JPWO2014050301A1 - Aqueous liquid - Google Patents
Aqueous liquid Download PDFInfo
- Publication number
- JPWO2014050301A1 JPWO2014050301A1 JP2014538250A JP2014538250A JPWO2014050301A1 JP WO2014050301 A1 JPWO2014050301 A1 JP WO2014050301A1 JP 2014538250 A JP2014538250 A JP 2014538250A JP 2014538250 A JP2014538250 A JP 2014538250A JP WO2014050301 A1 JPWO2014050301 A1 JP WO2014050301A1
- Authority
- JP
- Japan
- Prior art keywords
- aqueous liquid
- liquid preparation
- viscosity
- castor oil
- hydrogenated castor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000007788 liquid Substances 0.000 title claims abstract description 111
- 238000002360 preparation method Methods 0.000 claims abstract description 95
- -1 polyoxyethylene Polymers 0.000 claims abstract description 68
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 54
- 239000004359 castor oil Substances 0.000 claims abstract description 53
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 53
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 53
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 53
- 229960003943 hypromellose Drugs 0.000 claims abstract description 53
- 235000019438 castor oil Nutrition 0.000 claims abstract description 51
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims abstract description 51
- 230000007423 decrease Effects 0.000 claims abstract description 44
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims abstract description 38
- 229920002675 Polyoxyl Polymers 0.000 claims abstract description 38
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims abstract description 38
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims abstract description 37
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 49
- 239000007864 aqueous solution Substances 0.000 claims description 34
- 229920002678 cellulose Polymers 0.000 claims description 25
- 239000001913 cellulose Substances 0.000 claims description 25
- 239000002736 nonionic surfactant Substances 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 20
- 239000003889 eye drop Substances 0.000 claims description 17
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 16
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 claims description 12
- 229940099429 polyoxyl 40 stearate Drugs 0.000 claims description 12
- BYJAVTDNIXVSPW-UHFFFAOYSA-N tetryzoline Chemical compound N1CCN=C1C1C2=CC=CC=C2CCC1 BYJAVTDNIXVSPW-UHFFFAOYSA-N 0.000 claims description 12
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 claims description 9
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 claims description 9
- 239000003112 inhibitor Substances 0.000 claims description 9
- 229940101267 panthenol Drugs 0.000 claims description 9
- 235000020957 pantothenol Nutrition 0.000 claims description 9
- 239000011619 pantothenol Substances 0.000 claims description 9
- 229960003101 pranoprofen Drugs 0.000 claims description 9
- 150000003505 terpenes Chemical class 0.000 claims description 9
- 235000008160 pyridoxine Nutrition 0.000 claims description 8
- 239000011677 pyridoxine Substances 0.000 claims description 8
- 229940011671 vitamin b6 Drugs 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 6
- 229960000337 tetryzoline Drugs 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 241000047703 Nonion Species 0.000 claims description 2
- 230000000694 effects Effects 0.000 description 18
- 238000003860 storage Methods 0.000 description 16
- 238000012360 testing method Methods 0.000 description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 10
- 230000014759 maintenance of location Effects 0.000 description 10
- 239000000203 mixture Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 238000009472 formulation Methods 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- 229940012356 eye drops Drugs 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 6
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 6
- 229940068968 polysorbate 80 Drugs 0.000 description 6
- 229920000053 polysorbate 80 Polymers 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229940041616 menthol Drugs 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 4
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 4
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 4
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000783 alginic acid Substances 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 229960001126 alginic acid Drugs 0.000 description 3
- 150000004781 alginic acids Chemical class 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 230000007721 medicinal effect Effects 0.000 description 3
- 239000007923 nasal drop Substances 0.000 description 3
- 229940100662 nasal drops Drugs 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 150000005846 sugar alcohols Polymers 0.000 description 3
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 3
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 description 3
- 239000000341 volatile oil Substances 0.000 description 3
- NFLGAXVYCFJBMK-RKDXNWHRSA-N (+)-isomenthone Natural products CC(C)[C@H]1CC[C@@H](C)CC1=O NFLGAXVYCFJBMK-RKDXNWHRSA-N 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 2
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- 241000723346 Cinnamomum camphora Species 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- NFLGAXVYCFJBMK-UHFFFAOYSA-N Menthone Chemical compound CC(C)C1CCC(C)CC1=O NFLGAXVYCFJBMK-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 239000000654 additive Substances 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 210000005252 bulbus oculi Anatomy 0.000 description 2
- 229930008380 camphor Natural products 0.000 description 2
- 229960000846 camphor Drugs 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- RRAFCDWBNXTKKO-UHFFFAOYSA-N eugenol Chemical compound COC1=CC(CC=C)=CC=C1O RRAFCDWBNXTKKO-UHFFFAOYSA-N 0.000 description 2
- 230000004424 eye movement Effects 0.000 description 2
- 210000000744 eyelid Anatomy 0.000 description 2
- 238000012812 general test Methods 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 2
- CDOSHBSSFJOMGT-UHFFFAOYSA-N linalool Chemical compound CC(C)=CCCC(C)(O)C=C CDOSHBSSFJOMGT-UHFFFAOYSA-N 0.000 description 2
- 239000010687 lubricating oil Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 2
- 229930007503 menthone Natural products 0.000 description 2
- 229940049964 oleate Drugs 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 235000019477 peppermint oil Nutrition 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 229940037001 sodium edetate Drugs 0.000 description 2
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical class [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 229960003080 taurine Drugs 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000000230 xanthan gum Substances 0.000 description 2
- 235000010493 xanthan gum Nutrition 0.000 description 2
- 229920001285 xanthan gum Polymers 0.000 description 2
- 229940082509 xanthan gum Drugs 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 1
- FMCGSUUBYTWNDP-ONGXEEELSA-N (1R,2S)-2-(dimethylamino)-1-phenyl-1-propanol Chemical compound CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-ONGXEEELSA-N 0.000 description 1
- 239000001490 (3R)-3,7-dimethylocta-1,6-dien-3-ol Substances 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- CDOSHBSSFJOMGT-JTQLQIEISA-N (R)-linalool Natural products CC(C)=CCC[C@@](C)(O)C=C CDOSHBSSFJOMGT-JTQLQIEISA-N 0.000 description 1
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 1
- XPALGXXLALUMLE-UHFFFAOYSA-N 2-(dimethylamino)tetradecanoic acid Chemical compound CCCCCCCCCCCCC(N(C)C)C(O)=O XPALGXXLALUMLE-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- MUHFRORXWCGZGE-KTKRTIGZSA-N 2-hydroxyethyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCCO MUHFRORXWCGZGE-KTKRTIGZSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- WADQOGCINABPRT-UHFFFAOYSA-N 3-chloro-2-methylphenol Chemical compound CC1=C(O)C=CC=C1Cl WADQOGCINABPRT-UHFFFAOYSA-N 0.000 description 1
- NBOCQTNZUPTTEI-UHFFFAOYSA-N 4-[4-(hydrazinesulfonyl)phenoxy]benzenesulfonohydrazide Chemical compound C1=CC(S(=O)(=O)NN)=CC=C1OC1=CC=C(S(=O)(=O)NN)C=C1 NBOCQTNZUPTTEI-UHFFFAOYSA-N 0.000 description 1
- SVYBEBLNQGDRHF-UHFFFAOYSA-N 4-amino-N-(5-ethyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide Chemical compound S1C(CC)=NN=C1NS(=O)(=O)C1=CC=C(N)C=C1 SVYBEBLNQGDRHF-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- POJWUDADGALRAB-PVQJCKRUSA-N Allantoin Natural products NC(=O)N[C@@H]1NC(=O)NC1=O POJWUDADGALRAB-PVQJCKRUSA-N 0.000 description 1
- VKJGBAJNNALVAV-UHFFFAOYSA-M Berberine chloride (TN) Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 VKJGBAJNNALVAV-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- NPBVQXIMTZKSBA-UHFFFAOYSA-N Chavibetol Natural products COC1=CC=C(CC=C)C=C1O NPBVQXIMTZKSBA-UHFFFAOYSA-N 0.000 description 1
- 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 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- WTEVQBCEXWBHNA-UHFFFAOYSA-N Citral Natural products CC(C)=CCCC(C)=CC=O WTEVQBCEXWBHNA-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
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- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
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- ZZORFUFYDOWNEF-UHFFFAOYSA-N sulfadimethoxine Chemical compound COC1=NC(OC)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ZZORFUFYDOWNEF-UHFFFAOYSA-N 0.000 description 1
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- BRBKOPJOKNSWSG-UHFFFAOYSA-N sulfaguanidine Chemical compound NC(=N)NS(=O)(=O)C1=CC=C(N)C=C1 BRBKOPJOKNSWSG-UHFFFAOYSA-N 0.000 description 1
- 229960004936 sulfamethoxypyridazine Drugs 0.000 description 1
- VLYWMPOKSSWJAL-UHFFFAOYSA-N sulfamethoxypyridazine Chemical compound N1=NC(OC)=CC=C1NS(=O)(=O)C1=CC=C(N)C=C1 VLYWMPOKSSWJAL-UHFFFAOYSA-N 0.000 description 1
- 229960001873 sulfametomidine Drugs 0.000 description 1
- 229960004818 sulfaphenazole Drugs 0.000 description 1
- QWCJHSGMANYXCW-UHFFFAOYSA-N sulfaphenazole Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=NN1C1=CC=CC=C1 QWCJHSGMANYXCW-UHFFFAOYSA-N 0.000 description 1
- YZMCKZRAOLZXAZ-UHFFFAOYSA-N sulfisomidine Chemical compound CC1=NC(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 YZMCKZRAOLZXAZ-UHFFFAOYSA-N 0.000 description 1
- 229960001975 sulfisomidine Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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- 229940124597 therapeutic agent Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
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- 229940042585 tocopherol acetate Drugs 0.000 description 1
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 description 1
- 229960005342 tranilast Drugs 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011576 zinc lactate Substances 0.000 description 1
- 229940050168 zinc lactate Drugs 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
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- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
本発明の目的は、ヒプロメロース及び／又はヒドロキシエチルセルロースを含む水性液剤において、経時的な動粘度の低下を抑制する製剤技術を提供することである。ヒプロメロース及び／又はヒドロキシエチルセルロースと、ポリオキシエチレン硬化ヒマシ油及び／又はステアリン酸ポリオキシルとを組み合わせて配合した水性液剤は、経時的な粘度低下を抑制できる。An object of the present invention is to provide a preparation technique for suppressing a decrease in kinematic viscosity over time in an aqueous liquid preparation containing hypromellose and / or hydroxyethyl cellulose. An aqueous liquid prepared by combining hypromellose and / or hydroxyethyl cellulose with polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate can suppress a decrease in viscosity over time.
Description
本発明は、ヒプロメロース及び／又はヒドロキシエチルセルロースを含みながらも、経時的な粘度低下を抑制できる水性液剤に関する。 The present invention relates to an aqueous liquid preparation that can suppress a decrease in viscosity over time while containing hypromellose and / or hydroxyethyl cellulose.
