd | Composiciones farmaceuticas oftalmicas que comprenden una cantidad efectiva de analogos de 6-aminoimidazo[1,2b]piridazinas, utiles para el tratamiento del glaucoma y/o controlar la presion intraocular normal o elevada(iop). |
CN101611012B (zh) | 2006-12-27 | 2012-11-14 | 塞诺菲-安万特股份有限公司 | 环烷基胺取代的异喹啉衍生物 |
CA2673916C (en) | 2006-12-27 | 2015-02-17 | Sanofi-Aventis | Substituted isoquinolone and isoquinolinone derivatives as inhibitors of rho-kinase |
EP2125744B1 (en) | 2006-12-27 | 2011-04-13 | Sanofi-Aventis | Cycloalkylamine substituted isoquinolone and isoquinolinone derivatives |
BRPI0720859A2 (pt) | 2006-12-27 | 2014-03-25 | Sanofi Aventis | Derivados de isoquinolina e isoquinolinona substituídos com cicloalquilamina |
MX2009005862A (es) | 2006-12-27 | 2009-06-17 | Sanofi Aventis | Nuevos derivados de isoquinolina e isoquinolinona sustituidos. |
CN101573353B (zh) | 2006-12-27 | 2014-08-06 | 塞诺菲-安万特股份有限公司 | 取代的异喹啉和异喹啉酮衍生物 |
NZ577980A (en) | 2006-12-27 | 2012-01-12 | Sanofi Aventis | Cycloalkylamine substituted isoquinolone derivatives |
US8455513B2 (en) | 2007-01-10 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-aminoisoquinoline compounds |
US8415372B2 (en) | 2007-02-27 | 2013-04-09 | Asahi Kasei Pharma Corporation | Sulfonamide compound |
EP2136634A4 (en) | 2007-04-10 | 2011-07-06 | Boehringer Ingelheim Int | MIMETIC GLUCOCORTICOID SUBSTANCES, PREPARATION METHODS THEREOF, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF |
CN101801955B (zh) | 2007-07-05 | 2013-05-08 | 阵列生物制药公司 | 作为akt蛋白激酶抑制剂的嘧啶基环戊烷 |
CA2705562C (en) | 2007-11-16 | 2016-05-17 | Vertex Pharmaceuticals Incorporated | Isoquinoline modulators of atp-binding cassette transporters |
US8455514B2 (en) | 2008-01-17 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-and 7-amino isoquinoline compounds and methods for making and using the same |
US8450344B2 (en) | 2008-07-25 | 2013-05-28 | Aerie Pharmaceuticals, Inc. | Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds |
LT2318006T (lt) | 2008-08-15 | 2017-01-10 | Nivalis Therapeutics, Inc. | Nauji s-nitrozoglutationo reduktazės pirolo inhibitoriai, kaip terapiniai agentai |
WO2010146881A1 (ja) | 2009-06-19 | 2010-12-23 | 株式会社デ・ウエスタン・セラピテクス研究所 | 置換されたイソキノリン誘導体 |
WO2011085351A2 (en) | 2010-01-11 | 2011-07-14 | The Johns Hopkins University | Method of treating kcnq related disorders |
FR2961694B1 (fr) | 2010-06-29 | 2013-01-25 | Thea Lab | Systeme de delivrance polymerique d'une solution non visqueuse a base de prostaglandine sans conservateur |
US20130296363A1 (en) | 2010-09-01 | 2013-11-07 | Ambit Biosciences Corporation | Quinoline and isoquinoline derivatives for use as jak modulators |
JP2013035802A (ja) | 2011-08-10 | 2013-02-21 | D Western Therapeutics Institute Inc | 緑内障又は高眼圧症の予防又は治療剤 |
EP2671883A1 (en) | 2012-06-05 | 2013-12-11 | Bioprojet | New 6,11-dihydro-5H-benzo[d]imidazo[1,2-a]azepines derivatives as histamine H4 receptor ligands |
JP2014019650A (ja) | 2012-07-13 | 2014-02-03 | Santen Pharmaceut Co Ltd | スルホンアミド化合物とタフルプロストの組み合わせ |
AU2013299330B2 (en) | 2012-08-01 | 2018-01-25 | Merck Sharp & Dohme Llc | Alpha7 nicotinic acetylcholine receptor modulators and uses thereof-i |
JP6325449B2 (ja) | 2012-10-12 | 2018-05-16 | 武田薬品工業株式会社 | シクロプロパンアミン化合物およびその用途 |
CA2950238A1 (en) | 2014-07-17 | 2016-01-21 | Merck Patent Gmbh | Novel naphthyridines and isoquinolines and their use as cdk8/19 inhibitors |
WO2016123627A1 (en) | 2015-01-30 | 2016-08-04 | Vanderbilt University | Isoquiniline and napthalene-substituted compounds as mglur4 allosteric potentiators, compounds, and methods of treating neurological dysfunction |
US9770466B2 (en) | 2015-07-02 | 2017-09-26 | Veloce Biopharma, Llc | Ophthalmic composition and methods of use |
US9643927B1 (en) | 2015-11-17 | 2017-05-09 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
EP3500251A4 (en) | 2016-08-19 | 2020-04-08 | Aerie Pharmaceuticals, Inc. | BETA AMINO ISOCHINOLINYL AMIDE COMPOUNDS |
KR102568079B1 (ko) | 2016-08-31 | 2023-08-17 | 에어리 파마슈티컬즈, 인코포레이티드 | 안과용 조성물 |
MX2019011784A (es) | 2017-03-31 | 2019-11-18 | Aerie Pharmaceuticals Inc | Compuestos de aril ciclopropil-amino-isoquinolinil amida. |
EP3773580A4 (en) | 2018-03-30 | 2022-02-23 | Aerie Pharmaceuticals, Inc. | MONO-(ACID) SALTS OF 6-AMINOISOQUINOLINES AND THEIR USES |
