US20200353084A1 - Pharmaceutical composition containing pyridylaminoacetic acid compound - Google Patents
Pharmaceutical composition containing pyridylaminoacetic acid compound Download PDFInfo
- Publication number
- US20200353084A1 US20200353084A1 US16/942,877 US202016942877A US2020353084A1 US 20200353084 A1 US20200353084 A1 US 20200353084A1 US 202016942877 A US202016942877 A US 202016942877A US 2020353084 A1 US2020353084 A1 US 2020353084A1
- Authority
- US
- United States
- Prior art keywords
- pharmaceutical composition
- salt
- pyridin
- castor oil
- composition according
- 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.)
- Abandoned
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 102
- 150000001875 compounds Chemical class 0.000 title abstract description 32
- 239000002253 acid Substances 0.000 title description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 85
- 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 abstract description 39
- 229960001484 edetic acid Drugs 0.000 claims abstract description 26
- JIEXZSFMUWGAJW-UHFFFAOYSA-N propan-2-yl 2-[[6-[2-(4-pyrazol-1-ylphenyl)-1-(pyridin-3-ylsulfonylamino)ethyl]pyridin-2-yl]amino]acetate Chemical compound CC(C)OC(=O)CNC1=CC=CC(C(CC=2C=CC(=CC=2)N2N=CC=C2)NS(=O)(=O)C=2C=NC=CC=2)=N1 JIEXZSFMUWGAJW-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 13
- -1 polyoxyethylene Polymers 0.000 claims description 90
- 239000004359 castor oil Substances 0.000 claims description 49
- 235000019438 castor oil Nutrition 0.000 claims description 47
- 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 claims description 47
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 46
- 230000002335 preservative effect Effects 0.000 claims description 33
- 239000003755 preservative agent Substances 0.000 claims description 31
- 208000010412 Glaucoma Diseases 0.000 claims description 18
- 239000002736 nonionic surfactant Substances 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 15
- 229940011051 isopropyl acetate Drugs 0.000 claims description 15
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 12
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 12
- 239000000194 fatty acid Substances 0.000 claims description 12
- 229930195729 fatty acid Natural products 0.000 claims description 12
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 claims description 11
- 229920002675 Polyoxyl Polymers 0.000 claims description 10
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 10
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 10
- 229920000053 polysorbate 80 Polymers 0.000 claims description 10
- 229940068968 polysorbate 80 Drugs 0.000 claims description 10
- 239000004327 boric acid Substances 0.000 claims description 9
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 8
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 claims description 5
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 5
- 235000010199 sorbic acid Nutrition 0.000 claims description 5
- 239000004334 sorbic acid Substances 0.000 claims description 5
- 229940075582 sorbic acid Drugs 0.000 claims description 5
- 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
- 229920002696 Polyoxyl 40 castor oil Polymers 0.000 claims description 3
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 3
- 229920001219 Polysorbate 40 Polymers 0.000 claims description 3
- 229920002642 Polysorbate 65 Polymers 0.000 claims description 3
- 239000004147 Sorbitan trioleate Substances 0.000 claims description 3
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 claims description 3
- 230000004410 intraocular pressure Effects 0.000 claims description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 3
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims description 3
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 claims description 3
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims description 3
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims description 3
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 claims description 3
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 claims description 3
- 229940101027 polysorbate 40 Drugs 0.000 claims description 3
- 229940113124 polysorbate 60 Drugs 0.000 claims description 3
- 229940099511 polysorbate 65 Drugs 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 235000019337 sorbitan trioleate Nutrition 0.000 claims description 3
- 229960000391 sorbitan trioleate Drugs 0.000 claims description 3
- 238000004321 preservation Methods 0.000 abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 239000000203 mixture Substances 0.000 description 34
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 30
- 238000009472 formulation Methods 0.000 description 23
- 238000012360 testing method Methods 0.000 description 18
- 241000894006 Bacteria Species 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000008213 purified water Substances 0.000 description 15
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 13
- 229960000686 benzalkonium chloride Drugs 0.000 description 13
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 13
- 239000000654 additive Substances 0.000 description 12
- 239000012929 tonicity agent Substances 0.000 description 10
- 229940126062 Compound A Drugs 0.000 description 9
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 9
- 239000000825 pharmaceutical preparation Substances 0.000 description 9
- 229940127557 pharmaceutical product Drugs 0.000 description 9
- 239000000872 buffer Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000004094 surface-active agent Substances 0.000 description 7
- 239000003963 antioxidant agent Substances 0.000 description 6
- 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
- 238000002360 preparation method Methods 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 235000019799 monosodium phosphate Nutrition 0.000 description 5
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 5
- 229920001451 polypropylene glycol Polymers 0.000 description 5
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 5
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 229960002684 aminocaproic acid Drugs 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 239000002054 inoculum Substances 0.000 description 4
- 238000006116 polymerization reaction Methods 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 3
- 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
- 238000011156 evaluation Methods 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 3
- KIAAYEGYORLYQI-UHFFFAOYSA-N propane-1,2,3-triol;dihydrate Chemical compound O.O.OCC(O)CO KIAAYEGYORLYQI-UHFFFAOYSA-N 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 239000001509 sodium citrate Substances 0.000 description 3
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 3
- 229960000281 trometamol Drugs 0.000 description 3
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 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
- 241000228245 Aspergillus niger Species 0.000 description 2
- 241000222122 Candida albicans Species 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
- 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
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 239000003945 anionic surfactant Substances 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
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- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
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- 238000007796 conventional method Methods 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
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- 150000003904 phospholipids Chemical class 0.000 description 2
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Classifications
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- 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
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- 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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- 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
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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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- A61K9/0012—Galenical forms characterised by the site of application
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- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
Definitions
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising isopropyl (6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)acetate or a salt thereof, and a method for stabilizing the compound or salt thereof.
- Isopropyl (6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)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-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)acetate, and Patent Document 1 mentions, as eye drops of the pyridylaminoacetic acid compound, Formulation Examples comprising concentrated glycerol and Polysorbate 80.
