NZ721530B2 - Pyridylaminoacetic acid compound and polyoxyethylene castor oil-containing pharmaceutical composition - Google Patents
Pyridylaminoacetic acid compound and polyoxyethylene castor oil-containing pharmaceutical composition Download PDFInfo
- Publication number
- NZ721530B2 NZ721530B2 NZ721530A NZ72153015A NZ721530B2 NZ 721530 B2 NZ721530 B2 NZ 721530B2 NZ 721530 A NZ721530 A NZ 721530A NZ 72153015 A NZ72153015 A NZ 72153015A NZ 721530 B2 NZ721530 B2 NZ 721530B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- castor oil
- salt
- pharmaceutical composition
- polyoxyethylene castor
- aminomethyl
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 92
- -1 polyoxyethylene Polymers 0.000 title claims abstract description 81
- 239000004359 castor oil Substances 0.000 title claims abstract description 71
- 235000019438 castor oil Nutrition 0.000 title claims abstract description 70
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 title claims abstract description 70
- 229920003171 Poly (ethylene oxide) Polymers 0.000 title claims abstract description 58
- 239000002253 acid Substances 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 title abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 73
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 claims abstract description 16
- 229920002675 Polyoxyl Polymers 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 8
- 229920002696 Polyoxyl 40 castor oil Polymers 0.000 claims abstract description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 27
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 19
- 208000010412 Glaucoma Diseases 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- DODIDGRMHIBLHR-UHFFFAOYSA-N CC(C)OC(CNC1=NC(C(CC(C=C2)=CC=C2C2=NNC=C2)NS(C2=NC=CC=C2)(=O)=O)=CC=C1)=O Chemical compound CC(C)OC(CNC1=NC(C(CC(C=C2)=CC=C2C2=NNC=C2)NS(C2=NC=CC=C2)(=O)=O)=CC=C1)=O DODIDGRMHIBLHR-UHFFFAOYSA-N 0.000 claims description 14
- PCOWPAQKBXDXTC-UHFFFAOYSA-N O=S(C1=NC=CC=C1)(NC(CC(C=C1)=CC=C1C1=NNC=C1)C1=CC=CC=N1)=O Chemical compound O=S(C1=NC=CC=C1)(NC(CC(C=C1)=CC=C1C1=NNC=C1)C1=CC=CC=N1)=O PCOWPAQKBXDXTC-UHFFFAOYSA-N 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000004327 boric acid Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 8
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 7
- 229960001484 edetic acid Drugs 0.000 claims description 7
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 7
- 235000010199 sorbic acid Nutrition 0.000 claims description 7
- 239000004334 sorbic acid Substances 0.000 claims description 7
- 229940075582 sorbic acid Drugs 0.000 claims description 7
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 6
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 6
- 206010030043 Ocular hypertension Diseases 0.000 claims description 4
- 239000004698 Polyethylene Substances 0.000 claims description 4
- 229920000573 polyethylene Polymers 0.000 claims description 4
- 230000000087 stabilizing effect Effects 0.000 claims description 4
- 230000004410 intraocular pressure Effects 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- LSIXBBPOJBJQHN-UHFFFAOYSA-N 2,3-Dimethylbicyclo[2.2.1]hept-2-ene Chemical compound C1CC2C(C)=C(C)C1C2 LSIXBBPOJBJQHN-UHFFFAOYSA-N 0.000 claims 1
- PYJOGYOQBLYWHI-UHFFFAOYSA-N CC(C)C1=NC(C(CC(C=C2)=CC=C2C2=NNC=C2)NS(C2=NC=CC=C2)(=O)=O)=CC=C1 Chemical compound CC(C)C1=NC(C(CC(C=C2)=CC=C2C2=NNC=C2)NS(C2=NC=CC=C2)(=O)=O)=CC=C1 PYJOGYOQBLYWHI-UHFFFAOYSA-N 0.000 claims 1
- YEKDRHKEVBLHOE-UHFFFAOYSA-N CC(C)C1=NC(C(CC(C=C2)=CC=C2N2N=CC=C2)NS(C2=NC=CC=C2)(=O)=O)=CC=C1 Chemical compound CC(C)C1=NC(C(CC(C=C2)=CC=C2N2N=CC=C2)NS(C2=NC=CC=C2)(=O)=O)=CC=C1 YEKDRHKEVBLHOE-UHFFFAOYSA-N 0.000 claims 1
- 235000004443 Ricinus communis Nutrition 0.000 claims 1
- 239000003921 oil Substances 0.000 claims 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-N sorbic acid group Chemical group C(\C=C\C=C\C)(=O)O WSWCOQWTEOXDQX-MQQKCMAXSA-N 0.000 claims 1
- OAIAIDCOPBGOFO-UHFFFAOYSA-N 2-[[6-[2-(4-pyrazol-1-ylphenyl)-1-(pyridin-3-ylsulfonylamino)ethyl]pyridin-2-yl]amino]propan-2-yl acetate Chemical compound CC(=O)OC(C)(C)NC1=CC=CC(C(CC=2C=CC(=CC=2)N2N=CC=C2)NS(=O)(=O)C=2C=NC=CC=2)=N1 OAIAIDCOPBGOFO-UHFFFAOYSA-N 0.000 abstract 2
- 239000000203 mixture Substances 0.000 description 27
- 238000009472 formulation Methods 0.000 description 19
- 239000000654 additive Substances 0.000 description 10
- 239000012929 tonicity agent Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 8
- 229940011051 isopropyl acetate Drugs 0.000 description 8
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 8
- 239000000825 pharmaceutical preparation Substances 0.000 description 8
- 229940127557 pharmaceutical product Drugs 0.000 description 8
- 239000000872 buffer Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
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- 230000003078 antioxidant effect Effects 0.000 description 6
- 235000006708 antioxidants Nutrition 0.000 description 6
- 239000003889 eye drop Substances 0.000 description 6
- 229920006158 high molecular weight polymer Polymers 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- 230000002335 preservative effect Effects 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 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 5
- 239000008213 purified water Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 4
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 235000019799 monosodium phosphate Nutrition 0.000 description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 3
- 239000001509 sodium citrate Substances 0.000 description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 201000002862 Angle-Closure Glaucoma Diseases 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
