TW202408467A - 眼科組成物 - Google Patents
眼科組成物 Download PDFInfo
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- TW202408467A TW202408467A TW112125145A TW112125145A TW202408467A TW 202408467 A TW202408467 A TW 202408467A TW 112125145 A TW112125145 A TW 112125145A TW 112125145 A TW112125145 A TW 112125145A TW 202408467 A TW202408467 A TW 202408467A
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- ophthalmic composition
- salts
- acid
- buffer
- salt
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- 239000000203 mixture Substances 0.000 title claims abstract description 83
- 150000003839 salts Chemical class 0.000 claims abstract description 73
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229940123208 Biguanide Drugs 0.000 claims abstract description 24
- 230000002335 preservative effect Effects 0.000 claims abstract description 24
- 239000003755 preservative agent Substances 0.000 claims abstract description 23
- 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 17
- 229960004380 tramadol Drugs 0.000 claims abstract description 17
- 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 17
- 238000002156 mixing Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- 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 claims description 3
- 229960003260 chlorhexidine Drugs 0.000 claims description 2
- 239000000872 buffer Substances 0.000 description 51
- 238000012360 testing method Methods 0.000 description 33
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- -1 alkaline earth metal salts Chemical class 0.000 description 18
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 16
- 239000003889 eye drop Substances 0.000 description 14
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 13
- 229940050410 gluconate Drugs 0.000 description 13
- 230000003204 osmotic effect Effects 0.000 description 13
- 239000004327 boric acid Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 12
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 11
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 11
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- 239000011780 sodium chloride Substances 0.000 description 9
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 8
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 7
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- 238000009472 formulation Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 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 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 239000001384 succinic acid Substances 0.000 description 5
