JP2023093601A - Ophthalmic product - Google Patents
Ophthalmic product Download PDFInfo
- Publication number
- JP2023093601A JP2023093601A JP2023067366A JP2023067366A JP2023093601A JP 2023093601 A JP2023093601 A JP 2023093601A JP 2023067366 A JP2023067366 A JP 2023067366A JP 2023067366 A JP2023067366 A JP 2023067366A JP 2023093601 A JP2023093601 A JP 2023093601A
- Authority
- JP
- Japan
- Prior art keywords
- ophthalmic
- silver
- acid
- container
- zirconium phosphate
- 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.)
- Withdrawn
Links
- 229940023490 ophthalmic product Drugs 0.000 title claims abstract description 30
- 239000000203 mixture Substances 0.000 claims abstract description 84
- 239000003889 eye drop Substances 0.000 claims abstract description 73
- 229910000166 zirconium phosphate Inorganic materials 0.000 claims abstract description 48
- LEHFSLREWWMLPU-UHFFFAOYSA-B zirconium(4+);tetraphosphate Chemical compound [Zr+4].[Zr+4].[Zr+4].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O LEHFSLREWWMLPU-UHFFFAOYSA-B 0.000 claims abstract description 48
- 239000011347 resin Substances 0.000 claims abstract description 34
- 229920005989 resin Polymers 0.000 claims abstract description 34
- 229910052709 silver Inorganic materials 0.000 abstract description 14
- 239000004332 silver Substances 0.000 abstract description 14
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 abstract description 13
- 239000000243 solution Substances 0.000 abstract description 6
- -1 polyethylene Polymers 0.000 description 52
- 239000003755 preservative agent Substances 0.000 description 40
- 238000012360 testing method Methods 0.000 description 33
- 230000002335 preservative effect Effects 0.000 description 30
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 241000894006 Bacteria Species 0.000 description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 150000003839 salts Chemical class 0.000 description 18
- 239000004359 castor oil Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 16
- 235000019438 castor oil Nutrition 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- 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 description 15
- 239000003795 chemical substances by application Substances 0.000 description 14
- 229940012356 eye drops Drugs 0.000 description 14
- 238000009472 formulation Methods 0.000 description 12
- 235000014113 dietary fatty acids Nutrition 0.000 description 11
- 239000000194 fatty acid Substances 0.000 description 11
- 229930195729 fatty acid Natural products 0.000 description 11
- 239000002997 ophthalmic solution Substances 0.000 description 11
- 229940054534 ophthalmic solution Drugs 0.000 description 11
- 239000004094 surface-active agent Substances 0.000 description 11
- 239000012929 tonicity agent Substances 0.000 description 11
- 239000003002 pH adjusting agent Substances 0.000 description 10
- 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 9
- 229940079593 drug Drugs 0.000 description 9
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- 238000010998 test method Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000654 additive Substances 0.000 description 8
- 229910001385 heavy metal Inorganic materials 0.000 description 8
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 8
- 229920003023 plastic Polymers 0.000 description 8
- 239000004033 plastic Substances 0.000 description 8
- 239000003963 antioxidant agent Substances 0.000 description 7
- 235000006708 antioxidants Nutrition 0.000 description 7
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 7
- 239000004327 boric acid Substances 0.000 description 7
- 229920006158 high molecular weight polymer Polymers 0.000 description 7
- 230000003204 osmotic effect Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 229920001817 Agar Polymers 0.000 description 6
- 239000004743 Polypropylene Substances 0.000 description 6
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- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 6
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- NMLMACJWHPHKGR-NCOIDOBVSA-N P(1),P(4)-bis(uridin-5'-yl) tetraphosphate Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@H]2O)O)COP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@H]([C@@H](O2)N2C(NC(=O)C=C2)=O)O)O)C=CC(=O)NC1=O NMLMACJWHPHKGR-NCOIDOBVSA-N 0.000 description 5
- 229920001214 Polysorbate 60 Polymers 0.000 description 5
- 239000008186 active pharmaceutical agent Substances 0.000 description 5
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- 229950003529 diquafosol Drugs 0.000 description 5
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000007689 inspection Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000002736 nonionic surfactant Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 241001331781 Aspergillus brasiliensis Species 0.000 description 3
- 241000222122 Candida albicans Species 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 229920002675 Polyoxyl Polymers 0.000 description 3
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
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- 229940068968 polysorbate 80 Drugs 0.000 description 3
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- 238000004321 preservation Methods 0.000 description 3
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- 239000005720 sucrose Substances 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 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
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- 241000233866 Fungi Species 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
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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 2
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- 239000001110 calcium chloride Substances 0.000 description 2
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- 229940095731 candida albicans Drugs 0.000 description 2
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- 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
- 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
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-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
- 239000008215 water for injection Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
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- A—HUMAN NECESSITIES
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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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- 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
- A61K47/06—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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D1/00—Containers having bodies formed in one piece, e.g. by casting metallic material, by moulding plastics, by blowing vitreous material, by throwing ceramic material, by moulding pulped fibrous material, by deep-drawing operations performed on sheet material
-
- 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
- Y02W—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
- Y02W90/00—Enabling technologies or technologies with a potential or indirect contribution to greenhouse gas [GHG] emissions mitigation
- Y02W90/10—Bio-packaging, e.g. packing containers made from renewable resources or bio-plastics
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Abstract
Description
本発明は、銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品に関する。 TECHNICAL FIELD The present invention relates to an ophthalmic product in which an ophthalmic composition having a pH of less than 7 is accommodated in a multi-dose type eyedrop container made of a resin containing silver-supported zirconium phosphate.
点眼容器には、複数回使用可能なマルチドーズ型点眼容器と１回使い切りユニットドーズ型点眼容器がある。マルチドーズ型点眼容器は、一定期間複数回使用することから菌類等の繁殖を防止するために眼科用組成物に塩化ベンザルコニウムなどの防腐剤が配合されるのが一般的である。しかし、例えば、防腐剤である塩化ベンザルコニウムには細胞障害性があり、曝露量が増えると角膜上皮障害を引き起こす可能性があることから防腐剤を含まないことがより望ましい。そのため、防腐剤を含まない眼科用組成物を収容する点眼容器として、上述のユニットドーズ点眼容器が使用されている。また、近年では、導出孔に逆流防止弁を有することで防腐効果を発揮する容器やフィルター付きのデラミボトルとすることで防腐効果を発揮する容器など、物理的な構造によって防腐剤を含まずとも防腐効果を発揮するマルチドーズ型点眼容器（ＰＦＭＤ（Ｐｒｅｓｅｒｖａｔｉｖｅ Ｆｒｅｅ
Ｍｕｌｔｉ Ｄｏｓｅ）容器）も使用されている（例えば特許文献１など）。
Eye drop containers include multi-dose eye drop containers that can be used multiple times and single-use unit-dose eye drop containers. Since multi-dose eyedropper containers are used multiple times for a certain period of time, preservatives such as benzalkonium chloride are generally added to ophthalmic compositions to prevent the growth of fungi and the like. However, for example, benzalkonium chloride, which is a preservative, is cytotoxic and may cause damage to the corneal epithelium when exposed to an increased amount. Therefore, the above-mentioned unit dose eye drop container is used as an eye drop container containing an ophthalmic composition containing no preservative. In addition, in recent years, containers that exhibit a preservative effect by having a check valve in the outlet hole and a container that exhibits a preservative effect by making it a delaminated bottle with a filter have been developed. Effective multi-dose eyedropper (PFMD (Preservative Free
Multi Dose container) is also used (for example, Patent Document 1, etc.).
ところで、特許文献２には、容器の全面または所要部分に抗菌性ゼオライトが分散保持されたユニットドーズ型点眼容器が開示されており（技術分野、請求項１、２２など）、点眼容器の抗菌力が確認されたことが示されている（試験例－１）。しかし、一般にユニットドーズ型点眼容器は１回使い切りのためコストが高く、かさばる、あるいは開封がしにくいといった使用上の欠点もある。 By the way, Patent Document 2 discloses a unit-dose type eye drop container in which antibacterial zeolite is dispersed and retained on the entire surface or a required part of the container (technical field, claims 1, 22, etc.), and the antibacterial activity of the eye drop container is disclosed. is confirmed (Test Example-1). However, unit-dose type eyedropper containers are generally used up once, so they are expensive, bulky, and difficult to open.
本発明の一態様の課題は、上述の逆流防止弁やフィルター付きデラミボトルなど物理的な構造を施さなくても、一定期間複数回使用できる眼科用製品を提供することである。 An object of one aspect of the present invention is to provide an ophthalmic product that can be used multiple times for a certain period of time without applying a physical structure such as the anti-reflux valve or delaminated bottle with a filter.
本発明者は、上記課題を解決するために鋭意研究を行った結果、銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品が優れた保存効力を有することを見出し、本発明を完成させた。 As a result of intensive research to solve the above problems, the present inventors have found that an ophthalmic composition having a pH of less than 7 is accommodated in a multi-dose type eyedrop container formed of a resin containing silver-supported zirconium phosphate. The present inventors have completed the present invention based on the finding that the ophthalmic product prepared by the inventors has excellent preservative efficacy.
すなわち、本発明の一態様に係る眼科用製品は、銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された構成である。 That is, an ophthalmic product according to one aspect of the present invention has a configuration in which an ophthalmic composition having a pH of less than 7 is accommodated in a multi-dose eyedrop container formed of a resin containing silver-supported zirconium phosphate. .
また、本発明の他の態様に係る眼科用製品は、樹脂に対して、０．０８～１０％（ｗ／ｗ）の濃度の銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品であって、前記眼科用組成物と接触している前記樹脂の一部または全部が銀担持リン酸ジルコニウムを含み、前記銀担持リン酸ジルコニウムが、銀をイオン濃度で０．００１～２０％（ｗ／ｗ）含み、前記眼科用組成物が防腐剤を実質的に含有しない、構成である。 Further, an ophthalmic product according to another aspect of the present invention is a multi-dose eye drop made of a resin containing silver-supported zirconium phosphate at a concentration of 0.08 to 10% (w/w) with respect to the resin. An ophthalmic product, wherein a container contains an ophthalmic composition having a pH of less than 7, wherein part or all of the resin in contact with the ophthalmic composition comprises silver-supported zirconium phosphate; The silver-supported zirconium phosphate contains 0.001 to 20% (w/w) silver in ion concentration, and the ophthalmic composition is substantially free of preservatives.