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
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- 230000000052 comparative effect Effects 0.000 description 2
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- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
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- 238000006116 polymerization reaction Methods 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
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- 235000017281 sodium acetate Nutrition 0.000 description 2
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- 229940127230 sympathomimetic drug Drugs 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
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- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
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- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
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- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
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- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 1
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- OCUJLLGVOUDECM-UHFFFAOYSA-N dipivefrin Chemical compound CNCC(O)C1=CC=C(OC(=O)C(C)(C)C)C(OC(=O)C(C)(C)C)=C1 OCUJLLGVOUDECM-UHFFFAOYSA-N 0.000 description 1
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- 239000002526 disodium citrate Substances 0.000 description 1
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- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 1
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- IAVUPMFITXYVAF-XPUUQOCRSA-N dorzolamide Chemical compound CCN[C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-XPUUQOCRSA-N 0.000 description 1
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- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
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- 230000003211 malignant effect Effects 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
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- 230000010534 mechanism of action Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 201000003142 neovascular glaucoma Diseases 0.000 description 1
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- 150000002823 nitrates Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- AVTYONGGKAJVTE-OLXYHTOASA-L potassium L-tartrate Chemical compound [K+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O AVTYONGGKAJVTE-OLXYHTOASA-L 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 229940111695 potassium tartrate Drugs 0.000 description 1
- 208000036460 primary closed-angle glaucoma Diseases 0.000 description 1
- 201000006366 primary open angle glaucoma Diseases 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- QSKQVZWVLOIIEV-NSHDSACASA-N ripasudil Chemical compound C[C@H]1CNCCCN1S(=O)(=O)C1=CC=CC2=CN=CC(F)=C12 QSKQVZWVLOIIEV-NSHDSACASA-N 0.000 description 1
- 229950007455 ripasudil Drugs 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
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- 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 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000004320 sodium erythorbate Substances 0.000 description 1
- 235000010352 sodium erythorbate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- HLWRUJAIJJEZDL-UHFFFAOYSA-M sodium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC([O-])=O HLWRUJAIJJEZDL-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
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- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229960002368 travoprost Drugs 0.000 description 1
- 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 1
- 125000002827 triflate group Chemical class FC(S(=O)(=O)O*)(F)F 0.000 description 1
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
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- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- 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
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- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- 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
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
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- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- 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
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- A61P27/00—Drugs for disorders of the senses
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The purpose of the present invention is to provide: a pharmaceutical composition that contains the pyridylaminoacetic acid compound of the present invention, said pyridylaminoacetic acid compound being stable within the pharmaceutical composition; and a method for improving the stability of the pydridylaminoacetic acid compound within the pharmaceutical composition. The pharmaceutical composition contains: (6{[4-(pyrazol-1-yl)benzyl](pyridine-3-ylsulfonyl)aminomethyl}pyridine-2-ylamino)isopropyl acetate or a salt thereof; and polyoxyethylene castor oil. The polyoxyethylene castor oil preferably contains a polyoxyethylene castor oil selected from the group consisting of polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 castor oil. idylaminoacetic acid compound within the pharmaceutical composition. The pharmaceutical composition contains: (6{[4-(pyrazol-1-yl)benzyl](pyridine-3-ylsulfonyl)aminomethyl}pyridine-2-ylamino)isopropyl acetate or a salt thereof; and polyoxyethylene castor oil. The polyoxyethylene castor oil preferably contains a polyoxyethylene castor oil selected from the group consisting of polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 castor oil.