- pyridylaminoacetic acid compounds such as isopropyl (6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)acetate
- Patent Document 1 mentions, as eye drops of the pyridylaminoacetic acid compound, Formulation Examples comprising concentrated glycerol and Polysorbate 80.
- a pharmaceutical composition comprising isopropyl (6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)acetate or a salt thereof, which further comprises edetic acid or a salt thereof, and also there is absolutely no mention that stability of isopropyl (6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)acetate or a salt thereof in the pharmaceutical composition, and preservative effectiveness of the pharmaceutical composition are improved.
- 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
- the present inventors At a stage of development of a pharmaceutical composition comprising isopropyl (6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)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.
- the present inventors have intensively studied about additives in the composition comprising 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 further adding edetic acid or a salt thereof in the composition comprising the present compound, and that the pharmaceutical composition has excellent preservative effectiveness, thus completing the present invention.
- the present invention is related to the following.
- a pharmaceutical composition comprising isopropyl (6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)acetate or a salt thereof, which further comprises edetic acid or a salt thereof.
- a pharmaceutical composition comprising isopropyl (6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)acetate or a salt thereof and a nonionic surfactant, which further comprises edetic acid or a salt thereof.
- nonionic surfactant includes polyoxyethylene castor oil, polyoxyethylene hardened castor oil, polyoxyethylene sorbitan fatty acid ester, or vitamin E TPGS.
- 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.
- polyoxyethylene hardened castor oil includes polyoxyethylene castor oil selected from the group consisting of polyoxyethylene hardened castor oil 10, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 50, and polyoxyethylene hardened castor oil 60.
- polyoxyethylene sorbitan fatty acid ester includes polyoxyethylene castor oil selected from the group consisting of Polysorbate 80, Polysorbate 60, Polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and Polysorbate 65.
- composition according to any one of (1) to (13), wherein the content of edetic acid or a salt thereof is in a range of 0.1 to 1,000 parts by mass relative to 1 part by mass of 6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)isopropyl acetate or a salt thereof.
- a method for improving preservative effectiveness of a pharmaceutical composition comprising isopropyl (6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)acetate or a salt thereof by allowing the pharmaceutical composition to comprise edetic acid or a salt thereof.
- the present invention it is possible to provide a pharmaceutical composition in which the present compound in a pharmaceutical composition is stabilized over a long period of time, the pharmaceutical composition having excellent preservative effectiveness.
- the pharmaceutical composition of the present invention has enough safety as a pharmaceutical product.
- a salt of isopropyl (6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)acetate is not particularly limited as long as it is a pharmacologically acceptable salt.
- 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.
- hydrochlorides or trifluoroacetates are exemplified.
- the content of isopropyl (6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)acetate or a salt thereof is not particularly limited.
- 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 most 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).
- a surfactant typically polyoxyethylene castor oil
- 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).
- a surfactant typically polyoxyethylene castor oil
- surfactants so as to dissolve the present compound. It is possible to appropriately mix a cationic surfactant, an anionic surfactant, and a nonionic surfactant, which are usable as additives for a pharmaceutical product, in the pharmaceutical composition of the present invention as surfactants. Of these surfactants, a nonionic surfactant is preferable.
- Examples of the cationic surfactant include alkylamine salt, alkylaminepolyoxyethylene adduct, fatty acid triethanolamine monoester salt, acylaminoethyldiethylamine salt, fatty acid polyamine condensate, alkyltrimethylammonium salt, dialkyldimethylammonium salt, alkyldimethylbenzylammonium salt, alkylpyridinium salt, acylaminoalkyl type ammonium salt, acylaminoalkylpyridinium salt, diacyloxyethylammonium salt, alkylimidazoline, 1-acylaminoethyl-2-alkylimidazoline, 1-hydroxylethyl-2-alkylimidazoline, and the like.
- alkyldimethylbenzylammonium salt examples include benzalkonium chloride, cetalkonium chloride, and the like.
- anionic surfactant include phospholipid, and the like; and examples of the phospholipid include lecithin, and the like.
- nonionic surfactant examples include polyoxyethylene castor oil, polyoxyethylene hardened castor oil, polyoxyethylene sorbitan fatty acid ester, Vitamin E TPGS, polyoxyethylene fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, and the like.
- polyoxyethylene castor oil is preferable from a viewpoint of being capable of further improving stability.
- 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.
- polyoxyethylene hardened castor oil various polyoxyethylene hardened castor oils each exhibiting different number of polymerization of ethylene oxide.
- the number of polymerization of ethylene oxide is preferably in a range of 10 to 100, more preferably 20 to 80, particularly preferably 40 to 70, and most preferably 60.
- Specific examples of the polyoxyethylene hardened castor oil include polyoxyethylene hardened castor oil 10, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 50, polyoxyethylene hardened castor oil 60, and the like, and polyoxyethylene hardened castor oil 60 is most preferable.
- polyoxyethylene sorbitan fatty acid ester examples include Polysorbate 80, Polysorbate 60, Polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, Polysorbate 65, and the like, and Polysorbate 80 is most preferable.
- Vitamin E TPGS is also referred to as tocopherol polyethylene glycol 1000 succinate ester.
- polyoxyethylene fatty acid ester examples include polyoxyl 40 stearate, and the like.
- polyoxyethylene polyoxypropylene glycol examples include polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, and the like.
- sucrose fatty acid ester examples include sucrose stearic acid ester, and the like.
- the content of the surfactant is not particularly limited.
- 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 10% (w/v), more preferably 5% (w/v), still more preferably 4% (w/v), particularly preferably 3% (w/v), and most preferably 2% (w/v).
- 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).
- the above content is applied to any surfactant, and is particularly preferably for a nonionic surfactant.
- the content of the nonionic surfactant relative to 6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)isopropyl acetate or a salt thereof is not particularly limited.
- the lower limit of the content of the nonionic surfactant 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-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-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.
- the content of the nonionic surfactant 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-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)isopropyl acetate or a salt thereof.