従来、点眼剤や点鼻剤等の水性液剤において、セルロース系粘性剤を配合して粘性を付与することによって、使用感の向上、潤い感や清涼感の持続、薬物の滞留性の向上、薬効の増強等が図られることが知られており（特許文献１参照）、今日では、セルロース系粘性剤を配合した種々の水性液剤が実用化されている。 Conventionally, in aqueous liquids such as eye drops and nasal drops, by adding viscosity by adding a cellulose-based viscosity agent, it improves the feeling of use, sustains a moist feeling and a refreshing feeling, improves the retention of drugs, has a medicinal effect (Refer to Patent Document 1), and today, various aqueous liquid preparations containing a cellulose-based viscous agent have been put into practical use.
しかしながら、ヒプロメロースやヒドロキシエチルセルロース等のセルロース系粘性剤を水性液剤に配合すると、粘度安定性が低く、経時的に液剤の粘度が低下するという問題点がある。このような粘度の低下は、使用感を損なったり、所期の薬効を発現できなくしたりするため、これらのセルロース系粘性剤を配合した水性液剤（特に点眼剤）の製剤設計や品質保証の上で、経時的な粘度低下を抑制することが重要になっている。特に、点眼剤では、その粘度を涙液と同程度に設定することによって、角結膜の湿潤性の保持、乾燥の防止、眼球運動における眼瞼と眼球の間の潤滑油としての作用等を付与したり、点眼時の違和感を無くすように調整したりしている。それ故、点眼剤の粘度が低下すると、これらの機能の減弱化を招くことになるため、点眼剤の粘度安定性を向上させることはとりわけ重要である。 However, when a cellulose-based viscosity agent such as hypromellose or hydroxyethyl cellulose is added to an aqueous liquid, there is a problem that the viscosity stability is low and the viscosity of the liquid decreases with time. Such a decrease in viscosity impairs the feeling of use and makes it impossible to exhibit the desired medicinal effects. Therefore, the formulation and quality assurance of aqueous liquid preparations (especially eye drops) containing these cellulosic viscosities are important. Therefore, it is important to suppress a decrease in viscosity over time. In particular, in the case of eye drops, by setting the viscosity to the same level as that of tears, the wetness of the keratoconjunctiva is prevented, drying is prevented, and the action as a lubricating oil between the eyelid and the eyeball during eye movement is given. Or make adjustments to eliminate discomfort during instillation. Therefore, it is particularly important to improve the viscosity stability of the eye drop because the drop in the viscosity of the eye drop results in a decrease in these functions.
従来、ヒプロメロースやヒドロキシエチルセルロース等のセルロース系粘性剤を含む水性液剤における経時的な粘度の低下を抑制する製剤技術について報告されている。例えば、特許文献２では、マンニトール、グリセリン、ポリビニルアルコール等の多価アルコールを使用することによって、セルロース系粘性剤を含む水性液剤の経時的な粘度の低下を防止できることが開示されている。また、特許文献３には、ゴマ油等の特定の植物油を使用することによって、セルロース系粘性剤と非イオン性界面活性剤を含む水性液剤の粘度を安定化させ得ることが開示されている。 Conventionally, there has been reported a formulation technique for suppressing a decrease in viscosity over time in an aqueous liquid preparation containing a cellulose-based viscous agent such as hypromellose or hydroxyethyl cellulose. For example, Patent Document 2 discloses that by using a polyhydric alcohol such as mannitol, glycerin, or polyvinyl alcohol, it is possible to prevent a decrease in viscosity over time of an aqueous liquid preparation containing a cellulose-based viscous agent. Patent Document 3 discloses that by using a specific vegetable oil such as sesame oil, the viscosity of an aqueous liquid preparation containing a cellulose-based viscous agent and a nonionic surfactant can be stabilized.
しかしながら、近年、点眼剤や点鼻剤等の分野における製剤処方の開発には枚挙にいとまがなく、特許文献２及び３の製剤技術では、製剤設計上の制約から、近年開発されている製剤処方に適用できないこともある。そこで、ヒプロメロース及び／又はヒドロキシエチルセルロースを含む水性液剤の粘度低下を抑制する新たな製剤技術の確立が求められている。 However, in recent years, the development of pharmaceutical formulations in the field of eye drops, nasal drops, and the like has been enormous, and the formulation techniques of Patent Documents 2 and 3 have been developed in recent years due to limitations in formulation design. It may not be applicable to the prescription. Then, establishment of the new formulation technique which suppresses the viscosity fall of the aqueous liquid agent containing a hypromellose and / or hydroxyethyl cellulose is calculated | required.
一方、従来、非イオン性界面活性剤が、セルロース系粘性剤を含む水性液剤の粘度低下の要因になっていることが報告されており（特許文献３の段落０００５等参照）、従来技術からは、非イオン性界面活性剤は、ヒプロメロース及び／又はヒドロキシエチルセルロースを含む水性液剤の経時的な粘度低下を抑制するどころか、寧ろ経時的な粘度低下を助長すると考えられているのが現状である。 On the other hand, it has been reported that nonionic surfactants have been a factor in reducing the viscosity of aqueous liquid preparations containing cellulosic viscosity agents (see paragraph 0005 of Patent Document 3). The non-ionic surfactant is considered to promote the decrease in viscosity over time rather than suppressing the decrease in viscosity over time of the aqueous liquid preparation containing hypromellose and / or hydroxyethyl cellulose.
本発明の目的は、ヒプロメロース及び／又はヒドロキシエチルセルロースを含む水性液剤において、経時的な粘度の低下を抑制できる製剤技術を提供することである。 The objective of this invention is providing the formulation technique which can suppress the fall of a viscosity with time in the aqueous liquid agent containing a hypromellose and / or a hydroxyethyl cellulose.
本発明者は、前記課題を解決すべく鋭意検討を行ったところ、以下の知見を得た。即ち、従来技術では、非イオン性界面活性剤は、セルロース系粘性剤を含む水性液剤の経時的な粘度低下を助長すると考えられていたにも拘らず、非イオン性界面活性剤の中からポリオキシエチレン硬化ヒマシ油及び／又はステアリン酸ポリオキシルを選択し、これらの所定量を、ヒプロメロース及び／又はヒドロキシエチルセルロースと組み合わせて配合した水性液剤では、経時的な粘度低下を効果的に抑制できることを見出した。本発明は、かかる知見に基づいて、更に検討を重ねることにより完成したものである。 The present inventor conducted intensive studies to solve the above problems, and obtained the following knowledge. That is, in the prior art, a nonionic surfactant was considered to promote a decrease in viscosity over time of an aqueous liquid preparation containing a cellulose-based viscous agent, but a polyionic surfactant was selected from among nonionic surfactants. It has been found that an aqueous liquid preparation in which oxyethylene hydrogenated castor oil and / or polyoxyl stearate is selected and these predetermined amounts are combined with hypromellose and / or hydroxyethyl cellulose can effectively suppress a decrease in viscosity over time. . The present invention has been completed by further studies based on this finding.
即ち、本発明は、下記に掲げる態様の発明を提供する。
項１． (A)ヒプロメロース及びヒドロキシエチルセルロースよりなる群から選択される少なくとも１種のセルロース系粘性剤と、(B)ポリオキシエチレン硬化ヒマシ油及びステアリン酸ポリオキシルよりなる群から選択される少なくとも１種の非イオン性界面活性剤とを含有する、水性液剤。
項２． ポリオキシエチレン硬化ヒマシ油が、ポリオキシエチレン硬化ヒマシ油６０である、項１に記載の水性液剤。
項３． ステアリン酸ポリオキシルが、ステアリン酸ポリオキシル４０である、項１又は２に記載の水性液剤。
項４． 前記(A)成分を０．０１〜２w/v％の濃度で含む、項１〜３のいずれかに記載の水性液剤。
項５． ポリオキシエチレン硬化ヒマシ油を０．０１〜０．２w/v％の濃度で含む、項１〜４のいずれかに記載の水性液剤。
項６． ステアリン酸ポリオキシルを０．０１〜０．４w/v％の濃度で含む、項１〜４のいずれかに記載の水性液剤。
項７． ポリオキシエチレン硬化ヒマシ油及びステアリン酸ポリオキシル以外の非イオン性界面活性剤を実質的に含まない、項１〜６のいずれかに記載の水性液剤。
項８． 更に(C)パンテノール、テトラヒドロゾリン、ピリドキシン、プラノプロフェン、及びこれらの薬学的に許容される塩よりなる群から選択される少なくとも１種を含む、項１〜７のいずれかに記載の水性液剤。
項９． 更に(D)テルペノイドを含む、項１〜８のいずれかに記載の水性液剤。
項１０． 点眼剤である、項１〜９のいずれかに記載の水性液剤。
項１１． ウベローデ型粘度計を用いて測定される２０℃における動粘度が１．１〜５０．０ｍｍ2／ｓである、項１〜１０のいずれかに記載の水性液剤。
項１２． 水性液剤において、(A)ヒプロメロース及びヒドロキシエチルセルロースよりなる群から選択される少なくとも１種のセルロース系粘性剤と、(B)ポリオキシエチレン硬化ヒマシ油及びステアリン酸ポリオキシルよりなる群から選択される少なくとも１種の非イオン性界面活性剤とを共存させる、前記セルロース系粘性剤を含む水性液剤の粘度低下を抑制する方法。
項１３． ポリオキシエチレン硬化ヒマシ油及びステアリン酸ポリオキシルよりなる群から選択される少なくとも１種を有効成分とする、ヒプロメロース及びヒドロキシエチルセルロースよりなる群から選択される少なくとも１種のセルロース系粘性剤を含む水性液剤に対する粘度低下抑制剤。
項１４． ヒプロメロース及びヒドロキシエチルセルロースよりなる群から選択される少なくとも１種のセルロース系粘性剤を含む水性液剤に対する粘度低下抑制するための、ポリオキシエチレン硬化ヒマシ油及びステアリン酸ポリオキシルよりなる群から選択される少なくとも１種の使用。
項１５． ヒプロメロース及びヒドロキシエチルセルロースよりなる群から選択される少なくとも１種のセルロース系粘性剤を含む水性液剤に対する粘度低下抑制剤の製造のための、ポリオキシエチレン硬化ヒマシ油及びステアリン酸ポリオキシルよりなる群から選択される少なくとも１種の使用。
項１６． ヒプロメロース及びヒドロキシエチルセルロースよりなる群から選択される少なくとも１種のセルロース系粘性剤を含む水性液剤に対する粘度低下抑制に使用される、ポリオキシエチレン硬化ヒマシ油及び／又はステアリン酸ポリオキシル。That is, this invention provides the invention of the aspect hung up below.
Item 1. (A) at least one cellulose-based viscosity agent selected from the group consisting of hypromellose and hydroxyethyl cellulose; and (B) at least one non-ion selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyl stearate. An aqueous liquid preparation containing a surfactant.
