JP6073525B2 - セルロースエーテルを含む粘膜に適用するための組成物 - Google Patents
セルロースエーテルを含む粘膜に適用するための組成物 Download PDFInfo
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- JP6073525B2 JP6073525B2 JP2016515992A JP2016515992A JP6073525B2 JP 6073525 B2 JP6073525 B2 JP 6073525B2 JP 2016515992 A JP2016515992 A JP 2016515992A JP 2016515992 A JP2016515992 A JP 2016515992A JP 6073525 B2 JP6073525 B2 JP 6073525B2
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- 239000000203 mixture Substances 0.000 title claims description 141
- 229920003086 cellulose ether Polymers 0.000 title claims description 48
- 210000004877 mucosa Anatomy 0.000 title claims description 32
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000013543 active substance Substances 0.000 claims description 26
- 239000007788 liquid Substances 0.000 claims description 26
- 239000007864 aqueous solution Substances 0.000 claims description 21
- 239000003085 diluting agent Substances 0.000 claims description 21
- 239000007951 isotonicity adjuster Substances 0.000 claims description 17
- 239000012929 tonicity agent Substances 0.000 claims description 15
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 7
- 239000002671 adjuvant Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 5
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000008121 dextrose Substances 0.000 claims description 4
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 4
- 238000005507 spraying Methods 0.000 claims description 4
- 239000000811 xylitol Substances 0.000 claims description 4
- 235000010447 xylitol Nutrition 0.000 claims description 4
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 4
- 229960002675 xylitol Drugs 0.000 claims description 4
- 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 claims description 3
- 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 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 229910001508 alkali metal halide Inorganic materials 0.000 claims description 3
- 229910001615 alkaline earth metal halide Inorganic materials 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 235000001727 glucose Nutrition 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 37
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 37
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 36
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000000243 solution Substances 0.000 description 25
- 230000000052 comparative effect Effects 0.000 description 21
- -1 hydroxypropyl Chemical group 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 238000006467 substitution reaction Methods 0.000 description 14
- 239000008186 active pharmaceutical agent Substances 0.000 description 13
- 210000003928 nasal cavity Anatomy 0.000 description 13
- 229920003091 Methocel™ Polymers 0.000 description 12
- 238000001879 gelation Methods 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