- examples of the salt of edetic acid include monosodium edetate, disodium edetate, tetrasodium edetate, and the like.
- the content of edetic acid or a salt thereof is not particularly limited.
- the lower limit of the content is preferably 0.001% (w/v), more preferably 0.005% (w/v), still more preferably 0.01% (w/v), and most preferably 0.02% (w/v).
- the upper limit of the content is preferably 1.0% (w/v), more preferably 0.5% (w/v), still more preferably 0.1% (w/v), and most preferably 0.05% (w/v).
- the content of edetic acid or a salt thereof is preferably in a range of 0.001 to 1% (w/v), more preferably 0.005 to 0.5% (w/v), and most preferably 0.01 to 0.1% (w/v).
- the content of edetic acid or a salt thereof relative to 1 part by mass of 6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)isopropyl acetate or a salt thereof is not particularly limited.
- the lower limit of the content of edetic acid or a salt thereof is preferably 0.1 part by mass, more preferably 0.2 part by mass, still more preferably 0.5 part by mass, particularly preferably 1 part by mass, and most preferably 3 parts by mass, relative to 1 part by mass of 6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)isopropyl acetate or a salt thereof.
- the upper limit is preferably 1,000 parts by mass, more preferably 500 parts by mass, still more preferably 200 parts by mass, particularly preferably 100 parts by mass, and most preferably 50 parts by mass.
- the content of edetic acid or a salt thereof is preferably in a range of 0.1 to 1,000 parts by mass, more preferably 0.2 to 500 parts by mass, still more preferably 0.5 to 200 parts by mass, particularly preferably 1 to 100 parts by mass, and most preferably 3 to 50 parts by mass, relative to 1 part by mass of 6- ⁇ [4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)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.
- the buffer agent which is usable as additives for a pharmaceutical product, in the pharmaceutical composition of the present invention.
- 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, ⁇ -aminocaproic acid, trometamol, and the like.
- 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.
- 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).
- the tonicity agent which is usable as additives for a pharmaceutical product, in the pharmaceutical composition of the present invention.
- the tonicity agent include an ionic tonicity agent, a nonionic tonicity agent, and the like.
- 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.
- 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).
- the stabilizer which is usable as additives for a pharmaceutical product, in the pharmaceutical composition of the present invention.
- the stabilizer include sodium citrate, and the like.
- the content of the stabilizer can be appropriately adjusted according to the type of the stabilizer.
- the preservative which is usable as additives for a pharmaceutical product, in the pharmaceutical composition of the present invention.
- 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-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)isopropyl acetate or a salt thereof, it is desired not to include sorbic acid.
- 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).
- the antioxidant which is usable as additives for a pharmaceutical product, in the pharmaceutical composition of the present invention.
- the antioxidant include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite, and the like.
- 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).
- the high molecular weight polymer which is usable as additives for a pharmaceutical product, in the pharmaceutical composition of the present invention.
- 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.
- 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, still more preferably 5.0 to 7.0, and most preferably 5.5 to 6.5.
- the pharmaceutical composition of the present invention can be stored in a container made of various raw materials.
- 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.
- 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 a 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.
- 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.
- non-selective sympathomimetic agent an ⁇ 2 receptor agonist, an ⁇ 1 receptor antagonist, a ⁇ receptor antagonist, a parasympatholytic agent, a carbonate dehydratase inhibitor, prostaglandins, a Rho kinase inhibitor, and the like.
- non-selective sympathomimetic agent examples include dipivefrin; specific examples of the ⁇ 2 receptor agonist include brimonidine and apraclonidine; specific examples of the ⁇ 1 receptor antagonist include bunazosin; specific examples of the ⁇ 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.
- Typical Formulation Examples using the present compound will be shown below.
- the mixing amount of each component is the content in 100 mL of the composition.
- Types and mixing amounts of the present compound, nonionic surfactant, edetic acid, and additives in Formulation Examples 1 to 3 can be appropriately adjusted to obtain desired compositions.
- Example 1 To 5 g of polyoxyl 35 castor oil, 20 mL of a 10% sodium dihydrogen phosphate solution, 10 mL of a 5% disodium edetate dihydrate solution, and 900 mL of purified water were added and dissolved. 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-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl ⁇ pyridin-2-ylamino)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.
- purified water q.s.
- Example 2 Present compound A 0.0003 0.0003 0.0003 0.0003 0.0003 Disodium edetate dihydrate 0.05 0.05 — — Polyoxyethylene hardened 0.5 — 0.5 — castor oil 60 Polysorbate 80 — 0.5 — 0.5 Sodium dihydrogen phosphate 0.2 0.2 0.2 0.2 HCl/NaOH q.s. q.s. qs. qs. Purified water q.s. q.s. qs. qs. qs. pH 6.0 6.0 6.0 Remaining 60° C./ 96.9 93.6 24.2 69.5 rate(%) 1 Week
- Example 32 Present compound A 0.0003 0.0003 0.0003 Polysorbate 80 0.5 0.8 0.8 ⁇ -Aminocaproic acid 0.2 0.2 0.2 Disodium edetate dihydrate 0.02 0.02 0.02 Glycerol — 2.3 — Mannitol 4.5 — 4.5 Benzalkonium chloride 0.0013 0.0013 0.0013 HCl/NaOH q.s. q.s. q.s. Purified water q.s. q.s. q.s. pH 6.0 6.0 6.0 Remaining 60° C./ 90.2 93.2 93.9 rate(%) 2 Weeks
- Example34 Present compoundA 0.0003 0.0003 Polyoxyl 35 castor oil 0.8 0.8 Boric acid 1 1 Sorbic acid 0.1 — Disodium edetate dihydrate 0.05 0.05 Glycerol 1 1 Benzalkonium chloride 0.01 0.01 HCl/NaOH q.s. q.s. Purified water qs. q.s. pH 6.5 6.5 Remaining rate(%) 60° C./2 Weeks 89.1 92.5
- Staphylococcus aureus Staphylococcus aureus ATCC 6538
- Candida albicans Candida albicans ATCC 10231
- a test was performed in accordance with a preservative effectiveness test defined in Sixteenth Revised Japanese Pharmacopoeia. Namely, an inoculum solution was prepared so as to adjust the concentration in a range of 107 to 10 8 cfu/mL and each formulation of Examples 35 to 43 and Comparative Example 3 was aseptically inoculated with each inoculum solution so as to adjust the concentration in a range of 10′ to 10 6 cfu/mL, followed by uniform mixing to give samples. These samples were stored under light-shielded condition at 20 to 25° C. and, after 14 and 28 days, 1 mL of each sample was collected and the number of general viable bacteria was measured.