Item 2. Item 2. The aqueous liquid preparation according to Item 1, wherein the polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 60.
Item 3. Item 3. The aqueous liquid preparation according to Item 1 or 2, wherein the polyoxyl stearate is polyoxyl 40 stearate.
Item 4. Item 4. The aqueous liquid preparation according to any one of Items 1 to 3, comprising the component (A) at a concentration of 0.01 to 2 w / v%.
Item 5. Item 5. The aqueous liquid preparation according to any one of Items 1 to 4, comprising polyoxyethylene hydrogenated castor oil at a concentration of 0.01 to 0.2 w / v%.
Item 6. Item 5. The aqueous liquid preparation according to any one of Items 1 to 4, comprising polyoxyl stearate at a concentration of 0.01 to 0.4 w / v%.
Item 7. Item 7. The aqueous liquid preparation according to any one of Items 1 to 6, which is substantially free of nonionic surfactants other than polyoxyethylene hydrogenated castor oil and polyoxyl stearate.
Item 8. Item 8. The aqueous solution according to any one of Items 1 to 7, further comprising (C) at least one selected from the group consisting of panthenol, tetrahydrozoline, pyridoxine, pranoprofen, and pharmaceutically acceptable salts thereof. .
Item 9. Item 9. The aqueous liquid preparation according to any one of Items 1 to 8, further comprising (D) a terpenoid.
Item 10. Item 10. The aqueous liquid preparation according to any one of Items 1 to 9, which is an eye drop.
Item 11. Item 11. The aqueous liquid preparation according to any one of Items 1 to 10, wherein the kinematic viscosity at 20 ° C. measured using an Ubbelohde viscometer is 1.1 to 50.0 mm 2 / s.
Item 12. In the aqueous liquid preparation, (A) at least one cellulose-based viscous agent selected from the group consisting of hypromellose and hydroxyethyl cellulose; and (B) at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyl stearate. A method for suppressing a decrease in the viscosity of an aqueous liquid preparation containing the cellulose-based viscosity agent, which coexists with a nonionic surfactant.
Item 13. An aqueous liquid preparation comprising at least one cellulose-based viscous agent selected from the group consisting of hypromellose and hydroxyethyl cellulose, wherein the active ingredient is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyl stearate Viscosity reduction inhibitor.
Item 14. At least one selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyl stearate for suppressing a decrease in viscosity with respect to an aqueous solution containing at least one cellulose-based viscosity agent selected from the group consisting of hypromellose and hydroxyethyl cellulose Use of seeds.
Item 15. Selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyl stearate for the manufacture of a viscosity reduction inhibitor for an aqueous liquid comprising at least one cellulosic viscosity selected from the group consisting of hypromellose and hydroxyethylcellulose. At least one use.
Item 16. Polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate used for inhibiting a decrease in viscosity of an aqueous solution containing at least one cellulose-based viscous agent selected from the group consisting of hypromellose and hydroxyethyl cellulose.
本発明の水性液剤は、ヒプロメロース及び／又はヒドロキシエチルセルロースを含んでいながら、経時的な粘度低下を抑制できるので、使用感の向上、潤い感や清涼感の持続、薬物の滞留性の向上、薬効の増強等の、これらのセルロース系粘性剤によって付与される効果を長期間維持することができる。 Since the aqueous liquid preparation of the present invention contains hypromellose and / or hydroxyethyl cellulose, it can suppress a decrease in viscosity over time, so that it improves the feeling of use, maintains a moist feeling and a refreshing feeling, improves the retention of drugs, has a medicinal effect. The effects imparted by these cellulosic viscosity agents, such as enhancement of the viscosity, can be maintained for a long time.
また、本発明の水性液剤は、ヒプロメロース及び／又はヒドロキシエチルセルロースの濃度を所定範囲に設定することにより涙液に近い粘度に調整することができる。それ故、本発明の水性液剤を点眼剤として使用する場合には、点眼時の違和感を無くすことができ、更には涙液が担う機能（例えば、角結膜の湿潤性の保持、乾燥の防止、眼球運動における眼瞼と眼球の間の潤滑油としての作用等）を備えさせ、且つこれらの機能を長期間維持させることができる。 Moreover, the aqueous liquid preparation of this invention can be adjusted to the viscosity close | similar to tears by setting the density | concentration of a hypromellose and / or a hydroxyethyl cellulose to a predetermined range. Therefore, when using the aqueous liquid preparation of the present invention as an eye drop, it is possible to eliminate the uncomfortable feeling at the time of eye drop, and further, the function of tears (for example, retention of wetness of keratoconjunctiva, prevention of drying, And the like as a lubricating oil between the eyelid and the eyeball in eye movement), and these functions can be maintained for a long time.
１．水性液剤
本発明の水性液剤は、(A)ヒプロメロース及びヒドロキシエチルセルロースよりなる群から選択される少なくとも１種のセルロース系粘性剤と、(B)ポリオキシエチレン硬化ヒマシ油及びステアリン酸ポリオキシルよりなる群から選択される少なくとも１種とを含有することを特徴とする。以下に、本発明の水性液剤について詳述する。 1. Aqueous Solution The aqueous solution of the present invention comprises (A) at least one cellulose-based viscosity agent selected from the group consisting of hypromellose and hydroxyethyl cellulose, and (B) a group consisting of polyoxyethylene hydrogenated castor oil and polyoxyl stearate. It contains at least one selected. Below, the aqueous liquid preparation of this invention is explained in full detail.
本発明において、水性液剤とは、水を基剤として含み液状を呈する製剤である。また、本明細書において、各成分の濃度の単位「w/v％」は、第十六改正日本薬局方における質量対容量百分率を示し、ｇ／１００ｍＬと同義である。
また、本発明において、経時的な粘度低下の抑制とは、ヒプロメロース及び／又はヒドロキシエチルセルロースを含み、且つポリオキシエチレン硬化ヒマシ油及び／又はステアリン酸ポリオキシルを含まない水性液剤と比較して、経時的な動粘度の低下が改善されていることを示す。In the present invention, the aqueous liquid preparation is a preparation containing water as a base and exhibiting a liquid state. In the present specification, the unit of concentration “w / v%” of each component indicates a mass-to-volume percentage in the 16th revised Japanese Pharmacopoeia and is synonymous with g / 100 mL.
Further, in the present invention, the suppression of the decrease in viscosity over time refers to the time-lapse as compared with an aqueous solution containing hypromellose and / or hydroxyethyl cellulose and not containing polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate. It shows that the decrease in kinematic viscosity is improved.
本発明の水性液剤は、セルロース系粘性剤として、ヒプロメロース及び／又はヒドロキシエチルセルロース（以下、(A)成分と表記することもある）を含有する。本発明の水性液剤において、(A)成分として、ヒプロメロース又はヒドロキシエチルセルロースの一方を単独で使用してもよく、またこれらを組み合わせて使用してもよい。(A)成分の中でも、好ましくはヒプロメロースが挙げられる。 The aqueous liquid preparation of the present invention contains hypromellose and / or hydroxyethyl cellulose (hereinafter also referred to as component (A)) as the cellulose-based viscosity agent. In the aqueous liquid preparation of the present invention, as component (A), either hypromellose or hydroxyethyl cellulose may be used alone, or a combination thereof may be used. Among the components (A), hypromellose is preferable.
(A)成分として使用されるヒプロメロースの置換度タイプについては、特に制限されず、１８２８、２２０８、２９０６、２９１０のいずれであってもよいが、好ましくは２９０６の置換度タイプのものが挙げられる。また、本発明で使用されるヒプロメロースの分子量については、特に制限されないが、例えば、重量平均分子量として１万〜５０万、好ましくは１０万〜５０万、更に好ましくは３０万〜５０万が挙げられる。 The substitution degree type of hypromellose used as the component (A) is not particularly limited, and may be any of 1828, 2208, 2906, and 2910, and preferably a substitution degree type of 2906. Further, the molecular weight of hypromellose used in the present invention is not particularly limited, and examples include a weight average molecular weight of 10,000 to 500,000, preferably 100,000 to 500,000, and more preferably 300,000 to 500,000. .
(A)成分として使用されるヒドロキシエチルセルロースのヒドロキシエトキシ基のモル置換度（無水グルコース単位あたりに付加したヒドロキシエトキシ基の平均モル数）については、特に制限されない。当該ヒドロキシエトキシ基のモル置換度としては、例えば、１．５〜３．０程度であればよいが、好ましくは２．５が挙げられる。また、本発明で使用されるヒドロキシエチルセルロースの分子量についても、特に制限されない。当該分子量としては、例えば、重量平均分子量として1万〜１００万、好ましくは１０万〜１００万、更に好ましくは６０万〜８０万が挙げられる。 The molar substitution degree of hydroxyethoxy groups of hydroxyethyl cellulose used as component (A) (average number of moles of hydroxyethoxy groups added per anhydroglucose unit) is not particularly limited. The molar substitution degree of the hydroxyethoxy group may be, for example, about 1.5 to 3.0, preferably 2.5. Further, the molecular weight of hydroxyethyl cellulose used in the present invention is not particularly limited. Examples of the molecular weight include 10,000 to 1,000,000, preferably 100,000 to 1,000,000, and more preferably 600,000 to 800,000 as a weight average molecular weight.
また、本発明の水性液剤における(A)成分の濃度としては、水性液剤に所望の粘性を付与できる範囲であればよい。例えば、(A)成分の総量で０．０１〜２w/v％、好ましくは０．０２〜０．５w/v％、更に好ましくは０．０５〜０．２w/v％、最も好ましくは０．１w/v％が挙げられる。 In addition, the concentration of the component (A) in the aqueous liquid preparation of the present invention may be in a range that can impart a desired viscosity to the aqueous liquid preparation. For example, the total amount of component (A) is 0.01 to 2 w / v%, preferably 0.02 to 0.5 w / v%, more preferably 0.05 to 0.2 w / v%, and most preferably 0.00. 1 w / v%.
また、本発明の水性液剤は、前記(A)成分に加えて、ポリオキシエチレン硬化ヒマシ油及び／又はステアリン酸ポリオキシル（以下、(B)成分と表記することもある）を含有する。このように、ヒプロメロース及び／又はヒドロキシエチルセルロースと、ポリオキシエチレン硬化ヒマシ油及び／又はステアリン酸ポリオキシルとを共存させることによって、水性液剤の粘度安定性が向上し、経時的な粘度低下を抑制することが可能になる。 In addition to the component (A), the aqueous liquid preparation of the present invention contains polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate (hereinafter sometimes referred to as component (B)). Thus, by coexisting hypromellose and / or hydroxyethyl cellulose with polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate, the viscosity stability of the aqueous liquid agent is improved and the decrease in viscosity over time is suppressed. Is possible.