- 229960003107 tramadol hydrochloride Drugs 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229920000089 Cyclic olefin copolymer Polymers 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
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- 239000008363 phosphate buffer Substances 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- 235000011164 potassium chloride Nutrition 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229950010221 alexidine Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910021538 borax Inorganic materials 0.000 description 3
- 239000006172 buffering agent Substances 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 229940001447 lactate Drugs 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
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- 235000010339 sodium tetraborate Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Polymers CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 101150035093 AMPD gene Proteins 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical class [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 239000004713 Cyclic olefin copolymer Substances 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 229920002413 Polyhexanide Polymers 0.000 description 2
- 239000004642 Polyimide Substances 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 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
- 150000001642 boronic acid derivatives Chemical class 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- LVXHNCUCBXIIPE-UHFFFAOYSA-L disodium;hydrogen phosphate;hydrate Chemical compound O.[Na+].[Na+].OP([O-])([O-])=O LVXHNCUCBXIIPE-UHFFFAOYSA-L 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 229920001903 high density polyethylene Polymers 0.000 description 2
- 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
- 239000007788 liquid Substances 0.000 description 2
- 229920001684 low density polyethylene Polymers 0.000 description 2
- 239000004702 low-density polyethylene Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 229920001707 polybutylene terephthalate Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920000139 polyethylene terephthalate Polymers 0.000 description 2
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- 229920001721 polyimide Polymers 0.000 description 2
