JP2024090835A - Epinastine-containing aqueous composition for improving migration into tissue - Google Patents
Epinastine-containing aqueous composition for improving migration into tissue Download PDFInfo
- Publication number
- JP2024090835A JP2024090835A JP2022206978A JP2022206978A JP2024090835A JP 2024090835 A JP2024090835 A JP 2024090835A JP 2022206978 A JP2022206978 A JP 2022206978A JP 2022206978 A JP2022206978 A JP 2022206978A JP 2024090835 A JP2024090835 A JP 2024090835A
- Authority
- JP
- Japan
- Prior art keywords
- aqueous composition
- salt
- epinastine
- acid
- present
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 122
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 title claims abstract description 77
- 229960003449 epinastine Drugs 0.000 title claims abstract description 66
- 230000005012 migration Effects 0.000 title abstract 2
- 238000013508 migration Methods 0.000 title abstract 2
- 150000003839 salts Chemical class 0.000 claims abstract description 113
- 230000003204 osmotic effect Effects 0.000 claims abstract description 58
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 55
- 239000004327 boric acid Substances 0.000 claims abstract description 55
- 239000004480 active ingredient Substances 0.000 claims abstract description 11
- 235000002639 sodium chloride Nutrition 0.000 claims description 122
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 22
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 14
- 150000004677 hydrates Chemical class 0.000 claims description 13
- 239000011780 sodium chloride Substances 0.000 claims description 11
- 229960002548 epinastine hydrochloride Drugs 0.000 claims description 10
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 8
- 229910021538 borax Inorganic materials 0.000 claims description 7
- 235000011187 glycerol Nutrition 0.000 claims description 7
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 claims description 3
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 description 31
- 210000001519 tissue Anatomy 0.000 description 29
- -1 alkylamine salts Chemical class 0.000 description 28
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 22
- 239000003889 eye drop Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 210000001508 eye Anatomy 0.000 description 17
- 239000003814 drug Substances 0.000 description 16
- 239000003755 preservative agent Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 229940012356 eye drops Drugs 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- 230000002335 preservative effect Effects 0.000 description 12
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 11
- 239000003381 stabilizer Substances 0.000 description 11
- 239000002562 thickening agent Substances 0.000 description 11
- 238000012546 transfer Methods 0.000 description 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000003963 antioxidant agent Substances 0.000 description 10
- 235000006708 antioxidants Nutrition 0.000 description 10
- 239000004094 surface-active agent Substances 0.000 description 10
- 239000000654 additive Substances 0.000 description 9
- 230000000996 additive effect Effects 0.000 description 9
- 239000004359 castor oil Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 208000026935 allergic disease Diseases 0.000 description 8
- 230000003078 antioxidant effect Effects 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 235000019438 castor oil Nutrition 0.000 description 7
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 239000004698 Polyethylene Substances 0.000 description 5
- 229920002675 Polyoxyl Polymers 0.000 description 5
- 210000000795 conjunctiva Anatomy 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000003002 pH adjusting agent Substances 0.000 description 5
- 229920000573 polyethylene Polymers 0.000 description 5
- 229920001451 polypropylene glycol Polymers 0.000 description 5
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 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 4
- 229960000686 benzalkonium chloride Drugs 0.000 description 4
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 4
- 239000006172 buffering agent Substances 0.000 description 4
- 239000003093 cationic surfactant Substances 0.000 description 4
- 235000015165 citric acid Nutrition 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 239000004328 sodium tetraborate Substances 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 239000011975 tartaric acid Substances 0.000 description 4
- 235000002906 tartaric acid Nutrition 0.000 description 4
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 3
- 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 3
- 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 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 229920001214 Polysorbate 60 Polymers 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 208000002205 allergic conjunctivitis Diseases 0.000 description 3
- 229960002684 aminocaproic acid Drugs 0.000 description 3
- 208000024998 atopic conjunctivitis Diseases 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000006196 drop Substances 0.000 description 3
- 229960001484 edetic acid Drugs 0.000 description 3
- 235000013922 glutamic acid Nutrition 0.000 description 3
- 239000004220 glutamic acid Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000003945 anionic surfactant Substances 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose 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
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003221 ear drop Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 229920001903 high density polyethylene Polymers 0.000 description 2
- 239000004700 high-density polyethylene Substances 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229920001684 low density polyethylene Polymers 0.000 description 2
- 239000004702 low-density polyethylene Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007721 medicinal effect Effects 0.000 description 2
- 229920001179 medium density polyethylene Polymers 0.000 description 2
- 239000004701 medium-density polyethylene Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229920001707 polybutylene terephthalate Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000139 polyethylene terephthalate Polymers 0.000 description 2
- 239000005020 polyethylene terephthalate Substances 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 229940037001 sodium edetate Drugs 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000001433 sodium tartrate Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 235000010384 tocopherol Nutrition 0.000 description 2
- 229930003799 tocopherol Natural products 0.000 description 2
- 229960001295 tocopherol Drugs 0.000 description 2
- 239000011732 tocopherol Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 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 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- AENOKLOQCCSDAZ-UHFFFAOYSA-N 6-aminohexanoic acid;hydrochloride Chemical compound Cl.NCCCCCC(O)=O AENOKLOQCCSDAZ-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- ONAIRGOTKJCYEY-XXDXYRHBSA-N CCCCCCCCCCCCCCCCCC(O)=O.O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 ONAIRGOTKJCYEY-XXDXYRHBSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- WJLVQTJZDCGNJN-UHFFFAOYSA-N Chlorhexidine hydrochloride Chemical compound Cl.Cl.C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 WJLVQTJZDCGNJN-UHFFFAOYSA-N 0.000 description 1
- 229920000089 Cyclic olefin copolymer Polymers 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
- 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 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- QZKRHPLGUJDVAR-UHFFFAOYSA-K EDTA trisodium salt Chemical compound [Na+].[Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O QZKRHPLGUJDVAR-UHFFFAOYSA-K 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- QWZLBLDNRUUYQI-UHFFFAOYSA-M Methylbenzethonium chloride Chemical compound [Cl-].CC1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 QWZLBLDNRUUYQI-UHFFFAOYSA-M 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- OTIWYSKRSMXGNK-VHJGTCNUSA-K Polidronium chloride Chemical compound [Cl-].[Cl-].[Cl-].OCC[N+](CCO)(CCO)C/C=C/C[N+](C)(C)C\C=C\C[N+](CCO)(CCO)CCO OTIWYSKRSMXGNK-VHJGTCNUSA-K 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- 229920002696 Polyoxyl 40 castor oil Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920002642 Polysorbate 65 Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 210000002159 anterior chamber Anatomy 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960002233 benzalkonium bromide Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 229960003872 benzethonium Drugs 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 238000009530 blood pressure measurement Methods 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 229960002798 cetrimide Drugs 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- NFCRBQADEGXVDL-UHFFFAOYSA-M cetylpyridinium chloride monohydrate Chemical compound O.[Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NFCRBQADEGXVDL-UHFFFAOYSA-M 0.000 description 1
- 229960003333 chlorhexidine gluconate Drugs 0.000 description 1
- YZIYKJHYYHPJIB-UUPCJSQJSA-N chlorhexidine gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(Cl)=CC=C1NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NC1=CC=C(Cl)C=C1 YZIYKJHYYHPJIB-UUPCJSQJSA-N 0.000 description 1
- 229960004504 chlorhexidine hydrochloride Drugs 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- SIYLLGKDQZGJHK-UHFFFAOYSA-N dimethyl-(phenylmethyl)-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethyl]ammonium Chemical compound C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 SIYLLGKDQZGJHK-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- 239000002526 disodium citrate Substances 0.000 description 1
- 235000019262 disodium citrate Nutrition 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 235000019524 disodium tartrate Nutrition 0.000 description 1
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 1
- CDMADVZSLOHIFP-UHFFFAOYSA-N disodium;3,7-dioxido-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane;decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].O1B([O-])OB2OB([O-])OB1O2 CDMADVZSLOHIFP-UHFFFAOYSA-N 0.000 description 1
- LVXHNCUCBXIIPE-UHFFFAOYSA-L disodium;hydrogen phosphate;hydrate Chemical compound O.[Na+].[Na+].OP([O-])([O-])=O LVXHNCUCBXIIPE-UHFFFAOYSA-L 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000008378 epithelial damage Effects 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229960003707 glutamic acid hydrochloride Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 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 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 229940102728 methylbenzethonium Drugs 0.000 description 1
- 229960002285 methylbenzethonium chloride Drugs 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- LPUQAYUQRXPFSQ-DFWYDOINSA-M monosodium L-glutamate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CCC(O)=O LPUQAYUQRXPFSQ-DFWYDOINSA-M 0.000 description 1
- HWPKGOGLCKPRLZ-UHFFFAOYSA-M monosodium citrate Chemical compound [Na+].OC(=O)CC(O)(C([O-])=O)CC(O)=O HWPKGOGLCKPRLZ-UHFFFAOYSA-M 0.000 description 1
- 239000002524 monosodium citrate Substances 0.000 description 1
- 235000018342 monosodium citrate Nutrition 0.000 description 1
- 239000004223 monosodium glutamate Substances 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 235000019321 monosodium tartrate Nutrition 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229960000420 polidronium chloride Drugs 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940099511 polysorbate 65 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 239000001509 sodium citrate 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
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 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
- NKAAEMMYHLFEFN-ZVGUSBNCSA-M sodium;(2r,3r)-2,3,4-trihydroxy-4-oxobutanoate Chemical compound [Na+].OC(=O)[C@H](O)[C@@H](O)C([O-])=O NKAAEMMYHLFEFN-ZVGUSBNCSA-M 0.000 description 1
- 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
- HLWRUJAIJJEZDL-UHFFFAOYSA-M sodium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC([O-])=O HLWRUJAIJJEZDL-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- 229960005066 trisodium edetate Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、組織移行性を向上させるエピナスチン含有水性組成物、具体的には、０．１％（ｗ／ｖ）濃度のエピナスチン又はその塩と、０．０１～２％（ｗ／ｖ）濃度のほう酸及び／又はその塩と、浸透圧調節剤とを含有する水性組成物であって、浸透圧が１４０～３２０ｍＯｓｍである、水性組成物（以下、「本発明の水性組成物」ともいう）に関する。 The present invention relates to an epinastine-containing aqueous composition that improves tissue transport, specifically, an aqueous composition that contains epinastine or a salt thereof at a concentration of 0.1% (w/v), boric acid and/or a salt thereof at a concentration of 0.01-2% (w/v), and an osmotic pressure regulator, and has an osmotic pressure of 140-320 mOsm (hereinafter also referred to as the "aqueous composition of the present invention").