(B)成分として使用されるポリオキシエチレン硬化ヒマシ油について、その酸化エチレンの平均付加モル数は、特に制限されず、薬学的に許容される範囲であればよい。ポリオキシエチレン硬化ヒマシ油として、具体的には、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０等が挙げられる。これらのポリオキシエチレン硬化ヒマシ油の中でも、経時的な粘度低下をより一層効果的に抑制するという観点から、好ましくはポリオキシエチレン硬化ヒマシ油６０が挙げられる。本発明の水性液剤において、これらのポリオキシエチレン硬化ヒマシ油は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Regarding the polyoxyethylene hydrogenated castor oil used as component (B), the average number of moles of ethylene oxide added is not particularly limited as long as it is within a pharmaceutically acceptable range. Specific examples of the polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, and the like. Among these polyoxyethylene hydrogenated castor oils, polyoxyethylene hydrogenated castor oil 60 is preferably used from the viewpoint of more effectively suppressing a decrease in viscosity over time. In the aqueous liquid preparation of the present invention, these polyoxyethylene hydrogenated castor oils may be used singly or in combination of two or more.
また、(B)成分として使用されるステアリン酸ポリオキシルについて、その酸化エチレンの平均付加モル数は、特に制限されず、薬学的に許容される範囲であればよい。ステアリン酸ポリオキシルとしては、ステアリン酸ポリオキシル４０、ステアリン酸ポリオキシル４５、ステアリン酸ポリオキシル５５等が挙げられる。これらのステアリン酸ポリオキシルの中でも、経時的な粘度低下をより一層効果的に抑制するという観点から、好ましくはステアリン酸ポリオキシル４０が挙げられる。本発明の水性液剤において、これらのステアリン酸ポリオキシルは、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 In addition, regarding the polyoxyl stearate used as the component (B), the average number of moles of ethylene oxide added is not particularly limited as long as it is within a pharmaceutically acceptable range. Examples of polyoxyl stearate include polyoxyl stearate 40, polyoxyl stearate 45, polyoxyl stearate 55, and the like. Among these polyoxyl stearates, polyoxyl 40 stearate is preferably used from the viewpoint of more effectively suppressing the decrease in viscosity over time. In the aqueous liquid preparation of the present invention, these polyoxyl stearates may be used alone or in combination of two or more.
本発明の水性液剤は、(B)成分として、ポリオキシエチレン硬化ヒマシ油又はステアリン酸ポリオキシルの一方を単独で使用してもよく、またこれらを組み合わせて使用してもよい。 In the aqueous liquid preparation of the present invention, as component (B), one of polyoxyethylene hydrogenated castor oil or polyoxyl stearate may be used alone, or a combination thereof may be used.
また、本発明の水性液剤における(B)成分の濃度としては、例えば、(B)成分の総量で０．００５〜０．４５w/v％、好ましくは０．０１〜０．４w/v％、より好ましくは０．０１〜０．２w/v％が挙げられる。 The concentration of the component (B) in the aqueous liquid preparation of the present invention is, for example, 0.005 to 0.45 w / v%, preferably 0.01 to 0.4 w / v%, based on the total amount of the component (B), More preferably, 0.01-0.2 w / v% is mentioned.
また、本発明の水性液剤において、(B)成分として、ポリオキシエチレン硬化ヒマシ油及びステアリン酸ポリオキシルのいずれか一方を使用する場合であれば、水性液剤の経時的な粘度低下をより一層効果的に抑制するという観点から、以下の濃度が好適に例示される。
ポリオキシエチレン硬化ヒマシ油を使用する場合：好ましくは０．０１〜０．２w/v％、より好ましくは０．０５〜０．２w/v％、更に好ましくは０．1〜０．２w/v％。
ステアリン酸ポリオキシルを使用する場合：好ましくは０．０１〜０．４w/v％、より好ましくは０．０５〜０．４w/v％、更に好ましくは０．1〜０．２w/v％。Further, in the aqueous liquid preparation of the present invention, if any one of polyoxyethylene hydrogenated castor oil and polyoxyl stearate is used as the component (B), the viscosity reduction with time of the aqueous liquid preparation is more effective. From the viewpoint of suppression, the following concentrations are preferably exemplified.
When polyoxyethylene hydrogenated castor oil is used: preferably 0.01 to 0.2 w / v%, more preferably 0.05 to 0.2 w / v%, still more preferably 0.1 to 0.2 w / v %.
When using polyoxyl stearate: Preferably it is 0.01-0.4 w / v%, More preferably, it is 0.05-0.4 w / v%, More preferably, it is 0.1-0.2 w / v%.
更に、本発明の水性液剤は、必要に応じて、パンテノール、テトラヒドロゾリン、ピリドキシン、プラノプロフェン、及びそれらの薬学的に許容される塩よりなる群から選択される少なくとも１種（以下、(C)成分と表記することもある）を含有してもよい。本発明の水性液剤に(C)成分を含有させることにより、経時的な粘度低下の抑制効果を更に増強でき、より一層安定な水性液剤にすることが可能になる。 Furthermore, the aqueous liquid preparation of the present invention is optionally at least one selected from the group consisting of panthenol, tetrahydrozoline, pyridoxine, pranoprofen, and pharmaceutically acceptable salts thereof (hereinafter referred to as (C ) May be described as a component). By containing the component (C) in the aqueous liquid preparation of the present invention, the effect of suppressing the decrease in viscosity over time can be further enhanced, and a more stable aqueous liquid preparation can be obtained.
(C)成分として使用される薬学的に許容される塩については、塩を形成する化合物の種類に応じたものであればよい。例えば、テトラヒドロゾリンの薬学的に許容される塩としては、具体的には、塩酸塩、硝酸塩等の無機酸塩が挙げられる。ピリドキシンの薬学的に許容される塩としては、具体的には、塩酸塩、リン酸塩等の無機酸塩が挙げられる。プラノプロフェンの薬学的に許容される塩としては、具体的には、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、アルミニウム塩等の金属塩；トリエチルアミン塩、ジエチルアミン塩、モルホリン塩、ピペラジン塩等の有機塩基塩等が挙げられる。 The pharmaceutically acceptable salt used as the component (C) may be any one according to the type of the compound forming the salt. For example, specific examples of the pharmaceutically acceptable salt of tetrahydrozoline include inorganic acid salts such as hydrochloride and nitrate. Specific examples of the pharmaceutically acceptable salt of pyridoxine include inorganic acid salts such as hydrochloride and phosphate. Specific examples of pharmaceutically acceptable salts of pranoprofen include metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and aluminum salt; triethylamine salt, diethylamine salt, morpholine salt, piperazine salt, and the like. And organic base salts thereof.
これらの(C)成分は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。経時的な粘度低下の抑制効果の増強作用をより一層向上させるという観点から、(B)成分としてポリオキシエチレン硬化ヒマシ油を含む場合には、(C)成分として、ピリドキシン及び／又はその薬学的に許容される塩が好ましい。また、(B)成分としてステアリン酸ポリオキシルを含む場合には、(C)成分として、ピリドキシン及び／又はそれらの薬学的に許容される塩が好ましい。 These components (C) may be used alone or in combination of two or more. From the viewpoint of further improving the enhancing effect of the effect of suppressing the decrease in viscosity over time, when polyoxyethylene hydrogenated castor oil is included as component (B), pyridoxine and / or its pharmaceuticals as component (C) The salts that are acceptable are preferred. In addition, when polyoxyl stearate is included as component (B), pyridoxine and / or a pharmaceutically acceptable salt thereof is preferable as component (C).
本発明の水性液剤に(C)成分を含有させる場合、その濃度については、特に制限されず、使用する(C)成分の種類に応じて適宜設定される。例えば、(C)成分の総量で０．００１〜１w/v％、好ましくは０．０１〜０．２w/v％が挙げられる。より具体的には、経時的な粘度低下の抑制効果の増強作用を効果的に発揮させるという観点から、(C)成分の種類毎に以下の濃度が好適に例示される。
パンテノールを使用する場合：好ましくは０．００１〜１w/v％、より好ましくは０．００５〜０．５w/v％、更に好ましくは０．０１〜０．２w/v％。
テトラヒドロゾリン及び／又はその薬学的に許容される塩を使用する場合：好ましくは０．００１〜１w/v％、より好ましくは０．００５〜０．５w/v％、更に好ましくは０．０１〜０．１w/v％。
ピリドキシン及び／又はその薬学的に許容される塩を使用する場合：好ましくは０．００１〜１w/v％、より好ましくは０．００５〜０．５w/v％、更に好ましくは０．０１〜０．２w/v％。
プラノプロフェン及び／又はその薬学的に許容される塩を使用する場合：好ましくは０．００１〜１w/v％、より好ましくは０．００５〜０．５w/v％、更に好ましくは０．０１〜０．１w/v％。When the component (C) is contained in the aqueous liquid preparation of the present invention, the concentration thereof is not particularly limited, and is appropriately set according to the type of the component (C) to be used. For example, the total amount of component (C) is 0.001 to 1 w / v%, preferably 0.01 to 0.2 w / v%. More specifically, the following concentrations are preferably exemplified for each type of component (C) from the viewpoint of effectively exerting an enhancing effect of the effect of suppressing the decrease in viscosity over time.
When using panthenol: Preferably it is 0.001-1 w / v%, More preferably, it is 0.005-0.5 w / v%, More preferably, it is 0.01-0.2 w / v%.
When tetrahydrozoline and / or a pharmaceutically acceptable salt thereof is used: preferably 0.001-1 w / v%, more preferably 0.005-0.5 w / v%, still more preferably 0.01-0. .1 w / v%.
When pyridoxine and / or a pharmaceutically acceptable salt thereof is used: preferably 0.001-1 w / v%, more preferably 0.005-0.5 w / v%, still more preferably 0.01-0. .2w / v%.
When using pranoprofen and / or a pharmaceutically acceptable salt thereof: preferably 0.001-1 w / v%, more preferably 0.005-0.5 w / v%, still more preferably 0.01. ~ 0.1 w / v%.
更に、本発明の水性液剤は、前述する成分の他に、必要に応じて、清涼感の付与等を目的として、テルペノイド（以下、(D)成分と表記することもある）を含有してもよい。テルペノイドを含有させると、本発明の水性液剤に含まれるヒプロメロース及び／又はヒドロキシエチルセルロースの作用によって粘膜上でのテルペノイドの滞留性が向上するので、清涼感を持続的に発揮する水性液剤を提供することができる。 Furthermore, the aqueous liquid preparation of the present invention may contain a terpenoid (hereinafter also referred to as the component (D)) for the purpose of imparting a refreshing feeling, if necessary, in addition to the components described above. Good. When the terpenoid is contained, the retention property of the terpenoid on the mucous membrane is improved by the action of hypromellose and / or hydroxyethylcellulose contained in the aqueous liquid preparation of the present invention, so that an aqueous liquid preparation that continuously exhibits a refreshing feeling is provided. Can do.