- the number of general viable bacteria of bacteria, yeast fungus, and molds was measured in accordance with a most probable number method defined in a microbial limit test of Sixteenth Revised Japanese Pharmacopoeia.
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Abstract
Description
- The present application is a continuation under 35 U.S.C. § 120 of U.S. application Ser. No. 16/658,585, filed on Oct. 21, 2019 which was a continuation of U.S. application Ser. No. 16/173,299, filed on Oct. 29, 2018 the entire contents of both of which are incorporated herein by reference and priority to which is hereby claimed. U.S. application Ser. No. 16,173,299 is a continuation of U.S. application Ser. No. 15/204,507, filed on Jul. 7, 2016, the entire contents of which are incorporated herein by reference and priority to which is hereby claimed. U.S. application Ser. No. 15/204,507 is a continuation of PCT/JP2015/050334 filed on Jan. 8, 2015, which is incorporated herein reference and which claimed priority to Japanese Application No. 2014-002810, filed Jan. 10, 2014, the entire content of which is also incorporated herein by reference.
- The present invention relates to a pharmaceutical composition comprising isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof, and a method for stabilizing the compound or salt thereof.
- Isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)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-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, and Patent Document 1 mentions, as eye drops of the pyridylaminoacetic acid compound, Formulation Examples comprising concentrated glycerol and Polysorbate 80.
- However, there is not mentioned a pharmaceutical composition comprising isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof, which further comprises edetic acid or a salt thereof, and also there is absolutely no mention that stability of isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof in the pharmaceutical composition, and preservative effectiveness of the pharmaceutical composition are improved.
- 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
- At a stage of development of a pharmaceutical composition comprising isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)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, the pharmaceutical composition having excellent preservative effectiveness. Another object of the present invention is to provide a method for improving stability of the present compound in the pharmaceutical composition, and preservative effectiveness of the pharmaceutical composition.
- The present inventors have intensively studied about additives in the composition comprising 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 further adding edetic acid or a salt thereof in the composition comprising the present compound, and that the pharmaceutical composition has excellent preservative effectiveness, thus completing the present invention. Namely, the present invention is related to the following.
- (1) A pharmaceutical composition comprising isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof, which further comprises edetic acid or a salt thereof.
- (2) A pharmaceutical composition comprising isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof and a nonionic surfactant, which further comprises edetic acid or a salt thereof.
- (3) The pharmaceutical composition according to (2), wherein the nonionic surfactant includes polyoxyethylene castor oil, polyoxyethylene hardened castor oil, polyoxyethylene sorbitan fatty acid ester, or vitamin E TPGS.
- (4) The pharmaceutical composition according to (3), 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.
- (5) The pharmaceutical composition according to (3), wherein the polyoxyethylene hardened castor oil includes polyoxyethylene castor oil selected from the group consisting of polyoxyethylene hardened castor oil 10, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 50, and polyoxyethylene hardened castor oil 60.
- (6) The pharmaceutical composition according to (3), wherein the polyoxyethylene sorbitan fatty acid ester includes polyoxyethylene castor oil selected from the group consisting of Polysorbate 80, Polysorbate 60, Polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and Polysorbate 65.
- (7) The pharmaceutical composition according to any one of (2) to (6), wherein the content of the nonionic surfactant is in a range of 0.001 to 5% (w/v).
- (8) The pharmaceutical composition according to (7), wherein the content of the nonionic surfactant is in a range of 0.8 to 2% (w/v).
- (9) The pharmaceutical composition according to any one of (2) to (8), wherein the content of the nonionic surfactant is in a range of 1 to 20,000 parts by mass relative to 1 part by mass of 6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof.
- (10) The pharmaceutical composition according to any one of (1) to (9), wherein the content of 6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof is in a range of 0.0001 to 0.10% (w/v).
- (11) The pharmaceutical composition according to (10), wherein the content of 6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof is in a range of 0.001 to 0.003% (w/v).
- (12) The pharmaceutical composition according to any one of (1) to (11), wherein the content of edetic acid or a salt thereof is in a range of 0.001 to 1% (w/v).
- (13) The pharmaceutical composition according to (12), wherein the content of edetic acid or a salt thereof is in a range of 0.01 to 0.1% (w/v).
- (14) The pharmaceutical composition according to any one of (1) to (13), wherein the content of edetic acid or a salt thereof is in a range of 0.1 to 1,000 parts by mass relative to 1 part by mass of 6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof.
- (15) The pharmaceutical composition according to any one of (1) to (14), which further comprises boric acid or a salt thereof, citric acid or a salt thereof, or acetic acid or a salt thereof.
- (16) The pharmaceutical composition according to any one of (1) to (15), which does not comprise sorbic acid.
- (17) The pharmaceutical composition according to any one of (1) to (16), which is filled into a container made of polyethylene.
- (18) The pharmaceutical composition according to any one of (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-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof by allowing a pharmaceutical composition comprising isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof to comprise edetic acid or a salt thereof.
- (20) A method for improving preservative effectiveness of a pharmaceutical composition comprising isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof by allowing the pharmaceutical composition to comprise edetic acid or a salt thereof.
- The respective structures of the above-mentioned (1) to (20) can be combined by optionally selecting two or more structures therefrom.