Description
PYRIDYLAMINOACETIC ACID COMPOUND AND POLYOXYETHYLENE CASTOR OIL-CONTAINING PHARMACEUTICAL COMPOSITION TECHNICAL FIELD The present invention relates to a pharmaceutical composition comprising isopropyl (6-{[4-(pyrazol yl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin ylamino)acetate or a salt thereof, and a method for stabilizing the compound or salt thereof.
BACKGROUND ART Isopropyl (6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate is a compound represented by the following formula (1): Patent Document 1 and Patent Document 2 mention pyridylaminoacetic acid compounds such as isopropyl (6-{[4- (pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate, and Patent Document 1 mentions, as eye drops of the pyridylaminoacetic acid compound, Formulation Examples comprising concentrated glycerol and Polysorbate 80.
However, Patent Document 1 does not mention a pharmaceutical composition comprising isopropyl (6-{[4- (pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate or a salt thereof and polyoxyethylene castor oil, and also there is absolutely no mention that polyoxyethylene castor oil improves stability of the isopropyl (6-{[4-(pyrazol yl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin ylamino)acetate or salt thereof in the pharmaceutical composition.
Patent Document 1: U.S. Published Patent Application Publication, No. 2012/0190852, Specification Patent Document 2: U.S. Published Patent Application Publication, No. 2011/0054172, Specification DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention At a stage of development of a pharmaceutical composition comprising isopropyl (6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate or a salt thereof (hereinafter also referred to as "the present compound"), the present inventors have found that, in an aqueous composition comprising the present compound dissolved therein, stability of the present compound is inferior.
An object of the present invention is to provide a pharmaceutical composition comprising the present compound, in which the present compound in the pharmaceutical composition is stable. Another object of the present invention is to provide a method for improving stability of the present compound in the pharmaceutical composition.
Means for Solving the Problems The present inventors have intensively studied about a surfactant for dissolving the present compound so as to achieve the above objects, and found that the present compound in a pharmaceutical composition has a high remaining rate even under long-term storage when using polyoxyethylene castor oil, thus completing the present invention. Namely, the present invention is related to the following. (1) A pharmaceutical composition comprising isopropyl (6- {[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate or a salt thereof, and polyoxyethylene castor oil. (2) The pharmaceutical composition according to (1), wherein the polyoxyethylene castor oil includes polyoxyethylene castor oil selected from the group consisting of polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 castor oil. (3) The pharmaceutical composition according to (2), wherein the polyoxyethylene castor oil include polyoxyl 35 castor oil. (4) The pharmaceutical composition according to any one of (1) to (3), wherein the content of 6-{[4-(pyrazol yl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin ylamino)isopropyl acetate or a salt thereof is in a range of 0.0001 to 0.1% (w/v). (5) The pharmaceutical composition according to (4), wherein the content of 6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)isopropyl acetate or a salt thereof is in a range of 0.001 to 0.003% (w/v). (6) The pharmaceutical composition according to any one of (1) to (5), wherein the content of the polyoxyethylene castor oil is in a range of 0.001 to 5% (w/v). (7) The pharmaceutical composition according to (6), wherein the content of the polyoxyethylene castor oil is in a range of 0.8 to 2% (w/v). (8) The pharmaceutical composition according to any one of (1) to (7), wherein the content of the polyoxyethylene castor oil is in a range of 1 to 20,000 parts by mass relative to 1 part by mass of 6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)isopropyl acetate or a salt thereof. (9) The pharmaceutical composition according to (8), wherein the content of the polyoxyethylene castor oil is in a range of 200 to 2,000 parts by mass relative to 1 part by mass of 6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)isopropyl acetate or a salt thereof. (10) The pharmaceutical composition according to any one of (1) to (9), which further comprises edetic acid or a salt thereof. (11) The pharmaceutical composition according to any one of (1) to (10), which further comprises boric acid or a salt thereof, citric acid or a salt thereof, or acetic acid or a salt thereof. (12) The pharmaceutical composition according to any one of (1) to (11), which does not comprise sorbic acid. (13) The pharmaceutical composition according to any one of (1) to (12), which is filled into a container made of polyethylene. (14) The pharmaceutical composition according to any one of (1) to (13), for prevention or treatment of glaucoma or ocular hypertension, or for reduction of intraocular pressure. (15) A method for stabilizing isopropyl (6-{[4-(pyrazol- 1-yl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin ylamino)acetate or a salt thereof by allowing a pharmaceutical composition comprising isopropyl (6-{[4-(pyrazol yl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin ylamino)acetate or a salt thereof to comprise polyoxyethylene castor oil.