さらに、本発明のさらに他の態様に係る眼科用組成物は、ｐＨが７未満である眼科用組成物であって、前記眼科用組成物が、銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に収容されている。 Furthermore, an ophthalmic composition according to still another aspect of the present invention is an ophthalmic composition having a pH of less than 7, wherein the ophthalmic composition is formed of a resin containing silver-supported zirconium phosphate. It is housed in a multi-dose type eye drop container.
銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品は、優れた保存効力を有する。本発明の態様によれば、上述の逆流防止弁やフィルター付きデラミボトルなど物理的な構造を施さなくても、一定期間複数回使用でき、上述のユニットドーズ型点眼容器の欠点もないことから有用である。 An ophthalmic product in which an ophthalmic composition having a pH of less than 7 is accommodated in a multi-dose type eyedrop container made of a resin containing silver-supported zirconium phosphate has excellent preservative efficacy. According to the aspect of the present invention, it is useful because it can be used multiple times for a certain period of time without applying a physical structure such as the above-mentioned backflow prevention valve or delaminated bottle with a filter, and it does not have the above-mentioned drawbacks of the unit-dose type eyedropper. be.
以下、本発明の一実施形態に関してさらに詳しく説明する。なお、本明細書において特記しない限り、数値範囲を表す「Ａ～Ｂ」または「Ａ乃至Ｂ」は、「Ａ以上（Ａを含みかつＡよりも大きい）、Ｂ以下（Ｂを含みかつＢよりも小さい）」を意味する。また、「Ａ超乃至Ｂ」は、「Ａを超え（Ａより大きい）、Ｂ以下（Ｂを含みかつＢより小さい）」を意味する。 An embodiment of the present invention will be described in more detail below. In this specification, unless otherwise specified, "A to B" or "A to B" representing a numerical range is "A or more (including A and greater than A), B or less (including B and greater than B is smaller). Further, "greater than A to B" means "greater than A (greater than A) and less than or equal to B (including B and less than B)".
本発明の一実施形態は、銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器（以下、「本点眼容器」ともいう）に、ｐＨが７未満である眼科用組成物（以下、「本組成物」ともいう）が収容された眼科用製品（以下、「本製品」ともいう）を提供する。ここで、「本製品」としては、例えば、点眼剤の製品（「点眼剤製品」ともいう）が挙げられる。 In one embodiment of the present invention, an ophthalmic composition having a pH of less than 7 (hereinafter also referred to as a "present eye drop container") is placed in a multi-dose eye drop container (hereinafter also referred to as "the present eye drop container") made of a resin containing silver-supported zirconium phosphate. , also referred to as the "composition") is provided (hereinafter also referred to as the "product"). Here, the "present product" includes, for example, an eye drop product (also referred to as an "eye drop product").
本発明の一実施形態において、「眼科用組成物」とは、眼疾患などの予防および／または治療に使用するための組成物のことをいう。その剤型としては、例えば、点眼剤が挙げられる。ここで点眼剤とは点眼液または点眼薬と同義であり、コンタクトレンズ用点眼剤も点眼剤の定義に含まれる。 In one embodiment of the invention, "ophthalmic composition" refers to a composition for use in preventing and/or treating eye diseases and the like. Examples of dosage forms thereof include eye drops. Here, eye drops are synonymous with eye drops or eye drops, and eye drops for contact lenses are also included in the definition of eye drops.
本組成物の形態としては、特に制限されないが、例えば、水溶液、懸濁液、乳濁液、ゲルなどが挙げられる。 The form of the present composition is not particularly limited, but examples thereof include aqueous solutions, suspensions, emulsions, gels and the like.
本組成物が点眼剤、特に水性点眼剤である場合、溶媒として水を含有することが好ましい。水の例としては、滅菌精製水、注射用水等を挙げることができる。水の含有量としては、例えば、８０％（ｗ／ｖ）以上１００％（ｗ／ｖ）未満であることが好ましく、８５％（ｗ／ｖ）以上９９．５％（ｗ／ｖ）％以下であることがより好ましく、９０％（ｗ／ｖ）以上９９．２％（ｗ／ｖ）以下であることがさらに好ましい。 When the composition is an eye drop, especially an aqueous eye drop, it preferably contains water as a solvent. Examples of water include sterile purified water, water for injection, and the like. The water content is, for example, preferably 80% (w/v) or more and less than 100% (w/v), and 85% (w/v) or more and 99.5% (w/v) or less. and more preferably 90% (w/v) or more and 99.2% (w/v) or less.
本組成物は、保存効力をより発揮するために、添加物として防腐剤を含んでもよいが、後述の実施例に示すように、本製品は高い保存効力を有することから、眼科用組成物に一般に使用される防腐剤を含有しなくてもよい。防腐剤の例としては、例えば、ベンザルコニウム塩化物、ベンザルコニウム臭化物、ベンゼトニウム塩化物、ベンゾドデシニウム臭化物、ソルビン酸、ソルビン酸カリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル、クロロブタノール、クロルヘキシジンなどが挙げられる。 The present composition may contain a preservative as an additive in order to further exert its preservative effect. It may not contain commonly used preservatives. Examples of preservatives include, for example, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, benzododecinium bromide, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, chlorhexidine and the like.
本発明の一実施形態において、本組成物が防腐剤を実質的に含有しないことが好ましい。「防腐剤を実質的に含有しない」とは、防腐剤を全く含有しないか、または限られた量の防腐剤を含有することを意味する。ここで、「限られた量の防腐剤を含有する」とは、防腐剤の防腐効力を発揮しない量を意味する。例えば、防腐剤単独で医薬としての防腐効力を発揮しない量を意味することが挙げられる。具体的には、防腐剤の種類によっても異なるが、例えば、好ましくは約０．０１％（ｗ／ｗ）以下の防腐剤を含有することをいい、より好ましくは約０．００５％（ｗ／ｗ）以下の防腐剤を含有することをいい、さらに好ましくは約０．００１％（ｗ／ｗ）以下の防腐剤を含有することをいい、よりさらに好ましくは約０．０００５％（ｗ／ｗ）以下の防腐剤を含有することをいい、特に好ましくは約０．０００１％（ｗ／ｗ）以下の防腐剤を含有することをいう。 In one embodiment of the invention, it is preferred that the composition is substantially free of preservatives. "Substantially free of preservatives" means either no preservatives or limited amounts of preservatives. Here, "containing a limited amount of preservative" means an amount that does not exhibit the preservative efficacy of the preservative. For example, it means an amount in which the antiseptic alone does not exhibit antiseptic efficacy as a medicine. Specifically, although it varies depending on the type of preservative, for example, it preferably contains about 0.01% (w/w) or less of the preservative, and more preferably about 0.005% (w/w). w) contains no more than about 0.001% (w/w) preservatives, and even more preferably about 0.0005% (w/w) ) contains the following preservatives, particularly preferably about 0.0001% (w/w) or less of the preservatives.
本発明の一実施形態において、「マルチドーズ型点眼容器」は、本組成物を収容する容器本体、容器本体に収容された本組成物を注出する注出口を有する注出部、および注出口をふさぐキャップを備えた点眼容器であって、キャップの開封、再封を自由に行うことができる点眼容器のことをいう。ここで、マルチドーズ型点眼容器は、容器本体に装着可能な中栓を注出部として使用してもよいし、本組成物を収容する収容部（容器本体）と注出部が一体成型された容器本体および注出口をふさぐキャップから構成されていてもよい。当該容器の形状、大きさについては特に制限されるものではなく、収容する本組成物の含量、種類、性質等に応じて適宜設定することができる。 In one embodiment of the present invention, the "multi-dose eye drop container" includes a container main body containing the present composition, a spout portion having a spout for spouting the present composition contained in the container main body, and a spout It is an eye drop container equipped with a cap that closes the eye, and the cap can be freely opened and resealed. Here, in the multi-dose type eye drop container, an inner plug attachable to the container body may be used as the spout portion, or the storage portion (container main body) for containing the present composition and the spout portion are integrally molded. It may be composed of a container body and a cap that closes the spout. The shape and size of the container are not particularly limited, and can be appropriately set according to the content, type, properties, etc. of the present composition to be accommodated.
当該マルチドーズ型容器には、通常一定期間使用するために複数回分の眼科用組成物が収容されている。 The multi-dose container typically contains multiple doses of the ophthalmic composition for use over a period of time.
本発明の一実施形態において、マルチドーズ型点眼容器の容器本体の容量は眼科用製品に許容される範囲内にあれば特に制限されないが、５～２０ｍＬが好ましく、５～１５ｍＬがより好ましく、５～１０ｍＬがさらに好ましい。 In one embodiment of the present invention, the volume of the container body of the multi-dose eye drop container is not particularly limited as long as it is within the range allowed for ophthalmic products, but is preferably 5 to 20 mL, more preferably 5 to 15 mL, ~10 mL is even more preferred.
本発明の一実施形態において、マルチドーズ型点眼容器に収容される眼科用組成物の総容量は、眼科用製品に許容される範囲内にあれば特に制限されないが、２～２０ｍＬが好ましく、２～１０ｍＬがより好ましく、２～５ｍＬがさらに好ましい。 In one embodiment of the present invention, the total volume of the ophthalmic composition housed in the multi-dose eye drop container is not particularly limited as long as it is within the allowable range for ophthalmic products, but is preferably 2 to 20 mL. ~10 mL is more preferred, and 2-5 mL is even more preferred.