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- 238000003756 stirring Methods 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 229920000609 methyl cellulose Polymers 0.000 description 9
- 235000010981 methylcellulose Nutrition 0.000 description 9
- 239000000178 monomer Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 239000001923 methylcellulose Substances 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000006196 drop Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000000341 volatile oil Substances 0.000 description 5
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 4
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 210000002850 nasal mucosa Anatomy 0.000 description 4
- 239000008055 phosphate buffer solution Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 229920013820 alkyl cellulose Polymers 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000006172 buffering agent Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000002537 cosmetic Substances 0.000 description 3
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- 229940039227 diagnostic agent Drugs 0.000 description 3
- 229940009662 edetate Drugs 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 229940050176 methyl chloride Drugs 0.000 description 3
- 210000004400 mucous membrane Anatomy 0.000 description 3
- 235000016709 nutrition Nutrition 0.000 description 3
- 239000004302 potassium sorbate Substances 0.000 description 3
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- 229940069338 potassium sorbate Drugs 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- 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 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 2
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- 238000010438 heat treatment Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229960004931 histamine dihydrochloride Drugs 0.000 description 1
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 1
- 125000005113 hydroxyalkoxy group Chemical group 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229960001888 ipratropium Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229960003630 ketotifen fumarate Drugs 0.000 description 1
- YNQQEYBLVYAWNX-WLHGVMLRSA-N ketotifen fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 YNQQEYBLVYAWNX-WLHGVMLRSA-N 0.000 description 1
- 229950007325 lauralkonium chloride Drugs 0.000 description 1
- 229960001828 levocabastine hydrochloride Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229960002744 mometasone furoate Drugs 0.000 description 1
- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 description 1
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 229960004309 nafarelin acetate Drugs 0.000 description 1