- According to the present invention, it is possible to provide a pharmaceutical composition in which the present compound in a pharmaceutical composition is stabilized over a long period of time, the pharmaceutical composition having excellent preservative effectiveness. 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 to thereby improve preservative effectiveness of the pharmaceutical composition. According to the present invention, it is also possible to provide a method for using edetic acid or a salt thereof so as to produce a pharmaceutical composition in which the present compound in the pharmaceutical composition is stabilized over a long period of time, the pharmaceutical composition having excellent preservative effectiveness.
- Embodiments of the present invention will be described in detail below.
- It is possible to produce isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-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-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-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-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-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 most 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-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, it means that the content of isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-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 desired to mix surfactants so as to dissolve the present compound. It is possible to appropriately mix a cationic surfactant, an anionic surfactant, and a nonionic surfactant, which are usable as additives for a pharmaceutical product, in the pharmaceutical composition of the present invention as surfactants. Of these surfactants, a nonionic surfactant is preferable.
- Examples of the cationic surfactant include alkylamine salt, alkylaminepolyoxyethylene adduct, fatty acid triethanolamine monoester salt, acylaminoethyldiethylamine salt, fatty acid polyamine condensate, alkyltrimethylammonium salt, dialkyldimethylammonium salt, alkyldimethylbenzylammonium salt, alkylpyridinium salt, acylaminoalkyl type ammonium salt, acylaminoalkylpyridinium salt, diacyloxyethylammonium salt, alkylimidazoline, 1-acylaminoethyl-2-alkylimidazoline, 1-hydroxylethyl-2-alkylimidazoline, and the like. Examples of the alkyldimethylbenzylammonium salt include benzalkonium chloride, cetalkonium chloride, and the like. Examples of the anionic surfactant include phospholipid, and the like; and examples of the phospholipid include lecithin, and the like.
- Examples of the nonionic surfactant include polyoxyethylene castor oil, polyoxyethylene hardened castor oil, polyoxyethylene sorbitan fatty acid ester, Vitamin E TPGS, polyoxyethylene fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, and the like. Of these surfactants, polyoxyethylene castor oil is preferable from a viewpoint of being capable of further improving stability.
- 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.
- It is possible to use, as the polyoxyethylene hardened castor oil, various polyoxyethylene hardened castor oils each exhibiting different number of polymerization of ethylene oxide. The number of polymerization of ethylene oxide is preferably in a range of 10 to 100, more preferably 20 to 80, particularly preferably 40 to 70, and most preferably 60. Specific examples of the polyoxyethylene hardened castor oil include polyoxyethylene hardened castor oil 10, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 50, polyoxyethylene hardened castor oil 60, and the like, and polyoxyethylene hardened castor oil 60 is most preferable.
- Examples of the polyoxyethylene sorbitan fatty acid ester include Polysorbate 80, Polysorbate 60, Polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, Polysorbate 65, and the like, and Polysorbate 80 is most preferable.
- Vitamin E TPGS is also referred to as tocopherol polyethylene glycol 1000 succinate ester.
- Examples of the polyoxyethylene fatty acid ester include polyoxyl 40 stearate, and the like.
- Examples of the polyoxyethylene polyoxypropylene glycol include polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, and the like. Examples of the sucrose fatty acid ester include sucrose stearic acid ester, and the like.
- In the pharmaceutical composition of the present invention, the content of the surfactant 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 10% (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). The above content is applied to any surfactant, and is particularly preferably for a nonionic surfactant.
- In the pharmaceutical composition of the present invention, the content of the nonionic surfactant relative to 6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof is not particularly limited. Specifically, the lower limit of the content of the nonionic surfactant 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-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-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 nonionic surfactant 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-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof.
- In the pharmaceutical composition of the present invention, examples of the salt of edetic acid include monosodium edetate, disodium edetate, tetrasodium edetate, and the like.
- In the pharmaceutical composition of the present invention, the content of edetic acid or a salt thereof is not particularly limited. Specifically, the lower limit of the content is preferably 0.001% (w/v), more preferably 0.005% (w/v), still more preferably 0.01% (w/v), and most preferably 0.02% (w/v). The upper limit of the content is preferably 1.0% (w/v), more preferably 0.5% (w/v), still more preferably 0.1% (w/v), and most preferably 0.05% (w/v). More specifically, the content of edetic acid or a salt thereof is preferably in a range of 0.001 to 1% (w/v), more preferably 0.005 to 0.5% (w/v), and most preferably 0.01 to 0.1% (w/v).
- In the pharmaceutical composition of the present invention, the content of edetic acid or a salt thereof relative to 1 part by mass of 6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof is not particularly limited. Specifically, the lower limit of the content of edetic acid or a salt thereof is preferably 0.1 part by mass, more preferably 0.2 part by mass, still more preferably 0.5 part by mass, particularly preferably 1 part by mass, and most preferably 3 parts by mass, relative to 1 part by mass of 6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof. The upper limit is preferably 1,000 parts by mass, more preferably 500 parts by mass, still more preferably 200 parts by mass, particularly preferably 100 parts by mass, and most preferably 50 parts by mass. More specifically, the content of edetic acid or a salt thereof is preferably in a range of 0.1 to 1,000 parts by mass, more preferably 0.2 to 500 parts by mass, still more preferably 0.5 to 200 parts by mass, particularly preferably 1 to 100 parts by mass, and most preferably 3 to 50 parts by mass, relative to 1 part by mass of 6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)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 sodium citrate, and the like. 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.
- 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-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)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, still more preferably 5.0 to 7.0, and most preferably 5.5 to 6.5.
- 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 a 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 α2 receptor agonist, an α1 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 α2 receptor agonist include brimonidine and apraclonidine; specific examples of the α1 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.
- 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.
- 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.
- Present compound 0.001 g
- Boric acid 0.2 g
- Glycerol 2.0 g
- Polysorbate 80 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.
- Present compound 0.001 g
- Sodium dihydrogen phosphate 0.2 g
- Glycerol 2.0 g
- Vitamin E TPGS 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.