本発明の一実施形態において、マルチドーズ型点眼容器は樹脂で形成されるが、その材質は特に限定されない。例えば、ポリエチレン（ＰＥ；高密度ポリエチレン（ＨＤＰＥ）、低密度ポリエチレン（ＬＤＰＥ）、直鎖状低密度ポリエチレン（ＬＬＤＰＥ））、ポリプロピレン（ＰＰ）、ポリエチレンテレフタレート（ＰＥＴ）などの樹脂を挙げることができる。 In one embodiment of the present invention, the multi-dose eye drop container is made of resin, but the material is not particularly limited. Examples thereof include resins such as polyethylene (PE; high density polyethylene (HDPE), low density polyethylene (LDPE), linear low density polyethylene (LLDPE)), polypropylene (PP), and polyethylene terephthalate (PET).
本発明の一実施形態において、銀担持リン酸ジルコニウムはマルチドーズ型点眼容器の樹脂に含まれていれば特に制限されないが、眼科用組成物の保存効力を発揮させるためには、容器本体の樹脂に含まれていることが好ましく、本組成物と接触している樹脂の一部または全部に少なくとも含まれていることがより好ましい。また、銀担持リン酸ジルコニウムがマルチドーズ型点眼容器の樹脂に含まれるとは、銀担持リン酸ジルコニウムがマルチドーズ型点眼容器の樹脂に分散保持されていることを意味する。 In one embodiment of the present invention, the silver-supported zirconium phosphate is not particularly limited as long as it is contained in the resin of the multi-dose eye drop container. and more preferably at least in part or all of the resin in contact with the composition. In addition, the fact that silver-supported zirconium phosphate is contained in the resin of the multi-dose eyedrop container means that the silver-supported zirconium phosphate is dispersed and held in the resin of the multi-dose eyedrop container.
なお、本発明の一実施形態において、「ユニットドーズ型容器」とは、瓶口部にキャップが融着封止され、使用時に当該キャップと瓶形本体との融着部を破断開封して使用することを目的とした点眼容器のことをいう。当該ユニットドーズ型容器には、１回使い切りのために１回使用分の水性組成物が収容されているのが一般的である。また、一般に、ユニットドーズ型点眼容器の容器本体の容量は０．１～１ｍＬであり、通常０．１ｍＬ～０．５ｍＬの眼科用組成物が収容される。 In one embodiment of the present invention, a "unit dose type container" is one in which a cap is fused and sealed at the mouth of a bottle, and the fused portion between the cap and the bottle-shaped main body is broken open when used. It refers to an eye drop container intended to The unit-dose container generally contains a single-use aqueous composition for single-use. In general, the capacity of the container body of the unit dose type eye drop container is 0.1 to 1 mL, and usually 0.1 mL to 0.5 mL of the ophthalmic composition is accommodated therein.
一般に、眼科用組成物の単位容量あたりの容器本体への全接触面積は、マルチドーズ型点眼容器の方がユニットドーズ型点眼容器よりも小さい。 In general, the total contact area of the ophthalmic composition with the container body per unit volume is smaller in the multi-dose type eye drop container than in the unit dose type eye drop container.
本発明の一実施形態におけるマルチドーズ型点眼容器は、抗菌剤として銀が担持されたリン酸ジルコニウム（以下、単に「銀担持リン酸ジルコニウム」ともいう）を含む樹脂で形成されている。 A multi-dose eye drop container according to an embodiment of the present invention is made of a resin containing zirconium phosphate supporting silver as an antibacterial agent (hereinafter also simply referred to as “silver-supporting zirconium phosphate”).
銀担持リン酸ジルコニウムは、無機イオン交換体である六方晶リン酸ジルコニウムに、イオン交換法を用いて銀イオンを担持させたものである。 Silver-supported zirconium phosphate is obtained by supporting silver ions on hexagonal zirconium phosphate, which is an inorganic ion exchanger, using an ion exchange method.
銀担持リン酸ジルコニウムは、ノバロン（登録商標）ＡＧとして東亞合成株式会社から販売されている。 Silver-supported zirconium phosphate is sold by Toagosei Co., Ltd. as Novaron (registered trademark) AG.
銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器は、銀担持リン酸ジルコニウムを配合して練り込んだ加熱融解状の樹脂を成形することによって製造することができる。 A multi-dose type eyedrop container formed of a resin containing silver-supported zirconium phosphate can be produced by molding a heat-melted resin in which silver-supported zirconium phosphate is blended and kneaded.
本発明の一実施形態において、銀担持リン酸ジルコニウムは、樹脂に対して、０．０８～１０％（ｗ／ｗ）の濃度で含まれることが好ましく、０．０８超乃至１０％（ｗ／ｗ）以下の濃度で含まれることがより好ましく、０．０８超乃至５％（ｗ／ｗ）以下の濃度で含まれることがさらに好ましく、０．０８超乃至１％（ｗ／ｗ）以下の濃度で含まれることが特に好ましい。 In one embodiment of the present invention, silver-supported zirconium phosphate is preferably contained in a concentration of 0.08 to 10% (w/w) relative to the resin, and more than 0.08 to 10% (w/w). w) more preferably contained at a concentration of no more than 0.08 to 5% (w/w), more preferably from more than 0.08 to 1% (w/w) Concentrations are particularly preferred.
本発明の一実施形態において、銀担持リン酸ジルコニウム中の銀はイオン濃度で、０．００１～２０％（ｗ／ｗ）含むことが好ましく、０．０１～２０％（ｗ／ｗ）含むことがより好ましく、０．１～２０％（ｗ／ｗ）含むことがさらに好ましく、０．５～１５％（ｗ／ｗ）含むことがよりさらに好ましく、１～１５％（ｗ／ｗ）含むことがことさら好ましく、５～１５％（ｗ／ｗ）含むことが特に好ましい。 In one embodiment of the present invention, the ion concentration of silver in the silver-supported zirconium phosphate is preferably 0.001 to 20% (w/w), more preferably 0.01 to 20% (w/w). is more preferred, more preferably 0.1 to 20% (w/w), even more preferably 0.5 to 15% (w/w), 1 to 15% (w/w) is particularly preferred, and 5-15% (w/w) is particularly preferred.
本発明の一実施形態において、点眼容器は薄肉であることから、銀担持リン酸ジルコニウムの平均粒径は０．０１～３μｍであることが好ましく、０．１～２μｍであることがより好ましい。 In one embodiment of the present invention, since the eye drop container is thin, the silver-supported zirconium phosphate preferably has an average particle size of 0.01 to 3 μm, more preferably 0.1 to 2 μm.
本組成物は、種々の薬物を単独または適宜組み合わせて適当量含有してもよい。当該薬物は、医薬として許容される薬物であれば特に限定されない。例えば、眼疾患の予防及び／又は治療に使用される薬物が挙げられる。なお、ここで「薬物」は、薬の「有効成分」と同義である。 The composition may contain appropriate amounts of various drugs alone or in appropriate combination. The drug is not particularly limited as long as it is a drug that is pharmaceutically acceptable. Examples include drugs used for the prevention and/or treatment of eye diseases. In addition, the "drug" here is synonymous with the "active ingredient" of medicine.
本発明の一実施形態において、薬物としては、薬物の塩も含まれ、医薬として許容される塩であれば特に制限はなく、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸などの無機酸との塩、酢酸、フマル酸、マレイン酸、コハク酸、クエン酸、酒石酸、アジピン酸、グルコン酸、グルコヘプト酸、グルクロン酸、テレフタル酸、メタンスルホン酸、乳酸、馬尿酸、１，２－エタンジスルホン酸、イセチオン酸、ラクトビオン酸、オレイン酸、パモ酸、ポリガラクツロン酸、ステアリン酸、タンニン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、硫酸ラウリルエステル、硫酸メチル、ナフタレンスルホン酸、スルホサリチル酸などの有機酸との塩；臭化メチル、ヨウ化メチルなどとの四級アンモニウム塩；臭素イオン、塩素イオン、ヨウ素イオンなどのハロゲンイオンとの塩；リチウム、ナトリウム、カリウムなどのアルカリ金属との塩；カルシウム、マグネシウムなどのアルカリ土類金属との塩；鉄、亜鉛などとの金属塩；アンモニアとの塩；トリエチレンジアミン、２－アミノエタノール、２，２－イミノビス（エタノール）、１－デオキシ－１－（メチルアミノ）－２－Ｄ－ソルビトール、２－アミノ－２－（ヒドロキシメチル）－１，３－プロパンジオール、プロカイン、Ｎ，Ｎ－ビス（フェニルメチル）－１，２－エタンジアミンなどの有機アミンとの塩などが挙げられる。 In one embodiment of the present invention, the drug also includes drug salts, and is not particularly limited as long as it is a pharmaceutically acceptable salt. Salts with inorganic acids such as acids, acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1 , 2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate , naphthalenesulfonic acid, salts with organic acids such as sulfosalicylic acid; quaternary ammonium salts with methyl bromide, methyl iodide, etc.; salts with halogen ions such as bromide ion, chloride ion, iodide ion; lithium, sodium, salts with alkali metals such as potassium; salts with alkaline earth metals such as calcium and magnesium; metal salts with iron and zinc; salts with ammonia; triethylenediamine, 2-aminoethanol, 2,2-iminobis ( ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, N,N-bis(phenylmethyl)- Examples thereof include salts with organic amines such as 1,2-ethanediamine.
本組成物に含有される薬物またはその塩は、水和物または溶媒和物の形態をとってもよい。 The drug or its salt contained in the present composition may take the form of hydrate or solvate.
本組成物には、汎用されている技術を用い、必要に応じて製薬学的に許容される添加物を配合することができる。例えば、界面活性剤、緩衝剤、等張化剤、安定化剤、抗酸化剤、高分子量重合体等を配合することができる。好ましくは、本組成物は、界面活性剤および等張化剤からなる群から選択される少なくとも１種をさらに含む。 Pharmaceutically acceptable additives can be blended into the present composition as necessary using commonly used techniques. For example, surfactants, buffers, tonicity agents, stabilizers, antioxidants, high-molecular-weight polymers and the like can be blended. Preferably, the composition further comprises at least one selected from the group consisting of surfactants and tonicity agents.
界面活性剤としては、例えば、カチオン性界面活性剤、アニオン性界面活性剤、非イオン性界面活性剤を配合することができる。 As surfactants, for example, cationic surfactants, anionic surfactants, and nonionic surfactants can be blended.
アニオン性界面活性剤の例としては、硫酸塩系界面活性剤、リン脂質等が挙げられ、硫酸塩系界面活性剤としては、例えば、アルキル硫酸ナトリウム塩、アルキルベンゼン硫酸塩等が挙げられる。リン脂質としては、例えば、レシチン等が挙げられる。 Examples of anionic surfactants include sulfate-based surfactants and phospholipids. Examples of sulfate-based surfactants include sodium alkyl sulfates and alkylbenzene sulfates. Phospholipids include, for example, lecithin.
カチオン性界面活性剤の例としては、アルキルアミン塩、アルキルアミンポリオキシエチレン付加物、脂肪酸トリエタノールアミンモノエステル塩、アシルアミノエチルジエチルアミン塩、脂肪酸ポリアミン縮合物、アルキルイミダゾリン、１－アシルアミノエチル－２－アルキルイミダゾリン、１－ヒドロキシルエチル－２－アルキルイミダゾリン等が挙げられる。 Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyldiethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl- 2-alkylimidazoline, 1-hydroxyethyl-2-alkylimidazoline and the like.
非イオン性界面活性剤の例としては、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンヒマシ油、ポリオキシエチレンポリオキシプロピレングリコール、ショ糖脂肪酸エステル、ビタミンＥ ＴＰＧＳ等が挙げられる。 Examples of nonionic surfactants include polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid esters, vitamin E TPGS and the like.
ポリオキシエチレン脂肪酸エステルとしては、ステアリン酸ポリオキシル４０等が挙げられる。 Examples of polyoxyethylene fatty acid esters include polyoxyl 40 stearate.
ポリオキシエチレンソルビタン脂肪酸エステルとしては、ポリソルベート８０、ポリソルベート６０、ポリソルベート４０、ポリオキシエチレンソルビタンモノラウレート、ポリオキシエチレンソルビタントリオレート、ポリソルベート６５等が挙げられる。ポリソルベート８０が特に好ましい。 Polyoxyethylene sorbitan fatty acid esters include polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65 and the like. Polysorbate 80 is particularly preferred.
ポリオキシエチレン硬化ヒマシ油としては、酸化エチレンの重合数の異なる種々のポリオキシエチレン硬化ヒマシ油を用いることができ、酸化エチレンの重合数は１０～１００が好ましく、２０～８０がより好ましく、４０～７０が特に好ましく、６０が最も好ましい。ポリオキシエチレン硬化ヒマシ油の具体例としては、ポリオキシエチレン硬化ヒマシ油１０、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０等が挙げられる。 As the polyoxyethylene hydrogenated castor oil, various polyoxyethylene hydrogenated castor oils having different polymerization numbers of ethylene oxide can be used. ~70 is particularly preferred and 60 is most preferred. Specific examples of polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, and the like.
ポリオキシエチレンヒマシ油としては、酸化エチレンの重合数の異なる種々のポリオキシエチレンヒマシ油を用いることができ、酸化エチレンの重合数は５～１００が好ましく、２０～５０がより好ましく、３０～４０が特に好ましく、３５が最も好ましい。ポリオキシエチレンヒマシ油の具体例としては、ポリオキシル５ヒマシ油、ポリオキシル９ヒマシ油、ポリオキシル１５ヒマシ油、ポリオキシル３５ヒマシ油、ポリオキシル４０ヒマシ油等が挙げられる。 As the polyoxyethylene castor oil, various polyoxyethylene castor oils having different polymerization numbers of ethylene oxide can be used. is particularly preferred and 35 is most preferred. Specific examples of polyoxyethylene castor oil include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 castor oil.
ポリオキシエチレンポリオキシプロピレングリコールとしては、ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール、ポリオキシエチレン（４２）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（５４）ポリオキシプロピレン（３９）グリコール、ポリオキシエチレン（１９６）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（２０）ポリオキシプロピレン（２０）グリコール等が挙げられる。 Polyoxyethylene polyoxypropylene glycol includes 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.
ショ糖脂肪酸エステルとしては、ショ糖ステアリン酸エステル等が挙げられる。 Examples of sucrose fatty acid esters include sucrose stearate.
ビタミンＥ ＴＰＧＳは、トコフェロールポリエチレングリコール１０００コハク酸エステルともいう。 Vitamin E TPGS is also called tocopherol polyethylene glycol 1000 succinate.
本組成物に界面活性剤を配合する場合の界面活性剤の含有量は、界面活性剤の種類等により適宜調整することができるが、０．００１～１０％（ｗ／ｖ）が好ましく、０．０１～５％（ｗ／ｖ）がより好ましく、０．０１～３％（ｗ／ｖ）がさらに好ましく、０．０１～１％（ｗ／ｖ）がよりさらに好ましい。 The content of the surfactant when blending the surfactant in the present composition can be appropriately adjusted depending on the type of surfactant, etc., but is preferably 0.001 to 10% (w / v), and 0 0.01-5% (w/v) is more preferred, 0.01-3% (w/v) is more preferred, and 0.01-1% (w/v) is even more preferred.
これらの界面活性剤は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 These surfactants may be used singly or in any combination of two or more.
本組成物には、医薬品の添加物として使用可能な緩衝剤を配合することができる。例えば、リン酸又はその塩、クエン酸又はその塩、酢酸又はその塩、炭酸又はその塩、酒石酸又はその塩、ε－アミノカプロン酸、トロメタモール等が挙げられる。 The present composition may contain a buffering agent that can be used as an additive for pharmaceuticals. Examples include phosphoric acid or salts thereof, citric acid or salts thereof, acetic acid or salts thereof, carbonic acid or salts thereof, tartaric acid or salts thereof, ε-aminocaproic acid, trometamol and the like.
リン酸塩としては、リン酸ナトリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸カリウム、リン酸二水素カリウム、リン酸水素二カリウム等が挙げられ、クエン酸塩としては、クエン酸ナトリウム、クエン酸二ナトリウム等が挙げられ、酢酸塩としては、酢酸ナトリウム、酢酸カリウム等が挙げられ、炭酸塩としては、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられ、酒石酸塩としては、酒石酸ナトリウム、酒石酸カリウム等が挙げられる。 Phosphates include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and the like, and citrates include citric acid sodium, disodium citrate and the like; acetates include sodium acetate, potassium acetate and the like; carbonates include sodium carbonate, sodium hydrogen carbonate and the like; tartrates include sodium tartrate, and potassium tartrate.
本組成物に緩衝剤を配合する場合の緩衝剤の含有量は、緩衝剤の種類等により適宜調整することができるが、０．００１～１０％（ｗ／ｖ）が好ましく、０．０１～５％（ｗ／ｖ）がより好ましく、０．１～３％（ｗ／ｖ）がさらに好ましく、０．２～２％（ｗ／ｖ）が最も好ましい。 The content of the buffering agent when blending the buffering agent in the present composition can be appropriately adjusted depending on the type of the buffering agent, etc., but is preferably 0.001 to 10% (w / v), and 0.01 to 5% (w/v) is more preferred, 0.1-3% (w/v) is more preferred, and 0.2-2% (w/v) is most preferred.
これらの緩衝剤は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 These buffering agents may be used singly or in any combination of two or more.
本組成物には、医薬品の添加物として使用可能な等張化剤を適宜配合することができる。等張化剤の例としては、イオン性等張化剤、非イオン性等張化剤等が挙げられる。イオン性等張化剤としては、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、ホウ酸、ホウ砂などが挙げられ、非イオン性等張化剤としてはグリセリン、プロピレングリコール、ソルビトール、マンニトール等が挙げられる。本組成物に等張化剤を配合する場合の等張化剤の含有量は、等張化剤の種類等により適宜調整することができるが、０．０１～１０％（ｗ／ｖ）が好ましく、０．１～５％（ｗ／ｖ）がより好ましく、０．５～３％（ｗ／ｖ）が最も好ましい。 An isotonicity agent that can be used as a pharmaceutical additive can be appropriately blended into the present composition. Examples of tonicity agents include ionic tonicity agents, nonionic tonicity agents and the like. Examples of ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, boric acid, and borax. Examples of nonionic tonicity agents include glycerin, propylene glycol, sorbitol, mannitol, and the like. mentioned. The content of the tonicity agent when blending the tonicity agent with the present composition can be appropriately adjusted depending on the type of the tonicity agent. Preferably, 0.1-5% (w/v) is more preferred, and 0.5-3% (w/v) is most preferred.
これらの等張化剤は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 These isotonizing agents may be used singly or in any combination of two or more.
本組成物には、医薬品の添加物として使用可能な安定化剤を適宜配合することができる。例えば、エデト酸、エデト酸一ナトリウム、エデト酸二ナトリウム、エデト酸四ナトリウム、クエン酸ナトリウム等が挙げられ、エデト酸二ナトリウムが好ましく、エデト酸二ナトリウム二水和物が特に好ましい。本組成物に安定化剤を配合する場合の安定化剤の含有量は、安定化剤の種類等により適宜調整することができるが、０．０００１～０．５％（ｗ／ｖ）が好ましく、０．０００５～０．３％（ｗ／ｖ）がより好ましく、０．００１～０．１％（ｗ／ｖ）がさらに好ましく、０．００２～０．０８％（ｗ／ｖ）がもっと好ましく、０．００３～０．０７％（ｗ／ｖ）が一層好ましく、０．００５～０．０６％（ｗ／ｖ）が特に好ましく、０．００７～０．０５％（ｗ／ｖ）が最も好ましい。 The present composition can be appropriately blended with a stabilizer that can be used as an additive for pharmaceuticals. Examples thereof include edetic acid, monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate and the like. Disodium edetate is preferred, and disodium edetate dihydrate is particularly preferred. When a stabilizer is added to the present composition, the content of the stabilizer can be appropriately adjusted depending on the type of stabilizer, but is preferably 0.0001 to 0.5% (w/v). , more preferably 0.0005-0.3% (w/v), more preferably 0.001-0.1% (w/v), more preferably 0.002-0.08% (w/v) Preferably, 0.003 to 0.07% (w/v) is more preferred, 0.005 to 0.06% (w/v) is particularly preferred, and 0.007 to 0.05% (w/v) is Most preferred.
これらの安定化剤は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 These stabilizers may be used singly or in any combination of two or more.
本組成物には、医薬品の添加物として使用可能な抗酸化剤を適宜配合することができる。抗酸化剤の例としては、アスコルビン酸、トコフェロール、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、エリソルビン酸ナトリウム、没食子酸プロピル、亜硫酸ナトリウム等が挙げられる。本組成物に抗酸化剤を配合する場合の抗酸化剤の含有量は、抗酸化剤の種類等により適宜調整することができるが、０．０００１～１％（ｗ／ｖ）が好ましく、０．００１～０．１％（ｗ／ｖ）がより好ましく、０．００５～０．０１％（ｗ／ｖ）が最も好ましい。 The present composition may optionally contain an antioxidant that can be used as an additive for pharmaceuticals. Examples of antioxidants include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite, and the like. The content of the antioxidant when blending the antioxidant in the present composition can be appropriately adjusted depending on the type of antioxidant, etc., but is preferably 0.0001 to 1% (w / v). 0.001-0.1% (w/v) is more preferred, and 0.005-0.01% (w/v) is most preferred.
これらの抗酸化剤は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 These antioxidants may be used singly or in any combination of two or more.
本組成物には、医薬品の添加物として使用可能な高分子量重合体を適宜配合することができる。高分子量重合体の例としては、メチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース、ポリビニルピロリドン、ポリビニルアルコール、カルボキシビニルポリマー、ポリエチレングリコール等が挙げられる。本組成物に高分子量重合体を配合する場合の高分子量重合体の含有量は、高分子量重合体の種類等により適宜調整することができるが、０．００１～５％（ｗ／ｖ）が好ましく、０．０１～３％（ｗ／ｖ）がより好ましく、０．１～１％（ｗ／ｖ）が最も好ましい。 A high molecular weight polymer that can be used as an additive for pharmaceuticals can be appropriately blended into the present composition. Examples of high molecular weight polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, 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 when the high-molecular-weight polymer is blended in the present composition can be appropriately adjusted depending on the type of the high-molecular-weight polymer. Preferably, 0.01-3% (w/v) is more preferred, and 0.1-1% (w/v) is most preferred.
これらの高分子量重合体は、１種単独で使用してもよく、また２種以上を任意に組み合わせて使用してもよい。 These high-molecular-weight polymers may be used singly or in any combination of two or more.
更に、本組成物の浸透圧は特定の値に制限されないが、生体に許容される範囲とされる。本発明の水性組成物の浸透圧は、例えば、１００～１０００ｍＯｓｍ、好ましくは２００～５００ｍＯｓｍ、より好ましくは２５０～３５０ｍＯｓｍである。一般的に、水性組成物の浸透圧は少なからず水性組成物中の薬物や添加剤の量に影響を受ける。本発明において、浸透圧は浸透圧に影響を与え得るこれらの物質の量を適当に調整して、上記の範囲になるよう調整され得る。本発明の水性組成物の浸透圧は、通常の方法で測定されできることに留意すべきである。例えば、本発明の水性組成物の浸透圧は、第十五改正日本薬局方第の「浸透圧測定法（オスモル濃度測定法）」に記載の方法に従って測定できる。 Furthermore, the osmotic pressure of the composition is not limited to a specific value, but should be within a range acceptable to the body. The osmotic pressure of the aqueous composition of the present invention is, for example, 100-1000 mOsm, preferably 200-500 mOsm, more preferably 250-350 mOsm. In general, the osmotic pressure of an aqueous composition is not a little affected by the amount of drugs and additives in the aqueous composition. In the present invention, the osmotic pressure can be adjusted within the above range by appropriately adjusting the amounts of these substances that can affect the osmotic pressure. It should be noted that the osmotic pressure of the aqueous compositions of the invention can be measured by conventional methods. For example, the osmotic pressure of the aqueous composition of the present invention can be measured according to the method described in the Japanese Pharmacopoeia 15th Edition, "Osmolarity measurement method (osmolality measurement method)".
本組成物のｐＨは眼科用製品に許容される範囲内にあれば特に制限されないが、７未満が好ましく、３以上７未満がより好ましく、３以上６以下がさらに好ましく、４以上６以下がよりさらに好ましく、５の近傍が特に好ましい。より具体的には、例えば、３．０、３．１、３．２、３．３、３．４、３．５、３．６、３．７、３．８、３．９、４．０、４．１、４．２、４．３、４．４、４．５、４．６、４．７、４．８、４．９、５．０、５．１、５．２、５．３、５．４、５．５、５．６、５．７、５．８．５．９、６．０、６．１、６．２、６．３、６．４、６．５、６．６、６．７、６．８または６．９が挙げられる。本組成物のｐＨは、適宜、塩酸、硫酸、硝酸、ホウ酸および／または水酸化ナトリウムなどのｐＨ調節剤を添加物として配合して調節することができる。 The pH of the present composition is not particularly limited as long as it is within the range allowed for ophthalmic products, but is preferably less than 7, more preferably 3 or more and less than 7, still more preferably 3 or more and 6 or less, and more preferably 4 or more and 6 or less. It is more preferable, and the vicinity of 5 is particularly preferable. More specifically, for example, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4. 0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8.5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6. 5, 6.6, 6.7, 6.8 or 6.9. The pH of the present composition can be adjusted by appropriately adding a pH adjusting agent such as hydrochloric acid, sulfuric acid, nitric acid, boric acid and/or sodium hydroxide as an additive.
本発明は上述した実施形態に限定されるものではなく、請求項に示した範囲で種々の変更が可能であり、実施形態にそれぞれ開示された技術的手段を適宜組み合わせて得られる実施形態についても本発明の技術的範囲に含まれる。 The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims, and embodiments obtained by appropriately combining the technical means disclosed in the embodiments It is included in the technical scope of the present invention.
〔まとめ〕
以上のように、本発明の一態様は、以下に関する。
〔summary〕
As described above, one aspect of the present invention relates to the following.
〔１〕銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品。 [1] An ophthalmic product in which an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eyedrop container made of a resin containing silver-supported zirconium phosphate.
〔２〕前記眼科用組成物と接触している前記樹脂の一部または全部が銀担持リン酸ジルコニウムを含む、〔１〕に記載の眼科用製品。 [2] The ophthalmic product of [1], wherein part or all of the resin in contact with the ophthalmic composition comprises silver-supported zirconium phosphate.
〔３〕前記樹脂に対して、０．０８～１０％（ｗ／ｗ）の濃度の銀担持リン酸ジルコニウムを含む、〔１〕または〔２〕に記載の眼科用製品。 [3] The ophthalmic product according to [1] or [2], which contains silver-supported zirconium phosphate at a concentration of 0.08 to 10% (w/w) with respect to the resin.
〔４〕前記樹脂に対して、０．０８超乃至１０％（ｗ／ｗ）以下の濃度の銀担持リン酸ジルコニウムを含む、〔１〕または〔２〕に記載の眼科用製品。 [4] The ophthalmic product according to [1] or [2], which contains silver-supported zirconium phosphate at a concentration of more than 0.08 to 10% (w/w) with respect to the resin.
〔５〕前記樹脂に対して、０．０８超乃至５％（ｗ／ｗ）以下の濃度の銀担持リン酸ジルコニウムを含む、〔１〕または〔２〕に記載の眼科用製品。 [5] The ophthalmic product according to [1] or [2], containing silver-supported zirconium phosphate in a concentration of more than 0.08 to 5% (w/w) or less with respect to the resin.
〔６〕前記樹脂に対して、０．０８超乃至１％（ｗ／ｗ）以下の濃度の銀担持リン酸ジルコニウムを含む、〔１〕または〔２〕に記載の眼科用製品。 [6] The ophthalmic product according to [1] or [2], which contains silver-supported zirconium phosphate in a concentration of more than 0.08 to 1% (w/w) or less with respect to the resin.
〔７〕前記銀担持リン酸ジルコニウムが、銀をイオン濃度で０．００１～２０％（ｗ／ｗ）含む、〔１〕～〔６〕のいずれかに記載の眼科用製品。 [7] The ophthalmic product according to any one of [1] to [6], wherein the silver-supported zirconium phosphate contains silver in an ion concentration of 0.001 to 20% (w/w).
〔８〕前記眼科用組成物が防腐剤を実質的に含有しない、〔１〕～〔７〕のいずれかに記載の眼科用製品。 [8] The ophthalmic product according to any one of [1] to [7], wherein the ophthalmic composition does not substantially contain preservatives.
〔９〕樹脂に対して、０．０８～１０％（ｗ／ｗ）の濃度の銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品であって、前記眼科用組成物と接触している前記樹脂の一部または全部が銀担持リン酸ジルコニウムを含み、前記銀担持リン酸ジルコニウムが、銀をイオン濃度で０．００１～２０％（ｗ／ｗ）含み、前記眼科用組成物が防腐剤を実質的に含有しない、眼科用製品。 [9] An ophthalmic composition having a pH of less than 7, contained in a multi-dose type eye drop container formed of a resin containing silver-supported zirconium phosphate at a concentration of 0.08 to 10% (w/w) relative to the resin. wherein part or all of said resin in contact with said ophthalmic composition comprises silver-supported zirconium phosphate, said silver-supported zirconium phosphate reducing silver to an ionic concentration; and said ophthalmic composition is substantially free of preservatives.
〔１０〕前記眼科用組成物のｐＨが３以上、７未満である、〔１〕～〔９〕のいずれかに記載の眼科用製品。 [10] The ophthalmic product according to any one of [1] to [9], wherein the ophthalmic composition has a pH of 3 or more and less than 7.
〔１１〕前記眼科用組成物が、界面活性剤および等張化剤からなる群から選択される少なくとも１種をさらに含む、〔１〕～〔１０〕のいずれか１項に記載の眼科用製品。 [11] The ophthalmic product of any one of [1] to [10], wherein the ophthalmic composition further contains at least one selected from the group consisting of surfactants and tonicity agents. .
〔１２〕前記界面活性剤が、非イオン性界面活性剤である、〔１１〕に記載の眼科用製品。 [12] The ophthalmic product of [11], wherein the surfactant is a nonionic surfactant.
〔１３〕前記非イオン性界面活性剤が、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンヒマシ油、ポリオキシエチレンポリオキシプロピレングリコール、ショ糖脂肪酸エステルおよびビタミンＥ ＴＰＧＳからなる群から選択される少なくとも１種である、〔１２〕に記載の眼科用製品。 [13] The nonionic surfactant is polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester and vitamin E TPGS, which is at least one selected from the group consisting of [12].
〔１４〕前記等張化剤が、イオン性等張化剤および／または非イオン性等張化剤である、〔１１〕に記載の眼科用製品。 [14] The ophthalmic product of [11], wherein the tonicity agent is an ionic tonicity agent and/or a nonionic tonicity agent.
〔１５〕前記イオン性等張化剤が、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、ホウ酸およびホウ砂からなる群から選択される少なくとも１種である、〔１４〕に記載の眼科用製品。 [15] The ophthalmic composition of [14], wherein the ionic tonicity agent is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, boric acid and borax. product.
〔１６〕前記非イオン性等張化剤が、グリセリン、プロピレングリコール、ソルビトールおよびマンニトールからなる群から選択される少なくとも１種である、〔１４〕に記載の眼科用製品。 [16] The ophthalmic product of [14], wherein the nonionic isotonizing agent is at least one selected from the group consisting of glycerin, propylene glycol, sorbitol and mannitol.
〔１７〕前記マルチドーズ型点眼容器の容器本体の容量が５～２０ｍＬである、〔１〕～〔１６〕のいずれかに記載の眼科用製品。 [17] The ophthalmic product according to any one of [1] to [16], wherein the container body of the multi-dose eye drop container has a capacity of 5 to 20 mL.
〔１８〕前記眼科用組成物の総容量が２～２０ｍＬである、〔１〕～〔１７〕のいずれかに記載の眼科用製品。 [18] The ophthalmic product according to any one of [1] to [17], wherein the ophthalmic composition has a total volume of 2 to 20 mL.
〔１９〕前記眼科用組成物が点眼剤である、〔１〕～〔１８〕のいずれかに記載の眼科用製品。 [19] The ophthalmic product of any one of [1] to [18], wherein the ophthalmic composition is an eye drop.
〔２０〕前記眼科用製品が点眼剤製品である、〔１〕～〔１９〕のいずれかに記載の眼科用製品。 [20] The ophthalmic product according to any one of [1] to [19], wherein the ophthalmic product is an eye drop product.
〔２１〕ｐＨが７未満である眼科用組成物であって、前記眼科用組成物が、銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に収容されていることを特徴とする眼科用組成物。 [21] An ophthalmic composition having a pH of less than 7, wherein the ophthalmic composition is housed in a multi-dose eye drop container made of a resin containing silver-supported zirconium phosphate. ophthalmic composition for
以下に、試験結果および製剤例を示すが、これらの例は本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない。 Test results and formulation examples are shown below, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.
［保存効力試験－１］
銀担持体の種類が抗菌性能に及ぼす影響を検討した。
[Preservation efficacy test-1]
The effect of the type of silver carrier on the antibacterial performance was investigated.
（試料作製）
銀担持体が配合されたプラスチックプレートを作成した。
(Sample preparation)
A plastic plate containing a silver support was prepared.
＜銀担持リン酸ジルコニウム配合プレート＞
０．５％（ｗ／ｗ）の濃度の銀担持リン酸ジルコニウム（メーカー：東亞合成株式会社、製品名：ノバロン（登録商標）ＡＧ１１００）が配合されたポリプロピレンプレート（高さ２ｍｍ；プレートの表と裏の表面積の合計は１２０ｃｍ２である）を作成した。
<Silver-supported zirconium phosphate mixed plate>
A polypropylene plate (height 2 mm; plate surface and The total back surface area is 120 cm 2 ).
＜銀担持ゼオライト配合プレート＞
０．５％（ｗ／ｗ）の濃度の銀担持ゼオライト（メーカー：シナミンゼオミック、製品名：ＤＡＷ５０２）が配合されたポリエチレンプレート（高さ２ｍｍ；プレートの表と裏の表面積の合計は１２０ｃｍ２である）を作成した。
<Silver-supported zeolite mixed plate>
A polyethylene plate (height 2 mm; the total surface area of the front and back of the plate is 120 cm 2 ) was created.
（サンプル作成）
滅菌済みガラスパイレックス（登録商標）瓶に、作成したプラスチックプレートを入れ、次いで生理食塩水１５ｍＬを加え、当該プラスチックプレートを浸漬させて、試験に用いるサンプルを作成した。この場合、プラスチックプレートの生理食塩水との接液面積は８ｃｍ２／ｍＬである。
(Sample creation)
The prepared plastic plate was placed in a sterilized glass Pyrex (registered trademark) bottle, then 15 mL of physiological saline was added, and the plastic plate was immersed to prepare a sample to be used for the test. In this case, the wetted area of the plastic plate with the physiological saline is 8 cm 2 /mL.
（試験方法）
保存効力試験は、第十五改正日本薬局方の保存効力試験法を参考に行った。試験菌を接種し、１４日後、２８日後に菌数を測定した。本試験では、試験菌として、Ｅｓｈｅｒｉｃｈｉａ Ｃｏｌｉ（Ｅ．ｃｏｌｉ）、Ｐｓｅｕｄｏｍｏｎａｓ ａｅｒｕｇｉｎｏｓａ（Ｐ．ａｅｒｕｇｉｎｏｓａ）を用いた。
(Test method)
The preservative efficacy test was performed with reference to the preservative efficacy test method of the 15th revision of the Japanese Pharmacopoeia. The test bacteria were inoculated, and the number of bacteria was measured 14 days and 28 days later. In this test, Esherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) were used as test bacteria.
（試験結果）
試験結果を表１に示す。なお、表１の試験結果（初期値、１４日後、２８日後）は、菌数経時変化（個／ｍＬ）を示している。
(Test results)
Table 1 shows the test results. The test results in Table 1 (initial value, after 14 days, after 28 days) indicate changes in the number of bacteria over time (cells/mL).
表１に示すように、銀担持リン酸ジルコニウムは、銀担持ゼオライトよりも高い抗菌力を有することが示された。
As shown in Table 1, silver-supported zirconium phosphate was shown to have higher antibacterial activity than silver-supported zeolite.
［重金属評価試験］
試料中の重金属を評価した。
[Heavy metal evaluation test]
Heavy metals in the samples were evaluated.
（試料調製）
銀担持体が配合されたプラスチックプレートを作成した。
(Sample preparation)
A plastic plate containing a silver support was prepared.
＜銀担持リン酸ジルコニウム配合プレート＞
０．５％（ｗ／ｗ）または１．０％（ｗ／ｗ）の濃度の銀担持リン酸ジルコニウム（メーカー：東亞合成株式会社、製品名：ノバロン（登録商標）ＡＧ１１００）が配合されたポリプロピレンプレートをそれぞれ作成した。
<Silver-supported zirconium phosphate mixed plate>
Polypropylene compounded with silver-supported zirconium phosphate (manufacturer: Toagosei Co., Ltd., product name: Novaron (registered trademark) AG1100) at a concentration of 0.5% (w/w) or 1.0% (w/w) A plate was made for each.
＜銀担持ゼオライト配合プレート＞
１％（ｗ／ｗ）、２％（ｗ／ｗ）または３％（ｗ／ｗ）の濃度の銀担持ゼオライト（メーカー：カネボウ、製品名：ＢＭ－１０２ＴＧ）が配合されたポリプロピレンプレートをそれぞれ作成した。
<Silver-supported zeolite mixed plate>
A polypropylene plate containing 1% (w/w), 2% (w/w) or 3% (w/w) silver-supported zeolite (manufacturer: Kanebo, product name: BM-102TG) was prepared. bottom.
＜銀担持ガラス配合プレート＞
１％（ｗ／ｗ）の濃度の銀担持ガラス（メーカー：石塚ガラス、製品名：ＪＮ）が配合されたポリプロピレンプレートを作成した。
<Silver-supported glass compound plate>
A polypropylene plate containing silver-supported glass (manufacturer: Ishizuka Glass, product name: JN) at a concentration of 1% (w/w) was prepared.
（試験方法）
日局一般試験法「プラスチック製医薬品容器試験法」１灰化試験１・２重金属（点眼剤用プラスチック容器の規格及び試験法について（薬発３３６号（平成８年３月２８日））の別添、重金属）に準じて試料中の重金属を評価した。
(Test method)
Japan General Test Method "Plastic Pharmaceutical Container Test Method" 1 Ashing test 1.2 Heavy metal The heavy metals in the samples were evaluated according to Appendix, Heavy Metals).
（判定基準）
日局一般試験法「プラスチック製医薬品容器試験法」１灰化試験１・２重金属（点眼剤用プラスチック容器の規格及び試験法について（薬発３３６号（平成８年３月２８日））の別添、重金属）に準じて試験したとき、検液の色が比較液より濃くない（２０ｐｐｍ以下）場合を合格とする。ただし、容器切片採取量は１．０ｇとする。
(criterion)
Japan General Test Method "Plastic Pharmaceutical Container Test Method" 1 Ashing test 1.2 Heavy metal Addition, heavy metals), if the color of the test solution is not darker than the reference solution (20 ppm or less), it is considered acceptable. However, the amount of container cut pieces to be collected shall be 1.0 g.
（試験結果）
表２に試験結果を示す。
(Test results)
Table 2 shows the test results.
（考察）
以上の重金属評価試験の結果から、銀担持リン酸ジルコニウムが点眼剤用プラスチック容器に好ましいことが示された。
(Discussion)
From the results of the above heavy metal evaluation test, it was shown that silver-supported zirconium phosphate is preferable for eye drop plastic containers.
［保存効力試験－２］
銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器を用いて、保存効力試験を行った。
[Preservation efficacy test-2]
A preservative efficacy test was conducted using a multi-dose type eyedrop container made of a resin containing silver-supported zirconium phosphate.
（試料調製）
点眼液１：
表３に示す処方に従って、点眼液１を調製した。具体的には、ジクアホソルナトリウム（ＡＰＩ；３ｇ）、エデト酸ナトリウム（キレート剤；０．０１ｇ）、濃グリセリン（等張化剤；１．４ｇ）を水に溶解し、希塩酸（ｐＨ調節剤）を加えて、ｐＨを５付近とした後、水を適量加えて全量を１００ｍＬとした。
(Sample preparation)
Eye drops 1:
According to the formulation shown in Table 3, ophthalmic solution 1 was prepared. Specifically, diquafosol sodium (API; 3 g), sodium edetate (chelating agent; 0.01 g), concentrated glycerin (tonicity agent; 1.4 g) were dissolved in water, and diluted hydrochloric acid (pH adjuster ) was added to adjust the pH to around 5, and then an appropriate amount of water was added to bring the total amount to 100 mL.
点眼液２：
表３に示す処方に従って、点眼液２を調製した。具体的には、ジクアホソルナトリウム（ＡＰＩ；３ｇ）、エデト酸ナトリウム（キレート剤；０．０１ｇ）、ホウ酸（等張化剤；１．１ｇ）を水に溶解し、水酸化ナトリウム（ｐＨ調節剤）を加えて、ｐＨを５付近とした後、水を適量加えて全量を１００ｍＬとした。
Eye drops 2:
According to the formulation shown in Table 3, ophthalmic solution 2 was prepared. Specifically, diquafosol sodium (API; 3 g), sodium edetate (chelating agent; 0.01 g), boric acid (tonicity agent; 1.1 g) were dissolved in water, and sodium hydroxide (pH Adjusting agent) was added to bring the pH to around 5, and then an appropriate amount of water was added to bring the total volume to 100 mL.
点眼液３：
表３に示す処方に従って、点眼液３を調製した。具体的には、ジクアホソルナトリウム（ＡＰＩ；３ｇ）、エデト酸ナトリウム（キレート剤；０．０１ｇ）、濃グリセリン（等張化剤；１．４ｇ）を水に溶解し、希塩酸（ｐＨ調節剤）を加えて、ｐＨを５付近とした後、水を適量加えて全量を１００ｍＬとした。
Eye drops 3:
According to the formulation shown in Table 3, ophthalmic solution 3 was prepared. Specifically, diquafosol sodium (API; 3 g), sodium edetate (chelating agent; 0.01 g), concentrated glycerin (tonicity agent; 1.4 g) were dissolved in water, and diluted hydrochloric acid (pH adjuster ) was added to adjust the pH to around 5, and then an appropriate amount of water was added to bring the total amount to 100 mL.
点眼液４：
表３に示す処方に従って、点眼液４を調製した。具体的には、ジクアホソルナトリウム（ＡＰＩ；３ｇ）、エデト酸ナトリウム（キレート剤；０．０１ｇ）、ホウ酸（等張化剤；１．１ｇ）を水に溶解し、水酸化ナトリウム（ｐＨ調節剤）を加えて、ｐＨを５付近とした後、水を適量加えて全量を１００ｍＬとした。
Eye drops 4:
According to the formulation shown in Table 3, ophthalmic solution 4 was prepared. Specifically, diquafosol sodium (API; 3 g), sodium edetate (chelating agent; 0.01 g), boric acid (tonicity agent; 1.1 g) were dissolved in water, and sodium hydroxide (pH Adjusting agent) was added to bring the pH to around 5, and then an appropriate amount of water was added to bring the total volume to 100 mL.
なお、ＡＰＩとしてジクアホソルナトリウムを用いたが、点眼液中で保存すると目視可能な不溶性析出物が発生するおそれがあることからキレート剤であるエデト酸ナトリウムを添加した（国際公開ＷＯ２０１２－０９０９９４号パンフレット参照）。 Although diquafosol sodium was used as an API, edetate sodium, which is a chelating agent, was added because there is a risk that visible insoluble precipitates may occur when stored in an ophthalmic solution (International Publication No. WO2012-090994). (see brochure).
点眼容器：
加熱溶解したポリエチレン樹脂に、銀をイオン濃度で１０％（ｗ／ｗ）含む平均粒径１μｍの銀担持リン酸ジルコニウムを０．０８％（ｗ／ｗ）または１％（ｗ／ｗ）添加して均一に練り込み、点眼容器の容器本体（容積７．９ｍＬ、高さ４５．２ｍｍ、胴型１９．４５ｍｍ）を製造した。銀担持リン酸ジルコニウムは、東亞合成株式会社製の銀系無機抗菌剤「ノバロン（登録商標）ＡＧ」１１００を使用した。
Eye drop container:
0.08% (w/w) or 1% (w/w) of silver-supported zirconium phosphate having an average particle size of 1 μm containing 10% (w/w) silver in ion concentration was added to the polyethylene resin dissolved by heating. The mixture was kneaded uniformly to produce a container body of an eyedrop container (volume: 7.9 mL, height: 45.2 mm, barrel: 19.45 mm). As silver-supported zirconium phosphate, a silver-based inorganic antibacterial agent "Novaron (registered trademark) AG" 1100 manufactured by Toagosei Co., Ltd. was used.
保存効力試験は、第十七改正日本薬局方の保存効力試験法に準拠して行なった。本試験では、試験菌株として、Ｅｓｈｅｒｉｃｈｉａ Ｃｏｌｉ（Ｅ．ｃｏｌｉ）、Ｐｓｅｕｄｏｍｏｎａｓ ａｅｒｕｇｉｎｏｓａ（Ｐ．ａｅｒｕｇｉｎｏｓａ）、Ｓｔａｐｈｙｌｏｃｏｃｃｕｓ ａｕｒｅｕｓ（Ｓ．ａｕｒｅｕｓ）、Ｃａｎｄｉｄａ ａｌｂｉｃａｎｓ（Ｃ．ａｌｂｉｃａｎｓ）およびＡｓｐｅｒｇｉｌｌｕｓ ｂｒａｓｉｌｉｅｎｓｉｓ（Ａ．ｂｒａｓｉｌｉｅｎｓｉｓ）を用いた。これらの菌株をそれぞれカンテン斜面培地の表面に接種して前培養した。前培養用のカンテン培地としては、細菌の場合はソイビーン・カゼイン・ダイジェストカンテン培地を、真菌の場合はサブロー・ブドウ糖カンテン培地を用いた。細菌の場合は３０～３５℃で１８～２４時間、Ｃａｎｄｉｄａ ａｌｂｉｃａｎｓは２０～２５℃で４４～５２時間、Ａｓｐｅｒｇｉｌｌｕｓ ｂｒａｓｉｌｉｅｎｓｉｓは２０～２５℃で１週間又は十分な胞子が形成されるまで前培養した。
The preservative efficacy test was conducted according to the preservative efficacy test method of the 17th revision of the Japanese Pharmacopoeia. In this test, Esherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans) and Aspergillus brasiliensis ( A. brasiliensis) . Each of these strains was inoculated on the surface of an agar slant and precultured. As the agar medium for preculture, a soybean-casein-digest agar medium was used for bacteria, and a Sabouraud-dextrose agar medium was used for fungi. Bacteria were pre-cultured at 30-35°C for 18-24 hours, Candida albicans at 20-25°C for 44-52 hours, and Aspergillus brasiliensis at 20-25°C for 1 week or until sufficient spores were formed.
点眼液１～４を５本の滅菌済みの上記点眼容器に５ｍＬずつ分注し、中栓を装着し、キャップで密封した。６０℃で１か月遮光保存した後、前培養した試験菌を１０５～１０６個／ｍＬとなるよう接種した。なお、試験菌は混合せず、それぞれ単独に各検体に接種した。保存開始から１週、２週及び４週保存後に各混合試料から０．５ｍＬをサンプリングした液を培養し、生菌数の測定を行った。 Each of the eye drops 1 to 4 was dispensed into five sterilized eye drop containers, each containing 5 mL, and each container was fitted with an inner stopper and sealed with a cap. After storing at 60° C. for 1 month in the dark, precultured test bacteria were inoculated at 10 5 to 10 6 cells/mL. The test bacteria were inoculated individually to each specimen without being mixed. After 1 week, 2 weeks, and 4 weeks of storage from the start of storage, 0.5 mL of each mixed sample was sampled and cultured, and the number of viable bacteria was measured.
表４に従い、保存効力を判定した。 Preservative efficacy was determined according to Table 4.
試験結果を表５に示す。なお、表５の試験結果は検査時の生菌数が接種した菌数に比べてどの程度減少したかをｌｏｇ ｒｅｄｕｃｔｉｏｎで示しており、たとえば「１」の場合には、検査時の生菌数が接種菌数の１０％に減少したことを示している。
Table 5 shows the test results. The test results in Table 5 show how much the number of viable bacteria at the time of inspection decreased compared to the number of inoculated bacteria in log reduction. For example, in the case of "1", the number of viable bacteria at the time of inspection decreased to 10% of the inoculum number.