- FSBTYDWUUWLHBD-UDXTWCDOSA-N nafarelin acetate hydrate Chemical compound O.CC(O)=O.C([C@@H](C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 FSBTYDWUUWLHBD-UDXTWCDOSA-N 0.000 description 1
- 229960004760 naphazoline hydrochloride Drugs 0.000 description 1
- 229960004186 naphazoline nitrate Drugs 0.000 description 1
- 210000001989 nasopharynx Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000000422 nocturnal effect Effects 0.000 description 1
- 229960003139 olopatadine hydrochloride Drugs 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229960005162 oxymetazoline hydrochloride Drugs 0.000 description 1
- BEEDODBODQVSIM-UHFFFAOYSA-N oxymetazoline hydrochloride Chemical compound Cl.CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 BEEDODBODQVSIM-UHFFFAOYSA-N 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 239000008180 pharmaceutical surfactant Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- 229940096826 phenylmercuric acetate Drugs 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229950004954 prednisolone sulfobenzoate Drugs 0.000 description 1
- WVKSUFYQOHQCMM-YGZHYJPASA-N prednisolone sulfobenzoate Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)C1=CC=CC(S(O)(=O)=O)=C1 WVKSUFYQOHQCMM-YGZHYJPASA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 108010068072 salmon calcitonin Proteins 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000004911 serous fluid Anatomy 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 230000005586 smoking cessation Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960000658 sumatriptan succinate Drugs 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 239000011975 tartaric acid Chemical class 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 description 1
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008719 thickening Effects 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
- 229940033663 thimerosal Drugs 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 208000002670 vitamin B12 deficiency Diseases 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229960001095 xylometazoline hydrochloride Drugs 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Otolaryngology (AREA)
- Engineering & Computer Science (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Medicinal Preparation (AREA)
Description
i)等張化剤と、
ii)少なくとも55重量パーセントが水である液体希釈剤と、
iii)組成物の総重量に基づいて、0.1〜6重量パーセントのセルロースエーテルと、を含み、
セルロースエーテルが、2重量%水溶液として20℃、10s−1の剪断速度で測定される、1.2〜8000mPa・sの粘度を有し、
セルロースエーテルが、1〜4個の結合により接合されたアンヒドログルコース単位を有し、かつアンヒドログルコース単位のヒドロキシル基が、s23/s26が0.29以下となるようにメチル基で置換されるような、置換基としてのメチル基、ヒドロキシアルキル基、及び任意選択で、メチルとは異なるアルキル基を有し、
s23は、アンヒドログルコース単位の2位及び3位の2つのヒドロキシル基のみがメチル基で置換されるアンヒドログルコース単位のモル分率であり、
s26は、アンヒドログルコース単位の2位及び6位の2つのヒドロキシル基のみがメチル基で置換されるアンヒドログルコース単位のモル分率である、組成物である。
用語「メチル基で置換されるOH基」は、セルロース主鎖の炭素原子に直接結合するメチル化OH基だけでなく、ヒドロキシアルキル化後に形成されたメチル化OH基も含む。