(D)成分として使用されるテルペノイドとしては、具体的には、メントール、メントン、カンフル、ボルネオール、ゲラニオール、シネオール、リモネン、オイゲノール、シトラール、ピネン、リナロール、フェンチルアルコール、テルピネン等のモノテルペンが挙げられる。これらの中でも、好ましくはメントール、メントン、カンフル、更に好ましくはメントールが挙げられる。これらのテルペノイドは、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。また、これらのテルペノイドは、必ずしも精製した状態のものでなくてもよく、これらのテルペノイドを含む精油を使用してもよい。メントールを含む精油としては、例えば、ペパーミント油、スペアミント油、ハッカ油等が挙げられる。 Specific examples of terpenoids used as component (D) include monoterpenes such as menthol, menthone, camphor, borneol, geraniol, cineol, limonene, eugenol, citral, pinene, linalool, fentil alcohol, and terpinene. It is done. Among these, preferably menthol, menthone, camphor, and more preferably menthol. These terpenoids may be used individually by 1 type, and may be used in combination of 2 or more type. In addition, these terpenoids do not necessarily have to be in a purified state, and essential oils containing these terpenoids may be used. Examples of essential oils containing menthol include peppermint oil, spearmint oil, peppermint oil, and the like.
本発明の水性液剤に(D)成分を含有させる場合、その濃度については、特に制限されず、使用する(D)成分の種類、付与する清涼感の程度等に応じて適宜設定される。例えば０．０００１〜０．１w/v％、好ましくは０．０００１〜０．０５w/v％が挙げられる。 When the component (D) is contained in the aqueous liquid preparation of the present invention, the concentration thereof is not particularly limited and is appropriately set according to the type of the component (D) to be used, the degree of refreshing feeling to be imparted, and the like. For example, 0.0001 to 0.1 w / v%, preferably 0.0001 to 0.05 w / v% can be mentioned.
本発明の水性液剤は、ヒプロメロース及び／又はヒドロキシエチルセルロースと、ポリオキシエチレン硬化ヒマシ油及び／又はステアリン酸ポリオキシルとを含有することにより、経時的な粘度低下が抑制されている。このような粘度低下の抑制効果をより一層有効に奏させるためには、前記水性液剤にポリソルベート８０を実質的に含まないことが好ましく、ポリソルベートを実質的に含まないことが更に好ましく、(B)成分以外の非イオン性界面活性剤を実質的に含まないことが特に好ましい。ここで、前記各非イオン性界面活性剤を実質的に含まないとは、本発明の水性液剤において経時的な粘度の低下を抑制する効果が損なわれない範囲であることを意味し、具体的には前記各非イオン性界面活性剤の濃度として０．０００１w/v％未満、好ましくは０w/v％が挙げられる。 The aqueous liquid preparation of the present invention contains hypromellose and / or hydroxyethyl cellulose and polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate, so that a decrease in viscosity over time is suppressed. In order to exhibit such an effect of suppressing the decrease in viscosity even more effectively, the aqueous liquid preferably contains substantially no polysorbate 80, more preferably contains substantially no polysorbate, (B) It is particularly preferred that substantially no nonionic surfactant other than the components is contained. Here, the fact that each of the nonionic surfactants is substantially not included means that the effect of suppressing the decrease in viscosity over time in the aqueous liquid preparation of the present invention is within a range that is not impaired. The concentration of each nonionic surfactant is less than 0.0001 w / v%, preferably 0 w / v%.
更に、本発明の水性液剤は、油剤を実質的に含まないことが好ましい。油剤は、点眼剤における点眼時のベタツキの要因や、コンタクトレンズ用点眼剤におけるレンズ汚れの要因等になるので、油剤を実質的に含まないことによってこれらの不具合を防止することが可能になる。ここで、油剤とは、植物油、動物油、及び／又は鉱物油からなる成分であり、脂肪酸とグリセリンとのトリグリセリルエステル（即ち、トリグリセリド）、脂肪族炭化水素、脂肪酸、脂肪酸のモノアルキルエステル、高級アルコール等の不揮発性の疎水性物質の中の少なくとも１種を主成分とするものである。よって、油剤には、揮発性である精油は含まれない。また、油剤を実質的に含まないとは、具体的には油剤の濃度として０．００００１w/v％未満、好ましくは０w/v％が挙げられる。 Furthermore, the aqueous liquid preparation of the present invention preferably contains substantially no oil agent. The oil agent causes stickiness at the time of instillation in an eye drop, a factor of lens contamination in an eye drop for contact lenses, and the like, and it is possible to prevent these problems by substantially not containing the oil agent. Here, the oil agent is a component composed of vegetable oil, animal oil, and / or mineral oil, triglyceryl ester of fatty acid and glycerin (that is, triglyceride), aliphatic hydrocarbon, fatty acid, monoalkyl ester of fatty acid, higher grade. The main component is at least one of non-volatile hydrophobic substances such as alcohol. Therefore, the oil does not include essential oil that is volatile. Further, the phrase “substantially not containing an oil agent” specifically means that the oil agent concentration is less than 0.00001 w / v%, preferably 0 w / v%.
本発明の水性液剤は、上記成分の他に、本発明の効果を損なわない限りにおいて、薬理成分を含有することができる。配合可能な薬理成分としては、例えば、グリチルリチン酸二カリウム、アラントイン、イプシロンアミノカプロン酸、ブロムフェナク、ケトロラクトロメタミン、ネパフェナク、ベルベリン塩化物、硫酸ベルベリン、アズレンスルホン酸ナトリウム、硫酸亜鉛、乳酸亜鉛、リゾチーム塩酸塩等の消炎剤；クロルフェニラミンマレイン酸塩、ジフェンヒドラミン塩酸塩等の抗ヒスタミン剤；クロモグリク酸ナトリウム、ケトチフェンフマル酸塩、アシタザノラスト、アンレキサノクス、ペミロラストカリウム、トラニラスト、イブジラスト等の抗アレルギー剤；ノルフロキサシン、オフロキサシン、ロメフロキサシン、レボフロキサシン、ゲンタマイシン、ガチフロキサシン等の抗菌剤；アスコルビン酸、フラビンアデニンジヌクレオチドナトリウム、シアノコバラミン、トコフェロール酢酸エステル、レチノール酢酸エステル、レチノールパルミチン酸エステル、パントテン酸カルシウム、パントテン酸ナトリウム等のビタミン類；アスパラギン酸、タウリン、コンドロイチン硫酸ナトリウム等のアミノ酸類、ネオスチグミンメチル硫酸塩等の抗コリンエステラーゼ剤；ナファゾリン、エピネフリン、エフェドリン、フェニレフリン、ｄｌ−メチルエフェドリン等の血管収縮剤；ヒアルロン酸ナトリウム等の角結膜上皮障害治療薬；スルファジアジン、スルフイソキサゾール、スルフイソミジン、スルファジメトキシン、スルファメトキシピリダジン、スルファメトキサゾール、スルファエチドール、スルファメトミジン、スルファフェナゾール、スルファグアニジン、フタリルスルファチアゾール、スクシニルスルファチアゾール等のサルファ剤等が挙げられる。ここで例示する化合物は、薬学的に許容されることを限度として、塩の形態であっても、他の塩の形態であってもよい。 The aqueous liquid preparation of the present invention can contain a pharmacological component in addition to the above components as long as the effects of the present invention are not impaired. Examples of pharmacological ingredients that can be incorporated include dipotassium glycyrrhizinate, allantoin, epsilon aminocaproic acid, bromfenac, ketorolac tromethamine, nepafenac, berberine chloride, berberine sulfate, sodium azulenesulfonate, zinc sulfate, zinc lactate, lysozyme hydrochloride Anti-histamines such as chlorpheniramine maleate and diphenhydramine hydrochloride; antiallergic agents such as cromoglycate sodium, ketotifen fumarate, acitazanolast, amlexanox, pemirolast potassium, tranilast, ibudilast; , Ofloxacin, lomefloxacin, levofloxacin, gentamicin, gatifloxacin and other antibacterial agents; ascorbic acid, flavin adenine dinucleotide nato Vitamins such as um, cyanocobalamin, tocopherol acetate, retinol acetate, retinol palmitate, calcium pantothenate, sodium pantothenate; amino acids such as aspartic acid, taurine, sodium chondroitin sulfate, and anticholinesterase such as neostigmine methyl sulfate Agents: Vasoconstrictors such as naphazoline, epinephrine, ephedrine, phenylephrine, dl-methylephedrine; therapeutic agents for keratoconjunctival epithelial disorders such as sodium hyaluronate; sulfadiazine, sulfisoxazole, sulfisomidine, sulfadimethoxine, sulfamethoxypyridazine, sulfa Famethoxazole, sulfaethidol, sulfamethomidine, sulfaphenazole, sulfaguanidine, phthalyls Phosphatidyl azole, sulfa drugs such as succinyl Rusuru phosphatidyl azoles and the like. The compounds exemplified herein may be in the form of a salt or other salt as long as they are pharmaceutically acceptable.
更に、本発明の水性液剤は、必要に応じて、緩衝剤、等張化剤、溶解補助剤、粘性基剤、キレート剤、ｐＨ調整剤、防腐剤、安定化剤、非イオン性界面活性剤以外の界面活性剤等の添加剤を含有してもよい。 Furthermore, the aqueous liquid preparation of the present invention contains a buffering agent, an isotonic agent, a solubilizing agent, a viscous base, a chelating agent, a pH adjusting agent, a preservative, a stabilizer, a nonionic surfactant as necessary. You may contain additives, such as surfactant other than.
緩衝剤としては、例えば、リン酸緩衝剤、ホウ酸緩衝剤、クエン酸緩衝剤、酒石酸緩衝剤、酢酸緩衝剤、Tris緩衝剤、アミノ酸などが挙げられる。 Examples of the buffer include phosphate buffer, borate buffer, citrate buffer, tartaric acid buffer, acetate buffer, Tris buffer, amino acid, and the like.
等張化剤としては、ソルビトール、グルコース、マンニトール等の糖類；グリセリン、プロピレングリコール等の多価アルコール類；塩化ナトリウム等の塩類；ホウ酸等が挙げられる。 Examples of the isotonic agent include saccharides such as sorbitol, glucose and mannitol; polyhydric alcohols such as glycerin and propylene glycol; salts such as sodium chloride; boric acid and the like.
溶解補助剤としては、例えば、グリセリン、マクロゴール等の多価アルコール等が挙げられる。 Examples of the solubilizer include polyhydric alcohols such as glycerin and macrogol.
粘性基剤としては、例えば、ポリビニルピロリドン、ポリエチレングリコール、ポリビニルアルコール、カルボキシビニルポリマー等の水溶性高分子等が挙げられる。 Examples of the viscous base include water-soluble polymers such as polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, and carboxyvinyl polymer.
キレート剤としては、例えば、エデト酸ナトリウム、クエン酸等が挙げられる。 Examples of the chelating agent include sodium edetate and citric acid.
ｐＨ調整剤としては、例えば、水酸化ナトリウム、水酸化カリウム等のアルカリ；酢酸、クエン酸、塩酸、リン酸、酒石酸等の酸が挙げられる。 Examples of the pH adjuster include alkalis such as sodium hydroxide and potassium hydroxide; acids such as acetic acid, citric acid, hydrochloric acid, phosphoric acid and tartaric acid.