現在、アレルギー性結膜炎治療剤として、エピナスチン塩酸塩を有効成分とするアレジオン（登録商標）点眼液０．０５％があり、通常１回１滴、１日４回点眼の用法・用量で使用されている（非特許文献１）。また１日当たりの投薬の回数を減らした、エピナスチン塩酸塩を有効成分とするアレジオン（登録商標）ＬＸ点眼液０．１％があり、通常１回１滴、１日２回点眼の用法・用量で使用されている（非特許文献２）。 Currently, as a therapeutic agent for allergic conjunctivitis, there is Alesion (registered trademark) eye drops 0.05%, which contains epinastine hydrochloride as an active ingredient, and is usually used at a dosage of one drop per time, four times a day (Non-Patent Document 1). In addition, there is Alesion (registered trademark) LX eye drops 0.1%, which contains epinastine hydrochloride as an active ingredient and has a reduced number of daily doses, and is usually used at a dosage of one drop per time, two times a day (Non-Patent Document 2).
服薬アドヒアランスの観点から、点眼回数はできるだけ少ない方が望ましいが、点眼回数を減らすと眼組織中の有効濃度を維持できずに薬効を低減させる可能性があり、薬効を発揮するためには眼組織中の有効濃度を維持する必要がある。眼組織中の有効濃度を維持する方法として、有効成分の配合濃度を増大する方法、吸収促進剤を用いる方法、増粘剤を配合することにより組織滞留性を向上させる方法、特定の添加剤を配合する方法等が知られている。 From the viewpoint of medication adherence, it is desirable to apply eye drops as few times as possible; however, reducing the number of times eye drops are applied may result in the effective concentration in the ocular tissue not being maintained, reducing the efficacy of the drug; therefore, in order for the drug to be effective, it is necessary to maintain the effective concentration in the ocular tissue. Known methods for maintaining the effective concentration in the ocular tissue include increasing the concentration of the active ingredient, using an absorption enhancer, improving tissue retention by adding a thickener, and adding a specific additive.
例えば、特許文献１には、エピナスチン又はその塩と、低級脂肪族カルボン酸類とを含有する水性医薬組成物を、眼に点眼投与した場合にエピナスチンの眼組織への移行性が向上することが記載され、特許文献２には、エピナスチン又はその塩と、第四級アンモニウム化合物とを含有する水性医薬組成物を、眼に点眼投与した場合にエピナスチンの眼組織への移行性が向上することが記載されている。
しかしながら、エピナスチン又はその塩を含有する水性組成物において、ほう酸及び／又はその塩を添加することにより、エピナスチン又はその塩の眼組織への移行が向上して、眼組織中の有効濃度が維持されるとの報告はない。
For example, Patent Document 1 describes that when an aqueous pharmaceutical composition containing epinastine or a salt thereof and a lower aliphatic carboxylic acid is administered by eye drop administration, the transfer of epinastine to ocular tissue is improved, and Patent Document 2 describes that when an aqueous pharmaceutical composition containing epinastine or a salt thereof and a quaternary ammonium compound is administered by eye drop administration, the transfer of epinastine to ocular tissue is improved.
However, there have been no reports that the addition of boric acid and/or a salt thereof to an aqueous composition containing epinastine or a salt thereof improves the transfer of epinastine or a salt thereof to ocular tissue and maintains the effective concentration in ocular tissue.
特許文献３には、ほう酸又はその塩を含有する、ソフトコンタクトレンズの変質を抑制する眼科用組成物であって、エピナスチン又はその塩を含有し、前記ソフトコンタクトレンズは最長１か月装用可能なソフトコンタクトレンズである、眼科用組成物について記載され、エピナスチン又はその塩の濃度が０．１％（ｗ／ｖ）であること、そして、ほう酸又はその塩の濃度が０．０１～２％（ｗ／ｖ）であることは記載されている。しかしながら、特許文献３には、０．１％（ｗ／ｖ）濃度のエピナスチン又はその塩と、０．０１～２％（ｗ／ｖ）濃度のほう酸及び／又はその塩と含有する水性組成物を眼に点眼投与した場合に、エピナスチンの眼組織への移行性が向上するとの記載も示唆もない。
また、０．１％（ｗ／ｖ）濃度のエピナスチン又はその塩を含有する水性組成物において、特定の浸透圧下でほう酸及び／又はその塩を添加することにより、エピナスチン又はその塩の眼組織への移行が向上して、眼組織中の有効濃度が維持されるとの報告はない。
Patent Document 3 describes an ophthalmic composition containing boric acid or a salt thereof for suppressing deterioration of a soft contact lens, the ophthalmic composition containing epinastine or a salt thereof, the soft contact lens being a soft contact lens that can be worn for up to one month, and describes that the concentration of epinastine or a salt thereof is 0.1% (w/v) and that the concentration of boric acid or a salt thereof is 0.01 to 2% (w/v). However, Patent Document 3 does not describe or suggest that the transfer of epinastine to ocular tissues is improved when an aqueous composition containing epinastine or a salt thereof at a concentration of 0.1% (w/v) and boric acid and/or a salt thereof at a concentration of 0.01 to 2% (w/v) is administered by instillation into the eye.
Furthermore, there have been no reports that adding boric acid and/or a salt thereof under a specific osmotic pressure to an aqueous composition containing epinastine or a salt thereof at a concentration of 0.1% (w/v) improves the transfer of epinastine or a salt thereof to ocular tissue and maintains the effective concentration in ocular tissue.
したがって、優れた薬効をもたらすために有効成分の組織、特に眼組織への移行性を向上させることは非常に有用であり、有効成分としてエピナスチン又はその塩を含有する、組織、特に眼組織への移行性を向上させた水性組成物を提供することは興味深い課題である。 Therefore, it is very useful to improve the transferability of active ingredients to tissues, particularly ocular tissue, in order to achieve superior medicinal efficacy, and it is an interesting task to provide an aqueous composition containing epinastine or a salt thereof as an active ingredient and having improved transferability to tissues, particularly ocular tissue.
本発明者らは、エピナスチン又はその塩を含有する水性組成物について鋭意研究を行ったところ、浸透圧調節剤を含有して浸透圧を１４０～３２０ｍＯｓｍに調整した、０．１％（ｗ／ｖ）濃度のエピナスチン又はその塩と、０．０１～２％（ｗ／ｖ）濃度のほう酸及び／又はその塩とを含有する浸透圧調節剤水性組成物を眼に点眼投与した場合にエピナスチンの眼組織への移行性が向上することを見出し、また浸透圧を１４０～２４０ｍＯｓｍに調整した場合にその移行性がより顕著に向上することを見出し、本発明の完成に至った。 The present inventors have conducted extensive research into aqueous compositions containing epinastine or a salt thereof, and have discovered that when an aqueous osmotic pressure regulator composition containing epinastine or a salt thereof at a concentration of 0.1% (w/v) and boric acid and/or a salt thereof at a concentration of 0.01 to 2% (w/v), and containing an osmotic pressure regulator to adjust the osmotic pressure to 140 to 320 mOsm, is administered by instillation into the eye, the transfer of epinastine into ocular tissue is improved, and that when the osmotic pressure is adjusted to 140 to 240 mOsm, the transfer is improved even more significantly, leading to the completion of the present invention.
具体的に、本発明は以下を提供する。
（１）０．１％（ｗ／ｖ）濃度のエピナスチン又はその塩と、０．０１～２％（ｗ／ｖ）濃度のほう酸及び／又はその塩と、浸透圧調節剤とを含有する水性組成物であって、浸透圧が１４０～３２０ｍＯｓｍである、水性組成物。
（２）ほう酸及び／又はその塩が、ほう酸、ほう酸ナトリウム、ほう酸カリウム及びこれらの水和物からなる群より選択される少なくとも１以上である、（１）に記載の水性組成物。
（３）浸透圧調節剤が、塩化ナトリウム、塩化カリウム及びグリセリンからなる群より選択される少なくとも１以上である、（１）又は（２）に記載の水性組成物。
（４）浸透圧が１４０～２４０ｍＯｓｍである、（１）～（３）のいずれか１つに記載の水性組成物。
（５）ほう酸及び／又はその塩の濃度が０．５～１．４％（ｗ／ｖ）である、（１）～（４）のいずれか１つに記載の水性組成物。
（６）有効成分としてエピナスチン又はその塩のみを含有する、（１）～（５）のいずれか１つに記載の水性組成物。
（７）エピナスチン又はその塩が、エピナスチン塩酸塩である、（１）～（６）のいずれか１つに記載の水性組成物。
（８）０．１％（ｗ／ｖ）濃度のエピナスチン又はその塩と、０．０１～２％（ｗ／ｖ）濃度のほう酸及び／又はその塩と、浸透圧調節剤とを含有する水性組成物であって、浸透圧比が０．５～１．１である、水性組成物。
（９）浸透圧比が０．５～０．８である、（８）に記載の水性組成物。
（１０）ほう酸及び／又はその塩が、ほう酸のみである、（８）又は（９）に記載の水性組成物。
（１１）０．１％（ｗ／ｖ）濃度のエピナスチン又はその塩と、０．０１～２％（ｗ／ｖ）濃度のほう酸及び／又はその塩と、浸透圧調節剤とを含有する水性組成物であって、低張である、水性組成物。
（１２）点眼剤である、（１）～（１１）のいずれか１つに記載の水性組成物。（１３）０．１％（ｗ／ｖ）濃度のエピナスチン又はその塩と、０．０１～２％（ｗ／ｖ）濃度のほう酸及び／又はその塩と含有する水性組成物において、浸透圧調節剤を含有して浸透圧を１４０～３２０ｍＯｓｍに調整することによって、エピナスチン又はその塩の眼組織への移行性を向上させる方法。
（１４）眼組織が、結膜である、（１３）に記載の方法。
Specifically, the present invention provides the following:
(1) An aqueous composition containing epinastine or a salt thereof at a concentration of 0.1% (w/v), boric acid and/or a salt thereof at a concentration of 0.01-2% (w/v), and an osmotic pressure regulator, the aqueous composition having an osmotic pressure of 140-320 mOsm.