The respective structures of the above-mentioned (1) to (15) can be combined by optionally selecting two or more structures therefrom.
Effects of the Invention According to the present invention, it is possible to provide a pharmaceutical composition in which the present compound in the pharmaceutical composition is stabilized over a long period of time. The pharmaceutical composition of the present invention has enough safety as a pharmaceutical product. According to the present invention, it is also possible to provide a method for stabilizing the present compound in a pharmaceutical composition over a long period of time. According to the present invention, it is also possible to provide a method for using polyoxyethylene castor oil so as to produce a pharmaceutical composition in which the present compound in the pharmaceutical composition is stabilized over a long period of time.
PREFERRED MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described in detail below.
It is possible to produce isopropyl (6-{[4-(pyrazol yl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin ylamino)acetate or a salt thereof comprised in a pharmaceutical composition of the present invention in accordance with a conventional method in the technical field, such as a method mentioned in U.S. Published Patent Application Publication, No. 2012/0190852, Specification.
In the pharmaceutical composition of the present invention, a salt of isopropyl (6-{[4-(pyrazol yl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin ylamino)acetate is not particularly limited as long as it is a pharmacologically acceptable salt. Specifically, there are exemplified inorganic acid salts such as hydrochlorides, hydrobromates, hydroiodides, nitrates, sulfates, or phosphates; or organic acid salts such as acetates, trifluoroacetates, benzoates, oxalates, malonates, succinates, maleates, fumarates, tartrates, citrates, methanesulfonates, ethanesulfonates, trifluoromethanesulfonates, benzenesulfonates, p-toluenesulfonates, glutamates, or aspartates. Preferably, hydrochlorides or trifluoroacetates are exemplified.
In the pharmaceutical composition of the present invention, the content of isopropyl (6-{[4-(pyrazol yl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin ylamino)acetate or a salt thereof is not particularly limited.
Specifically, the lower limit is preferably 0.0001% (w/v), more preferably 0.0003% (w/v), still more preferably 0.0005% (w/v), and yet still more preferably 0.001% (w/v). The upper limit is preferably 0.1% (w/v), more preferably 0.03% (w/v), still more preferably 0.01% (w/v), yet still more preferably 0.008% (w/v), even still more preferably 0.005% (w/v), and particularly preferably 0.003% (w/v). More specifically, the content is preferably in a range of 0.0001 to 0.1% (w/v), more preferably 0.0003 to 0.03% (w/v), still more preferably 0.0005 to 0.01% (w/v), yet still more preferably 0.001 to 0.008% (w/v), even still more preferably 0.001 to 0.005% (w/v), and particularly preferably 0.001 to 0.003% (w/v). Comparatively small content of the present compound may enable a reduction in amount of a surfactant (typically polyoxyethylene castor oil), which is required to dissolve the present compound, so that the content of the present compound is preferably less than 0.01% (w/v). When comprising a salt of isopropyl (6-{[4- (pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate, it means that the content of isopropyl (6-{[4-(pyrazol yl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin ylamino)acetate falls in the above range in a state where the salt is isolated.
In the pharmaceutical composition of the present invention, it is possible to use, as the polyoxyethylene castor oil, various polyoxyethylene castor oils each exhibiting different number of polymerization of ethylene oxide. The number of polymerization of ethylene oxide is preferably in a range of 5 to 100, more preferably 20 to 50, particularly preferably 30 to 40, and most preferably 35.
Specific examples of the polyoxyethylene castor oil include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, and the like, and polyoxyl 35 castor oil is most preferable.
The polyoxyethylene castor oil as used herein is not polyoxyethylene hardened castor oil (provided that it is not excluded from the present invention that the pharmaceutical composition of the present invention further comprises polyoxyethylene hardened castor oil in the amount which does not exert an adverse influence on stability).
In the pharmaceutical composition of the present invention, the content of the polyoxyethylene castor oil is not particularly limited. Specifically, the lower limit is preferably 0.001% (w/v), more preferably 0.01% (w/v), still more preferably 0.1% (w/v), particularly preferably 0.5% (w/v), and most preferably 0.8% (w/v). The upper limit is preferably % (w/v), more preferably 5% (w/v), still more preferably 4% (w/v), particularly preferably 3% (w/v), and most preferably 2% (w/v). More specifically, the content is preferably in a range of 0.001 to 10% (w/v), more preferably 0.01 to 5% (w/v), still more preferably 0.1 to 4% (w/v), particularly preferably 0.5 to 3% (w/v), and most preferably 0.8 to 2% (w/v).