防腐剤としては、例えば、ソルビン酸、ソルビン酸カリウム、安息香酸ナトリウム、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、クロロブタノール、クロロヘキシジングルコン酸塩、ホウ酸、デヒドロ酢酸、デヒドロ酢酸ナトリウム、塩化ベンゼトニウム、ベンジルアルコール、塩化亜鉛、パラクロルメタキシレノール、クロルクレゾール、フェネチルアルコール、塩化ポリドロニウム、チメロサール等が挙げられる。 Examples of preservatives include sorbic acid, potassium sorbate, sodium benzoate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, chlorohexidine gluconate, boric acid, dehydroacetic acid, dehydro Examples thereof include sodium acetate, benzethonium chloride, benzyl alcohol, zinc chloride, parachlormetaxylenol, chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal and the like.
安定化剤としては、例えば、ポリビニルピロリドン、亜硫酸ナトリウム、モノエタノールアミン、グリセリン、プロピレングリコール、シクロデキストリン、デキストラン、アスコルビン酸、エデト酸ナトリウム、タウリン、トコフェロール等が挙げられる。 Examples of the stabilizer include polyvinyl pyrrolidone, sodium sulfite, monoethanolamine, glycerin, propylene glycol, cyclodextrin, dextran, ascorbic acid, sodium edetate, taurine, tocopherol and the like.
非イオン性界面活性剤以外の界面活性剤としては、例えば、アルキルジアミノエチルグリシン、ラウリルジメチルアミノ酢酸ベタイン等の両性界面活性剤；アルキル硫酸塩、Ｎ−アシルタウリン塩、ポリオキシエチレンアルキルエーテルリン酸塩、ポリオキシエチレンアルキルエーテル硫酸塩等の陰イオン界面活性剤；アルキルピリジニウム塩、アルキルアミン塩等の陽イオン界面活性剤等が挙げられる。 Examples of surfactants other than nonionic surfactants include amphoteric surfactants such as alkyldiaminoethylglycine and lauryldimethylaminoacetic acid betaine; alkyl sulfates, N-acyl taurine salts, polyoxyethylene alkyl ether phosphates Anionic surfactants such as salts and polyoxyethylene alkyl ether sulfates; and cationic surfactants such as alkylpyridinium salts and alkylamine salts.
本発明の水性液剤の動粘度については、当該水性液剤の用途等に応じて適宜設定されるが、例えば、２０℃における動粘度が１．１〜５０．０ｍｍ2／ｓ、好ましくは１．１〜３５．０ｍｍ2／ｓ、更に好ましくは１．２〜２８ｍｍ2／ｓが挙げられる。特に、本発明の水性液剤を眼科用製剤として使用する場合であれば、涙液と同程度の粘性を備えていることが好ましく、具体的には２０℃における動粘度として、好ましくは１．１〜３．０ｍｍ2／ｓ、更に好ましくは１．５〜２．５ｍｍ2／ｓが挙げられる。ここで、２０℃における動粘度は、ウベローデ型粘度計を用いて、第十六改正日本薬局に規定されている「一般試験法 ２．５３ 粘度試験法 １．第１法 毛細管粘度計法」に従って測定される値である。また、測定される粘度範囲に応じて、使用されるウベローデ型粘度計の毛細管の内径及と使用される球Ｂについては、実施例の欄の表１に示す通りである。The kinematic viscosity of the aqueous liquid preparation of the present invention is appropriately set according to the use of the aqueous liquid preparation, and the kinematic viscosity at 20 ° C. is 1.1 to 50.0 mm 2 / s, preferably 1.1. -35.0 mm < 2 > / s, More preferably, 1.2-28 mm < 2 > / s is mentioned. In particular, when the aqueous liquid preparation of the present invention is used as an ophthalmic preparation, it preferably has a viscosity comparable to that of tears. Specifically, the kinematic viscosity at 20 ° C. is preferably 1.1. -3.0 mm < 2 > / s, More preferably, 1.5-2.5 mm < 2 > / s is mentioned. Here, the kinematic viscosity at 20 ° C. is measured in accordance with “General Test Method 2.53 Viscosity Test Method 1. First Method Capillary Viscometer Method” stipulated in the 16th revision Japanese Pharmacy using an Ubbelohde viscometer. The value to be measured. Moreover, according to the viscosity range to be measured, the inner diameter of the capillary of the Ubbelohde viscometer used and the sphere B used are as shown in Table 1 in the column of Examples.
本発明の水性液剤のｐＨについては、特に制限されないが、例えば、５．５〜８．０、好ましくは６．５〜７．５が挙げられる。 Although there is no restriction | limiting in particular about pH of the aqueous liquid preparation of this invention, For example, 5.5-8.0, Preferably it is 6.5-7.5.
本発明の水性液剤の製剤形態については、特に制限されず、水溶液状、懸濁液状、乳液状等のいずれであってもよいが、好ましくは水溶液状が挙げられる。 The formulation form of the aqueous liquid preparation of the present invention is not particularly limited and may be any of an aqueous solution, a suspension, an emulsion, etc., preferably an aqueous solution.
本発明の水性液剤は、点眼剤（ソフトコンタクトレンズ用点眼剤を含む）、洗眼剤等の眼科用製剤；点鼻剤、点耳剤等の耳鼻科用製剤；コンタクトレンズ装着液、コンタクトレンズ用マルチパーパスソリューション等のコンタクトレンズケア用品として使用することができる。ソフトコンタクトレンズ用点眼剤とは、ソフトコンタクトレンズ装用中でも点眼可能な点眼剤である。これらの中でも、好ましくは眼科用製剤、更に好ましくは点眼剤が挙げられる。 The aqueous liquid preparation of the present invention comprises ophthalmic preparations such as eye drops (including eye drops for soft contact lenses) and eyewashes; otolaryngological preparations such as nasal drops and ear drops; contact lens mounting liquids and contact lenses It can be used as a contact lens care product such as a multi-purpose solution. An eye drop for a soft contact lens is an eye drop that can be applied even while wearing a soft contact lens. Among these, an ophthalmic preparation is preferable, and an eye drop is more preferable.
本発明の水性液剤は、その用途に応じて、自体公知の調製法に従って製造すればよく、例えば、第十六改正日本薬局方 製剤総則に記載された方法を用いて製造することができる。 The aqueous liquid preparation of the present invention may be produced according to a preparation method known per se according to its use. For example, it can be produced using the method described in the 16th revised Japanese Pharmacopoeia Preparation General Rules.
２．粘度低下抑制方法及び粘度低下抑制剤
本発明は、水性液剤において、(A)ヒプロメロース及び／又はヒドロキシエチルセルロースと、(B)ポリオキシエチレン硬化ヒマシ油及び／又はステアリン酸ポリオキシルとを共存させる、前記(A)成分を含む水性液剤の粘度低下を抑制する方法をも提供する。当該方法において、(A)成分の種類、(B)成分の種類、他に配合可能な成分の種類、これらの濃度、水性液剤の種類等については、前記「１．水性液剤」に記載の通りである。 2. Viscosity reduction inhibiting method and viscosity reduction inhibiting agentIn the aqueous liquid preparation , (A) hypromellose and / or hydroxyethyl cellulose and (B) polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate coexist. A method for suppressing a decrease in viscosity of an aqueous liquid preparation containing the component A) is also provided. In the method, the type of component (A), the type of component (B), the types of other components that can be blended, the concentration thereof, the type of aqueous liquid, and the like are as described in “1. It is.
また、本発明は、更に、ポリオキシエチレン硬化ヒマシ油及び／又はステアリン酸ポリオキシルを有効成分とする、ヒプロメロース及び／又はヒドロキシエチルセルロースを含む水性液剤に対する粘度低下抑制剤をも提供する。当該粘度低下抑制剤は、ヒプロメロース及び／又はヒドロキシエチルセルロースを含む水性液剤の経時的な粘度の低下を抑制する目的で配合される添加剤として使用される。当該粘度低下抑制剤の有効成分であるポリオキシエチレン硬化ヒマシ油及び／又はステアリン酸ポリオキシルの種類や使用量については、前記「１．水性液剤」に記載の通りである。 The present invention also provides a viscosity reduction inhibitor for an aqueous solution containing hypromellose and / or hydroxyethyl cellulose, which contains polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate as an active ingredient. The said viscosity fall inhibitor is used as an additive mix | blended in order to suppress the fall with time of the viscosity of the aqueous liquid agent containing a hypromellose and / or a hydroxyethyl cellulose. About the kind and usage-amount of polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate which are the active ingredients of the said viscosity fall inhibitor, it is as having described in said "1. aqueous liquid agent."
更に、当該粘度低下抑制剤には、必要に応じて、ポリオキシエチレン硬化ヒマシ油及び／又はステアリン酸ポリオキシル以外に、パンテノール、テトラヒドロゾリン、ピリドキシン、プラノプロフェン、及びこれらの薬学的に許容される塩よりなる群から選択される少なくとも１種を含んでいてもよい。これらの成分を含有することによって、当該粘度低下抑制剤による粘度低下抑制効果を更に増強させることも可能になる。これらの成分の種類や使用量等についても、前記「１．水性液剤」に記載の通りである。 In addition to the polyoxyethylene hydrogenated castor oil and / or polyoxyl stearate, the viscosity reduction inhibitor includes panthenol, tetrahydrozoline, pyridoxine, pranoprofen, and pharmaceutically acceptable products thereof, as necessary. It may contain at least one selected from the group consisting of salts. By containing these components, it is possible to further enhance the viscosity reduction inhibitory effect of the viscosity reduction inhibitor. The types and amounts used of these components are also as described in “1. Aqueous solution”.
また、当該粘度低下抑制剤において、適用対象となる水性液剤、それに含まれるヒプロメロース及び／又はヒドロキシエチルセルロースの種類や濃度等についても、前記「１．水性液剤」に記載の通りである。 In the viscosity reduction inhibitor, the aqueous liquid agent to be applied and the types and concentrations of hypromellose and / or hydroxyethyl cellulose contained therein are also as described in “1. Aqueous liquid agent”.