(2) The aqueous composition according to (1), wherein the boric acid and/or a salt thereof is at least one selected from the group consisting of boric acid, sodium borate, potassium borate, and hydrates thereof.
(3) The aqueous composition according to (1) or (2), wherein the osmotic pressure regulator is at least one selected from the group consisting of sodium chloride, potassium chloride and glycerin.
(4) The aqueous composition according to any one of (1) to (3), having an osmotic pressure of 140 to 240 mOsm.
(5) The aqueous composition according to any one of (1) to (4), wherein the concentration of boric acid and/or a salt thereof is 0.5 to 1.4% (w/v).
(6) The aqueous composition according to any one of (1) to (5), which contains only epinastine or a salt thereof as an active ingredient.
(7) The aqueous composition according to any one of (1) to (6), wherein the epinastine or a salt thereof is epinastine hydrochloride.
(8) An aqueous composition comprising epinastine or a salt thereof at a concentration of 0.1% (w/v), boric acid and/or a salt thereof at a concentration of 0.01-2% (w/v), and an osmotic pressure regulator, the aqueous composition having an osmotic pressure ratio of 0.5-1.1.
(9) The aqueous composition according to (8), having an osmotic pressure ratio of 0.5 to 0.8.
(10) The aqueous composition according to (8) or (9), wherein the boric acid and/or a salt thereof is boric acid alone.
(11) An aqueous composition comprising epinastine or a salt thereof at a concentration of 0.1% (w/v), boric acid and/or a salt thereof at a concentration of 0.01 to 2% (w/v), and an osmotic pressure adjusting agent, said aqueous composition being hypotonic.
(12) The aqueous composition according to any one of (1) to (11), which is an eye drop. (13) A method for improving the transfer of epinastine or a salt thereof to ocular tissues in an aqueous composition containing epinastine or a salt thereof at a concentration of 0.1% (w/v) and boric acid and/or a salt thereof at a concentration of 0.01 to 2% (w/v), by adding an osmotic pressure regulator to adjust the osmotic pressure to 140 to 320 mOsm.
(14) The method according to (13), wherein the ocular tissue is the conjunctiva.
なお、前記（１）から（１４）の各構成は、任意に２以上を選択して組み合わせることができる。 Note that any two or more of the configurations (1) to (14) above may be combined.
さらに、本発明は以下も提供する。
（１５）治療が必要な患者に、治療上の有効量の（１）～（１２）のいずれか１つに記載の水性組成物を投与することを特徴とする、アレルギー性疾患の治療方法。
（１６）アレルギー性疾患の治療に使用する、（１）～（１２）のいずれか１つに記載の水性組成物。
（１７）アレルギー性疾患を治療するための医薬を製造するための、（１）～（１２）のいずれか１つに記載の水性組成物の使用。
In addition, the present invention also provides the following:
(15) A method for treating an allergic disease, comprising administering to a patient in need of treatment a therapeutically effective amount of the aqueous composition according to any one of (1) to (12).
(16) The aqueous composition according to any one of (1) to (12), which is used for treating an allergic disease.
(17) Use of the aqueous composition according to any one of (1) to (12) for producing a medicament for treating an allergic disease.
本発明は、０．１％（ｗ／ｖ）濃度のエピナスチン又はその塩と、０．０１～２％（ｗ／ｖ）濃度のほう酸及び／又はその塩と含有する水性組成物において、浸透圧調節剤を含有して浸透圧を低張から等張の範囲に、より好ましくは低張に調整することにより、エピナスチン又はその塩の眼組織への移行性を向上させて優れた薬効をもたらし得る、水性組成物を提供する。 The present invention provides an aqueous composition that contains epinastine or a salt thereof at a concentration of 0.1% (w/v) and boric acid and/or a salt thereof at a concentration of 0.01 to 2% (w/v), and that contains an osmotic pressure regulator to adjust the osmotic pressure to a range from hypotonic to isotonic, and more preferably to hypotonic, thereby improving the transfer of epinastine or a salt thereof to ocular tissues and providing excellent medicinal effects.
以下に、本発明について詳細に説明する。本発明において、「ほう酸及び／又はその塩」は、「ほう酸又はその塩」と表記してもよい。 The present invention will be described in detail below. In the present invention, "boric acid and/or a salt thereof" may also be written as "boric acid or a salt thereof."
本発明において、「エピナスチン」とは、化学名（±）－３－Ａｍｉｎｏ－９，１３ｂ－ｄｉｈｙｄｒｏ－１Ｈ－ｄｉｂｅｎｚ［ｃ，ｆ］ｉｍｉｄａｚｏ［１，５－ａ］ａｚｅｐｉｎｅで表される化合物であり、また下記式：
本発明の水性組成物において、含有されるエピナスチンはラセミ体であってもよく、光学異性体であってもよい。 In the aqueous composition of the present invention, the epinastine contained may be a racemate or an optical isomer.
本発明の水性組成物において、含有されるエピナスチンは塩であってもよく、医薬として許容される塩であれば特に制限はない。塩としては例えば、無機酸との塩、有機酸との塩等が挙げられる。
無機酸との塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。
有機酸との塩としては、酢酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、クエン酸、酒石酸、アジピン酸、グルコン酸、グルコヘプト酸、グルクロン酸、テレフタル酸、メタンスルホン酸、アラニン、乳酸、馬尿酸、１，２－エタンジスルホン酸、イセチオン酸、ラクトビオン酸、オレイン酸、没食子酸、パモ酸、ポリガラクツロン酸、ステアリン酸、タンニン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、硫酸ラウリル、硫酸メチル、ナフタレンスルホン酸、スルホサリチル酸等との塩が挙げられる。
エピナスチンの塩としては、一塩酸塩（エピナスチン塩酸塩）が特に好ましい。
In the aqueous composition of the present invention, epinastine may be in the form of a salt, and there is no particular limitation as long as it is a medicamentously acceptable salt. Examples of salts include salts with inorganic acids and salts with organic acids.
Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
Examples of salts with organic acids include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid.
As a salt of epinastine, the monohydrochloride salt (epinastine hydrochloride) is particularly preferred.
本発明の水性組成物において、含有されるエピナスチン又はその塩は、水和物又は溶媒和物の形態をとってもよい。 In the aqueous composition of the present invention, epinastine or a salt thereof may be in the form of a hydrate or solvate.
本発明の水性組成物において、エピナスチン又はその塩の含有量は、薬効、点眼回数、ソフトコンタクトレンズへの影響の有無、服薬アドヒアランス等の様々な要素を鑑みた上で、０．１％（ｗ／ｖ）が好ましい。エピナスチン又はその塩の含有量が０．１％（ｗ／ｖ）より低いと、十分な薬効を得るために点眼量や点眼回数を増やさなければならない。また、その含有量を０．１％（ｗ／ｖ）超とすると、理論的にはさらに点眼回数を減少せしめる可能性はあるが、ソフトコンタクトレンズを変形させる作用を生じることもあり、ソフトコンタクトレンズ装用時への使用に影響を及ぼす可能性がある。
なお、本発明において、「％（ｗ／ｖ）」は、本発明の水性組成物１００ｍＬ中に含まれる対象成分の質量（ｇ）を意味する。本発明においてエピナスチンの塩が含有される場合、その値はエピナスチンの塩の含有量である。また、本発明において、エピナスチン又はその塩が水和物又は溶媒和物の形態をとって含有される場合、その値は、エピナスチン又はその塩の水和物又は溶媒和物の含有量である。以下、特に断りがない限り同様とする。
In the aqueous composition of the present invention, the content of epinastine or a salt thereof is preferably 0.1% (w/v), taking into consideration various factors such as efficacy, frequency of instillation, influence on soft contact lenses, and medication adherence. If the content of epinastine or a salt thereof is lower than 0.1% (w/v), the amount of instillation or frequency of instillation must be increased to obtain sufficient efficacy. In addition, if the content is more than 0.1% (w/v), theoretically, the frequency of instillation can be further reduced, but it may cause deformation of soft contact lenses, which may affect the use when wearing soft contact lenses.
In the present invention, "% (w/v)" means the mass (g) of the target component contained in 100 mL of the aqueous composition of the present invention. When a salt of epinastine is contained in the present invention, the value is the content of the salt of epinastine. In addition, when epinastine or a salt thereof is contained in the form of a hydrate or solvate in the present invention, the value is the content of the hydrate or solvate of epinastine or a salt thereof. The same applies hereinafter unless otherwise specified.