In the pharmaceutical composition of the present invention, the content of the polyoxyethylene castor oil relative to 6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)isopropyl acetate or a salt thereof is not particularly limited. Specifically, the lower limit of the content of the polyoxyethylene castor oil is preferably 1 part by mass, more preferably 10 parts by mass, still more preferably 50 parts by mass, yet still more preferably 100 parts by mass, and particularly preferably 200 parts by mass, relative to 1 part by mass of 6-{[4-(pyrazol yl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin ylamino)isopropyl acetate or a salt thereof. The upper limit is preferably 20,000 parts by mass, more preferably 10,000 parts by mass, still more preferably 5,000 parts by mass, yet still more preferably 3,000 parts by mass, and particularly preferably 2,000 parts by mass. More specifically, the content of the polyoxyethylene castor oil is preferably in a range of 1 to 20,000 parts by mass, more preferably 10 to 10,000 parts by mass, still more preferably 50 to 5,000 parts by mass, particularly preferably 100 to 3,000 parts by mass, and most preferably 200 to 2,000 parts by mass, relative to 1 part by mass of 6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)isopropyl acetate or a salt thereof.
Additives can be optionally used in the pharmaceutical composition of the present invention, and it is possible to add, as additives, a buffer agent, a tonicity agent, a stabilizer, a preservative, an antioxidant, a high molecular weight polymer, and the like.
It is possible to mix the buffer agent, which is usable as additives for a pharmaceutical product, in the pharmaceutical composition of the present invention. Examples of the buffer agent include phosphoric acid or a salt thereof, boric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ε-aminocaproic acid, trometamol, and the like. From a viewpoint of buffering capacity in a weak acid region, the buffer agent is preferably boric acid or a salt thereof, citric acid or a salt thereof, or acetic acid or a salt thereof, and particularly preferably citric acid or a salt thereof. Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and the like; examples of the borate include borax, sodium borate, potassium borate, and the like; examples of the citrate include sodium acetate, disodium citrate, trisodium citrate, and the like; examples of the acetate include sodium acetate, potassium acetate, and the like; examples of the carbonate include sodium carbonate, sodium hydrogen carbonate, and the like; and examples of the tartrate include sodium tartrate, potassium tartrate, and the like. When the buffer agent is mixed in the pharmaceutical composition of the present invention, the content of the buffer agent can be appropriately adjusted according to the type of the buffer agent, and is preferably in a range of 0.001 to 10% (w/v), more preferably 0.01 to 5% (w/v), still more preferably 0.1 to 3% (w/v), and most preferably 0.2 to 2% (w/v).
It is possible to appropriately mix the tonicity agent, which is usable as additives for a pharmaceutical product, in the pharmaceutical composition of the present invention.
Examples of the tonicity agent include an ionic tonicity agent, a nonionic tonicity agent, and the like. Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like; and examples of the nonionic tonicity agent include glycerol, propylene glycol, sorbitol, mannitol, and the like. When the tonicity agent is mixed in the pharmaceutical composition of the present invention, the content of the tonicity agent can be appropriately adjusted according to the type of the tonicity agent, and is preferably in a range of 0.01 to 10% (w/v), more preferably 0.02 to 7% (w/v), still more preferably 0.1 to 5% (w/v), particularly preferably 0.5 to 4% (w/v), and most preferably 0.8 to 3% (w/v).
It is possible to appropriately mix the stabilizer, which is usable as additives for a pharmaceutical product, in the pharmaceutical composition of the present invention. Examples of the stabilizer include edetic acid, monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate, and the like, and disodium edetate is particularly preferable. When the stabilizer is mixed in the pharmaceutical composition of the present invention, the content of the stabilizer can be appropriately adjusted according to the type of the stabilizer, and is preferably in a range of 0.001 to 1% (w/v), more preferably 0.005 to 0.5% (w/v), still more preferably 0.01 to 0.1% (w/v), and most preferably 0.02 to 0.05% (w/v).
It is possible to appropriately mix the preservative, which is usable as additives for a pharmaceutical product, in the pharmaceutical composition of the present invention.