メトキシル%及びヒドロキシプロポキシル%の決定は、米国薬局方(USP35、「Hypromellose」、3467〜3469頁)に従って実施した。得られる値は、メトキシル%及びヒドロキシプロポキシル%である。続いてこれらは、メトキシル置換基の置換度(DS)及びヒドロキシプロポキシル置換基のモル置換(MS)に変換される。塩の残留量が変換の考慮に入っている。
HPMCの2%水溶液を得るため、(HPMCの含水量を考慮して)3gの、挽いて粉砕し乾燥させたHPMCを、147gの水道水(20〜25℃の温度)に、室温で、三翼(翼=2cm)ブレード攪拌器付きオーバーヘッド実験室攪拌器を用いて750rpmで攪拌しながら添加した。次いで、溶液を約5℃に冷ました。5℃の温度に達した後、溶液を750rpmで5時間攪拌し、冷蔵庫で一晩貯蔵した。使用または分析前に、溶液を100rpmで15分間、氷浴内で攪拌した。
2重量%HPMC水溶液の定常剪断流粘度η(20℃、10s−1、2重量%HPMC)は、Anton Paar Physica MCR 501レオメーター及びカップ及び下げ振り取付具(CC−27)で、20℃、10s−1の剪断速度で測定した。
セルロースエーテルにおけるエーテル置換基の決定は、一般に知られ、例えば、Bengt Lindberg、Ulf Lindquist、及びOlle Stenbergによる、Carbohydrate Research,176(1988)137−144,Elsevier Science Publishers B.V.,Amsterdam,DISTRIBUTION OF SUBSTITUENTS IN O−ETHYL−O−(2−HYDROXYETHYL)CELLULOSEに記載される。
MRFモノマー=ECN2,3,6−Me/ECNモノマー
s23=[(23−Me+23−Me−6−HAMe+23−Me−6−HA+23−Me−6−HAHAMe+23−Me−6−HAHA]、及び
s26=[(26−Me+26−Me−3−HAMe+26−Me−3−HA+26−Me−3−HAHAMe+26−Me−3−HAHA]であり、
s23は、次の条件を満たすアンヒドログルコース単位のモル分率の合計である。
b)アンヒドログルコース単位の2位及び3位の2つのヒドロキシ基は、メチル基で置換され、6位はメチル化ヒドロキシアルキル(=23−Me−6−HAMe)または2つのヒドロキシアルキル基(=23−Me−6−HAHAMe)を含むメチル化側鎖で置換され、
c)アンヒドログルコース単位の2位及び3位の2つのヒドロキシ基は、メチル基で置換され、6位はヒドロキシアルキル(=23−Me−6−HA)または2つのヒドロキシアルキル基(=23−Me−6−HAHA)を含む側鎖で置換される。
a)アンヒドログルコース単位の2位及び6位の2つのヒドロキシ基は、メチル基で置換され、3位は、置換されず(=26−Me)、
b)アンヒドログルコース単位の2位及び6位の2つのヒドロキシ基は、メチル基で置換され、3位は、メチル化ヒドロキシアルキル(=26−Me−3−HAMe)または2つのヒドロキシアルキル基(=26−Me−3−HAHAMe)を含むメチル化側鎖で置換され、
c)アンヒドログルコース単位の2位及び6位の2つのヒドロキシ基は、メチル基で置換され、3位は、ヒドロキシアルキル(=26−Me−3−HA)または2つのヒドロキシアルキル基(=26−Me−3−HAHA)を含む側鎖で置換される。
ヒドロキシプロピルメチルセルロース(HPMC)を以下の方法に従って生成する。細かく粉砕した木材セルロースパルプを、ジャケット付き攪拌される反応器に充填する。酸素を除去するため、反応器を脱気し窒素でパージし、次いで再度脱気する。反応は、二段階で実施する。第1の段階において、水酸化ナトリウムの50重量パーセント水溶液を、セルロース中1モルのアンヒドログルコース単位毎に、2.0モルの量の水酸化ナトリウムをセルロースに噴霧し、温度を40℃に調整する。水酸化ナトリウム水溶液及びセルロースの混合物を、約20分間、40℃で攪拌後、1モルのアンヒドログルコース単位毎に、1.5モルのジメチルエーテル、2.5モルの塩化メチル、及び0.2モルの酸化プロプレンを反応器へ添加する。次に、反応器の内容物を、60分で80℃に加熱する。80℃に達しさせた後、第1の段階の反応を、30分間進行させる。
反応混合物に添加される酸化プロプレンの量が、1モルのアンヒドログルコース単位毎に0.4モルの酸化プロプレンであることを除き、実施例1を反復する。
反応混合物に添加される酸化プロプレンの量が、1モルのアンヒドログルコース単位毎に0.6モルの酸化プロプレンであることを除き、実施例1を反復する。
HPMC−A、HPMC−B、及びHPMC−Cを、粉末性試料を下記表1に列挙される時間及び温度を用いて塩化水素ガスで加熱することにより、部分的に解重合する。部分的に解重合されたヒドロキシプロピルメチルセルロースを、重炭酸ナトリウムで中和する。
METHOCEL(商標)E4M、METHOCEL(商標)F4M、METHOCEL(商標)K4M、METHOCEL(商標)F5、及びMETHOCEL(商標)E5セルロースエーテルは、The Dow Chemical Companyより市販され、E4M、F4M、K4M、F5、及びE5と略称される。
METHOCEL(商標)F4Mを、1gのヒドロキシプロピルメチルセルロース毎に1.5gのHClガスと、70℃の温度で50分間接触させることにより、部分的に解重合した。部分的解重合に使用されたMETHOCEL(商標)F4Mは、下記表2のF4Mと略称されるものとは異なるバッチから生じ、僅かに異なるDS及びMSを有した。続いてHCガスを、脱気によって除去した。ヒドロキシプロピルメチルセルロースを、室温に冷まし、続いて重炭酸ナトリウムで中和した。
下記の表4に列挙されるとおりの濃度を有する濃縮HPMC溶液は、良好な分散を達成するため、対応する量の乾燥HPMC粉末を、磁気攪拌棒を使用して>80℃の初期温度を有する水に添加することにより調製した。HPMCの混合物及び水を、同じ速度で攪拌しながら、20分以内で5℃に冷ました。HPMCの混合物及び水が5℃の温度に達した後、混合液をこの温度で追加の1時間攪拌した。これらの溶液を、冷蔵庫で一晩貯蔵した。
粘膜に適用する水性組成物の粘度は、カップ及び下げ振り取付具を有するARES RFS3レオメーター(TA−Instruments)を使用し、5℃及び10s−1の剪断温度で測定した。
HPMC、及び任意に緩衝剤のような等張化剤、ならびに/または生理学的活性剤を含む水溶液のレオロジー測定は、カップ及び下げ振り取付具を有するAres RFS3レオメーター(TA−Instruments)を用いて実施した。17ミリリットルの溶液をカップ取付具に移し、隙間を5mmに設定した。試料を、2%の一定歪み、及び1秒毎5ラジアンの一定角振動数により、1分毎1℃の速度、10〜50℃の温度範囲にわたって加熱した。