本発明の水性組成物において、ほう酸及び／又はその塩は、エピナスチン又はその塩の眼組織への移行性を向上させるものであるが、医薬品の添加剤、例えば緩衝剤、防腐剤、安定化剤、浸透圧調節剤、溶解補助剤、ｐＨ調節剤等としての作用も有する。そのため、ほう酸及び／又はその塩は、医薬品の添加剤としても使用することができる。
また、本発明の水性組成物において、ほう酸及び／又はその塩は、１種又は２種以上一緒に用いてもよい。
In the aqueous composition of the present invention, boric acid and/or a salt thereof improves the transferability of epinastine or a salt thereof to ocular tissues, but also acts as a pharmaceutical additive, for example, a buffer, a preservative, a stabilizer, an osmotic pressure regulator, a solubilizing agent, a pH regulator, etc. Therefore, boric acid and/or a salt thereof can also be used as a pharmaceutical additive.
In the aqueous composition of the present invention, one or more kinds of boric acid and/or salts thereof may be used in combination.
ほう酸及び／又はその塩としては、例えば、ほう酸、ほう酸ナトリウム、ほう酸カリウム等が挙げられ、これらは水和物であってもよい。ほう酸及び／又はその塩の水和物としては、例えば、ほう砂（四ほう酸ナトリウム十水和物）が挙げられる。ほう酸及び／又はその塩は、好ましくはほう酸及び／又はほう砂であり、より好ましくはほう酸である。 Examples of boric acid and/or its salts include boric acid, sodium borate, potassium borate, etc., which may be hydrates. Examples of hydrates of boric acid and/or its salts include borax (sodium tetraborate decahydrate). Boric acid and/or its salts are preferably boric acid and/or borax, and more preferably boric acid.
本発明の水性組成物において、ほう酸及び／又はその塩の含有量は、ほう酸及び／又はその塩の種類などにより適宜調整することができる。ほう酸及び／又はその塩の含有量が多すぎると浸透圧が高まるために、その含有量の上限は、例えば２％（ｗ／ｖ）であり、好ましくは１．５％（ｗ／ｖ）以下である。また、その含有量は、０．０１～２％（ｗ／ｖ）が好ましく、０．０５～１．５％（ｗ／ｖ）がより好ましく、０．１～１．５％（ｗ／ｖ）がさらに好ましく、０．５～１．４％（ｗ／ｖ）が特に好ましい。また、その含有量は、０．０５～０．５％（ｗ／ｖ）、０．１～０．５％（ｗ／ｖ）、０．５～１．０％（ｗ／ｖ）、１．０～１．５％（ｗ／ｖ）又は１．１～１．４％（ｗ／ｖ）であってもよい。 In the aqueous composition of the present invention, the content of boric acid and/or its salts can be appropriately adjusted depending on the type of boric acid and/or its salts. If the content of boric acid and/or its salts is too high, the osmotic pressure increases, so the upper limit of the content is, for example, 2% (w/v), preferably 1.5% (w/v) or less. The content is preferably 0.01 to 2% (w/v), more preferably 0.05 to 1.5% (w/v), even more preferably 0.1 to 1.5% (w/v), and particularly preferably 0.5 to 1.4% (w/v). The content may be 0.05 to 0.5% (w/v), 0.1 to 0.5% (w/v), 0.5 to 1.0% (w/v), 1.0 to 1.5% (w/v), or 1.1 to 1.4% (w/v).
本発明の水性組成物に含有される浸透圧調節剤は、等張化剤と読み換えてもよく、医薬品の添加剤として使用可能なものであれば特に限定されない。その例として、イオン性浸透圧調節剤、非イオン性浸透圧調節剤等が挙げられる。 The osmotic pressure regulator contained in the aqueous composition of the present invention may be read as an isotonicity agent, and is not particularly limited as long as it can be used as an additive for pharmaceuticals. Examples of such an agent include ionic osmotic pressure regulators and nonionic osmotic pressure regulators.
イオン性浸透圧調節剤としては、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム等が挙げられる。非イオン性浸透圧調節剤としては、グリセリン、濃グリセリン、プロピレングリコール、ポリエチレングリコール、ソルビトール、マンニトール、トレハロース、マルトース、スクロース、キシリトール等が挙げられる。
浸透圧調節剤は、好ましくはイオン性浸透圧調節剤であり、より好ましくは塩化ナトリウムである。また、浸透圧調節剤は、非イオン性浸透圧調節剤も好ましく、より好ましくはグリセリン又は濃グリセリンである。
Examples of ionic osmotic pressure regulators include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc. Examples of nonionic osmotic pressure regulators include glycerin, concentrated glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol, etc.
The osmotic pressure regulator is preferably an ionic osmotic pressure regulator, more preferably sodium chloride, and is also preferably a non-ionic osmotic pressure regulator, more preferably glycerin or concentrated glycerin.
本発明の水性組成物に含有される浸透圧調節剤の含有量は、浸透圧調節剤の種類などにより適宜調整することができる。その含有量は、０．００１～５％（ｗ／ｖ）が好ましく、０．０１～３％（ｗ／ｖ）がより好ましく、０．１～１％（ｗ／ｖ）がさらに好ましく、０．１～０．５％（ｗ／ｖ）が特に好ましい。例えば、浸透圧調節剤が塩化ナトリウムである場合、その含有量、は０．０１～１％（ｗ／ｖ）が好ましく、０．０１～０．８％（ｗ／ｖ）がより好ましく、０．０５～０．６％（ｗ／ｖ）がさらに好ましく、０．１～０．５％（ｗ／ｖ）が特に好ましい。また例えば、浸透圧調節剤が濃グリセリンである場合、その含有量は、０．０１～３％（ｗ／ｖ）が好ましく、０．１～２．５％（ｗ／ｖ）がより好ましく、０．１～２％（ｗ／ｖ）がさらに好ましく、０．５～１．５％（ｗ／ｖ）が特に好ましい。
また、本発明の水性組成物に含有される浸透圧調節剤は、１種又は２種以上一緒に用いてもよい。
The content of the osmotic pressure regulator contained in the aqueous composition of the present invention can be appropriately adjusted depending on the type of osmotic pressure regulator. The content is preferably 0.001 to 5% (w/v), more preferably 0.01 to 3% (w/v), even more preferably 0.1 to 1% (w/v), and particularly preferably 0.1 to 0.5% (w/v). For example, when the osmotic pressure regulator is sodium chloride, the content is preferably 0.01 to 1% (w/v), more preferably 0.01 to 0.8% (w/v), even more preferably 0.05 to 0.6% (w/v), and particularly preferably 0.1 to 0.5% (w/v). For example, when the osmotic pressure regulator is concentrated glycerin, the content is preferably 0.01 to 3% (w/v), more preferably 0.1 to 2.5% (w/v), even more preferably 0.1 to 2% (w/v), and particularly preferably 0.5 to 1.5% (w/v).
The osmotic pressure regulator contained in the aqueous composition of the present invention may be used alone or in combination of two or more kinds.
本発明の水性組成物の浸透圧は、生理食塩液（０．９％（ｗ／ｖ）、２８６ｍＯｓｍ）と等張又は生理食塩液より低張であることが好ましく、生理食塩液より低張であることがより好ましい。また、本発明の水性組成物の浸透圧は、１４０～３２０ｍＯｓｍが好ましく、１４０～２８０ｍＯｓｍがより好ましく、１４０～２６０ｍＯｓｍがさらに好ましく、１４０～２４０ｍＯｓｍがさらにより好ましく、１４０～２２０ｍＯｓｍが特に好ましい。
なお、本発明において、「Ｏｓｍ」は、オスモル濃度を意味する。例えば、１Ｏｓｍは、溶液１Ｌ中にアボガドロ数（６．０×１０２３／ｍｏｌ）に等しい個数の粒子が存在する濃度を表す。
The osmotic pressure of the aqueous composition of the present invention is preferably isotonic with physiological saline (0.9% (w/v), 286 mOsm) or hypotonic with physiological saline, and more preferably hypotonic with physiological saline. The osmotic pressure of the aqueous composition of the present invention is preferably 140 to 320 mOsm, more preferably 140 to 280 mOsm, even more preferably 140 to 260 mOsm, even more preferably 140 to 240 mOsm, and particularly preferably 140 to 220 mOsm.
In the present invention, "Osm" means osmolarity. For example, 1 Osm represents a concentration at which the number of particles in 1 L of a solution is equal to Avogadro's number (6.0×10 23 /mol).
本発明の水性組成物の浸透圧は、例えば第１７改正日本薬局方に記載の浸透圧測定法に準じて測定することができる。また、本発明の水性組成物に含有される物質量から算出してもよい。 The osmotic pressure of the aqueous composition of the present invention can be measured, for example, according to the osmotic pressure measurement method described in the 17th Edition of the Japanese Pharmacopoeia. It may also be calculated from the amount of substance contained in the aqueous composition of the present invention.
本発明の水性組成物の浸透圧比は、医薬品として許容される範囲内にあればよいが、０．５～１．１が好ましく、０．５～０．９がより好ましく、０．５～０．８がさらに好ましい。なお、本発明において、浸透圧比とは、生理食塩液のオスモル濃度に対する本発明の水性組成物のオスモル濃度の比を表し、浸透圧比が０．９未満を低張、浸透圧比が０．９～１．１を等張、浸透圧比が１．１超以上を高張とする。本発明の水性組成物の浸透圧比は、低張から等張の範囲であることが好ましく、低張であることがより好ましい。 The osmolality ratio of the aqueous composition of the present invention may be within a range acceptable for pharmaceutical use, but is preferably 0.5 to 1.1, more preferably 0.5 to 0.9, and even more preferably 0.5 to 0.8. In the present invention, the osmolality ratio refers to the ratio of the osmolality of the aqueous composition of the present invention to the osmolality of physiological saline, with an osmolality ratio of less than 0.9 being hypotonic, an osmolality ratio of 0.9 to 1.1 being isotonic, and an osmolality ratio of more than 1.1 being hypertonic. The osmolality ratio of the aqueous composition of the present invention is preferably in the range from hypotonic to isotonic, and more preferably hypotonic.