Examples of the preservative include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, and the like. From a viewpoint of stability of 6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)isopropyl acetate or a salt thereof, it is desired not to include sorbic acid. When the preservative is mixed in the pharmaceutical composition of the present invention, the content of the preservative can be appropriately adjusted according to the type of the preservative, and is preferably in a range of 0.0001 to 1% (w/v), more preferably 0.0005 to 0.1% (w/v), still more preferably 0.001 to 0.05% (w/v), and most preferably 0.002 to 0.01% (w/v).
It is possible to appropriately mix the antioxidant, which is usable as additives for a pharmaceutical product, in the pharmaceutical composition of the present invention.
Examples of the antioxidant include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite, and the like. When the antioxidant is mixed in the pharmaceutical composition of the present invention, the content of the antioxidant can be appropriately adjusted according to the type of the antioxidant, and is preferably in a range of 0.0001 to 1% (w/v), more preferably 0.0005 to 0.1% (w/v), still more preferably 0.001 to 0.02% (w/v), and most preferably 0.005 to 0.010% (w/v).
It is possible to appropriately mix the high molecular weight polymer, which is usable as additives for a pharmaceutical product, in the pharmaceutical composition of the present invention. Examples of the high molecular weight polymer include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, and the like. When the high molecular weight polymer is mixed in the pharmaceutical composition of the present invention, the content of the high molecular weight polymer can be appropriately adjusted according to the type of the high molecular weight polymer, and is preferably in a range of 0.001 to 5% (w/v), more preferably 0.01 to 1% (w/v), and still more preferably 0.1 to 0.5% (w/v).
The pH of the pharmaceutical composition of the present invention is preferably in a range of 4.0 to 8.0, more preferably 4.5 to 7.5, and most preferably 5.0 to 7.0.
The pharmaceutical composition of the present invention can be stored in a container made of various raw materials.
For example, it is possible to use containers made of polyethylene, polypropylene, and the like. From a viewpoint of ease of instillation (hardness of container) and stability of the present compound, it is preferred to store in a container made of polyethylene.
The dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it is usable as a pharmaceutical product. Examples of the dosage form include eye drop, ophthalmic injection, and the like, and eye drop is particularly preferable. They can be produced in accordance with a conventional method in the technical field.
The pharmaceutical composition of the present invention is basically a solution, and a solvent or dispersion medium thereof is preferably water.
The pharmaceutical composition of the present invention is useful for prevention or treatment of glaucoma or ocular hypertension, or for reduction of intraocular pressure.
Examples of glaucoma in the present invention include primary open-angle glaucoma, secondary open-angle glaucoma, normal tension glaucoma, hypersecretion glaucoma, primary closed- angle glaucoma, secondary closed-angle glaucoma, plateau iris glaucoma, mixed glaucoma, developmental glaucoma, steroid glaucoma, exfoliation glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma, capsular glaucoma, plateau iris syndrome, and the like.
The pharmaceutical composition of the present invention may comprise one or plurality of, preferably 1 to 3 of, and more preferably one or two other glaucoma or ocular hypertension therapeutic agent(s) or intraocular tension depressor(s). The other glaucoma therapeutic agents is not particularly limited. Specifically, the other glaucoma therapeutic agent is preferably a commercially available glaucoma therapeutic agent or a glaucoma therapeutic agent under development, more preferably a commercially available glaucoma therapeutic agent, and particularly preferably a commercially available glaucoma therapeutic agent whose mechanism of action is different from that of the present compound. More specifically, there are exemplified a non- selective sympathomimetic agent, an α receptor agonist, an α receptor antagonist, a β receptor antagonist, a parasympatholytic agent, a carbonate dehydratase inhibitor, prostaglandins, a Rho kinase inhibitor, and the like. Specific examples of the non-selective sympathomimetic agent include dipivefrin; specific examples of the α receptor agonist include brimonidine and apraclonidine; specific examples of the α receptor antagonist include bunazosin; specific examples of the β receptor antagonist include timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, and metipranolol; specific examples of the parasympatholytic agent include pilocarpine; specific examples of the carbonate dehydratase inhibitor include dorzolamide, brinzolamide, and acetazolamide; specific examples of prostaglandins include latanoprost, isopropyl unoprostone, bimatoprost, and travoprost; and specific examples of the Rho kinase inhibitor include ripasudil.
EXAMPLES Formulation Examples and test results will be shown below, but such are for better understanding of the present invention and do not limit the scope of the present invention.
Formulation Examples Typical Formulation Examples using the present compound will be shown below. In the following Formulation Examples, the mixing amount of each component is the content in 100 mL of the composition.
[Formulation Example 1] Eye drop (in 100 mL) Present compound 0.001 g Boric acid 0.2 g Glycerol 2.0 g Polyoxyl 35 castor oil 0.5 g Disodium edetate 0.05 g Benzalkonium chloride 0.005 g Dilute hydrochloric acid q.s.