- Present compound 0.001 g
- Trisodium citrate 0.2 g
- Glycerol 2.0 g
- Polyoxyethylene hardened castor oil 60 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, nonionic surfactant, edetic acid, and additives in Formulation Examples 1 to 3 can be appropriately adjusted to obtain desired compositions.
- An influence of edetic acid on stability of the present compound was studied.
- To 5 g of polyoxyl 35 castor oil, 20 mL of a 10% sodium dihydrogen phosphate solution, 10 mL of a 5% disodium edetate dihydrate solution, and 900 mL of purified water were added and dissolved. 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-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)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 Example 2 and Comparative Examples 1 to 2 shown in Table 1 were prepared.
- 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-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate was determined using high-performance liquid chromatography, and then a remaining rate (%) thereof was calculated.
- Test results are shown in Table 1.
-
TABLE 1 Compar- Compar- Exam- Exam- ative ative % (w/v) ple 1 ple 2 Example 1 Example 2 Present compound A 0.0003 0.0003 0.0003 0.0003 Disodium edetate dihydrate 0.05 0.05 — — Polyoxyethylene hardened 0.5 — 0.5 — castor oil 60 Polysorbate 80 — 0.5 — 0.5 Sodium dihydrogen phosphate 0.2 0.2 0.2 0.2 HCl/NaOH q.s. q.s. qs. qs. Purified water q.s. q.s. qs. qs. pH 6.0 6.0 6.0 6.0 Remaining 60° C./ 96.9 93.6 24.2 69.5 rate(%) 1 Week - As is apparent from Table 1, the formulations of Examples 1 to 2 maintained significantly high remaining rate at 60° C. for a week, 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.
- An influence of additives and pH in the pharmaceutical composition of the present invention was studied.
- In the same manner as in preparation method of Example 1, the formulations of Examples 3 to 34 shown in Tables 2 to 8 were prepared.
- 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-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl)pyridin-2-ylamino)acetate was determined using high-performance liquid chromatography, and then a remaining rate (%) thereof was calculated.
-
TABLE 2 Exam- Exam- Exam- Exam- Exam- % (w/v) ple3 ple4 ple5 ple6 ple7 Present compound A 0.01 0.0003 0.001 0.01 0.03 Polyoxyl 35 castor oil 0.8 0.5 0.8 2 2 Sodium dihydrogen 0.2 0.2 0.2 0.2 0.2 phosphate Disodium edetate 0.01 0.05 0.05 0.05 0.05 dihydrate Glycerol 2.3 — 2.3 2.3 2.3 Benzalkonium chloride 0.004 — 0.004 0.004 0.004 HCl/NaOH q.s. q.s. q.s. q.s. q.s. Purified water q.s. q.s. q.s. q.s. q.s. pH 5.8 6.0 5.8 5.8 5.8 Remaining 60° C./ 94.5 ND 93.02 94.0 94.1 rate(%) 1 Week 60° C./ 86.2 83.2 82.2 87.1 90.9 4 Weeks -
TABLE 3 Example Example Example Example Example Example Example % (w/v) 8 9 10 11 12 13 14 Present compound A 0.003 0.003 0.003 0.003 0.003 0.01 0.01 Polyoxyl 35 castor oil 0.8 0.8 0.8 0.8 0.8 0.8 0.8 Sodium dihydrogen 0.2 — — — — — — phosphate Boric acid — 1 — — — 1 — Trisodium — — 0.2 — — — — citratedihydrate Sodium acetatetrihydrate — — — 0.2 — — — ε-Aminocaproic acid — — — — 0.2 — — Trometamol — — — — — — 0.9 Disodium edetate 0.02 0.02 0.02 0.02 0.02 0.05 0.05 dihydrate Glycerol 2.2 1.0 2.2 2.2 2.2 1.4 0.8 Benzalkonium chloride 0.004 0.004 0.004 0.004 0.004 0.004 0.004 HCl/NaOH q.s. q.s. q.s. q.s. q.s. q.s. q.s. Purified water q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH 6.0 6.0 6.0 6.0 6.0 5.8 5.8 Remaining 60° C./ 94.6 94.0 95.1 94.3 94.4 93.1 92.6 rate (%) 2 Weeks -
TABLE 4 Exam- Exam- Exam- Exam- % (w/v) ple15 ple16 ple17 ple18 Present compound A 0.01 0.01 0.01 0.01 Polyoxyl 35 castor oil 0.8 0.8 0.8 0.8 Sodium dihydrogen phosphate 0.2 0.2 0.2 0.2 Disodium edetate dihydrate 0.05 0.05 0.05 0.05 Glycerol 2.3 2.3 2.3 2.3 Benzalkonium chloride 0.002 0.008 0.004 0.004 HCl/NaOH q.s. q.s. q.s. q.s. Purified water q.s. q.s. q.s. q.s. pH 5.8 5.8 5.0 6.5 Remaining 60° C./ 95.3 94.1 94.8 92.6 rate(%) 2 Weeks -
TABLE 5 Exam- Exam- Exam- Exam- % (w/v) ple19 ple20 ple21 ple22 Present compound A 0.003 0.003 0.003 0.003 Polyoxyl 35 castor oil 0.8 0.8 0.8 0.8 Boric acid 1 1 — — ε-Aminocaproic acid — — 0.2 0.2 Disodium edetate dihydrate 0.02 0.02 0.02 0.02 Glycerol 1 — 2.3 — Mannitol — 2.0 — 4.5 Benzalkonium chloride 0.0013 0.0013 0.0013 0.0013 HCl/NaOH q.s. q.s. q.s. q.s. Purified water q.s. q.s. q.s. q.s. pH 6.0 6.0 6.0 6.0 Remaining 60° C./ 93.3 93.0 93.4 93.6 rate(%) 2 Weeks -