本発明の水性組成物には、ほう酸及び／又はその塩、浸透圧調節剤の他に、必要に応じて医薬品の添加剤、例えば、緩衝剤、粘稠化剤、界面活性化剤、安定化剤、防腐剤、抗酸化剤、ｐＨ調節剤等を加えることができる。これらは、それぞれ単独で用いてもよく、また、２種以上を適宜組み合わせて用いてもよく、適量を含有することができる。 In addition to boric acid and/or its salts and osmotic pressure regulators, pharmaceutical additives such as buffers, thickening agents, surfactants, stabilizers, preservatives, antioxidants, pH regulators, etc. may be added to the aqueous composition of the present invention as necessary. These may be used alone or in appropriate combinations of two or more, and may be contained in appropriate amounts.
本発明の水性組成物に緩衝剤を含有する場合の緩衝剤は、医薬品の添加剤として使用可能な緩衝剤を適宜含有することができる。その例として、リン酸又はその塩、炭酸又はその塩、クエン酸又はその塩、酢酸又はその塩、酒石酸又はその塩、ε－アミノカプロン酸又はその塩、グルタミン酸又はその塩、有機アミン等が挙げられ、これらは水和物又は溶媒和物であってもよい。 When the aqueous composition of the present invention contains a buffering agent, the buffering agent may appropriately contain a buffering agent that can be used as an additive for pharmaceuticals. Examples of buffering agents include phosphoric acid or a salt thereof, carbonic acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, tartaric acid or a salt thereof, ε-aminocaproic acid or a salt thereof, glutamic acid or a salt thereof, and organic amines, which may be hydrates or solvates.
リン酸又はその塩としては、リン酸、リン酸ナトリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム（以下、リン酸水素ナトリウムともいう）、リン酸カリウム、リン酸二水素カリウム、リン酸水素二カリウム等が挙げられ、これらは水和物であってもよい。また本発明の水性組成物においては、リン酸又はその塩を含まないことも好ましい。 Examples of phosphoric acid or a salt thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate (hereinafter also referred to as sodium hydrogen phosphate), potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc., which may be hydrates. It is also preferable that the aqueous composition of the present invention does not contain phosphoric acid or a salt thereof.
炭酸又はその塩としては、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられ、これらは水和物であってもよい。 Carbonic acid or its salts include sodium carbonate, sodium bicarbonate, etc., which may be hydrates.
クエン酸又はその塩としては、クエン酸、クエン酸一ナトリウム、クエン酸二ナトリウム、クエン酸三ナトリウム等が挙げられ、これらは水和物であってもよい。 Examples of citric acid or its salts include citric acid, monosodium citrate, disodium citrate, trisodium citrate, etc., which may be hydrates.
酢酸又はその塩としては、酢酸、酢酸ナトリウム等が挙げられ、これらは水和物であってもよい。 Examples of acetic acid or its salts include acetic acid, sodium acetate, etc., which may be hydrates.
酒石酸又はその塩としては、酒石酸、酒石酸一ナトリウム、酒石酸二ナトリウム等が挙げられ、これらは水和物であってもよい。 Examples of tartaric acid or its salts include tartaric acid, monosodium tartrate, disodium tartrate, etc., which may be hydrates.
ε－アミノカプロン酸又はその塩としては、ε－アミノカプロン酸、ε－アミノカプロン酸ナトリウム、ε－アミノカプロン酸塩酸塩等が挙げられ、これらは水和物であってもよい。 Examples of ε-aminocaproic acid or salts thereof include ε-aminocaproic acid, sodium ε-aminocaproate, ε-aminocaproic acid hydrochloride, etc., which may be hydrates.
グルタミン酸又はその塩としては、グルタミン酸、グルタミン酸一ナトリウム、グルタミン酸二ナトリウム、グルタミン酸塩酸塩等が挙げられ、これらは水和物であってもよい。 Examples of glutamic acid or its salts include glutamic acid, monosodium glutamate, disodium glutamate, glutamic acid hydrochloride, etc., which may be hydrates.
有機アミンとしては、トロメタモール等が挙げられ、これらは水和物であってもよい。 Organic amines include trometamol, etc., which may be in the form of a hydrate.
本発明の水性組成物に緩衝剤を含有する場合の緩衝剤の含有量は、緩衝剤の種類などにより適宜調整することができる。その含有量は、０．００１～１０％（ｗ／ｖ）が好ましく、０．０１～５％（ｗ／ｖ）がより好ましく、０．１～５％（ｗ／ｖ）がさらに好ましく、０．１～２％（ｗ／ｖ）が特に好ましい。
また、本発明の水性組成物に緩衝剤を含有する場合には、緩衝剤を１種又は２種以上一緒に用いてもよい。
When the aqueous composition of the present invention contains a buffer, the content of the buffer can be appropriately adjusted depending on the type of the buffer, etc. The content is preferably 0.001 to 10% (w/v), more preferably 0.01 to 5% (w/v), further preferably 0.1 to 5% (w/v), and particularly preferably 0.1 to 2% (w/v).
When the aqueous composition of the present invention contains a buffer, one or more kinds of buffers may be used in combination.
本発明の水性組成物に粘稠化剤を含有する場合の粘稠化剤は、医薬品の添加剤として使用可能な粘稠化剤を適宜含有することができる。その例として、メチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース、ポリビニルピロリドン、ポリビニルアルコール、カルボキシビニルポリマー、ポリエチレングリコール、ヒアルロン酸ナトリウム等が挙げられる。 When the aqueous composition of the present invention contains a thickening agent, the thickening agent may appropriately contain a thickening agent that can be used as an additive for pharmaceuticals. Examples of the thickening agent include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate, etc.
本発明の水性組成物に粘稠化剤を含有する場合の粘稠化剤の含有量は、粘稠化剤の種類などにより適宜調整することができる。その含有量は、０．００１～５％（ｗ／ｖ）が好ましく、０．０１～３％（ｗ／ｖ）がより好ましく、０．１～２％（ｗ／ｖ）がさらに好ましい。
また、本発明の水性組成物に粘稠化剤を含有する場合には、粘稠化剤を１種又は２種以上一緒に用いてもよい。
When the aqueous composition of the present invention contains a thickener, the content of the thickener can be appropriately adjusted depending on the type of thickener, etc. The content is preferably 0.001 to 5% (w/v), more preferably 0.01 to 3% (w/v), and even more preferably 0.1 to 2% (w/v).
When the aqueous composition of the present invention contains a thickener, one or more types of thickeners may be used in combination.
本発明の水性組成物に界面活性化剤を含有する場合の界面活性化剤は、医薬品の添加剤として使用可能な界面活性化剤を適宜含有することができる。その例として、カチオン性界面活性化剤、アニオン性界面活性化剤、非イオン性界面活性化剤等が挙げられる。 When the aqueous composition of the present invention contains a surfactant, the surfactant may appropriately contain a surfactant that can be used as an additive for pharmaceuticals. Examples of such surfactants include cationic surfactants, anionic surfactants, and nonionic surfactants.
カチオン性界面活性化剤としては、アルキルアミン塩、アルキルアミンポリオキシエチレン付加物、脂肪酸トリエタノールアミンモノエステル塩、アシルアミノエチルジエチルアミン塩、脂肪酸ポリアミン縮合物、アルキルイミダゾリン、１－アシルアミノエチル－２－アルキルイミダゾリン、１－ヒドロキシルエチル－２－アルキルイミダゾリン等が挙げられる。なお、塩化ベンザルコニウム等の第四級アンモニウムカチオンは、カチオン性界面活性化剤の性質を有しているが、これらは本発明におけるカチオン性界面活性化剤には含まれない。 Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, 1-hydroxyethyl-2-alkylimidazolines, etc. Quaternary ammonium cations such as benzalkonium chloride have the properties of cationic surfactants, but these are not included in the cationic surfactants of the present invention.
アニオン性界面活性化剤としては、レシチン等のリン脂質等が挙げられる。 Anionic surfactants include phospholipids such as lecithin.
非イオン性界面活性化剤としては、ステアリン酸ポリオキシル４０等のポリオキシエチレン脂肪酸エステル；ポリソルベート８０、ポリソルベート６０、ポリソルベート４０、ポリオキシエチレンソルビタンモノラウレート、ポリオキシエチレンソルビタントリオレート、ポリソルベート６５等のポリオキシエチレンソルビタン脂肪酸エステル；ポリオキシエチレン硬化ヒマシ油１０、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０等のポリオキシエチレン硬化ヒマシ油；ポリオキシル５ヒマシ油、ポリオキシル９ヒマシ油、ポリオキシル１５ヒマシ油、ポリオキシル３５ヒマシ油、ポリオキシル４０ヒマシ油等のポリオキシルヒマシ油；ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール、ポリオキシエチレン（４２）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（５４）ポリオキシプロピレン（３９）グリコール、ポリオキシエチレン（１９６）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（２０）ポリオキシプロピレン（２０）グリコール等のポリオキシエチレンポリオキシプロピレングリコール；ショ糖ステアリン酸エステル等のショ糖脂肪酸エステル；トコフェロールポリエチレングリコール１０００コハク酸エステル（ビタミンＥ ＴＰＧＳ）等が挙げられる。 Nonionic surfactants include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and polysorbate 65; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60; polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, and polyoxyl Examples of suitable polyoxyl castor oils include polyoxyl 35 castor oil and polyoxyl 40 castor oil; polyoxyethylene polyoxypropylene glycols such as polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, and polyoxyethylene (20) polyoxypropylene (20) glycol; sucrose fatty acid esters such as sucrose stearate; and tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS).