Sodium hydroxide q.s.
Purified water q.s.
[Formulation Example 2] Eye drop (in 100 mL) Present compound 0.001 g Sodium dihydrogen phosphate 0.2 g Glycerol 2.0 g Polyoxyl 35 castor oil 0.8 g Disodium edetate 0.05 g Benzalkonium chloride 0.005 g Dilute hydrochloric acid q.s.
Sodium hydroxide q.s.
Purified water q.s.
[Formulation Example 3] Eye drop (in 100 mL) Present compound 0.001 g Trisodium citrate 0.2 g Glycerol 2.0 g Polyoxyl 35 castor oil 0.3 g Disodium edetate 0.05 g Benzalkonium chloride 0.005 g Dilute hydrochloric acid q.s.
Sodium hydroxide q.s.
Purified water q.s.
Types and mixing amounts of the present compound, polyoxyethylene castor oil, and additives in Formulation Examples 1 to 3 can be appropriately adjusted to obtain desired compositions. 1. Stability Evaluation Test (1) An influence of a surfactant on stability of the present compound was studied. 1-1. Preparation of Test Formulation To 5 g of polyoxyl 35 castor oil, 20 mL of a 10% sodium dihydrogen phosphate solution and 900 mL of purified water were added. After adjusting the pH to about 6 by adding a sodium hydroxide solution or dilute hydrochloric acid (q.s.), 0.003 g of isopropyl (6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate (hereinafter also referred to as the compound A) was added and dissolved.
To this was added purified water (q.s.) to make 1,000 mL in total, thus preparing a formulation of Example 1.
In the same manner as in preparation method of Example 1, formulations of Comparative Examples 1 and 2 shown in Table 1 were prepared. 1-2. Test Procedure After filling a glass ampule with 5 mL of a test formulation and storing at 60°C for an optional period, the content of isopropyl (6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate was determined using high-performance liquid chromatography, and then a remaining rate (%) thereof was calculated. 1-3. Test Results and Consideration Test results are shown in Table 1.
[Table 1] As is apparent from Table 1, the formulation of Example 1 maintained significantly high remaining rate at 60°C over 4 weeks, as compared with the formulations of Comparative Examples 1 and 2. The results revealed that the pharmaceutical composition of the present invention has excellent stability. 2. Stability Evaluation Test (2) An influence of additives and pH in the pharmaceutical composition of the present invention was studied. 2-1. Preparation of Test Formulation In the same manner as in preparation method of Example 1, the formulations of Examples 2 to 24 shown in Tables 2 to 6 were prepared. 2-2. Test Procedure After filling a glass ampule with 5 mL of a test formulation and storing at 60°C for an optional period, the content of isopropyl (6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate was determined using high-performance liquid chromatography, and then a remaining rate (%) thereof was calculated.
[Table 2] [Table 3] [Table 4] [Table 5] [Table 6] As is apparent from Tables 2 to 6, the formulations of Examples 2 to 24 maintained a high remaining rate at 60°C over 2 or 4 weeks.
I/
Claims (19)
1. A pharmaceutical composition comprising isopropyl (6-{[4- (pyrazolyl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin- 2-ylamino)acetate or a salt thereof, and polyoxyethylene castor oil.
2. The pharmaceutical composition according to claim 1, wherein the polyoxyethylene castor oil includes polyoxyethylene castor oil selected from the group consisting of polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 castor oil.
3. The pharmaceutical composition according to claim 2, wherein the polyoxyethylene castor oil includes polyoxyl 35 castor oil.
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the content of isopropyl 6-{[4-(pyrazol- 1-yl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin ylamino)acetate or a salt thereof is in a range of 0.0001 to 0.1% (w/v).
5. The pharmaceutical composition according to claim 4, wherein the content of isopropyl 6-{[4-(pyrazol yl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin ylamino)acetate or a salt thereof is in a range of 0.001 to 0.003% (w/v).
6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the content of the polyoxyethylene castor oil is in a range of 0.001 to 5% (w/v).
7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the content of the polyoxyethylene castor AH26(27013445_1):MBS oil is in a range of 0.5 to 3% (w/v).
8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the content of the polyoxyethylene castor oil is in a range of 1 to 20,000 parts by mass relative to 1 part by mass of isopropyl 6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate or a salt thereof.
9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the content of the polyoxyethylene castor oil is in a range of 200 to 2,000 parts by mass relative to 1 part by mass of isopropyl 6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate or a salt thereof.
10. The pharmaceutical composition according to any one of claims 1 to 9, which further comprises edetic acid or a salt thereof.