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- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 2
- 239000004328 sodium tetraborate Substances 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
- 239000008117 stearic acid Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 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
- 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
- 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
- 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
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- 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
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
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- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
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- 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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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
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- 150000004283 biguanides Chemical class 0.000 description 1
- 238000009530 blood pressure measurement Methods 0.000 description 1
- 125000005619 boric acid group Chemical group 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 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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- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 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
- 229940062672 calcium dihydrogen phosphate Drugs 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 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
- 239000001527 calcium lactate Substances 0.000 description 1
- 235000011086 calcium lactate Nutrition 0.000 description 1
- 229960002401 calcium lactate Drugs 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
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- 238000007796 conventional method Methods 0.000 description 1
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- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 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
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 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
- 238000001035 drying Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 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
- 229960003194 meglumine Drugs 0.000 description 1
- 229910001463 metal phosphate Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 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
- 239000002674 ointment Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920003207 poly(ethylene-2,6-naphthalate) Polymers 0.000 description 1
- 229920001230 polyarylate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 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
- 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
- 238000011160 research Methods 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
- 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
- 239000008362 succinate buffer 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
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000008054 sulfonate salts Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 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
- 238000005303 weighing Methods 0.000 description 1
Abstract
本發明係關於一種眼科組成物,其含有曲馬多(tramadol)或其鹽、及雙胍系防腐劑。
Description
本發明係關於一種眼科組成物。
雙胍系化合物由於具有防腐作用,故而廣泛用於眼科組成物中(例如專利文獻1)。
[先前技術文獻]
[專利文獻]
專利文獻1:日本特表2001-501605號公報
[發明所欲解決之課題]
本發明人等發現了下述新課題,即含有雙胍系防腐劑之眼科組成物之熱穩定性較弱。本發明之目的在於提供一種眼科組成物,其含有雙胍系防腐劑,且熱穩定性優異。
[解決課題之技術手段]
本發明人等為了解決上述課題而進行了積極研究,結果發現,藉由將曲馬多(tramadol)摻合於含有雙胍系防腐劑之眼科組成物中,該眼科組成物中之雙胍系防腐劑之熱穩定性意外地顯著提升,上述曲馬多被分類為弱類鴉片之非麻醉性鎮痛藥,且被用作癌性疼痛等全身性鎮痛藥。本發明係基於該見解而成者,提供以下各發明。
[1]
一種眼科組成物,其含有曲馬多或其鹽、及雙胍系防腐劑。
[2]
如[1]中所記載之眼科組成物,其中,上述雙胍系防腐劑為洛赫西定(chlorhexidine)或其鹽。
[3]
如[1]或[2]中所記載之眼科組成物,其中,以眼科組成物之總量作為基準,上述曲馬多或其鹽之含量為0.01 w/v%~10 w/v%。
[4]
一種提升眼科組成物中之雙胍系防腐劑之穩定性之方法,其包括:向含有雙胍系防腐劑之該眼科組成物摻合曲馬多或其鹽。
[發明之效果]
根據本發明,可提供一種眼科組成物,其含有雙胍系防腐劑,且熱穩定性優異。
以下,對本發明之實施方式進行詳細說明。但是,本發明並不限定於以下實施方式。
於本說明書中,只要未特別記載,則含量之單位「%」意指「w/v%」,與「g/100 mL」同義。
[1.眼科組成物]
本實施方式之眼科組成物含有(A)曲馬多或其鹽(亦簡稱為「(A)成分」)及(B)雙胍系防腐劑(亦簡稱為「(B)成分」)。
[(A)成分]
曲馬多為下式所表示之公知之化合物。
再者,為了方便起見,上述式顯示鏡像異構物中之一種,但本發明亦包括其他鏡像異構物。
曲馬多之鹽只要為醫藥上、藥理學上(製藥上)或生理學上所容許者即可,並無特別限制。作為此種鹽,具體而言,可例舉:與無機酸之鹽、與有機酸之鹽、與無機鹼之鹽、與有機鹼之鹽、與酸性胺基酸之鹽、與鹼性胺基酸之鹽等。
與無機酸之鹽例如可例舉:與鹽酸、氫溴酸、硫酸、硝酸、磷酸等之鹽。與有機酸之鹽例如可例舉:與乙酸、琥珀酸、反丁烯二酸、順丁烯二酸、酒石酸、檸檬酸、乳酸、硬脂酸、苯甲酸、甲磺酸(mesylate)、乙磺酸、對甲苯磺酸等之鹽。與無機鹼之鹽例如可例舉:鈉鹽、鉀鹽等鹼金屬鹽、鈣鹽、鎂鹽等鹼土類金屬鹽、鋁鹽、銨鹽等。與有機鹼之鹽例如可例舉:與二乙胺、二乙醇胺、葡甲胺(meglumine)、N,N-二苄基乙二胺等之鹽。與酸性胺基酸之鹽例如可例舉:與天冬胺酸、麩胺酸等之鹽。與鹼性胺基酸之鹽例如可例舉:與精胺酸、離胺酸、鳥胺酸等之鹽。作為曲馬多之鹽,較佳為與無機酸之鹽,更佳為鹽酸鹽。
本實施方式之眼科組成物含有曲馬多或其鹽作為有效成分,且例如可用於抑制疼痛。
本實施方式之眼科組成物中之(A)成分之含量並無特別限定,可根據其他摻合成分之種類及含量、製劑形態等而適宜地設定。就更加顯著地發揮本發明之效果之觀點而言,作為(A)成分之含量,以本實施方式之眼科組成物之總量作為基準,可為0.01 w/v%~10 w/v%、0.05 w/v%~5 w/v%、0.1 w/v%~4 w/v%、或3 w/v%。
[(B)成分]