本発明の水性組成物に界面活性化剤を含有する場合の界面活性化剤の含有量は、界面活性化剤の種類などにより適宜調整することができる。その含有量は、０．０１～１％（ｗ／ｖ）が好ましく、０．０５～０．５％（ｗ／ｖ）がより好ましく、０．０５～０．２％（ｗ／ｖ）がさらに好ましい。
また、本発明の水性組成物に界面活性化剤を含有する場合には、界面活性化剤を１種又は２種以上一緒に用いてもよい。
When the aqueous composition of the present invention contains a surfactant, the content of the surfactant can be appropriately adjusted depending on the type of surfactant, etc. The content is preferably 0.01 to 1% (w/v), more preferably 0.05 to 0.5% (w/v), and even more preferably 0.05 to 0.2% (w/v).
When the aqueous composition of the present invention contains a surfactant, one or more surfactants may be used in combination.
本発明の水性組成物に安定化剤を含有する場合の安定化剤は、医薬品の添加剤として使用可能な安定化剤を適宜含有することができる。その例として、エデト酸又はその塩、シクロデキストリン、チオ硫酸ナトリウム等が挙げられる。 When the aqueous composition of the present invention contains a stabilizer, the stabilizer may appropriately contain a stabilizer that can be used as an additive for pharmaceuticals. Examples of such stabilizers include edetic acid or a salt thereof, cyclodextrin, sodium thiosulfate, etc.
エデト酸又はその塩としては、エデト酸、エデト酸一ナトリウム、エデト酸二ナトリウム（以下、エデト酸ナトリウムともいう）、エデト酸三ナトリウム、エデト酸四ナトリウム等が挙げられ、これらは水和物であってもよい。 Examples of edetic acid or salts thereof include edetic acid, monosodium edetate, disodium edetate (hereinafter also referred to as sodium edetate), trisodium edetate, tetrasodium edetate, etc., which may be hydrates.
本発明の水性組成物に安定化剤を含有する場合の安定化剤の含有量は、安定化剤の種類などにより適宜調整することができる。その含有量は、０．００１～５％（ｗ／ｖ）が好ましく、０．０１～３％（ｗ／ｖ）がより好ましく、０．０１～１％（ｗ／ｖ）がさらに好ましい。
また、本発明の水性組成物に安定化剤を含有する場合には、安定化剤を１種又は２種以上一緒に用いてもよい。
When the aqueous composition of the present invention contains a stabilizer, the content of the stabilizer can be appropriately adjusted depending on the type of stabilizer, etc. The content is preferably 0.001 to 5% (w/v), more preferably 0.01 to 3% (w/v), and even more preferably 0.01 to 1% (w/v).
When the aqueous composition of the present invention contains a stabilizer, one or more stabilizers may be used in combination.
本発明の水性組成物に防腐剤を含有する場合の防腐剤は、医薬品の添加剤として使用可能な防腐剤を適宜含有することができる。その例として、塩化ベンザルコニウム、塩化ベンゼトニウム、塩化メチルベンゼトニウム、塩化ポリドロニウム、塩化セチルピリジニウム、臭化ベンザルコニウム、臭化ベンゼトニウム、臭化メチルベンゼトニウム、セトリミド、グルコン酸クロルヘキシジン、塩酸クロルヘキシジン、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル、亜塩素酸ナトリウム、クロロブタノール等が挙げられる。また、塩化ベンザルコニウムは細胞障害性があり、曝露量が増えると角膜上皮障害を引き起こす可能性が増大することから、塩化ベンザルコニウムを含有しないことも好ましい。 When the aqueous composition of the present invention contains a preservative, the preservative may be an appropriate preservative that can be used as an additive in pharmaceuticals. Examples of preservatives include benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, polidronium chloride, cetylpyridinium chloride, benzalkonium bromide, benzethonium bromide, methylbenzethonium bromide, cetrimide, chlorhexidine gluconate, chlorhexidine hydrochloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium chlorite, and chlorobutanol. In addition, benzalkonium chloride is cytotoxic, and as the amount of exposure increases, the possibility of causing corneal epithelial damage increases, so it is also preferable not to contain benzalkonium chloride.
本発明の水性組成物に防腐剤を含有する場合の防腐剤の含有量は、防腐剤の種類などにより適宜調整することができる。その含有量は、０．０００１～０．１％（ｗ／ｖ）が好ましく、０．００１～０．０５％（ｗ／ｖ）がより好ましい。また、本発明の水性組成物は、実質的に防腐剤を含有することなく、防腐効果を発揮し得るため、本発明の水性組成物においては、防腐剤を含有しなくてもよい。
また、本発明の水性組成物に防腐剤を含有する場合には、防腐剤を１種又は２種以上一緒に用いてもよい。
When the aqueous composition of the present invention contains a preservative, the content of the preservative can be appropriately adjusted depending on the type of preservative, etc. The content is preferably 0.0001 to 0.1% (w/v), more preferably 0.001 to 0.05% (w/v). In addition, since the aqueous composition of the present invention can exert a preservative effect without substantially containing a preservative, the aqueous composition of the present invention may not contain a preservative.
When the aqueous composition of the present invention contains a preservative, one or more preservatives may be used in combination.
本発明の水性組成物に抗酸化剤を含有する場合の抗酸化剤は、医薬品の添加剤として使用可能な抗酸化剤を適宜含有することができる。その例として、アスコルビン酸、トコフェロール、ジブチルヒドロキシトルエン、亜硫酸ナトリウム等が挙げられる。 When the aqueous composition of the present invention contains an antioxidant, the antioxidant may appropriately contain an antioxidant that can be used as an additive in pharmaceuticals. Examples of such antioxidants include ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite, etc.
本発明の水性組成物に抗酸化剤を含有する場合の抗酸化剤の含有量は、抗酸化剤の種類などにより適宜調整することができる。その含有量は、０．００１～５％（ｗ／ｖ）が好ましく、０．０１～３％（ｗ／ｖ）がより好ましく、０．１～２％（ｗ／ｖ）がさらに好ましい。
また、本発明の水性組成物に抗酸化剤を含有する場合には、抗酸化剤を１種又は２種以上一緒に用いてもよい。
When the aqueous composition of the present invention contains an antioxidant, the content of the antioxidant can be appropriately adjusted depending on the type of antioxidant, etc. The content is preferably 0.001 to 5% (w/v), more preferably 0.01 to 3% (w/v), and even more preferably 0.1 to 2% (w/v).
When the aqueous composition of the present invention contains an antioxidant, one or more kinds of antioxidants may be used in combination.
本発明の水性組成物にｐＨ調節剤を含有する場合のｐＨ調節剤は、医薬品の添加剤として使用可能なｐＨ調節剤を適宜含有することができる。ｐＨ調節剤は、例えば、酸又は塩基である。酸としては例えば、塩酸、リン酸等が挙げられ、塩基としては例えば、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられる。 When the aqueous composition of the present invention contains a pH adjuster, the pH adjuster may appropriately contain a pH adjuster that can be used as an additive for pharmaceuticals. The pH adjuster is, for example, an acid or a base. Examples of acids include hydrochloric acid and phosphoric acid, and examples of bases include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.
本発明の水性組成物において、ｐＨは、医薬品として許容される範囲内にあればよく、例えば４．０～８．５又は４．０～８．０の範囲内であり、６．０～８．０が好ましく、６．５～７．５がより好ましい。特に好ましいｐＨは、６．７～７．３であるが、６．７、６．８、６．９、７．０、７．１、７．２又は７．３であってもよい。 In the aqueous composition of the present invention, the pH may be within a medicamentously acceptable range, for example, within the range of 4.0 to 8.5 or 4.0 to 8.0, preferably 6.0 to 8.0, and more preferably 6.5 to 7.5. A particularly preferred pH is 6.7 to 7.3, but may also be 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, or 7.3.
本発明において、「眼組織」とは、例えば、結膜、角膜、涙液、房水、前房等が挙げられる。本発明の水性組成物を眼に投与する場合、眼組織へのエピナスチン又はその塩の移行量を増大（又は向上ともいう）させることができ、特に結膜へのエピナスチン又はその塩の移行量を増大させることが好ましい。 In the present invention, "ocular tissue" includes, for example, the conjunctiva, cornea, tears, aqueous humor, anterior chamber, etc. When the aqueous composition of the present invention is administered to the eye, it is possible to increase (or improve) the amount of epinastine or a salt thereof transferred to the ocular tissue, and it is particularly preferable to increase the amount of epinastine or a salt thereof transferred to the conjunctiva.
本発明において、「水性組成物」とは、水を含有する組成物を指す。本発明の水性組成物に含まれる水の含有量は特に制限はされないが、水性組成物の総重量に対して、１０％（ｗ／ｖ）以上が好ましく、３０％（ｗ／ｖ）以上がより好ましく、５０％（ｗ／ｖ）以上がさらに好ましい。さらには、水の含有量は、水性組成物の総重量に対して、７０％（ｗ／ｖ）以上が好ましく、９０％（ｗ／ｖ）以上がより好ましく、９５％（ｗ／ｖ）以上がさらに好ましい。 In the present invention, "aqueous composition" refers to a composition containing water. The content of water contained in the aqueous composition of the present invention is not particularly limited, but is preferably 10% (w/v) or more, more preferably 30% (w/v) or more, and even more preferably 50% (w/v) or more, based on the total weight of the aqueous composition. Furthermore, the content of water is preferably 70% (w/v) or more, more preferably 90% (w/v) or more, and even more preferably 95% (w/v) or more, based on the total weight of the aqueous composition.