TABLE 6 Example Example Example Example Example Example Example % (w/v) 23 24 25 26 27 28 29 Present compound A 0.0003 0.0003 0.0003 0.0003 0.0003 0.003 0.0003 Polysorbate 80 0.5 0.5 0.5 0.5 0.5 0.8 — Vitamin E TPGS — — — — — — 0.5 Sodium dihydrogen 0.2 0.2 — — — — — phosphate Boric acid — — 1 — — — 1 Sodium citratehydrate — — — 1 — — — Trometamol — — — — 1 — — Trisodium 0.2 citratedihydrate Disodium edetate 0.05 0.05 0.05 0.05 0.05 0.02 0.01 dihydrate Sodium chloride 0.8 — — — — — — Glycerol — 2.2 — — — 2.2 1.0 Benzalkonium chloride — — — — — 0.004 0.01 HCl/NaOH q.s. q.s. q.s. q.s. q.s. q.s. q.s. Purified water q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH 6.0 6.0 6.0 6.0 6.0 6.0 6.0 Remaining 60° C./ 93.8 95.3 96.0 93.7 96.1 94.0 86.0 rate (%) 2 Weeks -
TABLE 7 % (w/v) Example 30 Example 31 Example 32 Present compound A 0.0003 0.0003 0.0003 Polysorbate 80 0.5 0.8 0.8 ε-Aminocaproic acid 0.2 0.2 0.2 Disodium edetate dihydrate 0.02 0.02 0.02 Glycerol — 2.3 — Mannitol 4.5 — 4.5 Benzalkonium chloride 0.0013 0.0013 0.0013 HCl/NaOH q.s. q.s. q.s. Purified water q.s. q.s. q.s. pH 6.0 6.0 6.0 Remaining 60° C./ 90.2 93.2 93.9 rate(%) 2 Weeks -
TABLE 8 % (w/v) Example33 Example34 Present compoundA 0.0003 0.0003 Polyoxyl 35 castor oil 0.8 0.8 Boric acid 1 1 Sorbic acid 0.1 — Disodium edetate dihydrate 0.05 0.05 Glycerol 1 1 Benzalkonium chloride 0.01 0.01 HCl/NaOH q.s. q.s. Purified water qs. q.s. pH 6.5 6.5 Remaining rate(%) 60° C./2 Weeks 89.1 92.5 - As is apparent from Tables 2 to 8, the formulations of Examples 3 to 34 maintained a high remaining rate at 60° C. over 2 or 4 weeks.
- Preservative effectiveness of the pharmaceutical composition of the present invention was studied.
- In the same manner as in preparation method of Example 1, the formulations of Examples 35 to 43 and Comparative Example 3 shown in Tables 9 and 10 were prepared.
-
TABLE 9 Exam- Exam- Exam- Exam- Exam- % (w/v) ple35 ple36 ple37 ple38 ple39 Present compound A 0.003 0.0003 0.003 0.003 0.003 Polyoxyl 35 castor oil 0.8 0.8 0.8 0.2 0.8 Boric acid 1.0 1.0 1.0 1.0 1.0 Disodium edetate 0.005 0.02 0.05 0.01 0.01 dihydrate Glycerol 1.0 1.0 1.0 1.0 1.0 Benzalkonium chloride 0.0085 0.0085 0.0085 0.004 0.0085 HCl/NaOH q.s. q.s. q.s. q.s. q.s. Purified water q.s. q.s. q.s. q.s. q.s. pH 5.5 5.5 5.5 5.0 6.5 -
TABLE 10 Compar- Exam- Exam- Exam- Exam- ative % (w/v) ple40 ple41 ple42 ple43 Example 3 Present com- 0.003 0.0003 0.001 0.003 0.003 pound A Polyoxyl 35 0.8 0.8 1.4 — 0.8 castor oil Polysorbate 80 — — — 0.8 — Trisodium 0.2 0.2 0.14 0.2 — citratedihydrate Citric acidmono- — — 0.03 — — hydrtae Boric acid — — — — 1.0 Disodium edetate 0.02 0.02 0.02 0.02 — dihydrate Glycerol 2.2 2.2 2.3 2.2 1.0 Benzalkonium 0.0085 0.004 0.0085 0.004 0.0085 chloride HCl/NaOH q.s. q.s. q.s. q.s. q.s. Purified water q.s. q.s. q.s. q.s. q.s. pH 6.0 6.0 5.6 6.0 5.5 - The following strains were used as inoculum.
- Escherichia coli, Escherichia Coli ATCC 8739
- Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 9027
- Staphylococcus aureus, Staphylococcus aureus ATCC 6538
- Candida albicans, Candida albicans ATCC 10231
- Aspergillus niger, Aspergillus niger ATCC16404
- A test was performed in accordance with a preservative effectiveness test defined in Sixteenth Revised Japanese Pharmacopoeia. Namely, an inoculum solution was prepared so as to adjust the concentration in a range of 107 to 108 cfu/mL and each formulation of Examples 35 to 43 and Comparative Example 3 was aseptically inoculated with each inoculum solution so as to adjust the concentration in a range of 10′ to 106 cfu/mL, followed by uniform mixing to give samples. These samples were stored under light-shielded condition at 20 to 25° C. and, after 14 and 28 days, 1 mL of each sample was collected and the number of general viable bacteria was measured.
- The number of general viable bacteria of bacteria, yeast fungus, and molds was measured in accordance with a most probable number method defined in a microbial limit test of Sixteenth Revised Japanese Pharmacopoeia.
- From the number of general viable bacteria determined by the most probable number method, a remaining rate was determined on the assumption that an initial bacterial count determined from the inoculum solution is 100.
- The case where the number of general viable bacteria after 14 and 28 days satisfies criteria of Table 11 in all bacterial strains was judged as “Passed”. When all results in each sampling are judged as “Passed”, it was judged that “preservative effectiveness exists”.
-
TABLE 11 Sampling time Bacteria Yeast fungus and molds After 14 days 0.1% or less relative to Same level as that of inoculumnumber inoculumnumber or less After 28 days Same level as that of Same level as that of inoculumnumber or less inoculumnumber or less after 14 days - Test results and judgements are shown in Table 12.