AU2019337703B2 (en) | 2018-09-14 | 2023-02-02 | Aerie Pharmaceuticals, Inc. | Aryl cyclopropyl-amino-isoquinolinyl amide compounds |
-
2017
- 2017-08-30 KR KR1020207018902A patent/KR102568079B1/ko active IP Right Grant
- 2017-08-30 CN CN201780052915.9A patent/CN109640966A/zh active Pending
- 2017-08-30 MX MX2019002396A patent/MX2019002396A/es unknown
- 2017-08-30 WO PCT/US2017/049473 patent/WO2018045091A1/en unknown
- 2017-08-30 BR BR112019003945-7A patent/BR112019003945A2/pt active Search and Examination
- 2017-08-30 US US15/691,607 patent/US11389441B2/en active Active
- 2017-08-30 CA CA3035566A patent/CA3035566A1/en active Pending
- 2017-08-30 KR KR1020197008843A patent/KR102568082B1/ko active IP Right Grant
- 2017-08-30 EP EP17765001.7A patent/EP3506890A1/en active Pending
- 2017-08-30 JP JP2019531599A patent/JP6907319B2/ja active Active
- 2017-08-30 AU AU2017319520A patent/AU2017319520A1/en not_active Abandoned
-
2019
- 2019-02-27 MX MX2022011896A patent/MX2022011896A/es unknown
-
2020
- 2020-07-03 JP JP2020115537A patent/JP7083005B2/ja active Active
- 2020-08-20 AU AU2020220146A patent/AU2020220146B2/en active Active
-
2021
- 2021-06-30 JP JP2021108792A patent/JP7192049B2/ja active Active
-
2022
- 2022-06-15 US US17/841,433 patent/US20220304995A1/en active Pending
- 2022-07-06 US US17/858,889 patent/US11590123B2/en active Active
- 2022-08-24 US US17/894,809 patent/US11707460B2/en active Active
- 2022-11-17 AU AU2022271435A patent/AU2022271435A1/en active Pending
- 2022-12-07 JP JP2022195347A patent/JP2023016959A/ja active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002520368A (ja) * | 1998-07-14 | 2002-07-09 | アルコン ラボラトリーズ, インコーポレイテッド | プロスタグランジン製品 |
JP6141385B2 (ja) * | 2009-05-01 | 2017-06-07 | アエリエ・ファーマシューティカルズ・インコーポレーテッド | 疾患の治療のための二重機構阻害剤 |
JP2013543862A (ja) * | 2010-11-08 | 2013-12-09 | ヒールオア・リミテッド | 眼科用緩衝組成物およびその使用方法 |
JP2016130268A (ja) * | 2011-02-04 | 2016-07-21 | 興和株式会社 | 緑内障予防又は治療のための薬物療法 |
JP2016515520A (ja) * | 2013-03-15 | 2016-05-30 | アエリエ・ファーマシューティカルズ・インコーポレーテッド | 併用療法 |
Also Published As
Publication number | Publication date |
---|---|
MX2022011896A (es) | 2022-10-18 |
US11590123B2 (en) | 2023-02-28 |
JP2023016959A (ja) | 2023-02-02 |
CA3035566A1 (en) | 2018-03-08 |
US20180055833A1 (en) | 2018-03-01 |
JP7083005B2 (ja) | 2022-06-09 |
KR20190052014A (ko) | 2019-05-15 |
BR112019003945A2 (pt) | 2019-05-21 |
JP7192049B2 (ja) | 2022-12-19 |
WO2018045091A1 (en) | 2018-03-08 |
JP2019526629A (ja) | 2019-09-19 |
JP2021165285A (ja) | 2021-10-14 |
US11389441B2 (en) | 2022-07-19 |
US20220409607A1 (en) | 2022-12-29 |
AU2020220146A1 (en) | 2020-09-10 |
US11707460B2 (en) | 2023-07-25 |
AU2022271435A1 (en) | 2022-12-22 |
CN109640966A (zh) | 2019-04-16 |
JP6907319B2 (ja) | 2021-07-21 |
KR102568082B1 (ko) | 2023-08-17 |
AU2020220146B2 (en) | 2022-08-18 |
AU2017319520A1 (en) | 2019-03-07 |
US20220304995A1 (en) | 2022-09-29 |
EP3506890A1 (en) | 2019-07-10 |
US20220331308A1 (en) | 2022-10-20 |
MX2019002396A (es) | 2019-07-08 |
KR20200084061A (ko) | 2020-07-09 |
KR102568079B1 (ko) | 2023-08-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7083005B2 (ja) | 眼科用組成物 | |
JP2016515520A (ja) | 併用療法 | |
CA2841969A1 (en) | Fixed dose combination of bimatoprost and brimonidine | |
CN106455567A (zh) | 用于治疗青光眼的组合物和方法 | |
US11241426B2 (en) | Aqueous composition for ophthalmic or nasal administration | |
JP2020172486A (ja) | エピナスチン又はその塩を含有する水性医薬組成物 | |
JP7016880B2 (ja) | チオトロピウムを有効成分として含有する近視予防、近視治療および/または近視進行抑制剤 | |
JP7118579B1 (ja) | エピナスチン又はその塩を含有する水性組成物 | |
US11214569B2 (en) | Prodrugs of quinuclidine ring-containing muscarinic agonists and compositions and methods thereof | |
JP6963651B2 (ja) | エピナスチン又はその塩を含有する水性組成物 | |
US20210353584A1 (en) | Low-Dose Carbachol Compositions And Methods For Treatment Of Night Vision Disturbance |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20200828 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200914 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210928 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20211220 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20220510 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20220530 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7083005 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |