WO2024010044A1 - Ophthalmic composition - Google Patents
Ophthalmic composition Download PDFInfo
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- WO2024010044A1 WO2024010044A1 PCT/JP2023/024978 JP2023024978W WO2024010044A1 WO 2024010044 A1 WO2024010044 A1 WO 2024010044A1 JP 2023024978 W JP2023024978 W JP 2023024978W WO 2024010044 A1 WO2024010044 A1 WO 2024010044A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ophthalmic composition
- tramadol
- container
- salts
- present
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 99
- 150000003839 salts Chemical class 0.000 claims abstract description 59
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 claims abstract description 40
- 229960004380 tramadol Drugs 0.000 claims abstract description 40
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 claims abstract description 40
- 229920003023 plastic Polymers 0.000 claims abstract description 38
- 239000004033 plastic Substances 0.000 claims abstract description 38
- 230000001954 sterilising effect Effects 0.000 claims abstract description 24
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 23
- 238000010894 electron beam technology Methods 0.000 claims abstract description 20
- -1 polyethylene Polymers 0.000 claims description 24
- 239000007789 gas Substances 0.000 claims description 11
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 10
- 229920000089 Cyclic olefin copolymer Polymers 0.000 claims description 9
- 239000004698 Polyethylene Substances 0.000 claims description 8
- 229920000573 polyethylene Polymers 0.000 claims description 8
- 239000004713 Cyclic olefin copolymer Substances 0.000 claims description 7
- 239000004743 Polypropylene Substances 0.000 claims description 7
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 6
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- 239000000872 buffer Substances 0.000 description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 14
- 239000003755 preservative agent Substances 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- 239000003889 eye drop Substances 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 13
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 12
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- 238000000034 method Methods 0.000 description 11
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- 230000003204 osmotic effect Effects 0.000 description 9
- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
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- 230000002335 preservative effect Effects 0.000 description 8
- 229960003107 tramadol hydrochloride Drugs 0.000 description 8
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 7
- 239000008363 phosphate buffer Substances 0.000 description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 6
- 229940012356 eye drops Drugs 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000004310 lactic acid Substances 0.000 description 6
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- 235000015165 citric acid Nutrition 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 229920001155 polypropylene Polymers 0.000 description 5
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
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- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
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- 150000007530 organic bases Chemical class 0.000 description 3
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 101150035093 AMPD gene Proteins 0.000 description 2
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- 229940123208 Biguanide Drugs 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 239000004642 Polyimide Substances 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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- 239000007983 Tris buffer Substances 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- 229960003260 chlorhexidine Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
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- 239000004700 high-density polyethylene Substances 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 229920001684 low density polyethylene Polymers 0.000 description 2
- 239000004702 low-density polyethylene Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
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- 229920001707 polybutylene terephthalate Polymers 0.000 description 2
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- 229920001721 polyimide Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
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- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- KZQSXALQTHVPDQ-UHFFFAOYSA-M sodium;butanedioate;hydron Chemical compound [Na+].OC(=O)CCC([O-])=O KZQSXALQTHVPDQ-UHFFFAOYSA-M 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000008362 succinate buffer Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Polymers CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
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- 206010058019 Cancer Pain Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
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- 229920010126 Linear Low Density Polyethylene (LLDPE) Polymers 0.000 description 1
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- 229910019142 PO4 Inorganic materials 0.000 description 1
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- FZQSLXQPHPOTHG-UHFFFAOYSA-N [K+].[K+].O1B([O-])OB2OB([O-])OB1O2 Chemical compound [K+].[K+].O1B([O-])OB2OB([O-])OB1O2 FZQSLXQPHPOTHG-UHFFFAOYSA-N 0.000 description 1
- 239000004676 acrylonitrile butadiene styrene Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229950010221 alexidine Drugs 0.000 description 1
- LFVVNPBBFUSSHL-UHFFFAOYSA-N alexidine Chemical compound CCCCC(CC)CNC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NCC(CC)CCCC LFVVNPBBFUSSHL-UHFFFAOYSA-N 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910000316 alkaline earth metal phosphate Inorganic materials 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
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- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
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- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
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- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
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- YYRMJZQKEFZXMX-UHFFFAOYSA-L calcium bis(dihydrogenphosphate) Chemical compound [Ca+2].OP(O)([O-])=O.OP(O)([O-])=O YYRMJZQKEFZXMX-UHFFFAOYSA-L 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
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- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
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- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
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- 159000000007 calcium salts Chemical class 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
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- 229960003333 chlorhexidine gluconate Drugs 0.000 description 1
- YZIYKJHYYHPJIB-UUPCJSQJSA-N chlorhexidine gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(Cl)=CC=C1NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NC1=CC=C(Cl)C=C1 YZIYKJHYYHPJIB-UUPCJSQJSA-N 0.000 description 1
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- 150000001875 compounds Chemical class 0.000 description 1
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- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002526 disodium citrate Substances 0.000 description 1
- 235000019262 disodium citrate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000000806 elastomer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000004388 gamma ray sterilization Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 230000008642 heat stress Effects 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- GXHMMDRXHUIUMN-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O GXHMMDRXHUIUMN-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- OLXYLDUSSBULGU-UHFFFAOYSA-N methyl pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1 OLXYLDUSSBULGU-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000019691 monocalcium phosphate Nutrition 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- HWPKGOGLCKPRLZ-UHFFFAOYSA-M monosodium citrate Chemical compound [Na+].OC(=O)CC(O)(C([O-])=O)CC(O)=O HWPKGOGLCKPRLZ-UHFFFAOYSA-M 0.000 description 1
- 239000002524 monosodium citrate Substances 0.000 description 1
- 235000018342 monosodium citrate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940023490 ophthalmic product Drugs 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920003207 poly(ethylene-2,6-naphthalate) Polymers 0.000 description 1
- 229920001230 polyarylate Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 239000011112 polyethylene naphthalate Substances 0.000 description 1
- 229940093158 polyhexanide Drugs 0.000 description 1
- 239000011116 polymethylpentene Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229960004109 potassium acetate Drugs 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- PHZLMBHDXVLRIX-UHFFFAOYSA-M potassium lactate Chemical compound [K+].CC(O)C([O-])=O PHZLMBHDXVLRIX-UHFFFAOYSA-M 0.000 description 1
- 239000001521 potassium lactate Substances 0.000 description 1
- 235000011085 potassium lactate Nutrition 0.000 description 1
- 229960001304 potassium lactate Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- JVUYWILPYBCNNG-UHFFFAOYSA-N potassium;oxido(oxo)borane Chemical compound [K+].[O-]B=O JVUYWILPYBCNNG-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000012744 reinforcing agent Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid 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
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- WYXIGTJNYDDFFH-UHFFFAOYSA-Q triazanium;borate Chemical compound [NH4+].[NH4+].[NH4+].[O-]B([O-])[O-] WYXIGTJNYDDFFH-UHFFFAOYSA-Q 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Definitions
- the present invention relates to an ophthalmic composition.
- Tramadol is a non-narcotic analgesic classified as a weak opioid, and is used as a systemic analgesic for cancer pain and the like (Non-Patent Document 1).
- An object of the present invention is to provide a novel tramadol-containing ophthalmic composition in which tramadol-derived impurities are reduced.
- the present inventors have discovered that when a tramadol-containing ophthalmic composition is stored in a plastic container sterilized by means other than electron beams, impurities derived from tramadol are reduced regardless of the tramadol content in the ophthalmic composition.
- impurities derived from tramadol are reduced when the composition is stored in a plastic container sterilized by electron beams.
- the present invention is based on this knowledge and provides the following inventions.
- An ophthalmological composition which is housed in a container which has been sterilized by electron beam.
- the ophthalmic composition according to any one of [1] to [3], wherein the plastic is at least one selected from the group consisting of polyethylene, polypropylene, and cyclic olefin copolymers.
- the ophthalmic composition according to the present embodiment contains (A) tramadol or a salt thereof (also simply referred to as “component (A)").
- the salt of tramadol is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmacologically) or physiologically acceptable.
- Specific examples of such salts include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with acidic amino acids, salts with basic amino acids, etc. .
- salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
- Salts with organic acids include, for example, acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid (mesylic acid), ethanesulfonic acid, p-toluenesulfonic acid.
- Examples include salts such as Examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, and ammonium salts.
- salts with organic bases include salts with diethylamine, diethanolamine, meglumine, N,N-dibenzylethylenediamine, and the like.
- salts with acidic amino acids include salts with aspartic acid and glutamic acid.
- salts with basic amino acids include salts with arginine, lysine, ornithine, and the like.
- a salt with an inorganic acid is preferable, and a hydrochloride is more preferable.
- the ophthalmic composition according to the present embodiment contains tramadol or a salt thereof as an active ingredient, and can be used, for example, to suppress pain.
- the content of component (A) is not particularly limited, and the types and contents of other ingredients, the formulation It is set as appropriate depending on the format etc.
- the content of component (A) is 0.01 w/v% to 10 w/v%, 0.01 w/v% to 10 w/v%, based on the total amount of the ophthalmological composition according to the present embodiment, from the viewpoint of achieving more remarkable effects of the present invention. It may be 0.05 w/v% to 5 w/v%, 0.1 w/v% to 4 w/v%, or 3 w/v%.
- the content of component (A) is 1.0 w/v % to 3.0 w/v % based on the total amount of the ophthalmic composition. It is 0 w/v%.
- the ophthalmic composition according to this embodiment may further contain a buffer.
- a buffering agent When the ophthalmic composition further contains a buffering agent, the effects of the present invention are more prominently exhibited.
- the buffering agent is not particularly limited as long as it is medicinally, pharmacologically (pharmacologically) or physiologically acceptable.
- the buffer include inorganic buffers that are buffers derived from inorganic acids, and organic buffers that are buffers derived from organic acids or organic bases.
- Examples of inorganic buffers include boric acid buffers, phosphate buffers, carbonate buffers, and the like.
- the boric acid buffer include boric acid or a salt thereof (alkali metal boric acid salt, alkaline earth metal boric acid salt, etc.).
- the phosphate buffer include phosphoric acid or a salt thereof (alkali metal phosphate, alkaline earth metal phosphate, etc.).
- the carbonate buffer include carbonic acid or a salt thereof (alkali metal carbonate, alkaline earth metal carbonate, etc.).
- a hydrate of borate, phosphate, or carbonate may be used as the borate buffer, phosphate buffer, or carbonate buffer.
- boric acid or its salts sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.
- boric acid buffer sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.
- phosphoric acid or its salts as a phosphate buffer
- Salts sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.
- carbonate buffer carbonate or salts thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.).
- organic buffers include citrate buffer, acetate buffer, lactic acid buffer, succinate buffer, Tris buffer, AMPD buffer, and the like.
- citric acid buffer include citric acid or a salt thereof (alkali metal citrate, alkaline earth metal citrate, etc.).
- acetic acid buffer include acetic acid or a salt thereof (alkali metal acetate, alkaline earth metal acetate, etc.).
- lactic acid buffer include lactic acid or a salt thereof (alkali metal lactate, alkaline earth metal lactate, etc.).
- succinic acid buffer include succinic acid or a salt thereof (such as an alkali metal succinic salt).
- citrate buffer hydrates of citrate, acetate, lactate, or succinate may be used as the citrate buffer, acetate buffer, lactate buffer, or succinate buffer. More specific examples include citric acid or its salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.) as a citric acid buffer; acetic acid as an acetic acid buffer; or its salts (ammonium acetate, sodium acetate, potassium acetate, calcium acetate, etc.); As a lactic acid buffer, lactic acid or its salts (sodium lactate, potassium lactate, calcium lactate, etc.); As a succinic acid buffer, succinic acid or its salts ( Examples include monosodium succinate, disodium succinate, etc. Examples of the Tris buffer include trometamol or a salt thereof (such as trometamol hydrochloride). Examples of the AMPD buffer include 2-amino-2-methyl-1,3-propanedi
- the buffering agent is preferably a boric acid buffer, a phosphate buffer, or a citrate buffer, more preferably a boric acid buffer or a phosphate buffer, and even more preferably boric acid or a salt thereof, or phosphoric acid or a salt thereof.
- a commercially available buffer may be used.
- One kind of buffering agent may be used alone, or two or more kinds of buffering agents may be used in combination.
- the content of the buffering agent in the ophthalmic composition according to the present embodiment is not particularly limited, and may be set as appropriate depending on the type of buffering agent, the type and content of other ingredients, the use of the ophthalmic composition, the formulation form, etc. Ru.
- the content of the buffering agent is preferably 0.01 w/v% to 10 w/v%, for example, based on the total amount of the ophthalmological composition, from the viewpoint of achieving more remarkable effects of the present invention, and 0.01 w/v% to 10 w/v%, for example. It is more preferably from 0.05 w/v% to 5 w/v%, and even more preferably from 0.1 w/v% to 3 w/v%.
- the buffer is a borate buffer, it is preferably 0.01 w/v% to 10 w/v%, more preferably 0.05 w/v% to 5 w/v%, and 0.1 w/v%. It is more preferably v% to 3w/v%, particularly preferably 0.5w/v% to 2w/v%.
- the buffer is a citrate buffer or a phosphate buffer, it is preferably 0.01 w/v% to 10 w/v%, more preferably 0.05 w/v% to 5 w/v%.
- w/v% it is preferably 0.1 w/v% to 3 w/v%, even more preferably 0.1 w/v% to 1 w/v%, and even more preferably 0.1 w/v% to 0.3 w/v%. Particularly preferred is v%.
- the content ratio of the buffering agent to the component (A) is not particularly limited, and the types of the component (A) and the buffering agent, the types and contents of other ingredients, and the content of the ophthalmic composition. It is set as appropriate depending on the use, formulation form, etc. From the viewpoint of further enhancing the effects of the present invention, the content ratio of the buffering agent to the component (A) is, for example, per 1 part by mass of the total content of the component (A) contained in the ophthalmic composition according to the present embodiment. The amount may be 0.001 to 1000 parts by weight, 0.01 to 100 parts by weight, or 0.025 to 30 parts by weight.
- the ophthalmic composition according to this embodiment may further contain inorganic salts.
- the ophthalmological composition further contains an inorganic salt, the effects of the present invention are more pronounced.
- the inorganic salts are not particularly limited as long as they are medicinally, pharmacologically (pharmacologically) or physiologically acceptable.
- inorganic salts examples include chloride salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. As the inorganic salts, sodium chloride and potassium chloride are preferred.
- inorganic salts may be used. Inorganic salts may be used alone or in combination of two or more.
- the content of inorganic salts in the ophthalmic composition according to the present embodiment is not particularly limited, and may be set as appropriate depending on the type of inorganic salt, the type and content of other ingredients, the use of the ophthalmic composition, the formulation form, etc. Ru.
- the content of the inorganic salts is preferably 0.00001 w/v % to 3 w/v %, for example, based on the total amount of the ophthalmological composition, from the viewpoint of achieving more remarkable effects of the present invention. It is more preferably from 0.001 w/v% to 2 w/v%, even more preferably from 0.001 w/v% to 1.5 w/v%.
- the ophthalmic composition according to this embodiment may further contain a preservative.
- a preservative By further containing a preservative, the effects of the present invention are more prominently exhibited.
- Preservatives include biguanide preservatives such as chlorhexidine, alexidine, polyhexanide, or their salts; quaternary ammonium salt preservatives such as benzalkonium chloride and benzethonium chloride; methyl paraoxybenzoate, ethyl paraoxybenzoate, and paraoxybenzoate. Examples include paraben preservatives such as propyl benzoate and butyl paraoxybenzoate.
- the preservative is preferably a biguanide preservative, more preferably chlorhexidine or a salt thereof, and even more preferably chlorhexidine gluconate, from the viewpoint of more significantly exerting the effects of the present invention.
- preservatives may be used.
- the preservatives may be used alone or in combination of two or more.
- the content of the preservative in the ophthalmic composition according to the present embodiment is not particularly limited, and may be set as appropriate depending on the type of preservative, the type and content of other ingredients, the use of the ophthalmic composition, the formulation form, etc. Ru.
- the content of the preservative is preferably 0.00001 w/v% to 2 w/v%, and 0.00005 w/v% based on the total amount of the ophthalmological composition, from the viewpoint of achieving more remarkable effects of the present invention. It is more preferably v% to 1w/v%, and particularly preferably 0.00008w/v% to 0.8w/v%.
- 0.00005 w/v% to 0.5 w/v% and 0.0001 w/v% to 0.025 w/v% can also be presented as preferred contents.
- the pH of the ophthalmic composition according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmacologically) or physiologically acceptable range.
- the pH of the aqueous composition according to the present embodiment may be, for example, 4.5 to 7.5, preferably 5.0 to 7.0, and preferably 5.5 to 6.5. is even more preferable.
- the osmotic pressure ratio of the ophthalmic composition according to the present embodiment can be adjusted to be within a range acceptable to living organisms, if necessary.
- An appropriate osmotic pressure ratio can be appropriately set depending on the use, formulation form, method of use, etc. of the ophthalmic composition, and can be, for example, 0.4 to 5.0.
- the osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w/v% sodium chloride aqueous solution) based on the 18th edition of the Japanese Pharmacopoeia, and the osmotic pressure is determined by the osmotic pressure measurement method described in the Japanese Pharmacopoeia.
- the standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution) is prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650°C for 40 to 50 minutes, and then drying it in a desiccator (silica gel). Allow to cool, then accurately weigh 0.900 g and dissolve in purified water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w/v % sodium chloride aqueous solution).
- the viscosity of the ophthalmic composition according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmacologically) or physiologically acceptable range.
- the viscosity of the ophthalmic composition according to the present embodiment is, for example, a viscosity of 1 at 20°C measured with a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' x R24). ⁇ 10000mPa ⁇ s may be possible
- the ophthalmic composition according to the present embodiment can be prepared, for example, by adding and mixing component (A) and, if necessary, other components to a desired content. Specifically, it can be prepared, for example, by dissolving or suspending the above components in purified water and sterilizing the solution by filtration sterilization or the like.
- the ophthalmological composition according to the present embodiment can take various dosage forms depending on the purpose, such as a liquid, a gel, a semi-solid (ointment, etc.), and the like.
- eye drops also referred to as eye drops or eye drops.
- Eye drops include eye drops that can be instilled while wearing contact lenses), artificial tears, etc. It can be used as a liquid or an eyewash (also referred to as an eyewash or an eyewash.
- Eyewashes include eyewashes that can be used to wash the eyes while wearing contact lenses).
- contact lenses include hard contact lenses and soft contact lenses (including both ionic and nonionic lenses, and includes both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).
- the ophthalmic composition according to the present embodiment is preferably an eye drop (including an eye drop that can be instilled while wearing contact lenses) because it can more significantly exhibit the effects of the present invention.
- the ophthalmic composition according to the present embodiment is an eye drop
- the usage and dosage thereof are not particularly limited as long as they are effective and have few side effects.
- examples include a method of instilling 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops into the eyes 1 to 4 times a day, or 5 to 6 times a day.
- the ophthalmic composition according to the present embodiment is provided in a container (also simply referred to as a "plastic container") in which part or all of the part that comes into contact with the ophthalmic composition is made of plastic.
- plastics examples include polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyethylene naphthalate, polyarylate, polycarbonate, polyethylene (PE; high density polyethylene (HDPE), low density polyethylene (LDPE), Linear low density polyethylene (LLDPE)), polypropylene (PP), polystyrene (PS), acrylonitrile butadiene styrene (ABS), polymethylpentene (PMP), polyimide (PI), cyclic olefin polymer (COP), cyclic olefin copolymer (COC), copolymers of monomers constituting these, and mixtures of two or more of these.
- Preferred polymers constituting the plastic include polyethylene (PE), polypropylene (PP), and cyclic olefin copolymer (COC).
- the plastic may also include an elastomer.
- the plastic may contain additives such as stabilizers. Furthermore, the plastic may be reinforced by containing a reinforcing agent such as glass fiber.
- plastics can be used without any particular restrictions.
- the plastic container containing the ophthalmological composition may be a container commonly used in the ophthalmological field, and specifically may be, for example, an eye drop container or an eye wash container.
- the type of container is preferably an eye drop container.
- part or all of the part that comes into contact with the ophthalmic composition is made of plastic.
- the plastic container has a perforated inner stopper (nozzle)
- only the perforated inner stopper may be made of plastic
- the housing parts other than the perforated inner stopper may be made of plastic.
- the entire container may be made of plastic.
- part of the part that comes into contact with the ophthalmic composition may be made of plastic, but from the viewpoint of achieving even more remarkable effects of the present invention, the part that comes into contact with the ophthalmic composition should be made of plastic. Preferably, it is made entirely of plastic. Furthermore, the plastic container may be made of one type of plastic alone or may be made of two or more types of plastic.
- the shape and capacity of the container are not particularly limited and may be set appropriately depending on the purpose. Further, the container may be a container in which an amount of the ophthalmic composition for multiple uses is accommodated (a multi-dose type container), or a container in which an amount of the ophthalmic composition for a single use is accommodated (a unit dose type container). ).
- the volume When the container is a multi-dose type container, the volume may be, for example, 1.5 to 7.5 mL, 2 to 6 mL, or 2.5 to 5.0 mL. Further, when the container is a unit dose type container, the volume may be, for example, 0.1 to 1.0 mL, 0.2 to 0.9 mL, or 0.3 to 0.8 mL.
- sterilization methods include electron beam sterilization, gamma ray sterilization, hydrogen peroxide gas (VHP) sterilization, and ethylene oxide gas (EOG) sterilization.
- sterilization using means other than electron beams include sterilization using gamma rays, sterilization using hydrogen peroxide gas (VHP), and sterilization using ethylene oxide gas (EOG).
- Sterilization using VHP) and ethylene oxide gas (EOG) are preferred. Sterilization using electron beams, gamma rays, hydrogen peroxide gas (VHP), and ethylene oxide gas (EOG) can be performed by methods known to those skilled in the art.
- the content of tramadol in the ophthalmic composition can be controlled within a specific range (e.g., 1.0 to 100% based on the total amount of the ophthalmic composition). 3.0 w/v%), the effect of reducing tramadol-derived impurities is achieved. Further, if the plastic container containing the ophthalmic composition according to the present embodiment is sterilized by means other than electron beam, the effect of reducing tramadol-derived impurities is achieved regardless of the tramadol content in the ophthalmic composition. be done.
- the ophthalmic composition according to this embodiment may also be provided as a containerized ophthalmic composition.
- the present invention can also be understood as an ophthalmic product (such as eye drops) in which the ophthalmic composition of the present invention is housed in a container.
- Ophthalmic compositions were prepared according to conventional methods with the compositions shown in Tables 1 and 2. Each of the prepared ophthalmic compositions was filtered and sterilized using a 0.2 ⁇ m membrane filter. Thereafter, the ophthalmic composition was filled into eye drop bottles (material: polyethylene or COC, capacity: 5 mL) that had been previously treated with each sterilization method, and stored under the conditions described in the upper left column of the table while shielding from light. The content of impurities (tramadol related substances) contained in the aqueous composition after storage was measured by HPLC method, and the production rate (%) of tramadol related substances with respect to the blended amount of tramadol hydrochloride was calculated.
- impurities tramadol related substances
- ophthalmic composition was prepared according to a conventional method using the composition shown in Table 3. Each of the prepared ophthalmic compositions was filtered and sterilized using a 0.2 ⁇ m membrane filter. Thereafter, the ophthalmic composition was filled into eye drop bottles (material: polyethylene or polypropylene, capacity: 5 mL) that had been previously treated with each sterilization method, and stored under the conditions described in the left column of the table while shielding from light. The content of impurities (tramadol related substances) contained in the aqueous composition after storage was measured by HPLC method, and the production rate (%) of tramadol related substances with respect to the blended amount of tramadol hydrochloride was calculated.
- impurities tramadol related substances
- tramadol related substances When filled into a plastic container sterilized by means other than electron beams such as EOG sterilization and VHP sterilization, tramadol related substances are not produced as shown in Test Examples 8 and 9, and tramadol hydrochloride exists stably. This was confirmed.
Abstract
The present invention relates to an ophthalmic composition containing tramadol or a salt thereof, wherein the ophthalmic composition is accommodated in a container of which part or all of a portion coming into contact with the ophthalmic composition is formed from a plastic, and the container is subjected to a sterilization treatment by a means other than an electron beam.
Description
本発明は、眼科組成物に関する。
The present invention relates to an ophthalmic composition.
トラマドールは弱オピオイドに分類される非麻薬性鎮痛薬であり、癌性疼痛などの全身性鎮痛薬として用いられている（非特許文献１）。
Tramadol is a non-narcotic analgesic classified as a weak opioid, and is used as a systemic analgesic for cancer pain and the like (Non-Patent Document 1).
他方、トラマドールを眼科領域における疾患の治療薬として用いる場合、眼科製剤中におけるトラマドールに由来する不純物が一定量未満であることが求められるが、これまでトラマドールを含有する眼科製剤におけるトラマドール由来の不純物に関する知見は全く報告されていない。本発明は、トラマドール由来の不純物が低減された新規なトラマドール含有眼科組成物を提供することを目的とする。
On the other hand, when tramadol is used as a therapeutic agent for diseases in the ophthalmological field, it is required that the tramadol-derived impurities in the ophthalmic preparation be less than a certain amount. No findings were reported. An object of the present invention is to provide a novel tramadol-containing ophthalmic composition in which tramadol-derived impurities are reduced.
本発明者らは、トラマドール含有眼科組成物を電子線以外の手段で滅菌処理したプラスチック容器に収容すると、眼科組成物におけるトラマドールの含有量にかかわらずトラマドール由来の不純物が低減すること、また、眼科組成物におけるトラマドールの含有量を特定範囲とすることで、電子線により滅菌処理されたプラスチック容器に収容した場合にトラマドール由来の不純物が低減することを初めて見出した。本発明は、この知見に基づくものであり、以下の各発明を提供するものである。
The present inventors have discovered that when a tramadol-containing ophthalmic composition is stored in a plastic container sterilized by means other than electron beams, impurities derived from tramadol are reduced regardless of the tramadol content in the ophthalmic composition. For the first time, we have discovered that by setting the content of tramadol in a composition within a specific range, impurities derived from tramadol are reduced when the composition is stored in a plastic container sterilized by electron beams. The present invention is based on this knowledge and provides the following inventions.
［１］
トラマドール又はその塩を含有する眼科組成物であって、該眼科組成物と接する部分の一部又は全部がプラスチックで形成された容器に収容してなり、該容器が電子線以外の手段により滅菌処理されている、眼科組成物。
［２］
前記電子線以外の手段による滅菌処理が、過酸化水素ガスによる滅菌又はエチレンオキシドガスによる滅菌である、［１］に記載の眼科組成物。
［３］
眼科組成物の総量を基準として１．０～３．０ｗ／ｖ％のトラマドール又はその塩を含有する眼科組成物であって、該眼科組成物と接する部分の一部又は全部がプラスチックで形成された容器に収容してなり、該容器が電子線により滅菌処理されている、眼科組成物。
［４］
前記プラスチックが、ポリエチレン、ポリプロピレン及び環状オレフィンコポリマーからなる群より選択される少なくとも１種である、［１］～［３］のいずれかに記載の眼科組成物。 [1]
An ophthalmic composition containing tramadol or a salt thereof, which is housed in a container in which part or all of the part that comes into contact with the ophthalmic composition is made of plastic, and the container is sterilized by means other than electron beams. ophthalmological composition.
[2]
The ophthalmic composition according to [1], wherein the sterilization treatment by a means other than electron beam is sterilization with hydrogen peroxide gas or sterilization with ethylene oxide gas.
[3]
An ophthalmic composition containing 1.0 to 3.0 w/v% of tramadol or its salt based on the total amount of the ophthalmic composition, wherein part or all of the part that comes into contact with the ophthalmic composition is formed of plastic. 1. An ophthalmological composition, which is housed in a container which has been sterilized by electron beam.
[4]
The ophthalmic composition according to any one of [1] to [3], wherein the plastic is at least one selected from the group consisting of polyethylene, polypropylene, and cyclic olefin copolymers.
トラマドール又はその塩を含有する眼科組成物であって、該眼科組成物と接する部分の一部又は全部がプラスチックで形成された容器に収容してなり、該容器が電子線以外の手段により滅菌処理されている、眼科組成物。
［２］
前記電子線以外の手段による滅菌処理が、過酸化水素ガスによる滅菌又はエチレンオキシドガスによる滅菌である、［１］に記載の眼科組成物。
［３］
眼科組成物の総量を基準として１．０～３．０ｗ／ｖ％のトラマドール又はその塩を含有する眼科組成物であって、該眼科組成物と接する部分の一部又は全部がプラスチックで形成された容器に収容してなり、該容器が電子線により滅菌処理されている、眼科組成物。
［４］
前記プラスチックが、ポリエチレン、ポリプロピレン及び環状オレフィンコポリマーからなる群より選択される少なくとも１種である、［１］～［３］のいずれかに記載の眼科組成物。 [1]
An ophthalmic composition containing tramadol or a salt thereof, which is housed in a container in which part or all of the part that comes into contact with the ophthalmic composition is made of plastic, and the container is sterilized by means other than electron beams. ophthalmological composition.
[2]
The ophthalmic composition according to [1], wherein the sterilization treatment by a means other than electron beam is sterilization with hydrogen peroxide gas or sterilization with ethylene oxide gas.
[3]
An ophthalmic composition containing 1.0 to 3.0 w/v% of tramadol or its salt based on the total amount of the ophthalmic composition, wherein part or all of the part that comes into contact with the ophthalmic composition is formed of plastic. 1. An ophthalmological composition, which is housed in a container which has been sterilized by electron beam.
[4]
The ophthalmic composition according to any one of [1] to [3], wherein the plastic is at least one selected from the group consisting of polyethylene, polypropylene, and cyclic olefin copolymers.
本発明によれば、トラマドール由来の不純物が低減された新規なトラマドール含有眼科組成物を提供することができる。
According to the present invention, it is possible to provide a novel tramadol-containing ophthalmic composition in which tramadol-derived impurities are reduced.
以下、本発明を実施するための形態について詳細に説明する。ただし、本発明は以下の実施形態に限定されるものではない。
Hereinafter, modes for carrying out the present invention will be described in detail. However, the present invention is not limited to the following embodiments.
本明細書において、特に記載のない限り、含有量の単位「％」は「ｗ／ｖ％」を意味し、「ｇ／１００ｍＬ」と同義である。
In this specification, unless otherwise specified, the content unit "%" means "w/v%" and is synonymous with "g/100mL".
本実施形態に係る眼科組成物は、（Ａ）トラマドール又はその塩（単に「（Ａ）成分」とも表記する。）を含有する。
The ophthalmic composition according to the present embodiment contains (A) tramadol or a salt thereof (also simply referred to as "component (A)").
〔（Ａ）成分〕
トラマドールは、下記式：
で表される公知の化合物である。なお、上記式では便宜上鏡像異性体のうちの一つを表しているが、他の鏡像異性体も本発明に含まれる。
[(A) component]
Tramadol has the following formula:
This is a known compound represented by Note that although the above formula represents one of the enantiomers for convenience, other enantiomers are also included in the present invention.
トラマドールは、下記式：
Tramadol has the following formula:
トラマドールの塩は、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば、特に制限されない。このような塩として具体的には、無機酸との塩、有機酸との塩、無機塩基との塩、有機塩基との塩、酸性アミノ酸との塩、塩基性アミノ酸との塩などが挙げられる。
The salt of tramadol is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmacologically) or physiologically acceptable. Specific examples of such salts include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with acidic amino acids, salts with basic amino acids, etc. .
無機酸との塩は、例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸などとの塩が挙げられる。有機酸との塩は、例えば、酢酸、コハク酸、フマル酸、マレイン酸、酒石酸、クエン酸、乳酸、ステアリン酸、安息香酸、メタンスルホン酸（メシル酸）、エタンスルホン酸、ｐ－トルエンスルホン酸などとの塩が挙げられる。無機塩基との塩は、例えば、ナトリウム塩、カリウム塩などのアルカリ金属塩、カルシウム塩、マグネシウム塩などのアルカリ土類金属塩、アルミニウム塩、アンモニウム塩などが挙げられる。有機塩基との塩は、例えば、ジエチルアミン、ジエタノールアミン、メグルミン、Ｎ，Ｎ－ジベンジルエチレンジアミンなどとの塩が挙げられる。酸性アミノ酸との塩は、例えば、アスパラギン酸、グルタミン酸などとの塩が挙げられる。塩基性アミノ酸との塩は、例えば、アルギニン、リジン、オルニチンなどとの塩が挙げられる。トラマドールの塩としては、無機酸との塩が好ましく、塩酸塩がより好ましい。
Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts with organic acids include, for example, acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid (mesylic acid), ethanesulfonic acid, p-toluenesulfonic acid. Examples include salts such as Examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, and ammonium salts. Examples of salts with organic bases include salts with diethylamine, diethanolamine, meglumine, N,N-dibenzylethylenediamine, and the like. Examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid. Examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and the like. As the salt of tramadol, a salt with an inorganic acid is preferable, and a hydrochloride is more preferable.
本実施形態に係る眼科組成物は、トラマドール又はその塩を有効成分として含有しており、例えば、疼痛の抑制に用いることができる。
The ophthalmic composition according to the present embodiment contains tramadol or a salt thereof as an active ingredient, and can be used, for example, to suppress pain.
本実施形態に係る眼科組成物が電子線以外の手段により滅菌処理された容器に収容される場合、（Ａ）成分の含有量は特に限定されず、他の配合成分の種類及び含有量、製剤形態等に応じて適宜設定される。（Ａ）成分の含有量としては、本発明による効果をより顕著に奏する観点から、本実施形態に係る眼科組成物の総量を基準として、０．０１ｗ／ｖ％～１０ｗ／ｖ％、０．０５ｗ／ｖ％～５ｗ／ｖ％、０．１ｗ／ｖ％～４ｗ／ｖ％、又は３ｗ／ｖ％であってもよい。
When the ophthalmic composition according to the present embodiment is stored in a container that has been sterilized by means other than electron beams, the content of component (A) is not particularly limited, and the types and contents of other ingredients, the formulation It is set as appropriate depending on the format etc. The content of component (A) is 0.01 w/v% to 10 w/v%, 0.01 w/v% to 10 w/v%, based on the total amount of the ophthalmological composition according to the present embodiment, from the viewpoint of achieving more remarkable effects of the present invention. It may be 0.05 w/v% to 5 w/v%, 0.1 w/v% to 4 w/v%, or 3 w/v%.
本実施形態に係る眼科組成物が電子線により滅菌処理された容器に収容される場合、（Ａ）成分の含有量は、眼科組成物の総量を基準として、１．０ｗ／ｖ％～３．０ｗ／ｖ％である。
When the ophthalmic composition according to the present embodiment is stored in a container sterilized by electron beam, the content of component (A) is 1.0 w/v % to 3.0 w/v % based on the total amount of the ophthalmic composition. It is 0 w/v%.
〔緩衝剤〕
本実施形態に係る眼科組成物は、緩衝剤を更に含有してもよい。眼科組成物が緩衝剤を更に含有することで、本発明による効果がより顕著に奏される。緩衝剤は、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば、特に制限されない。緩衝剤としては、例えば、無機酸由来の緩衝剤である無機緩衝剤、及び有機酸又は有機塩基由来の緩衝剤である有機緩衝剤が挙げられる。 [Buffer]
The ophthalmic composition according to this embodiment may further contain a buffer. When the ophthalmic composition further contains a buffering agent, the effects of the present invention are more prominently exhibited. The buffering agent is not particularly limited as long as it is medicinally, pharmacologically (pharmacologically) or physiologically acceptable. Examples of the buffer include inorganic buffers that are buffers derived from inorganic acids, and organic buffers that are buffers derived from organic acids or organic bases.
本実施形態に係る眼科組成物は、緩衝剤を更に含有してもよい。眼科組成物が緩衝剤を更に含有することで、本発明による効果がより顕著に奏される。緩衝剤は、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば、特に制限されない。緩衝剤としては、例えば、無機酸由来の緩衝剤である無機緩衝剤、及び有機酸又は有機塩基由来の緩衝剤である有機緩衝剤が挙げられる。 [Buffer]
The ophthalmic composition according to this embodiment may further contain a buffer. When the ophthalmic composition further contains a buffering agent, the effects of the present invention are more prominently exhibited. The buffering agent is not particularly limited as long as it is medicinally, pharmacologically (pharmacologically) or physiologically acceptable. Examples of the buffer include inorganic buffers that are buffers derived from inorganic acids, and organic buffers that are buffers derived from organic acids or organic bases.
無機緩衝剤としては、例えば、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤等が挙げられる。ホウ酸緩衝剤としては、ホウ酸又はその塩（ホウ酸アルカリ金属塩、ホウ酸アルカリ土類金属塩等）が挙げられる。リン酸緩衝剤としては、リン酸又はその塩（リン酸アルカリ金属塩、リン酸アルカリ土類金属塩等）が挙げられる。炭酸緩衝剤としては、炭酸又はその塩（炭酸アルカリ金属塩、炭酸アルカリ土類金属塩等）が挙げられる。また、ホウ酸緩衝剤、リン酸緩衝剤又は炭酸緩衝剤として、ホウ酸塩、リン酸塩又は炭酸塩の水和物を用いてもよい。より具体的な例として、ホウ酸緩衝剤として、ホウ酸又はその塩（ホウ酸ナトリウム、テトラホウ酸カリウム、メタホウ酸カリウム、ホウ酸アンモニウム、ホウ砂等）；リン酸緩衝剤として、リン酸又はその塩（リン酸水素二ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウム、リン酸三ナトリウム、リン酸三カリウム、リン酸一水素カルシウム、リン酸二水素カルシウム等）；炭酸緩衝剤として、炭酸又はその塩（炭酸水素ナトリウム、炭酸ナトリウム、炭酸アンモニウム、炭酸カリウム、炭酸カルシウム、炭酸水素カリウム、炭酸マグネシウム等）などが例示できる。
Examples of inorganic buffers include boric acid buffers, phosphate buffers, carbonate buffers, and the like. Examples of the boric acid buffer include boric acid or a salt thereof (alkali metal boric acid salt, alkaline earth metal boric acid salt, etc.). Examples of the phosphate buffer include phosphoric acid or a salt thereof (alkali metal phosphate, alkaline earth metal phosphate, etc.). Examples of the carbonate buffer include carbonic acid or a salt thereof (alkali metal carbonate, alkaline earth metal carbonate, etc.). Furthermore, a hydrate of borate, phosphate, or carbonate may be used as the borate buffer, phosphate buffer, or carbonate buffer. More specific examples include boric acid or its salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) as a boric acid buffer; phosphoric acid or its salts as a phosphate buffer; Salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); As a carbonate buffer, carbonate or salts thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.).
有機緩衝剤としては、例えば、クエン酸緩衝剤、酢酸緩衝剤、乳酸緩衝剤、コハク酸緩衝剤、トリス緩衝剤、ＡＭＰＤ緩衝剤等が挙げられる。クエン酸緩衝剤としては、クエン酸又はその塩（クエン酸アルカリ金属塩、クエン酸アルカリ土類金属塩等）が挙げられる。酢酸緩衝剤としては、酢酸又はその塩（酢酸アルカリ金属塩、酢酸アルカリ土類金属塩等）が挙げられる。乳酸緩衝剤としては、乳酸又はその塩（乳酸アルカリ金属塩、乳酸アルカリ土類金属塩等）が挙げられる。コハク酸緩衝剤としては、コハク酸又はその塩（コハク酸アルカリ金属塩等）が挙げられる。また、クエン酸緩衝剤、酢酸緩衝剤、乳酸緩衝剤又はコハク酸緩衝剤として、クエン酸塩、酢酸塩、乳酸塩又はコハク酸塩の水和物を用いてもよい。より具体的な例として、クエン酸緩衝剤として、クエン酸又はその塩（クエン酸ナトリウム、クエン酸カリウム、クエン酸カルシウム、クエン酸二水素ナトリウム、クエン酸二ナトリウム等）；酢酸緩衝剤として、酢酸又はその塩（酢酸アンモニウム、酢酸ナトリウム、酢酸カリウム、酢酸カルシウム等）；乳酸緩衝剤として、乳酸又はその塩（乳酸ナトリウム、乳酸カリウム、乳酸カルシウム等）；コハク酸緩衝剤としてコハク酸又はその塩（コハク酸一ナトリウム、コハク酸二ナトリウム等）などが例示できる。トリス緩衝剤としては、例えば、トロメタモール又はその塩（トロメタモール塩酸塩等）が挙げられる。ＡＭＰＤ緩衝剤としては、例えば、２－アミノ－２－メチル－１，３－プロパンジオール又はその塩が挙げられる。
Examples of organic buffers include citrate buffer, acetate buffer, lactic acid buffer, succinate buffer, Tris buffer, AMPD buffer, and the like. Examples of the citric acid buffer include citric acid or a salt thereof (alkali metal citrate, alkaline earth metal citrate, etc.). Examples of the acetic acid buffer include acetic acid or a salt thereof (alkali metal acetate, alkaline earth metal acetate, etc.). Examples of the lactic acid buffer include lactic acid or a salt thereof (alkali metal lactate, alkaline earth metal lactate, etc.). Examples of the succinic acid buffer include succinic acid or a salt thereof (such as an alkali metal succinic salt). Furthermore, hydrates of citrate, acetate, lactate, or succinate may be used as the citrate buffer, acetate buffer, lactate buffer, or succinate buffer. More specific examples include citric acid or its salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.) as a citric acid buffer; acetic acid as an acetic acid buffer; or its salts (ammonium acetate, sodium acetate, potassium acetate, calcium acetate, etc.); As a lactic acid buffer, lactic acid or its salts (sodium lactate, potassium lactate, calcium lactate, etc.); As a succinic acid buffer, succinic acid or its salts ( Examples include monosodium succinate, disodium succinate, etc. Examples of the Tris buffer include trometamol or a salt thereof (such as trometamol hydrochloride). Examples of the AMPD buffer include 2-amino-2-methyl-1,3-propanediol or a salt thereof.
緩衝剤としては、ホウ酸緩衝剤、リン酸緩衝剤、クエン酸緩衝剤が好ましく、ホウ酸緩衝剤、リン酸緩衝剤がより好ましく、ホウ酸又はその塩、リン酸又はその塩が更に好ましい。
The buffering agent is preferably a boric acid buffer, a phosphate buffer, or a citrate buffer, more preferably a boric acid buffer or a phosphate buffer, and even more preferably boric acid or a salt thereof, or phosphoric acid or a salt thereof.
緩衝剤は、市販されているものを使用してもよい。緩衝剤は、１種を単独で使用してもよく、又は２種以上を組み合わせて使用してもよい。
A commercially available buffer may be used. One kind of buffering agent may be used alone, or two or more kinds of buffering agents may be used in combination.
本実施形態に係る眼科組成物における緩衝剤の含有量は特に限定されず、緩衝剤の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。緩衝剤の含有量としては、本発明による効果をより顕著に奏する観点から、例えば、眼科組成物の総量を基準として、０．０１ｗ／ｖ％～１０ｗ／ｖ％であることが好ましく、０．０５ｗ／ｖ％～５ｗ／ｖ％であることがより好ましく、０．１ｗ／ｖ％～３ｗ／ｖ％であることが更に好ましい。緩衝剤がホウ酸緩衝剤の場合は、０．０１ｗ／ｖ％～１０ｗ／ｖ％であることが好ましく、０．０５ｗ／ｖ％～５ｗ／ｖ％であることがより好ましく、０．１ｗ／ｖ％～３ｗ／ｖ％であることが更に好ましく、０．５ｗ／ｖ％～２ｗ／ｖ％が特に好ましい。緩衝剤がクエン酸緩衝剤、又はリン酸緩衝剤の場合は、０．０１ｗ／ｖ％～１０ｗ／ｖ％であることが好ましく、０．０５ｗ／ｖ％～５ｗ／ｖ％であることがより好ましく、０．１ｗ／ｖ％～３ｗ／ｖ％であることが更に好ましく、０．１ｗ／ｖ％～１ｗ／ｖ％であることが更により好ましく、０．１ｗ／ｖ％～０．３ｗ／ｖ％であることが特に好ましい。
The content of the buffering agent in the ophthalmic composition according to the present embodiment is not particularly limited, and may be set as appropriate depending on the type of buffering agent, the type and content of other ingredients, the use of the ophthalmic composition, the formulation form, etc. Ru. The content of the buffering agent is preferably 0.01 w/v% to 10 w/v%, for example, based on the total amount of the ophthalmological composition, from the viewpoint of achieving more remarkable effects of the present invention, and 0.01 w/v% to 10 w/v%, for example. It is more preferably from 0.05 w/v% to 5 w/v%, and even more preferably from 0.1 w/v% to 3 w/v%. When the buffer is a borate buffer, it is preferably 0.01 w/v% to 10 w/v%, more preferably 0.05 w/v% to 5 w/v%, and 0.1 w/v%. It is more preferably v% to 3w/v%, particularly preferably 0.5w/v% to 2w/v%. When the buffer is a citrate buffer or a phosphate buffer, it is preferably 0.01 w/v% to 10 w/v%, more preferably 0.05 w/v% to 5 w/v%. It is preferably 0.1 w/v% to 3 w/v%, even more preferably 0.1 w/v% to 1 w/v%, and even more preferably 0.1 w/v% to 0.3 w/v%. Particularly preferred is v%.
本実施形態に係る眼科組成物における、（Ａ）成分に対する緩衝剤の含有比率は特に限定されず、（Ａ）成分及び緩衝剤の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。（Ａ）成分に対する緩衝剤の含有比率としては、本発明による効果をより一層高める観点から、例えば、本実施形態に係る眼科組成物に含まれる（Ａ）成分の総含有量１質量部に対して、０．００１～１０００質量部、０．０１～１００質量部、又は０．０２５～３０質量部であってもよい。
In the ophthalmic composition according to the present embodiment, the content ratio of the buffering agent to the component (A) is not particularly limited, and the types of the component (A) and the buffering agent, the types and contents of other ingredients, and the content of the ophthalmic composition. It is set as appropriate depending on the use, formulation form, etc. From the viewpoint of further enhancing the effects of the present invention, the content ratio of the buffering agent to the component (A) is, for example, per 1 part by mass of the total content of the component (A) contained in the ophthalmic composition according to the present embodiment. The amount may be 0.001 to 1000 parts by weight, 0.01 to 100 parts by weight, or 0.025 to 30 parts by weight.
〔無機塩類〕
本実施形態に係る眼科組成物は、無機塩類を更に含有してもよい。眼科組成物が無機塩類を更に含有することで、本発明による効果がより顕著に奏される。無機塩類は、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば、特に制限されない。 [Inorganic salts]
The ophthalmic composition according to this embodiment may further contain inorganic salts. When the ophthalmological composition further contains an inorganic salt, the effects of the present invention are more pronounced. The inorganic salts are not particularly limited as long as they are medicinally, pharmacologically (pharmacologically) or physiologically acceptable.
本実施形態に係る眼科組成物は、無機塩類を更に含有してもよい。眼科組成物が無機塩類を更に含有することで、本発明による効果がより顕著に奏される。無機塩類は、医薬上、薬理学的に（製薬上）又は生理学的に許容されるものであれば、特に制限されない。 [Inorganic salts]
The ophthalmic composition according to this embodiment may further contain inorganic salts. When the ophthalmological composition further contains an inorganic salt, the effects of the present invention are more pronounced. The inorganic salts are not particularly limited as long as they are medicinally, pharmacologically (pharmacologically) or physiologically acceptable.
無機塩類としては、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム等の塩化物塩が挙げられる。無機塩類としては、塩化ナトリウム、塩化カリウムが好ましい。
Examples of inorganic salts include chloride salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. As the inorganic salts, sodium chloride and potassium chloride are preferred.
無機塩類は、市販されているものを使用してもよい。無機塩類は、１種を単独で使用してもよく、又は２種以上を組み合わせて使用してもよい。
Commercially available inorganic salts may be used. Inorganic salts may be used alone or in combination of two or more.
本実施形態に係る眼科組成物における無機塩類の含有量は特に限定されず、無機塩類の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。無機塩類の含有量としては、本発明による効果をより顕著に奏する観点から、例えば、眼科組成物の総量を基準として、０．００００１ｗ／ｖ％～３ｗ／ｖ％であることが好ましく、０．０００１ｗ／ｖ％～２ｗ／ｖ％であることがより好ましく、０．００１ｗ／ｖ％～１．５ｗ／ｖ％であることが更に好ましい。
The content of inorganic salts in the ophthalmic composition according to the present embodiment is not particularly limited, and may be set as appropriate depending on the type of inorganic salt, the type and content of other ingredients, the use of the ophthalmic composition, the formulation form, etc. Ru. The content of the inorganic salts is preferably 0.00001 w/v % to 3 w/v %, for example, based on the total amount of the ophthalmological composition, from the viewpoint of achieving more remarkable effects of the present invention. It is more preferably from 0.001 w/v% to 2 w/v%, even more preferably from 0.001 w/v% to 1.5 w/v%.
〔防腐剤〕
本実施形態に係る眼科組成物は、防腐剤を更に含有してもよい。防腐剤を更に含有することで、本発明による効果がより顕著に奏される。 〔Preservative〕
The ophthalmic composition according to this embodiment may further contain a preservative. By further containing a preservative, the effects of the present invention are more prominently exhibited.
本実施形態に係る眼科組成物は、防腐剤を更に含有してもよい。防腐剤を更に含有することで、本発明による効果がより顕著に奏される。 〔Preservative〕
The ophthalmic composition according to this embodiment may further contain a preservative. By further containing a preservative, the effects of the present invention are more prominently exhibited.
防腐剤としては、クロルヘキシジン、アレキシジン、ポリヘキサニド又はそれらの塩等のビグアニド系防腐剤；塩化ベンザルコニウム、塩化ベンゼトニウム等の第四級アンモニウム塩系防腐剤；パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル等のパラベン系防腐剤等が挙げられる。
Preservatives include biguanide preservatives such as chlorhexidine, alexidine, polyhexanide, or their salts; quaternary ammonium salt preservatives such as benzalkonium chloride and benzethonium chloride; methyl paraoxybenzoate, ethyl paraoxybenzoate, and paraoxybenzoate. Examples include paraben preservatives such as propyl benzoate and butyl paraoxybenzoate.
防腐剤としては、本発明による効果をより顕著に奏する観点から、ビグアニド系防腐剤が好ましく、クロルヘキシジン又はその塩がより好ましく、クロルヘキシジングルコン酸塩が更に好ましい。
The preservative is preferably a biguanide preservative, more preferably chlorhexidine or a salt thereof, and even more preferably chlorhexidine gluconate, from the viewpoint of more significantly exerting the effects of the present invention.
防腐剤は、市販されているものを使用してもよい。防腐剤は、１種を単独で使用してもよく、又は２種以上を組み合わせて使用してもよい。
Commercially available preservatives may be used. The preservatives may be used alone or in combination of two or more.
本実施形態に係る眼科組成物における防腐剤の含有量は特に限定されず、防腐剤の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。防腐剤の含有量としては、本発明による効果をより顕著に奏する観点から、眼科組成物の総量を基準として、０．００００１ｗ／ｖ％～２ｗ／ｖ％であることが好ましく、０．００００５ｗ／ｖ％～１ｗ／ｖ％であることがより好ましく、０．００００８ｗ／ｖ％～０．８ｗ／ｖ％であることが特に好ましい。別の態様として、０．００００５ｗ／ｖ％～０．５ｗ／ｖ％、０．０００１ｗ／ｖ％～０．０２５ｗ／ｖ％も好ましい含有量として提示することができる。
The content of the preservative in the ophthalmic composition according to the present embodiment is not particularly limited, and may be set as appropriate depending on the type of preservative, the type and content of other ingredients, the use of the ophthalmic composition, the formulation form, etc. Ru. The content of the preservative is preferably 0.00001 w/v% to 2 w/v%, and 0.00005 w/v% based on the total amount of the ophthalmological composition, from the viewpoint of achieving more remarkable effects of the present invention. It is more preferably v% to 1w/v%, and particularly preferably 0.00008w/v% to 0.8w/v%. As another aspect, 0.00005 w/v% to 0.5 w/v% and 0.0001 w/v% to 0.025 w/v% can also be presented as preferred contents.
本実施形態に係る眼科組成物のｐＨは、医薬上、薬理学的に（製薬上）又は生理学的に許容される範囲内であれば特に限定されるものではない。本実施形態に係る水性組成物のｐＨとしては、例えば、４．５～７．５であってよく、５．０～７．０であることが好ましく、５．５～６．５であることが更に好ましい。
The pH of the ophthalmic composition according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmacologically) or physiologically acceptable range. The pH of the aqueous composition according to the present embodiment may be, for example, 4.5 to 7.5, preferably 5.0 to 7.0, and preferably 5.5 to 6.5. is even more preferable.
本実施形態に係る眼科組成物は、必要に応じて、生体に許容される範囲内の浸透圧比に調節することができる。適切な浸透圧比は、眼科組成物の用途、製剤形態、使用方法等に応じて適宜設定され得るが、例えば、０．４～５．０とすることができる。浸透圧比は、第十八改正日本薬局方に基づき、２８６ｍＯｓｍ（０．９ｗ／ｖ％塩化ナトリウム水溶液の浸透圧）に対する試料の浸透圧の比とし、浸透圧は日本薬局方記載の浸透圧測定法（凝固点降下法）を参考にして測定する。なお、浸透圧比測定用標準液（０．９ｗ／ｖ％塩化ナトリウム水溶液）は、塩化ナトリウム（日本薬局方標準試薬）を５００～６５０℃で４０～５０分間乾燥した後、デシケーター（シリカゲル）中で放冷し、その０．９００ｇを正確に量り、精製水に溶かし正確に１００ｍＬとして調製するか、市販の浸透圧比測定用標準液（０．９ｗ／ｖ％塩化ナトリウム水溶液）を用いることができる。
The osmotic pressure ratio of the ophthalmic composition according to the present embodiment can be adjusted to be within a range acceptable to living organisms, if necessary. An appropriate osmotic pressure ratio can be appropriately set depending on the use, formulation form, method of use, etc. of the ophthalmic composition, and can be, for example, 0.4 to 5.0. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w/v% sodium chloride aqueous solution) based on the 18th edition of the Japanese Pharmacopoeia, and the osmotic pressure is determined by the osmotic pressure measurement method described in the Japanese Pharmacopoeia. (Freezing point depression method) as a reference. The standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution) is prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650°C for 40 to 50 minutes, and then drying it in a desiccator (silica gel). Allow to cool, then accurately weigh 0.900 g and dissolve in purified water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w/v % sodium chloride aqueous solution).
本実施形態に係る眼科組成物の粘度は、医薬上、薬理学的に（製薬上）又は生理学的に許容される範囲内であれば、特に限定されるものではない。本実施形態に係る眼科組成物の粘度としては、例えば、回転粘度計（ＴＶ－２０型粘度計、東機産業社製、ローター；１°３４’×Ｒ２４）で測定した２０℃における粘度が１～１００００ｍＰａ・ｓであってもよい
The viscosity of the ophthalmic composition according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmacologically) or physiologically acceptable range. The viscosity of the ophthalmic composition according to the present embodiment is, for example, a viscosity of 1 at 20°C measured with a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' x R24). ~10000mPa・s may be possible
本実施形態に係る眼科組成物は、例えば、（Ａ）成分、及び必要に応じて他の含有成分を所望の含有量となるように添加及び混和することにより調製することができる。具体的には、例えば、精製水で上記成分を溶解又は懸濁させ、濾過滅菌等により滅菌処理することで調製できる。
The ophthalmic composition according to the present embodiment can be prepared, for example, by adding and mixing component (A) and, if necessary, other components to a desired content. Specifically, it can be prepared, for example, by dissolving or suspending the above components in purified water and sterilizing the solution by filtration sterilization or the like.
本実施形態に係る眼科組成物は、目的に応じて種々の剤型をとることができ、例えば、液剤、ゲル剤、半固形剤（軟膏等）等が挙げられる。
The ophthalmological composition according to the present embodiment can take various dosage forms depending on the purpose, such as a liquid, a gel, a semi-solid (ointment, etc.), and the like.
本実施形態に係る眼科組成物が液剤である場合、例えば、点眼剤（点眼液又は点眼薬ともいう。また、点眼剤にはコンタクトレンズ装用中に点眼可能な点眼剤を含む。）、人工涙液、洗眼剤（洗眼液又は洗眼薬ともいう。また、洗眼剤にはコンタクトレンズ装用中に洗眼可能な洗眼剤を含む。）として用いることができる。なお、「コンタクトレンズ」は、ハードコンタクトレンズ、ソフトコンタクトレンズ（イオン性及び非イオン性の双方を包含し、シリコーンハイドロゲルコンタクトレンズ及び非シリコーンハイドロゲルコンタクトレンズの双方を包含する）を含む。
When the ophthalmic composition according to the present embodiment is a liquid, for example, eye drops (also referred to as eye drops or eye drops. Eye drops include eye drops that can be instilled while wearing contact lenses), artificial tears, etc. It can be used as a liquid or an eyewash (also referred to as an eyewash or an eyewash. Eyewashes include eyewashes that can be used to wash the eyes while wearing contact lenses). Note that "contact lenses" include hard contact lenses and soft contact lenses (including both ionic and nonionic lenses, and includes both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).
本実施形態に係る眼科組成物は、本発明による効果をより顕著に発揮できることから、点眼剤（コンタクトレンズ装用中に点眼可能な点眼剤を含む。）であることが好ましい。本実施形態に係る眼科組成物が点眼剤である場合、その用法・用量としては、効果を奏し、副作用の少ない用法・用量であれば特に限定されないが、例えば成人（１５歳以上）及び７歳以上の小児の場合、１回１～３滴、１～２滴、又は２～３滴を１日１～４回、又は５～６回点眼して用いる方法を例示できる。
The ophthalmic composition according to the present embodiment is preferably an eye drop (including an eye drop that can be instilled while wearing contact lenses) because it can more significantly exhibit the effects of the present invention. When the ophthalmic composition according to the present embodiment is an eye drop, the usage and dosage thereof are not particularly limited as long as they are effective and have few side effects. In the case of children above, examples include a method of instilling 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops into the eyes 1 to 4 times a day, or 5 to 6 times a day.
〔容器〕
本実施形態に係る眼科組成物は、該眼科組成物と接する部分の一部又は全部がプラスチックで形成された容器（単に「プラスチック容器」とも表記する。）に収容して提供される。 〔container〕
The ophthalmic composition according to the present embodiment is provided in a container (also simply referred to as a "plastic container") in which part or all of the part that comes into contact with the ophthalmic composition is made of plastic.
本実施形態に係る眼科組成物は、該眼科組成物と接する部分の一部又は全部がプラスチックで形成された容器（単に「プラスチック容器」とも表記する。）に収容して提供される。 〔container〕
The ophthalmic composition according to the present embodiment is provided in a container (also simply referred to as a "plastic container") in which part or all of the part that comes into contact with the ophthalmic composition is made of plastic.
プラスチックを構成するポリマーとしては、例えば、ポリエチレンテレフタレート（ＰＥＴ）、ポリブチレンテレフタレート（ＰＢＴ）、ポリエチレンナフタレート、ポリアリレート、ポリカーボネート、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）、ポリスチレン（ＰＳ）、アクリロニトリルブタジエンスチレン（ＡＢＳ）、ポリメチルペンテン（ＰＭＰ）、ポリイミド（ＰＩ）、環状オレフィンポリマー（ＣＯＰ）、環状オレフィンコポリマー（ＣＯＣ）、及びこれらを構成するモノマーの共重合体、並びにこれら２種以上を混合したものが挙げられる。プラスチックを構成するポリマーとしては、ポリエチレン（ＰＥ）、ポリプロピレン（ＰＰ）、環状オレフィンコポリマー（ＣＯＣ）が好ましい。また、プラスチックは、エラストマーを含んでいてもよい。
Examples of polymers constituting plastics include polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyethylene naphthalate, polyarylate, polycarbonate, polyethylene (PE; high density polyethylene (HDPE), low density polyethylene (LDPE), Linear low density polyethylene (LLDPE)), polypropylene (PP), polystyrene (PS), acrylonitrile butadiene styrene (ABS), polymethylpentene (PMP), polyimide (PI), cyclic olefin polymer (COP), cyclic olefin copolymer (COC), copolymers of monomers constituting these, and mixtures of two or more of these. Preferred polymers constituting the plastic include polyethylene (PE), polypropylene (PP), and cyclic olefin copolymer (COC). The plastic may also include an elastomer.
プラスチックは、安定化剤等の添加剤を含んでいてもよい。また、プラスチックは、ガラス繊維などの補強剤を含んで強化したものであってもよい。
The plastic may contain additives such as stabilizers. Furthermore, the plastic may be reinforced by containing a reinforcing agent such as glass fiber.
プラスチックは、市販されているものを特に制限なく用いることができる。
Commercially available plastics can be used without any particular restrictions.
眼科組成物を収容するプラスチック容器としては、眼科分野で一般的に使用されている容器であってよく、具体的には、例えば、点眼容器、洗眼液容器であってよい。容器の種類は、点眼容器であることが好ましい。
The plastic container containing the ophthalmological composition may be a container commonly used in the ophthalmological field, and specifically may be, for example, an eye drop container or an eye wash container. The type of container is preferably an eye drop container.