一般に、眼科用組成物の単位容量あたりの容器本体への全接触面積は、マルチドーズ型点眼容器の方がユニットドーズ型点眼容器よりも小さい。マルチドーズ型点眼容器であっても本製品が優れた保存効力を有することが示された。 In general, the total contact area of the ophthalmic composition with the container body per unit volume is smaller in the multi-dose type eye drop container than in the unit dose type eye drop container. It was shown that the product has excellent preservative efficacy even in a multi-dose type eye drop container.
［保存効力試験－３］
銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器を用いて、保存効力試験を行った。
[Preservation efficacy test-3]
A preservative efficacy test was conducted using a multi-dose type eyedrop container made of a resin containing silver-supported zirconium phosphate.
（試料調製）
点眼液：
表６に示す処方に従って、点眼液５を調製した。具体的には、濃グリセリン（１．３ｇ）、リン酸水素ナトリウム水和物（１．０ｇ）を水に溶解し、ｐＨ調節剤（１Ｎ水酸化ナトリウム溶液／硫酸）を加えて、ｐＨを５．０とした後、水を適量加えて全量を１００ｍＬとした。点眼液６～８も表６に示す処方に従って、点眼液５と同様に調製した。
(Sample preparation)
Eye drops:
According to the formulation shown in Table 6, ophthalmic solution 5 was prepared. Specifically, concentrated glycerin (1.3 g) and sodium hydrogen phosphate hydrate (1.0 g) were dissolved in water, and a pH adjuster (1N sodium hydroxide solution/sulfuric acid) was added to adjust the pH to 5. After adjusting to 0.0, an appropriate amount of water was added to bring the total volume to 100 mL. Eye drops 6 to 8 were prepared in the same manner as eye drop 5 according to the formulations shown in Table 6.
点眼容器：
加熱溶解したポリエチレン樹脂に、銀をイオン濃度で１０％（ｗ／ｗ）含む平均粒径１μｍの銀担持リン酸ジルコニウムを０．５％（ｗ／ｗ）添加して均一に練り込み、点眼容器の容器本体（容積７．９ｍＬ、高さ４５．２ｍｍ、胴型１９．４５ｍｍ）を製造した。銀担持リン酸ジルコニウムは、東亞合成株式会社製の銀系無機抗菌剤「ノバロン（登録商標）ＡＧ」１１００を使用した。
Eye drop container:
0.5% (w/w) of silver-supported zirconium phosphate having an average particle size of 1 μm containing 10% (w/w) of silver in ion concentration is added to the heat-dissolved polyethylene resin and kneaded uniformly into an eyedropper container. A container body (volume 7.9 mL, height 45.2 mm, barrel type 19.45 mm) was manufactured. As silver-supported zirconium phosphate, a silver-based inorganic antibacterial agent "Novaron (registered trademark) AG" 1100 manufactured by Toagosei Co., Ltd. was used.
保存効力試験は、第十七改正日本薬局方の保存効力試験法を参考に行なった。本試験では、試験菌株として、Ｅｓｈｅｒｉｃｈｉａ Ｃｏｌｉ（Ｅ．ｃｏｌｉ）、Ｐｓｅｕｄｏｍｏｎａｓ ａｅｒｕｇｉｎｏｓａ（Ｐ．ａｅｒｕｇｉｎｏｓａ）およびＳｔａｐｈｙｌｏｃｏｃｃｕｓ ａｕｒｅｕｓ（Ｓ．ａｕｒｅｕｓ）を用いた。これらの菌株をそれぞれカンテン斜面培地の表面に接種して前培養した。前培養用のカンテン培地としては、ソイビーン・カゼイン・ダイジェストカンテン培地を用いた。３０～３５℃で１８～２４時間前培養した。
The preservative efficacy test was performed with reference to the preservative efficacy test method of the 17th revision of the Japanese Pharmacopoeia. In this test, Esherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) were used as test strains. Each of these strains was inoculated on the surface of an agar slant and precultured. A soybean/casein/digest agar medium was used as the agar medium for preculture. It was pre-incubated at 30-35°C for 18-24 hours.
点眼液５～８を５本の滅菌済みの上記点眼容器に５ｍＬずつ分注し、中栓を装着し、キャップで密封した。６０℃で１か月遮光保存後、前培養した試験菌を１０５～１０６個／ｍＬとなるよう接種した。なお、試験菌は混合せず、それぞれ単独に各検体に接種した。保存開始から１週及び２週保存後に各混合試料から０．５ｍＬをサンプリングした液を培養し、生菌数の測定を行った。 5 mL each of the eye drops 5 to 8 was dispensed into five sterilized eye drop containers, and the containers were sealed with inner plugs and caps. After being stored at 60° C. for one month in the dark, precultured test bacteria were inoculated at 10 5 to 10 6 cells/mL. The test bacteria were inoculated individually to each specimen without being mixed. After 1 week and 2 weeks of storage from the start of storage, 0.5 mL of each mixed sample was sampled and cultured, and the number of viable bacteria was measured.
表７に従い、保存効力を判定した。 Preservative efficacy was determined according to Table 7.
試験結果を表８に示す。なお、表８の試験結果は検査時の生菌数が接種した菌数に比べてどの程度減少したかをｌｏｇ ｒｅｄｕｃｔｉｏｎで示しており、たとえば「１」の場合には、検査時の生菌数が接種菌数の１０％に減少したことを示している。
Table 8 shows the test results. The test results in Table 8 show how much the number of viable bacteria at the time of inspection decreased compared to the number of inoculated bacteria in log reduction. For example, in the case of "1", the number of viable bacteria at the time of inspection decreased to 10% of the inoculum number.
［製剤例］
製剤例を挙げて本発明をさらに具体的に説明するが、本発明はこれらの製剤例にのみに限定されるものでない。
[Formulation example]
The present invention will be described more specifically with formulation examples, but the present invention is not limited only to these formulation examples.
（製剤例１：水性点眼液）
１００ｍＬ中
リン酸水素ナトリウム ０．２ｇ
濃グリセリン ２．４ｇ
エデト酸ナトリウム ０．０１ｇ
ｐＨ調節剤 適量
水 適量
リン酸水素ナトリウム（０．２ｇ）、濃グリセリン（２．４ｇ）、エデト酸ナトリウム（０．０１ｇ）を水に溶解し、ｐＨ調節剤（塩酸または水酸化ナトリウム溶液）を加えて、ｐＨを５．０とした後、水を適量加えて全量を１００ｍＬとし、十分に撹拌することで点眼液を調製できる。
(Formulation Example 1: Aqueous ophthalmic solution)
0.2 g of sodium hydrogen phosphate in 100 mL
Concentrated glycerin 2.4g
Sodium edetate 0.01g
pH adjuster Appropriate amount Water Appropriate amount Sodium hydrogen phosphate (0.2 g), concentrated glycerin (2.4 g), sodium edetate (0.01 g) are dissolved in water, and a pH adjuster (hydrochloric acid or sodium hydroxide solution) is added. In addition, after adjusting the pH to 5.0, an appropriate amount of water is added to make the total amount 100 mL, and the solution is sufficiently stirred to prepare an ophthalmic solution.
（製剤例２：水性点眼液）
１００ｍＬ中
濃グリセリン １．２ｇ
ホウ酸 １．０ｇ
ｐＨ調節剤 適量
水 適量
濃グリセリン（１．２ｇ）、ホウ酸（１．０ｇ）を水に溶解し、ｐＨ調節剤（塩酸または水酸化ナトリウム溶液）を加えて、ｐＨを５．０とした後、水を適量加えて全量を１００ｍＬとし、十分に撹拌することで点眼液を調製できる。
(Formulation Example 2: Aqueous ophthalmic solution)
1.2 g of concentrated glycerin in 100 mL
Boric acid 1.0g
pH adjuster Appropriate amount Water Appropriate amount Concentrated glycerin (1.2 g) and boric acid (1.0 g) are dissolved in water, and a pH adjuster (hydrochloric acid or sodium hydroxide solution) is added to adjust the pH to 5.0. , an appropriate amount of water is added to make the total amount 100 mL, and the ophthalmic solution can be prepared by sufficiently stirring.
銀担持リン酸ジルコニウムを含む樹脂で形成されたマルチドーズ型点眼容器に、ｐＨが７未満である眼科用組成物が収容された眼科用製品が優れた保存効力を有する。本発明は、上述の逆流防止弁やフィルター付きデラミボトルなど物理的な構造を施さなくても、一定期間複数回使用でき、上述のユニットドーズ型点眼容器の欠点もないことから有用である。 An ophthalmic product in which an ophthalmic composition having a pH of less than 7 is contained in a multi-dose type eyedrop container made of a resin containing silver-supported zirconium phosphate has excellent preservative efficacy. INDUSTRIAL APPLICABILITY The present invention is useful because it can be used multiple times for a certain period of time without the use of a physical structure such as the anti-reflux valve or filter-equipped delaminated bottle, and it does not have the drawbacks of the unit-dose eyedropper container described above.
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| JP2017232133 | 2017-12-01 | ||
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| EP4129341A4 (en) * | 2020-03-31 | 2024-04-24 | Santen Pharmaceutical Co., Ltd. | Silver-salt-containing ophthalmic aqueous composition with which resin container is filled |
| JP7230169B2 (en) * | 2020-12-25 | 2023-02-28 | 参天製薬株式会社 | Aqueous ophthalmic solution containing diquafosol or its salt, silver salt and ionic tonicity agent |
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| JPH0871124A (en) * | 1994-08-31 | 1996-03-19 | Shinotesuto:Kk | Container containing antimicrobial material and storing method of the material |
| JP2002282338A (en) | 2001-03-23 | 2002-10-02 | Terumo Corp | Hook for intravenous drip |
| JP4863589B2 (en) | 2001-09-28 | 2012-01-25 | ロート製薬株式会社 | Aqueous composition |
| JP5301069B2 (en) | 2004-04-15 | 2013-09-25 | ロート製薬株式会社 | Azulene-containing aqueous solution |
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