雙胍系防腐劑意指分子內包含以下所示之雙胍之化合物,且係具有防腐作用之化合物。
作為雙胍系防腐劑,例如可例舉:洛赫西定或其鹽、阿來西定(alexidine)或其鹽、聚六亞甲基雙胍(polyhexanide)或其鹽。
洛赫西定係亦稱為1,1'-六亞甲基-雙-[5-(4-氯苯基)雙胍]之公知化合物。又,阿來西定係亦稱為1,1'-六亞甲基-雙-[5-(2-乙基己基)雙胍]之公知化合物。
作為洛赫西定之鹽、阿來西定之鹽,例如可例舉:無機酸鹽、有機酸鹽及磺酸鹽。作為無機酸鹽,例如可例舉:與鹽酸、氫溴酸、硫酸、硼酸、磷酸及硝酸之鹽。作為有機酸鹽,例如可例舉:與乙酸、葡萄糖酸、順丁烯二酸、抗壞血酸、硬脂酸、酒石酸及檸檬酸之鹽。作為磺酸鹽,例如可例舉:與甲磺酸、2-羥乙磺酸、苯磺酸及對甲苯磺酸之鹽。
作為雙胍系防腐劑,就更加顯著地發揮本發明之效果之觀點而言,較佳為洛赫西定或其鹽,更佳為葡萄糖酸洛赫西定。
(B)成分亦可使用市售者。(B)成分可單獨使用1種,或亦可組合2種以上使用。
本實施方式之眼科組成物中之(B)成分之含量並無特別限定,可根據(B)成分之種類、其他摻合成分之種類及含量、眼科組成物之用途及製劑形態等而適宜地設定。作為(B)成分之含量,就更加顯著地發揮本發明之效果之觀點而言,以眼科組成物之總量作為基準,較佳為0.00001 w/v%~2 w/v%,更佳為0.00005 w/v%~1 w/v%,尤佳為含有0.00008 w/v%~0.8 w/v%。作為另一態樣,0.00005 w/v%~0.5 w/v%、0.0001 w/v%~0.025 w/v%亦可作為較佳含量而呈現。
本實施方式之眼科組成物中之(B)成分相對於(A)成分之含有比率並無特別限定,可根據(A)成分及(B)成分之種類、其他摻合成分之種類及含量、眼科組成物之用途及製劑形態等而適宜地設定。關於(B)成分相對於(A)成分之含有比率,就更加顯著地發揮本發明之效果之觀點而言,(B)成分相對於本實施方式之眼科組成物中所包含之(A)成分之總含量1質量份,可為0.000001~200質量份、0.00001~10質量份、或0.000025~0.25質量份。
[緩衝劑]
本實施方式之眼科組成物較佳為進而含有緩衝劑。藉由使眼科組成物進而含有緩衝劑,可以更加顯著地發揮本發明之效果。緩衝劑只要為醫藥上、藥理學上(製藥上)或生理學上所容許者即可,並無特別限制。作為緩衝劑,例如可例舉:源自無機酸之緩衝劑即無機緩衝劑、及源自有機酸或有機鹼之緩衝劑即有機緩衝劑。
作為無機緩衝劑,例如可例舉:硼酸緩衝劑、磷酸緩衝劑、碳酸緩衝劑等。作為硼酸緩衝劑,可例舉:硼酸或其鹽(硼酸鹼金屬鹽、硼酸鹼土類金屬鹽等)。作為磷酸緩衝劑,可例舉:磷酸或其鹽(磷酸鹼金屬鹽、磷酸鹼土類金屬鹽等)。作為碳酸緩衝劑,可例舉:碳酸或其鹽(碳酸鹼金屬鹽、碳酸鹼土類金屬鹽等)。又,作為硼酸緩衝劑、磷酸緩衝劑或碳酸緩衝劑,亦可使用硼酸鹽、磷酸鹽或碳酸鹽之水合物。作為更具體之例,可例示:作為硼酸緩衝劑之硼酸或其鹽(硼酸鈉、四硼酸鉀、偏硼酸鉀、硼酸銨、硼砂等);作為磷酸緩衝劑之磷酸或其鹽(磷酸氫二鈉、磷酸二氫鈉、磷酸二氫鉀、磷酸三鈉、磷酸三鉀、磷酸氫鈣、磷酸二氫鈣等);作為碳酸緩衝劑之碳酸或其鹽(碳酸氫鈉、碳酸鈉、碳酸銨、碳酸鉀、碳酸鈣、碳酸氫鉀、碳酸鎂等)等。
作為有機緩衝劑,例如可例舉:檸檬酸緩衝劑、乙酸緩衝劑、乳酸緩衝劑、琥珀酸緩衝劑、三羥甲基胺基甲烷(tris)緩衝劑、AMPD緩衝劑等。作為檸檬酸緩衝劑,可例舉:檸檬酸或其鹽(檸檬酸鹼金屬鹽、檸檬酸鹼土類金屬鹽等)。作為乙酸緩衝劑,可例舉:乙酸或其鹽(乙酸鹼金屬鹽、乙酸鹼土類金屬鹽等)。作為乳酸緩衝劑,可例舉:乳酸或其鹽(乳酸鹼金屬鹽、乳酸鹼土類金屬鹽等)。作為琥珀酸緩衝劑,可例舉:琥珀酸或其鹽(琥珀酸鹼金屬鹽等)。又,檸檬酸緩衝劑、乙酸緩衝劑、乳酸緩衝劑或琥珀酸緩衝劑亦可使用檸檬酸鹽、乙酸鹽、乳酸鹽或琥珀酸鹽之水合物。作為更具體之例,可例示:作為檸檬酸緩衝劑之檸檬酸或其鹽(檸檬酸鈉、檸檬酸鉀、檸檬酸鈣、檸檬酸二氫鈉、檸檬酸二鈉等);作為乙酸緩衝劑之乙酸或其鹽(乙酸銨、乙酸鈉、乙酸鉀、乙酸鈣等);作為乳酸緩衝劑之乳酸或其鹽(乳酸鈉、乳酸鉀、乳酸鈣等);作為琥珀酸緩衝劑之琥珀酸或其鹽(琥珀酸一鈉、琥珀酸二鈉等)等。作為三羥甲基胺基甲烷緩衝劑,例如可例舉:胺丁三醇(trometamol)或其鹽(胺丁三醇鹽酸鹽等)。作為AMPD緩衝劑,例如可例舉:2-胺基-2-甲基-1,3-丙二醇或其鹽。
作為緩衝劑,較佳為硼酸緩衝劑、磷酸緩衝劑、檸檬酸緩衝劑,更佳為硼酸緩衝劑、磷酸緩衝劑,進而較佳為硼酸或其鹽、磷酸或其鹽。
緩衝劑亦可使用市售者。緩衝劑可單獨使用1種,或亦可組合2種以上使用。
本實施方式之眼科組成物中之緩衝劑之含量並無特別限定,可根據緩衝劑之種類、其他摻合成分之種類及含量、眼科組成物之用途及製劑形態等而適宜地設定。作為緩衝劑之含量,就更加顯著地發揮本發明之效果之觀點而言,例如以眼科組成物之總量作為基準,較佳為0.01 w/v%~10 w/v%,更佳為0.05 w/v%~5 w/v%,進而較佳為0.1 w/v%~3 w/v%。於緩衝劑為硼酸緩衝劑之情形時,較佳為0.01 w/v%~10 w/v%,更佳為0.05 w/v%~5 w/v%,進而較佳為0.1 w/v%~3 w/v%,尤佳為0.5 w/v%~2.0 w/v%。於緩衝劑為檸檬酸緩衝劑或磷酸緩衝劑之情形時,較佳為0.01 w/v%~10 w/v%,更佳為0.05 w/v%~5 w/v%,進而較佳為0.1 w/v%~3 w/v%,進而更佳為0.1 w/v%~1 w/v%,尤佳為0.1 w/v%~0.3 w/v%。