本実施形態に係るプラスチック容器は、眼科組成物と接する部分の一部又は全部がプラスチックで形成されている。例えば、プラスチック容器が穴あき中栓（ノズル）を有する容器の場合、穴あき中栓部分のみがプラスチックで形成されていてもよく、穴あき中栓以外の収容部分等がプラスチックで形成されていてもよく、また、容器全体がプラスチックで形成されていてもよい。
In the plastic container according to this embodiment, part or all of the part that comes into contact with the ophthalmic composition is made of plastic. For example, if the plastic container has a perforated inner stopper (nozzle), only the perforated inner stopper may be made of plastic, and the housing parts other than the perforated inner stopper may be made of plastic. Alternatively, the entire container may be made of plastic.
本実施形態に係るプラスチック容器は、眼科組成物と接する部分の一部がプラスチックで形成されていればよいが、本発明による効果をより一層顕著に奏するという観点から、眼科組成物と接する部分の全部がプラスチックで形成されていることが好ましい。また、プラスチック容器は１種単独のプラスチックで形成されていてもよく、２種以上のプラスチックで形成されていてもよい。
In the plastic container according to the present embodiment, part of the part that comes into contact with the ophthalmic composition may be made of plastic, but from the viewpoint of achieving even more remarkable effects of the present invention, the part that comes into contact with the ophthalmic composition should be made of plastic. Preferably, it is made entirely of plastic. Furthermore, the plastic container may be made of one type of plastic alone or may be made of two or more types of plastic.
容器の形状及び容量は特に限定されず、用途に応じて適宜設定すればよい。また、容器は、複数回の使用量の眼科組成物が収容される容器（マルチドーズ型容器）であってもよく、単回の使用量の眼科組成物が収容される容器（ユニットドーズ型容器）であってもよい。
The shape and capacity of the container are not particularly limited and may be set appropriately depending on the purpose. Further, the container may be a container in which an amount of the ophthalmic composition for multiple uses is accommodated (a multi-dose type container), or a container in which an amount of the ophthalmic composition for a single use is accommodated (a unit dose type container). ).
容器がマルチドーズ型容器の場合、例えば、容量が１．５～７．５ｍＬ、２～６ｍＬ、又は２．５～５．０ｍＬであってもよい。また、容器がユニットドーズ型容器の場合、例えば、容量が０．１～１．０ｍＬ、０．２～０．９ｍＬ、又は０．３～０．８ｍＬであってもよい。
When the container is a multi-dose type container, the volume may be, for example, 1.5 to 7.5 mL, 2 to 6 mL, or 2.5 to 5.0 mL. Further, when the container is a unit dose type container, the volume may be, for example, 0.1 to 1.0 mL, 0.2 to 0.9 mL, or 0.3 to 0.8 mL.
〔滅菌処理〕
本実施形態に係る眼科組成物を収容するプラスチック容器は、滅菌処理されている。 [Sterilization]
The plastic container containing the ophthalmic composition according to this embodiment is sterilized.
本実施形態に係る眼科組成物を収容するプラスチック容器は、滅菌処理されている。 [Sterilization]
The plastic container containing the ophthalmic composition according to this embodiment is sterilized.
滅菌処理の手段としては、例えば、電子線による滅菌処理、ガンマ線による滅菌処理、過酸化水素ガス（ＶＨＰ）による滅菌処理、エチレンオキシドガス（ＥＯＧ）による滅菌処理が挙げられる。電子線以外の手段による滅菌処理としては、例えば、ガンマ線による滅菌処理、過酸化水素ガス（ＶＨＰ）による滅菌処理、エチレンオキシドガス（ＥＯＧ）による滅菌処理が挙げられ、これらの中でも、過酸化水素ガス（ＶＨＰ）による滅菌処理、エチレンオキシドガス（ＥＯＧ）による滅菌処理が好ましい。電子線による滅菌処理、ガンマ線による滅菌処理、過酸化水素ガス（ＶＨＰ）による滅菌処理、エチレンオキシドガス（ＥＯＧ）による滅菌処理は、当業者に公知の方法で実施することができる。
Examples of sterilization methods include electron beam sterilization, gamma ray sterilization, hydrogen peroxide gas (VHP) sterilization, and ethylene oxide gas (EOG) sterilization. Examples of sterilization using means other than electron beams include sterilization using gamma rays, sterilization using hydrogen peroxide gas (VHP), and sterilization using ethylene oxide gas (EOG). Sterilization using VHP) and ethylene oxide gas (EOG) are preferred. Sterilization using electron beams, gamma rays, hydrogen peroxide gas (VHP), and ethylene oxide gas (EOG) can be performed by methods known to those skilled in the art.
本実施形態に係る眼科組成物を収容するプラスチック容器が電子線により滅菌処理されていると、眼科組成物におけるトラマドールの含有量を特定範囲（例えば、眼科組成物の総量を基準として１．０～３，０ｗ／ｖ％）とすることで、トラマドール由来の不純物が低減する効果が奏される。また、本実施形態に係る眼科組成物を収容するプラスチック容器が電子線以外の手段で滅菌処理されていると、眼科組成物におけるトラマドールの含有量にかかわらずトラマドール由来の不純物が低減する効果が奏される。
When the plastic container containing the ophthalmic composition according to the present embodiment is sterilized by electron beam, the content of tramadol in the ophthalmic composition can be controlled within a specific range (e.g., 1.0 to 100% based on the total amount of the ophthalmic composition). 3.0 w/v%), the effect of reducing tramadol-derived impurities is achieved. Further, if the plastic container containing the ophthalmic composition according to the present embodiment is sterilized by means other than electron beam, the effect of reducing tramadol-derived impurities is achieved regardless of the tramadol content in the ophthalmic composition. be done.
本実施形態に係る眼科組成物は、容器入り眼科組成物としても提供され得る。本発明はまた、容器に本発明の眼科組成物が収容された眼科用製品（点眼剤等）と捉えることもできる。
The ophthalmic composition according to this embodiment may also be provided as a containerized ophthalmic composition. The present invention can also be understood as an ophthalmic product (such as eye drops) in which the ophthalmic composition of the present invention is housed in a container.
以下、試験例に基づいて本発明を具体的に説明するが、本発明はこれらに限定されるものではない。また、特に記載がない限り、表中の各成分の単位はｗ／ｖ％である。
Hereinafter, the present invention will be specifically explained based on test examples, but the present invention is not limited thereto. Moreover, unless otherwise specified, the unit of each component in the table is w/v%.
〔試験例１：熱過酷試験〕
表１及び表２に示す組成で、常法に従い眼科組成物を調製した。調製した各眼科組成物を、０．２μｍメンブランフィルターでろ過し滅菌した。その後、眼科組成物を予め各滅菌方法で処理した点眼瓶（材質：ポリエチレンまたはＣＯＣ、容量：５ｍＬ）に充填し、遮光かつ表左上欄に記載の条件下にて保管した。保管後の水性組成物中に含まれる不純物（トラマドール類縁物質）の含有量をＨＰＬＣ法によって測定し、トラマドール塩酸塩の配合量に対するトラマドール類縁物質の生成率（％）を算出した。また、算出したトラマドール類縁物質の生成率から下記式に従いトラマドール類縁物質低減率を求めた。結果を表１及び表２に示す。
試験例２及び３のトラマドール類縁物質低減率（％）＝｛１００×（試験例１の生成率－各試験例の生成率）｝／試験例１の生成率
試験例５及び６のトラマドール類縁物質低減率（％）＝｛１００×（試験例４の生成率－各試験例の生成率）｝／試験例４の生成率 [Test Example 1: Thermal Severity Test]
Ophthalmic compositions were prepared according to conventional methods with the compositions shown in Tables 1 and 2. Each of the prepared ophthalmic compositions was filtered and sterilized using a 0.2 μm membrane filter. Thereafter, the ophthalmic composition was filled into eye drop bottles (material: polyethylene or COC, capacity: 5 mL) that had been previously treated with each sterilization method, and stored under the conditions described in the upper left column of the table while shielding from light. The content of impurities (tramadol related substances) contained in the aqueous composition after storage was measured by HPLC method, and the production rate (%) of tramadol related substances with respect to the blended amount of tramadol hydrochloride was calculated. In addition, the reduction rate of tramadol related substances was determined from the calculated production rate of tramadol related substances according to the following formula. The results are shown in Tables 1 and 2.
Reduction rate of tramadol related substances in Test Examples 2 and 3 (%) = {100×(Production rate of Test Example 1 - Production rate of each test example)}/Production rate of Test Example 1 Tramadol related substances of Test Examples 5 and 6 Reduction rate (%) = {100 x (production rate of Test Example 4 - production rate of each test example)} / production rate of Test Example 4
表１及び表２に示す組成で、常法に従い眼科組成物を調製した。調製した各眼科組成物を、０．２μｍメンブランフィルターでろ過し滅菌した。その後、眼科組成物を予め各滅菌方法で処理した点眼瓶（材質：ポリエチレンまたはＣＯＣ、容量：５ｍＬ）に充填し、遮光かつ表左上欄に記載の条件下にて保管した。保管後の水性組成物中に含まれる不純物（トラマドール類縁物質）の含有量をＨＰＬＣ法によって測定し、トラマドール塩酸塩の配合量に対するトラマドール類縁物質の生成率（％）を算出した。また、算出したトラマドール類縁物質の生成率から下記式に従いトラマドール類縁物質低減率を求めた。結果を表１及び表２に示す。
試験例２及び３のトラマドール類縁物質低減率（％）＝｛１００×（試験例１の生成率－各試験例の生成率）｝／試験例１の生成率
試験例５及び６のトラマドール類縁物質低減率（％）＝｛１００×（試験例４の生成率－各試験例の生成率）｝／試験例４の生成率 [Test Example 1: Thermal Severity Test]
Ophthalmic compositions were prepared according to conventional methods with the compositions shown in Tables 1 and 2. Each of the prepared ophthalmic compositions was filtered and sterilized using a 0.2 μm membrane filter. Thereafter, the ophthalmic composition was filled into eye drop bottles (material: polyethylene or COC, capacity: 5 mL) that had been previously treated with each sterilization method, and stored under the conditions described in the upper left column of the table while shielding from light. The content of impurities (tramadol related substances) contained in the aqueous composition after storage was measured by HPLC method, and the production rate (%) of tramadol related substances with respect to the blended amount of tramadol hydrochloride was calculated. In addition, the reduction rate of tramadol related substances was determined from the calculated production rate of tramadol related substances according to the following formula. The results are shown in Tables 1 and 2.