-
TABLE 12 Results and judgments of preservative effectiveness Bacterial After After test strains 14 days 28 days Judgment Example 35 Bacteria Passed Passed Preservative Yeast fungus and Passed Passed effectiveness molds exists Example 36 Bacteria Passed Passed Preservative Yeast fungus and Passed Passed effectiveness molds exists Example 37 Bacteria Passed Passed Preservative Yeast fungus and Passed Passed effectiveness molds exists Example 38 Bacteria Passed Passed Preservative Yeast fungus and Passed Passed effectiveness molds exists Example 39 Bacteria Passed Passed Preservative Yeast fungus and Passed Passed effectiveness molds exists Example 40 Bacteria Passed Passed Preservative Yeast fungus and Passed Passed effectiveness molds exists Example 41 Bacteria Passed Passed Preservative Yeast fungus and Passed Passed effectiveness molds exists Example 42 Bacteria Passed Passed Preservative Yeast fungus and Passed Passed effectiveness molds exists Example 43 Bacteria Passed Passed Preservative Yeast fungus and Passed Passed effectiveness molds exists Comparative Bacteria Not Passed Passed No preservative Example 3 Yeast fungus and Passed Passed effectiveness molds exists - As is apparent from Table 12, the formulations of Examples 35 to 43 have preservative effectiveness which conforms to standards of a preservative effectiveness test defined in Sixteenth Revised Japanese Pharmacopoeia. These results revealed that the pharmaceutical composition of the present invention has excellent preservative effectiveness.
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WO2015105134A1 (en) * | 2014-01-10 | 2015-07-16 | 参天製薬株式会社 | Pyridylaminoacetic acid compound and polyoxyethylene castor oil-containing pharmaceutical composition |
US20180200239A1 (en) | 2015-07-09 | 2018-07-19 | Santen Pharmaceutical Co., Ltd. | Prophylactic and/or therapeutic agent containing pyridylaminoacetic acid compound |
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US20200121652A1 (en) | 2017-06-16 | 2020-04-23 | The Doshisha | Compounds having caspase inhibitory activity, pharmaceutical agent containing said compounds and for treating or preventing corneal endothelial symptoms, disorders, or diseases, and application of said pharmaceutical agent |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140018350A1 (en) * | 2012-07-13 | 2014-01-16 | Asahi Glass Co., Ltd. | Combination of sulfonamide compound and tafluprost |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4960799A (en) * | 1988-09-13 | 1990-10-02 | Ciba-Geigy Corporation | Stabilized aqueous solutions of pharmaceutically acceptable salts of ortho-(2,6-dichlorophenyl)-aminophenylacetic acid for opthalmic use |
US5631287A (en) | 1994-12-22 | 1997-05-20 | Alcon Laboratories, Inc. | Storage-stable prostaglandin compositions |
JP3297969B2 (en) | 1994-12-26 | 2002-07-02 | ライオン株式会社 | Eye drops |
EP0938896A1 (en) * | 1998-01-15 | 1999-09-01 | Novartis AG | Autoclavable pharmaceutical compositions containing a chelating agent |
US6235781B1 (en) | 1998-07-14 | 2001-05-22 | Alcon Laboratories, Inc. | Prostaglandin product |
BR9906597A (en) | 1998-07-14 | 2000-07-18 | Alcon Lab Inc | Prostaglandin product |
US20020009507A1 (en) | 2000-01-19 | 2002-01-24 | Alcon Universal Ltd. | Use of polyethoxylated castor oil for the treatment of dry eye |
JP2002356420A (en) * | 2001-03-27 | 2002-12-13 | Santen Pharmaceut Co Ltd | Table aqueous liquid medicine |
JP5460996B2 (en) * | 2007-10-19 | 2014-04-02 | 大正製薬株式会社 | Ophthalmic agent |
PT2264009T (en) * | 2008-03-12 | 2019-04-29 | Ube Industries | Pyridylaminoacetic acid compound |
PL2415763T3 (en) * | 2009-03-30 | 2016-05-31 | Ube Industries | Pharmaceutical composition for treating or preventing glaucoma |
JP2011057633A (en) * | 2009-09-11 | 2011-03-24 | Ube Industries Ltd | Medicine containing pyridylaminoacetic acid compound |
TW201309343A (en) * | 2011-02-10 | 2013-03-01 | 參天製藥股份有限公司 | Aqueous composition with improved drug migration properties of hydrophilic drug |
WO2012141334A1 (en) * | 2011-04-12 | 2012-10-18 | R-Tech Ueno, Ltd. | Aqueous ophthalmic composition |
CN104136019A (en) | 2012-02-27 | 2014-11-05 | 日本乐敦制药株式会社 | Ophthalmic composition kit |
TR201820073T4 (en) * | 2012-03-26 | 2019-01-21 | Santen Pharmaceutical Co Ltd | Eye drops containing diquafosol. |
WO2014010354A1 (en) | 2012-07-09 | 2014-01-16 | シャープ株式会社 | Light emission device, illumination device, and insulating substrate |
JP2014019650A (en) * | 2012-07-13 | 2014-02-03 | Santen Pharmaceut Co Ltd | Combination of sulfonamide compound and tafluprost |
WO2014010654A2 (en) * | 2012-07-13 | 2014-01-16 | 参天製薬株式会社 | Sulfonamide compound combination |
US9339496B2 (en) * | 2012-07-13 | 2016-05-17 | Santen Pharmaceutical Co., Ltd. | Composition for treating or preventing glaucoma comprising a sulfonamide compound, and a beta-receptor antagonist |
WO2015105134A1 (en) * | 2014-01-10 | 2015-07-16 | 参天製薬株式会社 | Pyridylaminoacetic acid compound and polyoxyethylene castor oil-containing pharmaceutical composition |
EP3093019B1 (en) | 2014-01-10 | 2021-05-26 | Santen Pharmaceutical Co., Ltd | Pharmaceutical composition containing pyridylamino acetic acid compound |
CA2936026C (en) | 2014-01-10 | 2022-04-19 | Santen Pharmaceutical Co., Ltd. | Pharmaceutical preparation containing pyridylaminoacetic acid compound |
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