本實施方式之眼科組成物中之緩衝劑相對於(A)成分之含有比率並無特別限定,可根據(A)成分及緩衝劑之種類、其他摻合成分之種類及含量、眼科組成物之用途及製劑形態等而適宜地設定。關於緩衝劑相對於(A)成分之含有比率,就更進一步提高本發明之效果之觀點而言,例如緩衝劑相對於本實施方式之眼科組成物中所包含之(A)成分之總含量1質量份,可為0.001~1000質量份、0.01~100質量份或0.025~30質量份。
[無機鹽類]
本實施方式之眼科組成物亦可進而含有無機鹽類。藉由使眼科組成物進而含有無機鹽類,可更加顯著地發揮本發明之效果。無機鹽類只要為醫藥上、藥理學上(製藥上)或生理學上所容許者即可,並無特別限制。
作為無機鹽類,可例舉:氯化鈉、氯化鉀、氯化鈣、氯化鎂等氯化物鹽。作為無機鹽類,較佳為氯化鈉、氯化鉀。
無機鹽類亦可使用市售者。無機鹽類可單獨使用1種,或亦可組合2種以上使用。
本實施方式之眼科組成物中之無機鹽類之含量並無特別限定,可根據無機鹽類之種類、其他摻合成分之種類及含量、眼科組成物之用途及製劑形態等而適宜地設定。作為無機鹽類之含量,就更加顯著地發揮本發明之效果之觀點而言,例如以眼科組成物之總量作為基準,較佳為0.00001 w/v%~3 w/v%,更佳為0.0001 w/v%~2 w/v%,進而較佳為0.001 w/v%~1.5 w/v%。
本實施方式之眼科組成物之pH只要處於醫藥上、藥理學上(製藥上)或生理學上所容許之範圍內即可,並無特別限定。作為本實施方式之眼科組成物之pH,例如可為4.5~7.5,較佳為5.0~7.0,更佳為5.5~6.5。
本實施方式之眼科組成物視需要可調節為生物體所容許之範圍內之滲透壓比。適當之滲透壓比可根據眼科組成物之用途、製劑形態、使用方法等而適宜地設定,例如可設為0.4~5.0。滲透壓比較佳為0.6~3.0,更佳為0.7~2.0。滲透壓比基於第十八修訂版日本藥典,設為試樣之滲透壓相對於286 mOsm(0.9 w/v%氯化鈉水溶液之滲透壓)之比,滲透壓係參考日本藥典所記載之滲透壓測定法(凝固點降低法)來進行測定。再者,滲透壓比測定用標準液(0.9 w/v%氯化鈉水溶液)可將氯化鈉(日本藥典標準試劑)於500~650℃乾燥40~50分鐘後,於乾燥器(矽膠)中放置冷卻,準確地稱量其0.900 g,溶解於純化水中,準確地製備為100 mL;或使用市售之滲透壓比測定用標準液(0.9 w/v%氯化鈉水溶液)。
本實施方式之眼科組成物之黏度只要處於醫藥上、藥理學上(製藥上)或生理學上所容許之範圍內即可,並無特別限定。關於本實施方式之眼科組成物之黏度,例如,利用旋轉黏度計(TV-20型黏度計,東機產業公司製造,轉子:1°34'×R24)所測得之於20℃之黏度可為1~10000 mPa・s。
本實施方式之眼科組成物例如可藉由將(A)成分、(B)成分、及視需要使用之其他含有成分以成為所需含量之方式進行添加及混合而製備。具體而言,例如可藉由以下方法製備:利用純化水使上述成分溶解或懸浮,並藉由過濾殺菌等進行殺菌處理。
本實施方式之眼科組成物可根據目的而採用各種劑型,例如可例舉:液劑、凝膠劑、半固體劑(軟膏等)等。
於本實施方式之眼科組成物為液劑之情形時,例如可用作滴眼劑(亦稱為滴眼液或滴眼藥。又,滴眼劑包括於隱形眼鏡配戴時能夠滴眼之滴眼劑)、人工淚液、洗眼劑(亦稱為洗眼液或洗眼藥。又,洗眼劑包括於隱形眼鏡配戴時能夠洗眼之洗眼劑)。再者,「隱形眼鏡」包括硬性隱形眼鏡、軟性隱形眼鏡(包含離子性及非離子性這兩者,且包含聚矽氧水凝膠隱形眼鏡及非聚矽氧水凝膠隱形眼鏡這兩者)。
就可更加顯著地發揮本發明之效果之方面而言,本實施方式之眼科組成物較佳為滴眼劑(包括於隱形眼鏡配戴時能夠實現滴眼之滴眼劑)。於本實施方式之眼科組成物為滴眼劑之情形時,作為其用法、用量,只要為發揮效果且副作用較少之用法、用量即可,並無特別限定,例如於成人(15歲以上)及7歲以上之兒童之情形時,可例示以如下方式使用之方法:1次1~3滴、1~2滴、或2~3滴,1天滴眼1~4次、或5~6次。
本實施方式之眼科組成物係收容於任意容器而提供。收容本實施方式之眼科組成物之容器並無特別限制,例如,可為玻璃製,又,亦可為塑膠製。較佳為塑膠製。作為塑膠,例如可例舉:聚對苯二甲酸乙二酯(PET)、聚對苯二甲酸丁二酯(PBT)、聚萘二甲酸乙二酯、聚芳酯、聚碳酸酯、聚乙烯(PE;高密度聚乙烯(HDPE)、低密度聚乙烯(LDPE)、直鏈狀低密度聚乙烯(LLDPE))、聚丙烯(PP)、聚苯乙烯(PS)、丙烯腈-丁二烯-苯乙烯(ABS)、聚甲基戊烯(PMP)、聚醯亞胺(PI)、環狀烯烴聚合物(COP)、環狀烯烴共聚物(COC)、及構成其等之單體之共聚物、以及混合該等2種以上而成者。
作為收容眼科組成物之容器,可為眼科領域中一般使用之容器,具體而言,例如可為滴眼容器、洗眼液容器。容器之種類較佳為滴眼容器。
容器之形狀及容量並無特別限定,根據用途而適宜地設定即可。又,容器可為收容複數次使用量之眼科組成物之容器(多劑量(multi-dose)型容器),亦可為收容單次使用量之眼科組成物之容器(單一劑量型容器)。
於容器為多劑量型容器之情形時,例如,容量可為1.5~7.5 mL、2~6 mL、或2.5~5.0 mL。又,於容器為單一劑量型容器之情形時,例如,容量可為0.1~1.0 mL、0.2~0.9 mL、或0.3~0.8 mL。
本實施方式之眼科組成物亦能夠以裝入容器之眼科組成物之形式提供。又,本發明亦可理解為於容器中收容有本發明之眼科組成物之眼科用製品(滴眼劑等)。
[2.提升眼科組成物中之雙胍系防腐劑之穩定性之方法]
藉由使「含有(B)雙胍系防腐劑之眼科組成物」中含有(A)曲馬多或其鹽,可於該眼科組成物中提升(B)雙胍系防腐劑之穩定性。因此,作為本發明之一實施方式,提供一種提升眼科組成物中之雙胍系防腐劑之穩定性之方法,其包括:向含有(B)雙胍系防腐劑之該眼科組成物摻合(A)曲馬多或其鹽。