以下に、実施例を挙げて、本発明を具体的に説明するが、本発明はこれらによって何ら限定されるものではない。 EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
なお、以下の実施例及び比較例において、ヒプロメロースは商品名「METOLOSE 65SH-4000」（置換度タイプ２９０６、重量平均分子量35万、信越化学工業株式会社製）、ヒドロキシエチルセルロースは商品名「NATROSOL 250M PHARM」（重量平均分子量72万、Ashland Industries）、ヒドロキシプロピルセルロースは商品名「HPC-H」（日本曹達株式会社製）、カルメロースナトリウムは商品名「セロゲンPR-S 日局」（第一工業製薬株式会社製）、アルギン酸は商品名「アルギン酸」（株式会社キミカ製）、キサンタンガムは商品名「エコーガムT」（DSP五協フード＆ケミカル株式会社製）、ポリオキシエチレン硬化ヒマシ油60は商品名「NIKKOL HCO-60」（日光ケミカルズ株式会社製）、ステアリン酸ポリオキシル40は商品名「NIKKOL MYS-40V」（日光ケミカルズ株式会社製）、ポリソルベート80は商品名「ポリソルベート80」（日油株式会社製）、ポリオキシエチレンオレイン酸グリセリルは商品名「NIKKOL TMGO-15」（日光ケミカルズ株式会社製）、モノオレイン酸ポリエチレングリコールは商品名「NIKKOL MYO-10V」（日光ケミカルズ株式会社製）をそれぞれ使用した。 In the following examples and comparative examples, hypromellose is trade name “METOLOSE 65SH-4000” (substitution degree type 2906, weight average molecular weight 350,000, manufactured by Shin-Etsu Chemical Co., Ltd.), and hydroxyethyl cellulose is trade name “NATROSOL 250M PHARM”. (Weight average molecular weight 720,000, Ashland Industries), hydroxypropylcellulose is trade name “HPC-H” (manufactured by Nippon Soda Co., Ltd.), carmellose sodium is trade name “Serogen PR-S JP” (Daiichi Kogyo Seiyaku) Co., Ltd.), Alginic acid is trade name "Alginic acid" (Kimika Co., Ltd.), Xanthan gum is trade name "Echo Gum T" (DSP Gokyo Food & Chemical Co., Ltd.), Polyoxyethylene hydrogenated castor oil 60 is trade name " NIKKOL HCO-60 "(manufactured by Nikko Chemicals Co., Ltd.), polyoxyl 40 stearate is the product name" NIKKOL MYS-40V "(manufactured by Nikko Chemicals Co., Ltd.), Resolvate 80 is trade name “Polysorbate 80” (manufactured by NOF Corporation), polyoxyethylene oleate glyceryl is trade name “NIKKOL TMGO-15” (manufactured by Nikko Chemicals Corporation), monooleate polyethylene glycol is trade name “NIKKOL” MYO-10V "(manufactured by Nikko Chemicals Co., Ltd.) was used.
試験例１：セルロース系粘性剤を含む水性液剤の粘度に対して非イオン性界面活性剤が及ぼす影響
表２に示す各成分を常法により混合し、０．２２μｍのメンブランフィルターを用いて濾過滅菌することによって、各水性液剤を調製した。調製直後の各水性液剤の動粘度を測定した後に、各水性液剤１５ｍＬを１５ｍＬ容ポリエチレンテレフタレート製容器に充填して密封し、遮光条件下、５０℃で２週間保存した。保存後の各水性液剤について動粘度を測定し、下記式に従って、動粘度保持率（％）を算出した。 Test Example 1: Effect of Nonionic Surfactant on Viscosity of Aqueous Solution Containing Cellulosic Viscosity Agents shown in Table 2 were mixed by a conventional method and sterilized by filtration using a 0.22 μm membrane filter. Thus, each aqueous liquid preparation was prepared. After measuring the kinematic viscosity of each aqueous solution immediately after preparation, 15 mL of each aqueous solution was filled in a 15 mL polyethylene terephthalate container, sealed, and stored at 50 ° C. for 2 weeks under light-shielding conditions. The kinematic viscosity was measured for each aqueous liquid after storage, and the kinematic viscosity retention rate (%) was calculated according to the following formula.
なお、各水性液剤の動粘度は、測定温度を２０℃に設定してウベローデ型粘度計（株式会社相互理化学硝子製作所製）を用いて、第十六改正日本薬局に規定されている「一般試験法 ２．５３ 粘度試験法 １．第１法 毛細管粘度計法」に従って測定した。動粘度は、１サンプル当たり２回測定し、その平均値を測定値とした。また、各水性液剤の動粘度の測定は、粘度の測定範囲毎に、ウベローデ型粘度計と球Ｂは、表１に示すものを使い分けて行った。 The kinematic viscosities of each aqueous liquid preparation are set in the “General Test” defined in the 16th revision Japanese Pharmacy using a Ubbelohde viscometer (manufactured by Mutual Riken Glass Co., Ltd.) at a measurement temperature of 20 ° C. Method 2.53 Viscosity Test Method 1. Measured according to “First Method Capillary Viscometer Method”. The kinematic viscosity was measured twice per sample, and the average value was taken as the measured value. Further, the kinematic viscosity of each aqueous liquid was measured by using the Ubbelohde viscometer and the sphere B as shown in Table 1 for each viscosity measurement range.
得られた結果を表２に示す。この結果から、ヒプロメロースとポリオキシエチレン硬化ヒマシ油６０を共存させた水性液剤（実施例１）、及びヒプロメロースとステアリン酸ポリオキシル４０を共存させた水性液剤（実施例２）では、ヒプロメロースを含み、非イオン性界面活性剤を含まない水性液剤（比較例１）に比べて、５０℃で２週間保存後の粘度低下を抑制できていた。一方、ヒプロメロースと共に、ポリソルベート８０、ポリオキシエチレンオレイン酸グリセリル又はモノオレイン酸ポリエチレングリコールを共存させた水性液剤（比較例２−４）では、比較例１の水性液剤よりも、５０℃で２週間保存後の粘度低下が大きくなっていた。 The obtained results are shown in Table 2. From this result, the aqueous liquid agent (Example 1) in which hypromellose and polyoxyethylene hydrogenated castor oil 60 coexist and the aqueous liquid agent (Example 2) in which hypromellose and polyoxyl 40 stearate coexist contain hypromellose. Compared with the aqueous liquid agent (Comparative Example 1) which does not contain an ionic surfactant, the viscosity reduction after storage at 50 ° C. for 2 weeks could be suppressed. On the other hand, the aqueous solution (Comparative Example 2-4) in which polysorbate 80, polyglyceryl polyoxyethylene oleate or polyethylene glycol monooleate coexisted with hypromellose is stored at 50 ° C. for 2 weeks, compared with the aqueous solution of Comparative Example 1. Later viscosity drop was greater.
以上の結果から、セルロース系粘性剤を含む水性液剤の経時的な粘度低下は、ポリオキシエチレン硬化ヒマシ油又はステアリン酸ポリオキシルによって抑制できることが明らかとなった。 From the above results, it has been clarified that the decrease in viscosity over time of an aqueous liquid preparation containing a cellulose-based viscosity agent can be suppressed by polyoxyethylene hydrogenated castor oil or polyoxyl stearate.
試験例２：各種粘性剤を含む水性液剤の粘度に対して非イオン性界面活性剤が及ぼす影響
表３及び４に示す各成分を常法により混合し、０．２２μｍのメンブランフィルターを用いて濾過滅菌することによって各水性液剤を調製し、上記試験例１と同様の方法で、各水性液剤について調製直後の動粘度、５０℃で２週間保存後の動粘度、及び動粘度保持率を求めた。 Test Example 2: Effect of Nonionic Surfactant on Viscosity of Aqueous Solution Containing Various Viscos Agents Each component shown in Tables 3 and 4 is mixed by a conventional method and filtered using a 0.22 μm membrane filter. Each aqueous solution was prepared by sterilization, and the kinematic viscosity immediately after preparation, kinematic viscosity after storage for 2 weeks at 50 ° C., and kinematic viscosity retention rate were determined for each aqueous solution in the same manner as in Test Example 1 above. .
得られた結果を表３及び４に示す。この結果から、ヒドロキシエチルセルロースとポリオキシエチレン硬化ヒマシ油６０を共存させた水性液剤でも、５０℃で２週間保存後の動粘度の低下を抑制できることが確認された。一方、表３及び４から明らかなように、ヒプロメロース及びヒドロキシエチルセルロース以外のセルロース系粘性剤、或いはアルギン酸又はキサンタンガムを含む水性液剤では、非イオン性界面活性剤を配合せずに５０℃で２週間保存しても、動粘度の低下は認められなかった。即ち、経時的な動粘度の低下は、セルロース系粘性剤の中でも、ヒプロメロース及び／又はヒドロキシエチルセルロースを含む水性液剤に特有の問題であることが明らかとなった。 The results obtained are shown in Tables 3 and 4. From these results, it was confirmed that even an aqueous liquid agent in which hydroxyethyl cellulose and polyoxyethylene hydrogenated castor oil 60 coexisted can suppress a decrease in kinematic viscosity after storage at 50 ° C. for 2 weeks. On the other hand, as is apparent from Tables 3 and 4, cellulose-based viscous agents other than hypromellose and hydroxyethyl cellulose, or aqueous liquids containing alginic acid or xanthan gum are stored at 50 ° C. for 2 weeks without a nonionic surfactant. However, no decrease in kinematic viscosity was observed. That is, it has been clarified that the decrease in kinematic viscosity over time is a problem peculiar to an aqueous liquid preparation containing hypromellose and / or hydroxyethyl cellulose among cellulose-based viscous agents.
試験例３：セルロース系粘性剤を含む水性液剤の粘度に対して非イオン性界面活性剤の濃度が及ぼす影響
表５及び６に示す各成分を常法により混合し、０．２２μｍのメンブランフィルターを用いて濾過滅菌することによって各水性液剤を調製し、上記試験例１と同様の方法で、各水性液剤について調製直後の動粘度、５０℃で２週間保存後の動粘度、及び動粘度保持率を求めた。 Test Example 3: Effect of concentration of nonionic surfactant on viscosity of aqueous liquid containing cellulose-based viscosity agent Each component shown in Tables 5 and 6 was mixed by a conventional method, and a 0.22 μm membrane filter was prepared. Each aqueous solution is prepared by sterilizing by filtration and using the same method as in Test Example 1 above, kinematic viscosity immediately after preparation, kinematic viscosity after storage at 50 ° C. for 2 weeks, and kinematic viscosity retention rate for each aqueous solution Asked.
得られた結果を表５及び６に示す。この結果から、ヒプロメロースを含む水性液剤において、ポリオキシエチレン硬化ヒマシ油６０を０．０１〜０．２w/v％、とりわけ０．１〜０．２w/v％の濃度で配合することによって、５０℃で２週間保存後の動粘度低下を効果的に抑制できていた。また、ヒプロメロースを含む水性液剤において、ステアリン酸ポリオキシル４０を０．０１〜０．４w/v％、とりわけ０．１〜０．４w/v％の濃度で配合することによって、５０℃で２週間保存後の動粘度低下を効果的に抑制できていた。一方、ヒプロメロースを含む水性液剤に、ポリソルベート８０を０．０５〜０．５w/v％の濃度で配合しても、５０℃で２週間保存後の動粘度低下を抑制することはできなかった。 The results obtained are shown in Tables 5 and 6. From this result, in an aqueous solution containing hypromellose, 50% polyoxyethylene hydrogenated castor oil 60 was blended at a concentration of 0.01 to 0.2 w / v%, especially 0.1 to 0.2 w / v%. The decrease in kinematic viscosity after storage at 2 ° C. for 2 weeks could be effectively suppressed. Further, in an aqueous solution containing hypromellose, polyoxyl 40 stearate is blended at a concentration of 0.01 to 0.4 w / v%, particularly 0.1 to 0.4 w / v%, and stored at 50 ° C. for 2 weeks. The subsequent decrease in kinematic viscosity was effectively suppressed. On the other hand, even when polysorbate 80 was added to an aqueous liquid containing hypromellose at a concentration of 0.05 to 0.5 w / v%, the decrease in kinematic viscosity after storage at 50 ° C. for 2 weeks could not be suppressed.