本発明において、「アレルギー性疾患」とは、外部からの抗原に対する免疫反応によって引き起こされる疾患又はその症状を指す。外部からの抗原とは、例えば花粉である。アレルギー性疾患の例として、アレルギー性結膜炎が挙げられるが、これに限定されるものではない。本発明において、アレルギー性疾患の治療とは、アレルギー性疾患又はその症状のあらゆる治療（例えば、治癒、改善、軽減、進行の抑制等）及びその予防を指す。また、アレルギー性疾患の再発の阻止も含まれる。 In the present invention, "allergic disease" refers to a disease or its symptoms caused by an immune response to an external antigen. An example of an external antigen is pollen. An example of an allergic disease is allergic conjunctivitis, but is not limited to this. In the present invention, treatment of an allergic disease refers to any treatment (e.g., cure, improvement, relief, inhibition of progression, etc.) and prevention of an allergic disease or its symptoms. It also includes prevention of recurrence of an allergic disease.
本発明において、「患者」とは、ヒトのみに限らずその他の動物、例えば、イヌ、ネコ、ウマなども意味する。患者は、好ましくは哺乳動物であり、より好ましくはヒトである。本発明において、「治療上の有効量」とは、未治療対象と比べて、疾患及びその症状の治療効果をもたらす量、又は疾患及びその症状の進行の遅延をもたらす量などを指す。 In the present invention, the term "patient" refers not only to humans but also to other animals, such as dogs, cats, and horses. The patient is preferably a mammal, and more preferably a human. In the present invention, the term "therapeutically effective amount" refers to an amount that provides a therapeutic effect for a disease and its symptoms, or an amount that delays the progression of a disease and its symptoms, compared to an untreated subject.
本発明の水性組成物は、医薬として用いられることが特に好ましく、非経口（例えば、局所）投与に適している。本発明の水性組成物の非経口投与経路としては、医薬品として許容される局所投与経路、例えば、眼への局所投与（例えば、点眼投与）、点鼻（経鼻）投与、耳への局所投与（例えば、点耳投与）、吸入投与、噴霧投与、経皮投与、皮膚上投与、注射投与などが挙げられる。好ましくは、眼への局所投与である。 The aqueous composition of the present invention is particularly preferably used as a medicine and is suitable for parenteral (e.g., topical) administration. Parenteral administration routes for the aqueous composition of the present invention include medicamentously acceptable local administration routes, such as local administration to the eye (e.g., eye drop administration), nasal (transnasal) administration, local administration to the ear (e.g., ear drop administration), inhalation administration, spray administration, transdermal administration, epicutaneous administration, and injection administration. Topical administration to the eye is preferred.
本発明の水性組成物は、眼科用製剤、耳鼻科用製剤、吸入用製剤、経皮吸収用製剤として用いることができ、その剤形は、医薬品として使用可能なものであれば特に制限されるものではない。剤形としては、例えば、点眼剤、点鼻剤、点耳剤、吸入剤（吸入粉末剤、吸入液剤、吸入エアゾール剤）、軟膏剤、クリーム剤、ゲル剤、経皮吸収型製剤、貼付剤（テープ剤、パップ剤）、外用液剤（ローション剤、リニメント剤）、外用固形剤（外用散剤）、スプレー剤（ポンプスプレー剤、外用エアゾール剤）、注射剤（輸液剤、埋め込み注射剤、持続性注射剤）等の局所投与剤が挙げられる。好ましくは点眼剤、眼科用経皮吸収型製剤又は眼科用注射剤であり、より好ましくは点眼剤である。これらは当該技術分野における通常の方法に従って製造することができる。 The aqueous composition of the present invention can be used as an ophthalmic preparation, an otolaryngological preparation, an inhalation preparation, or a transdermal preparation, and the dosage form is not particularly limited as long as it can be used as a pharmaceutical. Examples of dosage forms include eye drops, nasal drops, ear drops, inhalants (inhalation powders, inhalation liquids, inhalation aerosols), ointments, creams, gels, transdermal preparations, patches (tapes, poultices), external liquids (lotions, liniments), external solids (external powders), sprays (pump sprays, external aerosols), and injections (infusions, implant injections, sustained release injections). Eye drops, ophthalmic transdermal preparations, or ophthalmic injections are preferred, and eye drops are more preferred. These can be manufactured according to conventional methods in the art.
本発明の水性組成物は、構成成分が全て溶解又は一部懸濁していてもよく、またエマルション、半固体状の形態であってもよい。本発明の水性組成物は、構成成分が全て溶解している溶液状態であることがより好ましく、水溶液であることが最も好ましい。例えば、眼科用であれば点眼剤（点眼液）が特に好ましい。 The aqueous composition of the present invention may be in the form of an emulsion or semi-solid, in which all of the components are dissolved or partially suspended. The aqueous composition of the present invention is more preferably in the form of a solution in which all of the components are dissolved, and most preferably in the form of an aqueous solution. For example, for ophthalmic use, eye drops (eye drops) are particularly preferred.
本発明の水性組成物がエマルションである場合は、水中油型エマルション（水相を連続相として、水相と分散した油性液滴から構成されるエマルション）であっても油中水型エマルション（油相を連続相として、油と分散した水性液滴から構成されるエマルション）であってもよい。 When the aqueous composition of the present invention is an emulsion, it may be an oil-in-water emulsion (an emulsion in which the aqueous phase is the continuous phase and oily droplets are dispersed in the aqueous phase) or a water-in-oil emulsion (an emulsion in which the oil phase is the continuous phase and aqueous droplets are dispersed in the oil).
本発明の水性組成物を眼科用製剤として使用する場合は、特にアレルギー性結膜炎の治療剤として有用である。また、本発明の水性組成物は、特に断りのない限り、エピナスチン又はその塩以外の医薬品活性成分、例えば他の点眼剤に用いられる有効成分を含んでいてもよいし、エピナスチン又はその塩のみを唯一の有効成分として含んでいてもよい。 When the aqueous composition of the present invention is used as an ophthalmic preparation, it is particularly useful as a therapeutic agent for allergic conjunctivitis. Furthermore, unless otherwise specified, the aqueous composition of the present invention may contain a pharmaceutical active ingredient other than epinastine or a salt thereof, for example, an active ingredient used in other eye drops, or may contain only epinastine or a salt thereof as the only active ingredient.
本発明の水性組成物を点眼剤として眼に投与する場合、所望の薬効を奏するのに十分であれば用法用量に特に制限はない。本発明の水性組成物は、１回１又は２滴、１日１～１０回、好ましくは１日１～６回、より好ましくは１日１～４回、さらに好ましくは１日１回又は１日２回、特に好ましくは１日２回に分けて点眼することができる。 When the aqueous composition of the present invention is administered to the eye as an eye drop, there is no particular limitation on the dosage and administration as long as it is sufficient to achieve the desired medicinal effect. The aqueous composition of the present invention can be administered in divided doses, 1 or 2 drops at a time, 1 to 10 times a day, preferably 1 to 6 times a day, more preferably 1 to 4 times a day, even more preferably once or twice a day, and particularly preferably twice a day.
本発明の水性組成物を点眼剤として使用する場合、本発明の水性組成物は、マルチドーズ型容器、１回使い切りのユニットドーズ型容器又はＰＦＭＤ（Ｐｒｅｓｅｒｖａｔｉｖｅ Ｆｒｅｅ Ｍｕｌｔｉ Ｄｏｓｅ）容器のいずれに収容されていてもよい。なお、容器の素材に特に制限はなく、一般に汎用される点眼剤の容器であればよいが、好ましくは樹脂製容器である。樹脂製容器として、例えば、ポリエチレン（ＰＥ）製、ポリプロピレン（ＰＰ）製、ポリエチレンテレフタレート（ＰＥＴ）製、ポリブチレンテレフタレート（ＰＢＴ）製、ポリプロピレン－ポリエチレンコポリマー製、ポリ塩化ビニル製、アクリル製、ポリスチレン製、ポリ環状オレフィンコポリマー製等の容器を用いることができる。例えば、樹脂製容器の材質がポリエチレンである場合、ポリエチレンはその密度によって分類されることから、樹脂製容器として、低密度ポリエチレン（ＬＤＰＥ）製、中密度ポリエチレン（ＭＤＰＥ）製、高密度ポリエチレン（ＨＤＰＥ）製等の容器を用いることができる。 When the aqueous composition of the present invention is used as an eye drop, the aqueous composition of the present invention may be contained in any of a multi-dose container, a single-use unit dose container, or a PFMD (Preservative Free Multi Dose) container. The material of the container is not particularly limited, and any generally used eye drop container may be used, but a resin container is preferable. Examples of resin containers that can be used include containers made of polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, and polycyclic olefin copolymer. For example, when the material of the resin container is polyethylene, since polyethylene is classified according to its density, containers made of low-density polyethylene (LDPE), medium-density polyethylene (MDPE), high-density polyethylene (HDPE), and the like can be used as the resin container.
本発明は、エピナスチン又はその塩の眼組織への移行性を向上させる方法を提供するものである。上記の本発明の水性組成物の詳細な説明は、本発明のエピナスチン又はその塩の眼組織への移行性を向上させる方法にも適用される。
本発明において、エピナスチン又はその塩の眼組織への移行性を向上させる方法は、０．１％（ｗ／ｖ）濃度のエピナスチン又はその塩と、０．０１～２％（ｗ／ｖ）濃度のほう酸及び／又はその塩と浸透圧調節剤を含有する水性組成物において、浸透圧調節剤を含有して浸透圧を１４０～３２０ｍＯｓｍに調整することによって、エピナスチン又はその塩の眼組織への移行性を向上させる方法であることが好ましい。
The present invention provides a method for improving the transferability of epinastine or a salt thereof to ocular tissues. The above detailed description of the aqueous composition of the present invention also applies to the method for improving the transferability of epinastine or a salt thereof to ocular tissues of the present invention.