(態様1)
粘膜に適用するための組成物であって、
i)等張化剤と、
ii)少なくとも55重量パーセントが水である液体希釈剤と、
iii)前記組成物の総重量に基づいて、0.1〜6重量パーセントのセルロースエーテルと、を含み、
前記セルロースエーテルが、2重量%水溶液として20℃、10s −1 の剪断速度で測定される、1.2〜8000mPa・sの粘度を有し、
前記セルロースエーテルが、1〜4個の結合により接合されたアンヒドログルコース単位を有し、かつアンヒドログルコース単位のヒドロキシル基が、s23/s26が0.29以下となるようにメチル基で置換されるような、置換基としてのメチル基、ヒドロキシアルキル基、及び任意選択で、メチルとは異なるアルキル基を有し、
s23は、前記アンヒドログルコース単位の2位及び3位の2つのヒドロキシル基のみがメチル基で置換されるアンヒドログルコース単位のモル分率であり、
s26は、前記アンヒドログルコース単位の2位及び6位の2つのヒドロキシル基のみがメチル基で置換されるアンヒドログルコース単位のモル分率である、前記組成物。
(態様2)
前記等張化剤は、アルカリもしくはアルカリ性土類金属ハロゲン化物、デキストロース、キシリトール、グルコース、マンニトール、またはソルビトールである、態様1に記載の前記組成物。
(態様3)
生理学的活性剤を追加的に含む、態様1または2に記載の前記組成物。
(態様4)
前記セルロースエーテルは、2重量%水溶液として20℃、10s −1 の剪断速度で測定される、1.8〜6000mPa・sの粘度を有する、態様1〜3のいずれか一項に記載の前記組成物。
(態様5)
前記セルロースエーテルは、2重量%水溶液として20℃、10s −1 の剪断速度で測定される、2.4〜1000mPa・sの粘度を有する、態様1〜4のいずれか一項に記載の前記組成物。
(態様6)
前記セルロースエーテルは、0.05〜0.35のMS(ヒドロキシアルキル)を有する、態様1〜5のいずれか一項に記載の前記組成物。
(態様7)
前記組成物の総重量に基づいて、0.1〜10重量パーセントの等張化剤を含む、態様1〜6のいずれか一項に記載の前記組成物。
(態様8)
5℃及び10s −1 の剪断速度で測定される、2.4〜8000mPa・sの粘度を有する、態様1〜7のいずれか一項に記載の前記組成物。
(態様9)
18〜37℃のゲル化温度を示す、態様1〜8のいずれか一項に記載の前記組成物。
(態様10)
鼻腔内投与のための、態様1〜9のいずれか一項に記載の前記組成物。
(態様11)
前記組成物の総重量に基づいて、0.1〜6パーセントの前記セルロースエーテル、0.1〜10パーセントの等張化剤、0〜20パーセントの生理学的活性剤、及び0〜30パーセントの1つ以上の任意の補助剤を含み、残部が前記液体希釈剤である、態様1〜10のいずれか一項に記載の前記組成物。
(態様12)
前記生理学的活性剤が、1つ以上の薬物、1つ以上の診断剤、1つ以上の精油、または美容もしくは栄養上の目的に有用である1つ以上の生理学的活性剤から選択される、態様1〜11のいずれか一項に記載の前記組成物。
(態様13)
前記精油が、メントールまたはサリチル酸メチルである、態様12に記載の前記組成物。
(態様14)
態様1〜13のいずれか一項に記載の前記組成物を含む容器であって、噴霧により、または滴薬として前記組成物を放出するように設計されている、前記容器。
(態様15)
生理学的活性剤を個体に経粘膜投与する方法であって、態様3〜13のいずれか一項に記載の前記組成物が前記個体の粘膜に適用される、前記方法。
Claims (9)
- 粘膜に適用するための組成物であって、
i)前記組成物の総重量に基づいて、0.1〜10重量パーセントの等張化剤と、
ii)少なくとも55重量パーセントが水である液体希釈剤と、
iii)前記組成物の総重量に基づいて、0.1〜6重量パーセントのセルロースエーテルと、を含み、
前記セルロースエーテルが、2重量%水溶液として20℃、10s−1の剪断速度で測定される、1.2〜8000mPa・sの粘度を有し、
前記セルロースエーテルが、1〜4個の結合により接合されたアンヒドログルコース単位を有し、かつアンヒドログルコース単位のヒドロキシル基が、s23/s26が0.29以下となるようにメチル基で置換されるような、置換基としてのメチル基、ヒドロキシアルキル基、及び任意選択で、メチルとは異なるアルキル基を有し、
s23は、前記アンヒドログルコース単位の2位及び3位の2つのヒドロキシル基のみがメチル基で置換されるアンヒドログルコース単位のモル分率であり、
s26は、前記アンヒドログルコース単位の2位及び6位の2つのヒドロキシル基のみがメチル基で置換されるアンヒドログルコース単位のモル分率であり、そして、
前記組成物が18〜37℃のゲル化温度を示す、前記組成物。 - 前記等張化剤は、アルカリもしくはアルカリ性土類金属ハロゲン化物、デキストロース、キシリトール、グルコース、マンニトール、またはソルビトールである、請求項1に記載の前記組成物。
- 生理学的活性剤を追加的に含む、請求項1または2に記載の前記組成物。
- 前記セルロースエーテルは、2重量%水溶液として20℃、10s−1の剪断速度で測定される、1.8〜6000mPa・sの粘度を有する、請求項1〜3のいずれか一項に記載の前記組成物。
- 前記セルロースエーテルは、0.05〜0.35のMS(ヒドロキシアルキル)を有する、請求項1〜4のいずれか一項に記載の前記組成物。
- 5℃及び10s−1の剪断速度で測定される、2.4〜8000mPa・sの粘度を有する、請求項1〜5のいずれか一項に記載の前記組成物。
- 鼻腔内投与のための、請求項1〜6のいずれか一項に記載の前記組成物。
- 前記組成物の総重量に基づいて、0.1〜6パーセントの前記セルロースエーテル、0.1〜10パーセントの等張化剤、0〜20パーセントの生理学的活性剤、及び0〜30パーセントの1つ以上の任意の補助剤を含み、残部が前記液体希釈剤である、請求項1〜7のいずれか一項に記載の前記組成物。
- 請求項1〜8のいずれか一項に記載の前記組成物を含む容器であって、噴霧により、または滴薬として前記組成物を放出するように設計されている、前記容器。
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