試験例４：セルロース系粘性剤及び非イオン性界面活性剤を含む水性液剤の粘度に対してセルロース系粘性剤の濃度が及ぼす影響
表７及び８に示す各成分を常法により混合し、０．２２μｍのメンブランフィルターを用いて濾過滅菌することによって各水性液剤を調製し、上記試験例１と同様の方法で、各水性液剤について調製直後の動粘度、５０℃で２週間保存後の動粘度、及び動粘度保持率を求めた。 Test Example 4: Effect of Cellulose Viscosity Concentration on Viscosity of Aqueous Solution Containing Cellulose Viscosity Agent and Nonionic Surfactant Each component shown in Tables 7 and 8 was mixed by a conventional method. Each aqueous solution was prepared by sterilizing by filtration using a 22 μm membrane filter, and kinematic viscosity immediately after preparation for each aqueous solution in the same manner as in Test Example 1 above, kinematic viscosity after storage at 50 ° C. for 2 weeks, The kinematic viscosity retention was determined.
得られた結果を表７及び８に示す。この結果から、ヒプロメロースを含み、非イオン性界面活性剤を含まない水性液剤において、ヒプロメロース濃度が高くなると共に、５０℃で２週間保存後の動粘度の低下が著しくなる傾向があったが（比較例１１−１７）、ポリオキシエチレン硬化ヒマシ油６０又はステアリン酸ポリオキシル４０を配合した場合では、５０℃で２週間保存後の動粘度の低下を抑制できていた(実施例１８−３１)。一方、本試験結果からも、ポリソルベート８０では、ヒプロメロースを含む水性液剤の５０℃で２週間保存後の動粘度の低下を抑制できないことが確認された（比較例１８−２４）。 The results obtained are shown in Tables 7 and 8. From this result, in the aqueous liquid preparation containing hypromellose and containing no nonionic surfactant, the hypromellose concentration tended to increase and the kinematic viscosity decreased after storage at 50 ° C. for 2 weeks. In the case of blending Example 11-17), polyoxyethylene hydrogenated castor oil 60 or polyoxyl 40 stearate, the decrease in kinematic viscosity after storage at 50 ° C. for 2 weeks could be suppressed (Examples 18-31). On the other hand, from this test result, it was also confirmed that polysorbate 80 could not suppress a decrease in kinematic viscosity after storage for 2 weeks at 50 ° C. of an aqueous liquid preparation containing hypromellose (Comparative Examples 18-24).
試験例５：セルロース系粘性剤及び非イオン性界面活性剤を含む水性液剤の粘度に油剤が及ぼす影響
表９に示す各成分を常法により混合し、０．２２μｍのメンブランフィルターを用いて濾過滅菌することによって各水性液剤を調製し、上記試験例１と同様の方法で、各水性液剤について調製直後の動粘度、５０℃で２週間保存後の動粘度、及び動粘度保持率を求めた。 Test Example 5: Effect of oil on viscosity of aqueous liquid containing cellulosic viscosity agent and nonionic surfactant Each component shown in Table 9 was mixed by a conventional method, and sterilized by filtration using a 0.22 μm membrane filter. Thus, each aqueous solution was prepared, and the kinematic viscosity immediately after preparation, the kinematic viscosity after storage for 2 weeks at 50 ° C., and the kinematic viscosity retention rate were determined for each aqueous solution in the same manner as in Test Example 1 above.
得られた結果を表９に示す。この結果から、ヒプロメロースを含む水溶液にポリソルベート８０を添加した場合、５０℃で２週間保存後の動粘度が低下したが（比較例２）、ヒマシ油の更なる添加により動粘度の低下は抑制された（参考例１４）。一方、ヒプロメロースとポリオキシエチレン硬化ヒマシ油６０を含む水溶液にヒマシ油をさらに添加しても、動粘度低下抑制効果は認められなかった（実施例３２）。ポリオキシエチレン硬化ヒマシ油６０をステアリン酸ポリオキシル４０に置き換えても、同様であった（実施例３３）。 Table 9 shows the obtained results. From this result, when polysorbate 80 was added to an aqueous solution containing hypromellose, the kinematic viscosity after storage for 2 weeks at 50 ° C. decreased (Comparative Example 2), but the decrease in kinematic viscosity was suppressed by further addition of castor oil. (Reference Example 14). On the other hand, even when castor oil was further added to an aqueous solution containing hypromellose and polyoxyethylene hydrogenated castor oil 60, the effect of suppressing the decrease in kinematic viscosity was not observed (Example 32). The same was true when polyoxyethylene hydrogenated castor oil 60 was replaced with polyoxyl 40 stearate (Example 33).
試験例６：パンテノール、テトラヒドロゾリン塩酸塩、ピリドキシン塩酸塩、及びプラノプロフェンが粘度低下抑制効果に及ぼす影響
表１０に示す各成分を常法により混合し、０．２２μｍのメンブランフィルターを用いて濾過滅菌することによって各水性液剤を調製し、上記試験例１と同様の方法で、各水性液剤について調製直後の動粘度、５０℃で２週間保存後の動粘度、及び動粘度保持率を求めた。 Test Example 6: Influence of panthenol, tetrahydrozoline hydrochloride, pyridoxine hydrochloride, and pranoprofen on the viscosity reduction inhibitory effect Each component shown in Table 10 was mixed by a conventional method and filtered using a 0.22 μm membrane filter. Each aqueous solution was prepared by sterilization, and the kinematic viscosity immediately after preparation, kinematic viscosity after storage for 2 weeks at 50 ° C., and kinematic viscosity retention rate were determined for each aqueous solution in the same manner as in Test Example 1 above. .
得られた結果を表１０に示す。この結果から、ヒプロメロースと、ポリオキシエチレン硬化ヒマシ油６０又はステアリン酸ポリオキシル４０とを含む水性液剤において、更にパンテノール、テトラヒドロゾリン塩酸塩、ピリドキシン塩酸塩、又はプラノプロフェンを配合すると、５０℃で２週間保存後の動粘度の低下抑制作用が増強されることが明らかとなった。とりわけ、ヒプロメロースとステアリン酸ポリオキシル４０とを含む水性液剤にパンテノールを配合した場合、及びヒプロメロースと、ポリオキシエチレン硬化ヒマシ油６０又はステアリン酸ポリオキシル４０とを含む水性液剤にピリドキシン塩酸塩を配合した場合において、５０℃で２週間保存後の動粘度の低下抑制作用が格段顕著に増強されることも確認された。一方、ヒプロメロースと、ポリオキシエチレン硬化ヒマシ油６０又はステアリン酸ポリオキシル４０とを含む水性液剤において、上記以外の数種の薬理成分を添加したところ、動粘度の低下抑制作用に影響を及ぼすことはなかった。即ち、本試験例で示された動粘度の低下抑制作用の増強効果は、更に添加する薬理成分として、パンテノール、テトラヒドロゾリン塩酸塩、ピリドキシン塩酸塩、及び／又はプラノプロフェンを選択したことによる特有の効果であることが確認された。 Table 10 shows the obtained results. From this result, in an aqueous liquid preparation containing hypromellose and polyoxyethylene hydrogenated castor oil 60 or polyoxyl 40 stearate, when panthenol, tetrahydrozoline hydrochloride, pyridoxine hydrochloride, or pranoprofen is further blended, It was clarified that the effect of suppressing the decrease in kinematic viscosity after weekly storage was enhanced. In particular, when panthenol is added to an aqueous solution containing hypromellose and polyoxyl 40 stearate, and when pyridoxine hydrochloride is added to an aqueous solution containing hypromellose and polyoxyethylene hydrogenated castor oil 60 or polyoxyl 40 stearate. It was also confirmed that the effect of suppressing the decrease in kinematic viscosity after storage at 50 ° C. for 2 weeks was remarkably enhanced. On the other hand, in the aqueous liquid preparation containing hypromellose and polyoxyethylene hydrogenated castor oil 60 or polyoxyl 40 stearate, the addition of several pharmacological components other than the above does not affect the effect of suppressing the decrease in kinematic viscosity. It was. That is, the enhancement effect of the kinematic viscosity reduction inhibitory action shown in this test example is peculiar by selecting panthenol, tetrahydrozoline hydrochloride, pyridoxine hydrochloride, and / or pranoprofen as a pharmacological component to be added. It was confirmed that this was the effect.
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| PCT/JP2013/070765 WO2014050301A1 (en) | 2012-09-27 | 2013-07-31 | Aqueous liquid medicine |
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| CN (1) | CN104661682B (en) |
| HK (1) | HK1210589A1 (en) |
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|---|---|---|---|---|
| JP6537223B2 (en) * | 2014-03-05 | 2019-07-03 | ロート製薬株式会社 | Composition for soft contact lens |
| WO2018235935A1 (en) * | 2017-06-23 | 2018-12-27 | 参天製薬株式会社 | Medicinal composition containing water-soluble thickening agent |
| JP7037349B2 (en) * | 2017-06-23 | 2022-03-16 | 参天製薬株式会社 | Pharmaceutical composition containing a water-soluble thickening agent |
| JP6267394B1 (en) * | 2017-09-07 | 2018-01-24 | 参天製薬株式会社 | Pharmaceutical composition containing water-soluble thickening agent |
| JP6687781B1 (en) * | 2019-03-08 | 2020-04-28 | ロート製薬株式会社 | Ophthalmic composition with suppressed irritation |
| JP2019174830A (en) * | 2019-06-04 | 2019-10-10 | ロート製薬株式会社 | Composition for soft contact lens |
| WO2021107033A1 (en) * | 2019-11-29 | 2021-06-03 | 千寿製薬株式会社 | Pharmaceutical composition |
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Also Published As
| Publication number | Publication date |
|---|---|
| JP2018111730A (en) | 2018-07-19 |
| TW201818922A (en) | 2018-06-01 |
| WO2014050301A1 (en) | 2014-04-03 |
| JP2019142979A (en) | 2019-08-29 |
| CN104661682A (en) | 2015-05-27 |
| CN104661682B (en) | 2018-05-11 |
| JP6538920B2 (en) | 2019-07-03 |
| TW201412343A (en) | 2014-04-01 |
| HK1210589A1 (en) | 2016-04-29 |
| JP6832390B2 (en) | 2021-02-24 |
| JP6353365B2 (en) | 2018-07-04 |
| TWI605836B (en) | 2017-11-21 |
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