In the present invention, the method for improving the transferability of epinastine or a salt thereof into ocular tissue is preferably a method for improving the transferability of epinastine or a salt thereof into ocular tissue in an aqueous composition containing epinastine or a salt thereof at a concentration of 0.1% (w/v), boric acid and/or a salt thereof at a concentration of 0.01 to 2% (w/v), and an osmotic pressure regulator, by adding an osmotic pressure regulator to adjust the osmotic pressure to 140 to 320 mOsm.
以下に、製剤例及び試験例を示すが、これらは本発明をより良く理解するためのものであり、本発明の範囲を限定するものではない。 The following formulation examples and test examples are provided to aid in understanding the present invention and are not intended to limit the scope of the present invention.
製剤例
以下に本発明の代表的な製剤例を示す。なお、下記製剤例において各成分の含有量は製剤１ｍＬ中の含量である。
Formulation Examples Representative formulation examples of the present invention are shown below. Note that the content of each ingredient in the following formulation examples is the content per 1 mL of the formulation.
製剤例１
エピナスチン塩酸塩 １ｍｇ
ほう酸 １５ｍｇ
塩化ナトリウム １ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ７．０
Formulation Example 1
Epinastine hydrochloride 1mg
Boric acid 15mg
Sodium chloride 1mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0
製剤例２
エピナスチン塩酸塩 １ｍｇ
ほう酸 １４ｍｇ
ほう砂 １．４ｍｇ
塩化ナトリウム １．４ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ７．０
Formulation Example 2
Epinastine hydrochloride 1mg
Boric acid 14mg
Borax 1.4mg
Sodium chloride 1.4mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0
製剤例３
エピナスチン塩酸塩 １ｍｇ
ほう酸 １３ｍｇ
塩化ナトリウム １ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ７．０
Formulation Example 3
Epinastine hydrochloride 1mg
Boric acid 13mg
Sodium chloride 1mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0
製剤例４
エピナスチン塩酸塩 １ｍｇ
ほう酸 １２ｍｇ
ほう砂 １．２ｍｇ
エデト酸ナトリウム水和物 ０．５ｍｇ
塩化ナトリウム ０．５ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
ｐＨ ７．０
Formulation Example 4
Epinastine hydrochloride 1mg
Boric acid 12mg
Borax 1.2mg
Sodium edetate hydrate 0.5mg
Sodium chloride 0.5mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0
試験例
１．眼内動態試験
（１）被験製剤の調製
下表１の濃度になるように、エピナスチン塩酸塩、ほう酸（又はリン酸二水素ナトリウム水和物及びリン酸水素二ナトリウム水和物）、塩化ナトリウムを水に溶解し、ｐＨ調節剤（希塩酸及び／又は水酸化ナトリウム）と水を加えて全量を１０ｍＬとし、濾過滅菌を行うことにより、製剤１～８を調製した。なお、下表１の浸透圧比になるように、各製剤の浸透圧を塩化ナトリウムの量で調整した。
（２）試験方法
同じ浸透圧比におけるほう酸及び／又はその塩を含むほう酸製剤（製剤１、３、５及び７）と、リン酸又はその塩を含むリン酸製剤（製剤２、４、６及び８）とを点眼投与した際の眼内動態を比較するため、ラットの片眼にほう酸製剤を投与し、その反対眼にはリン酸製剤を投与することによって、動物の個体差による影響を最小限にするようにした。より具体的には、製剤１を片眼に投与した群では、その反対眼に製剤２を投与し、製剤３を片眼に投与した群では、その反対眼に製剤４を投与し、製剤５を片眼に投与した群では、その反対眼に製剤６を投与し、製剤７を片眼に投与した群では、その反対眼に製剤８を投与した。
各被験製剤５μＬをラットに１回点眼投与し（ｎ＝６）、点眼投与後１時間の時点で屠殺処分後の眼球を摘出した。その結膜中のエピナスチン濃度を測定して下記の通りリン酸製剤に対するほう酸製剤のエピナスチン濃度比を個体ごとに算出し、さらにその平均値を算出した。
エピナスチン濃度比＝（ほう酸製剤投与後の組織中エピナスチン濃度）／（リン酸製剤投与後の組織中エピナスチン濃度）
(2) Test method In order to compare the intraocular dynamics when the boric acid preparations containing boric acid and/or its salts (preparations 1, 3, 5, and 7) and the phosphoric acid preparations containing phosphoric acid or its salts (preparations 2, 4, 6, and 8) with the same osmotic pressure ratio were instilled, the boric acid preparation was administered to one eye of the rats, and the phosphoric acid preparation was administered to the other eye, so as to minimize the influence of individual differences of the animals. More specifically, in the group in which preparation 1 was administered to one eye, preparation 2 was administered to the other eye, in the group in which preparation 3 was administered to one eye, preparation 4 was administered to the other eye, in the group in which preparation 5 was administered to one eye, preparation 6 was administered to the other eye, and in the group in which preparation 7 was administered to one eye, preparation 8 was administered to the other eye.
5 μL of each test formulation was instilled into the eyes of rats (n=6) once, and the rats were sacrificed and their eyeballs were removed 1 hour after administration. The epinastine concentration in the conjunctiva was measured, and the epinastine concentration ratio of the boric acid formulation to the phosphoric acid formulation was calculated for each individual rat, and the average value was calculated.
Epinastine concentration ratio = (epinastine concentration in tissue after administration of boric acid preparation) / (epinastine concentration in tissue after administration of phosphate preparation)
（３）試験結果及び考察
試験結果を表２に示す。
表２に示されるように、エピナスチンの結膜への移行性を、同じ浸透圧比においてリン酸又はその塩を含むリン酸製剤と、ほう酸及び／又はその塩を含むほう酸製剤とを比較すると、特に浸透圧が低張においてはほう酸製剤の方がリン酸製剤よりも移行性がより高くなる傾向があることが示された。 As shown in Table 2, when comparing the transfer of epinastine to the conjunctiva between a phosphate preparation containing phosphoric acid or its salts and a boric acid preparation containing boric acid and/or its salts at the same osmotic pressure ratio, it was shown that the boric acid preparation tends to have a higher transfer rate than the phosphate preparation, especially when the osmotic pressure is hypotonic.
本発明は、０．１％（ｗ／ｖ）濃度のエピナスチン又はその塩と、０．０１～２％（ｗ／ｖ）濃度のほう酸及び／又はその塩と、浸透圧調節剤とを含有する水性組成物であって、浸透圧が１４０～３２０ｍＯｓｍである、水性組成物を提供する。 The present invention provides an aqueous composition containing epinastine or a salt thereof at a concentration of 0.1% (w/v), boric acid and/or a salt thereof at a concentration of 0.01-2% (w/v), and an osmotic pressure regulator, the aqueous composition having an osmotic pressure of 140-320 mOsm.
Claims (10)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2022206978A JP2024090835A (en) | 2022-12-23 | 2022-12-23 | Epinastine-containing aqueous composition for improving migration into tissue |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2022206978A JP2024090835A (en) | 2022-12-23 | 2022-12-23 | Epinastine-containing aqueous composition for improving migration into tissue |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2024090835A true JP2024090835A (en) | 2024-07-04 |
Family
ID=91714833
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2022206978A Pending JP2024090835A (en) | 2022-12-23 | 2022-12-23 | Epinastine-containing aqueous composition for improving migration into tissue |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2024090835A (en) |
-
2022
- 2022-12-23 JP JP2022206978A patent/JP2024090835A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11911379B2 (en) | Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization | |
| EA034839B1 (en) | Ophthalmic solution | |
| US20210228587A1 (en) | Preservative free brimonidine and timolol solutions | |
| US20170105987A1 (en) | Formulations and Methods for Treating High Intraocular Pressure | |
| JP2021518352A (en) | Pharmaceutical composition containing timolol | |
| JP6934581B2 (en) | Aqueous pharmaceutical composition containing epinastine or a salt thereof | |
| JP4933897B2 (en) | Intraocular transfer-promoting aqueous eye drops | |
| EP3593788B1 (en) | Ophthalmic compositions containing a nitric oxide releasing prostamide | |
| JP6963651B2 (en) | Aqueous composition containing epinastine or a salt thereof | |
| JP7114668B2 (en) | Pollen burst inhibitor containing epinastine or its salt | |
| JP2024090835A (en) | Epinastine-containing aqueous composition for improving migration into tissue | |
| JP7118579B1 (en) | Aqueous composition containing epinastine or its salt | |
| US11433021B2 (en) | Palonosetron for the treatment or prevention of nausea and vomiting | |
| WO2024135837A1 (en) | Epinastine-containing aqueous composition for improving tissue transferability and preservative effect | |
| CN115397430B (en) | Aqueous compositions containing epinastine or salts thereof | |
| US11850221B2 (en) | Ophthalmic pharmaceutical compositions and uses thereof | |
| WO2024034592A1 (en) | Aqueous pharmaceutical composition containing udca or salt thereof | |
| JP2024090829A (en) | Epinastine-containing aqueous pharmaceutical composition to be accommodated in sterilized container | |
| RU2781022C2 (en) | Ophthalmic compositions containing prostamide releasing nitrogen oxide | |
| JPH1036255A (en) | Collyria for depressing intraocular tension | |
| TW202241448A (en) | Pharmaceutical composition for transdermal administration containing epinastine or salt thereof and containing sulfur-based antioxidant | |
| WO2023079427A1 (en) | Ophthalmic compositions and methods thereof | |
| WO2019245015A1 (en) | Pharmaceutical composition comprising desloratadine or salt thereof | |
| JP2011011984A (en) | Therapeutic agent for pseudomyopia |