Reduction rate of tramadol related substances in Test Examples 2 and 3 (%) = {100×(Production rate of Test Example 1 - Production rate of each test example)}/Production rate of Test Example 1 Tramadol related substances of Test Examples 5 and 6 Reduction rate (%) = {100 x (production rate of Test Example 4 - production rate of each test example)} / production rate of Test Example 4
トラマドール塩酸塩を含有する眼科組成物について、電子線で滅菌されたプラスチック容器に充填し熱過酷試験を実施すると、試験例１で示すようにトラマドール類縁物質が生成することが確認された一方、ＶＨＰ滅菌のように電子線以外の手段で滅菌されたプラスチック容器に充填した場合は、試験例２及び３で示すようにトラマドール類縁物質が生成されず、トラマドール塩酸塩が安定に存在することが確認された。さらに、トラマドール塩酸塩を含有する眼科組成物が電子線で滅菌されたプラスチック容器に充填された場合であっても、試験例５及び６で示すようにトラマドール塩酸塩の配合量が１％以上である場合には、試験例４のように低濃度の場合に比べてトラマドール塩酸塩がより安定に存在することが確認された。
When an ophthalmic composition containing tramadol hydrochloride was filled into a plastic container sterilized by electron beams and subjected to a heat stress test, it was confirmed that tramadol related substances were produced as shown in Test Example 1, while VHP When filled into a plastic container that has been sterilized by a method other than electron beam, as shown in Test Examples 2 and 3, it was confirmed that tramadol-related substances were not produced and tramadol hydrochloride existed stably. Ta. Furthermore, even when an ophthalmic composition containing tramadol hydrochloride is filled into a plastic container sterilized by electron beam, as shown in Test Examples 5 and 6, if the amount of tramadol hydrochloride is 1% or more, In some cases, as in Test Example 4, it was confirmed that tramadol hydrochloride existed more stably than in cases where the concentration was low.
〔試験例２：熱過酷試験〕
表３に示す組成で、常法に従い眼科組成物を調製した。調製した各眼科組成物を、０．２μｍメンブランフィルターでろ過し滅菌した。その後、眼科組成物を予め各滅菌方法で処理した点眼瓶（材質：ポリエチレンまたはポリプロピレン、容量：５ｍＬ）に充填し、遮光かつ表左欄に記載の条件下にて保管した。保管後の水性組成物中に含まれる不純物（トラマドール類縁物質）の含有量をＨＰＬＣ法によって測定し、トラマドール塩酸塩の配合量に対するトラマドール類縁物質の生成率（％）を算出した。また、算出したトラマドール類縁物質の生成率から下記式に従いトラマドール類縁物質低減率を求めた。結果を表３に示す。
試験例８～１０のトラマドール類縁物質低減率（％）＝｛１００×（試験例７の生成率－各試験例の生成率）｝／試験例７の生成率 [Test Example 2: Thermal Severity Test]
An ophthalmic composition was prepared according to a conventional method using the composition shown in Table 3. Each of the prepared ophthalmic compositions was filtered and sterilized using a 0.2 μm membrane filter. Thereafter, the ophthalmic composition was filled into eye drop bottles (material: polyethylene or polypropylene, capacity: 5 mL) that had been previously treated with each sterilization method, and stored under the conditions described in the left column of the table while shielding from light. The content of impurities (tramadol related substances) contained in the aqueous composition after storage was measured by HPLC method, and the production rate (%) of tramadol related substances with respect to the blended amount of tramadol hydrochloride was calculated. Furthermore, the reduction rate of tramadol related substances was determined from the calculated production rate of tramadol related substances according to the following formula. The results are shown in Table 3.
Tramadol related substance reduction rate (%) of Test Examples 8 to 10 = {100×(Production rate of Test Example 7 - Production rate of each Test Example)}/Production rate of Test Example 7
表３に示す組成で、常法に従い眼科組成物を調製した。調製した各眼科組成物を、０．２μｍメンブランフィルターでろ過し滅菌した。その後、眼科組成物を予め各滅菌方法で処理した点眼瓶（材質：ポリエチレンまたはポリプロピレン、容量：５ｍＬ）に充填し、遮光かつ表左欄に記載の条件下にて保管した。保管後の水性組成物中に含まれる不純物（トラマドール類縁物質）の含有量をＨＰＬＣ法によって測定し、トラマドール塩酸塩の配合量に対するトラマドール類縁物質の生成率（％）を算出した。また、算出したトラマドール類縁物質の生成率から下記式に従いトラマドール類縁物質低減率を求めた。結果を表３に示す。
試験例８～１０のトラマドール類縁物質低減率（％）＝｛１００×（試験例７の生成率－各試験例の生成率）｝／試験例７の生成率 [Test Example 2: Thermal Severity Test]
An ophthalmic composition was prepared according to a conventional method using the composition shown in Table 3. Each of the prepared ophthalmic compositions was filtered and sterilized using a 0.2 μm membrane filter. Thereafter, the ophthalmic composition was filled into eye drop bottles (material: polyethylene or polypropylene, capacity: 5 mL) that had been previously treated with each sterilization method, and stored under the conditions described in the left column of the table while shielding from light. The content of impurities (tramadol related substances) contained in the aqueous composition after storage was measured by HPLC method, and the production rate (%) of tramadol related substances with respect to the blended amount of tramadol hydrochloride was calculated. Furthermore, the reduction rate of tramadol related substances was determined from the calculated production rate of tramadol related substances according to the following formula. The results are shown in Table 3.
Tramadol related substance reduction rate (%) of Test Examples 8 to 10 = {100×(Production rate of Test Example 7 - Production rate of each Test Example)}/Production rate of Test Example 7
ＥＯＧ滅菌及びＶＨＰ滅菌のように電子線以外の手段で滅菌されたプラスチック容器に充填した場合は、試験例８及び９で示すようにトラマドール類縁物質が生成されず、トラマドール塩酸塩が安定に存在することが確認された。
When filled into a plastic container sterilized by means other than electron beams such as EOG sterilization and VHP sterilization, tramadol related substances are not produced as shown in Test Examples 8 and 9, and tramadol hydrochloride exists stably. This was confirmed.
Claims (4)
- トラマドール又はその塩を含有する眼科組成物であって、該眼科組成物と接する部分の一部又は全部がプラスチックで形成された容器に収容してなり、該容器が電子線以外の手段により滅菌処理されている、眼科組成物。 An ophthalmic composition containing tramadol or a salt thereof, which is housed in a container in which part or all of the part that comes into contact with the ophthalmic composition is made of plastic, and the container is sterilized by means other than electron beams. ophthalmological composition.
- 前記電子線以外の手段による滅菌処理が、過酸化水素ガスによる滅菌又はエチレンオキシドガスによる滅菌である、請求項１に記載の眼科組成物。 The ophthalmological composition according to claim 1, wherein the sterilization treatment by means other than electron beam is sterilization with hydrogen peroxide gas or sterilization with ethylene oxide gas.
- 眼科組成物の総量を基準として１．０～３．０ｗ／ｖ％のトラマドール又はその塩を含有する眼科組成物であって、該眼科組成物と接する部分の一部又は全部がプラスチックで形成された容器に収容してなり、該容器が電子線により滅菌処理されている、眼科組成物。 An ophthalmic composition containing 1.0 to 3.0 w/v% of tramadol or its salt based on the total amount of the ophthalmic composition, wherein part or all of the part that comes into contact with the ophthalmic composition is formed of plastic. 1. An ophthalmological composition, which is housed in a container which has been sterilized by electron beam.
- 前記プラスチックが、ポリエチレン、ポリプロピレン及び環状オレフィンコポリマーからなる群より選択される少なくとも１種である、請求項１～３のいずれか一項に記載の眼科組成物。 The ophthalmic composition according to any one of claims 1 to 3, wherein the plastic is at least one selected from the group consisting of polyethylene, polypropylene, and cyclic olefin copolymers.
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| JP2014513073A (en) * | 2011-04-05 | 2014-05-29 | オプトソルヴ リミテッド ライアビリティー パートナーシップ | Ophthalmic treatment |
| JP2015131820A (en) * | 2006-03-31 | 2015-07-23 | ビスタコン・フアーマシユーチカルズ・エルエルシー | Ocular allergy treatments |
| WO2019026992A1 (en) * | 2017-08-03 | 2019-02-07 | 参天製薬株式会社 | Medicinal composition containing chlorhexidine |
| US20190224114A1 (en) * | 2015-09-09 | 2019-07-25 | Farmalider, S.A. | Pharmaceutical tramadol composition for ophthalmic use |
| JP2021130657A (en) * | 2020-11-18 | 2021-09-09 | 千寿製薬株式会社 | Pharmaceutical product |
| WO2021222368A1 (en) * | 2020-04-30 | 2021-11-04 | Irenix Medical, Inc. | Sodium chlorite compositions with enhanced anti-viral and anti-microbial efficacy and reduced toxicity |
| JP2022044701A (en) * | 2022-01-24 | 2022-03-17 | 参天製薬株式会社 | Aqueous suspension contained in injection blow molded multi-dose eye drop container |
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| JP2015131820A (en) * | 2006-03-31 | 2015-07-23 | ビスタコン・フアーマシユーチカルズ・エルエルシー | Ocular allergy treatments |
| JP2014513073A (en) * | 2011-04-05 | 2014-05-29 | オプトソルヴ リミテッド ライアビリティー パートナーシップ | Ophthalmic treatment |
| US20190224114A1 (en) * | 2015-09-09 | 2019-07-25 | Farmalider, S.A. | Pharmaceutical tramadol composition for ophthalmic use |
| WO2019026992A1 (en) * | 2017-08-03 | 2019-02-07 | 参天製薬株式会社 | Medicinal composition containing chlorhexidine |
| WO2021222368A1 (en) * | 2020-04-30 | 2021-11-04 | Irenix Medical, Inc. | Sodium chlorite compositions with enhanced anti-viral and anti-microbial efficacy and reduced toxicity |
| JP2021130657A (en) * | 2020-11-18 | 2021-09-09 | 千寿製薬株式会社 | Pharmaceutical product |
| JP2022044701A (en) * | 2022-01-24 | 2022-03-17 | 参天製薬株式会社 | Aqueous suspension contained in injection blow molded multi-dose eye drop container |
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