11. The pharmaceutical composition according to any one of claims 1 to 10, which further comprises boric acid or a salt thereof, citric acid or a salt thereof, or acetic acid or a salt thereof.
12. The pharmaceutical composition according to any one of claims 1 to 11, which does not comprise sorbic acid.
13. A pharmaceutical composition comprising isopropyl (6-{[4- (pyrazolyl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin- 2-ylamino)acetate or a salt thereof,and polyoxyethylene castor oil, and edetic acid or a salt thereof, and boric acid or a salt thereof, citric acid or a salt thereof, or AH26(27013445_1):MBS acetic acid or a salt thereof, and glycerol, and water, wherein the pharmaceutical composition does not comprise sorbic acid, the polyoxyethylene castor oil includes polyoxyl 35 castor oil, the content of the polyoxyethylene castor oil is 0.5 to 3% (w/v) in the pharmaceutical composition, and the content of the polyoxyethylene castor oil is in a range of 200 to 2,000 parts by mass relative to 1 part by mass of the isopropyl 6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate or a salt thereof.
14. A pharmaceutical composition comprising isopropyl (6-{[4- (pyrazolyl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin- 2-ylamino)acetate or a salt thereof, and polyoxyethylene castor oil, and edetic acid or a salt thereof, and boric acid or a salt thereof, citric acid or a salt thereof, or acetic acid or a salt thereof, and glycerol, and sodium hydroxide and/or hydrochloric acid, and water, wherein the pharmaceutical composition does not comprise sorbic acid, the polyoxyethylene castor oil includes polyoxyl 35 castor oil, the content of the polyoxyethylene castor oil is 0.5 to 3% (w/v) in the pharmaceutical composition, and the content of the polyoxyethylene castor oil is in a range of 200 to 2,000 parts by mass relative to 1 part by mass of the isopropyl 6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate or a salt thereof. AH26(27013445_1):MBS
15. A pharmaceutical composition comprising isopropyl (6-{[4- (pyrazolyl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin- 2-ylamino)acetate or a salt thereof, and polyoxyethylene castor oil, and edetic acid or a salt thereof, and boric acid or a salt thereof, citric acid or a salt thereof, or acetic acid or a salt thereof, and glycerol, and benzalkonium chloride, and water, wherein the pharmaceutical composition does not comprise sorbic acid, the polyoxyethylene castor oil includes polyoxyl 35 castor oil, the content of the polyoxyethylene castor oil is 0.5 to 3% (w/v) in the pharmaceutical composition, and the content of the polyoxyethylene castor oil is in a range of 200 to 2,000 parts by mass relative to 1 part by mass of the isopropyl 6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate or a salt thereof.
16. A pharmaceutical composition comprising isopropyl (6-{[4- (pyrazolyl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin- 2-ylamino)acetate or a salt thereof, and polyoxyethylene castor oil, and edetic acid or a salt thereof, and boric acid or a salt thereof, citric acid or a salt thereof, or acetic acid or a salt thereof, and glycerol, and benzalkonium chloride, and sodium hydroxide and/or hydrochloric acid, and water, wherein the pharmaceutical composition does not comprise sorbic AH26(27013445_1):MBS acid, the polyoxyethylene castor oil includes polyoxyl 35 castor oil, the content of the polyoxyethylene castor oil is 0.5 to 3% (w/v) in the pharmaceutical composition, and the content of the polyoxyethylene castor oil is in a range of 200 to 2,000 parts by mass relative to 1 part by mass of the isopropyl 6-{[4-(pyrazolyl)benzyl](pyridin ylsulfonyl)aminomethyl}pyridinylamino)acetate or a salt thereof.
17. The pharmaceutical composition according to any one of claims 1 to 16, which is filled into a container made of polyethylene.
18. The pharmaceutical composition according to any one of claims 1 to 17, for prevention or treatment of glaucoma or ocular hypertension, or for reduction of intraocular pressure.
19. A method for stabilizing isopropyl (6-{[4-(pyrazol yl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin ylamino)acetate or a salt thereof by allowing a pharmaceutical composition comprising isopropyl (6-{[4-(pyrazol yl)benzyl](pyridinylsulfonyl)aminomethyl}pyridin ylamino)acetate or a salt thereof to comprise polyoxyethylene castor oil. Santen Pharmaceutical Co., Ltd. By the Attorneys for the Applicant SPRUSON & FERGUSON Per: AH26(27013445_1):MBS
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PCT/JP2015/050333 WO2015105134A1 (en) | 2014-01-10 | 2015-01-08 | Pyridylaminoacetic acid compound and polyoxyethylene castor oil-containing pharmaceutical composition |
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