該方法中之(A)成分及(B)成分之種類及含量等、其他成分之種類及含量等、眼科組成物之製劑形態及用途等如[1.眼科組成物]中說明所示。
[實施例]
以下,基於試驗例具體地對本發明進行說明,但本發明並不限定於其等。又,只要未特別記載,則表中之各成分之單位為w/v%。
[試驗例1:熱嚴酷試驗]
以表1~3所示之組成,按照常規方法製備眼科組成物。將所製備之各眼科組成物填充於聚乙烯製滴眼瓶,於表之左上欄所記載之條件下實施熱嚴酷試驗。藉由HPLC法測定剛製備後之眼科組成物及存放後之眼科組成物中所包含之葡萄糖酸洛赫西定之含量,根據下式算出葡萄糖酸洛赫西定殘存率。又,降低率及穩定性改善度以下述步驟求出。將結果示於表1~3。
葡萄糖酸洛赫西定殘存率(%)=(存放品之葡萄糖酸洛赫西定含有率/剛製備後之葡萄糖酸洛赫西定含有率×100)-透濕
透濕(%)=(剛製備後之填充品重量-存放後之填充品重量)/(剛製備後之填充品重量-滴眼瓶之空瓶重量)×100
葡萄糖酸洛赫西定降低率=100-殘存率(%)
試驗例2~4之殘存改善率(%)=100×(試驗例1之降低率-各試驗例之降低率)/(試驗例1之降低率)
試驗例6及7之殘存改善率(%)=100×(試驗例5之降低率-各試驗例之降低率)/(試驗例5之降低率)
試驗例9及10之殘存改善率(%)=100×(試驗例8之降低率-各試驗例之降低率)/(試驗例8之降低率)
試驗例12及13之殘存改善率(%)=100×(試驗例11之降低率-各試驗例之降低率)/(試驗例11之降低率)
[表1]
40℃、3個月 | 試驗例1 | 試驗例2 | 試驗例3 | 試驗例4 |
曲馬多鹽酸鹽 | - | 0.3 | 1 | 3 |
葡萄糖酸洛赫西定液 | 0.01 | 0.01 | 0.01 | 0.01 |
磷酸二氫鈉水合物 | 0.3 | 0.3 | 0.3 | 0.3 |
磷酸氫鈉水合物 | 0.14 | 0.14 | 0.13 | 0.12 |
氯化鈉 | 0.7 | 0.65 | 0.5 | 0.1 |
氯化鉀 | 0.1 | 0.1 | 0.1 | 0.1 |
純化水 | 餘量 | 餘量 | 餘量 | 餘量 |
總量 | 100 mL | 100 mL | 100 mL | 100 mL |
pH | 6.0 | 6.0 | 6.0 | 6.0 |
滲透壓(mOsm) | 288 | 292 | 290 | 292 |
殘存改善率(%) | - | 23.7 | 36.6 | 47.3 |
[表2]
50℃、1個月 | 試驗例5 | 試驗例6 | 試驗例7 | 試驗例8 | 試驗例9 | 試驗例10 |
曲馬多鹽酸鹽 | - | 0.1 | 5.0 | - | 0.1 | 5.0 |
葡萄糖酸洛赫西定液 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 |
磷酸二氫鈉水合物 | 0.3 | 0.3 | 0.3 | 0.3 | 0.3 | 0.3 |
磷酸氫鈉水合物 | 0.015 | 0.015 | 0.015 | 0.4 | 0.4 | 0.4 |
氯化鈉 | 0.7 | 0.7 | - | 0.7 | 0.7 | - |
氯化鉀 | 0.1 | 0.1 | - | 0.1 | 0.1 | - |
稀鹽酸 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 |
氫氧化鈉 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 |
純化水 | 餘量 | 餘量 | 餘量 | 餘量 | 餘量 | 餘量 |
總量 | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL |
pH | 5.1 | 5.1 | 5.1 | 6.5 | 6.5 | 6.5 |
滲透壓(mOsm) | 279 | 287 | 336 | 304 | 311 | 372 |
殘存改善率(%) | - | 55.9 | 47.5 | - | 38.1 | 29.2 |
[表3]
50℃、1個月 | 試驗例11 | 試驗例12 | 試驗例13 |
曲馬多鹽酸鹽 | - | 0.1 | 1 |
葡萄糖酸洛赫西定液 | 0.005 | 0.005 | 0.005 |
硼酸 | 1 | 1 | 1 |
硼砂 | 0.008 | 0.008 | 0.008 |
氯化鈉 | 0.3 | 0.3 | 0.3 |
純化水 | 餘量 | 餘量 | 餘量 |
總量 | 100 mL | 100 mL | 100 mL |
pH | 6.1 | 6.1 | 6.1 |
滲透壓(mOsm) | 261 | 268 | 297 |
殘存改善率(%) | - | 21.0 | 28.6 |
由表1~3可確認,於不含曲馬多鹽酸鹽之眼科組成物中,葡萄糖酸洛赫西定之穩定性降低,但藉由摻合曲馬多鹽酸鹽而使葡萄糖酸洛赫西定之殘存率大幅度改善,曲馬多提高了葡萄糖酸洛赫西定對熱之穩定性。
無
無
Claims (4)
- 一種眼科組成物,其含有曲馬多(tramadol)或其鹽、及雙胍系防腐劑。
- 如請求項1之眼科組成物,其中,上述雙胍系防腐劑為洛赫西定(chlorhexidine)或其鹽。
- 如請求項1或2之眼科組成物,其中,以眼科組成物之總量作為基準,上述曲馬多或其鹽之含量為0.01 w/v%~10 w/v%。
- 一種提升眼科組成物中之雙胍系防腐劑之穩定性之方法,其包括:向含有雙胍系防腐劑之該眼科組成物摻合曲馬多或其鹽。
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