JP4890829B2 - Azulene-containing aqueous solution - Google Patents
Azulene-containing aqueous solution Download PDFInfo
- Publication number
- JP4890829B2 JP4890829B2 JP2005288784A JP2005288784A JP4890829B2 JP 4890829 B2 JP4890829 B2 JP 4890829B2 JP 2005288784 A JP2005288784 A JP 2005288784A JP 2005288784 A JP2005288784 A JP 2005288784A JP 4890829 B2 JP4890829 B2 JP 4890829B2
- Authority
- JP
- Japan
- Prior art keywords
- salt
- aqueous liquid
- berberine
- sodium
- liquid preparation
- 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.)
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- 239000007864 aqueous solution Substances 0.000 title claims description 22
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 title description 36
- 150000003839 salts Chemical class 0.000 claims description 91
- 239000007788 liquid Substances 0.000 claims description 75
- 238000002360 preparation method Methods 0.000 claims description 55
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 claims description 45
- 229940093265 berberine Drugs 0.000 claims description 45
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 claims description 45
- 229960003291 chlorphenamine Drugs 0.000 claims description 30
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 19
- 239000002736 nonionic surfactant Substances 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- KXKPYJOVDUMHGS-OSRGNVMNSA-N chondroitin sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 KXKPYJOVDUMHGS-OSRGNVMNSA-N 0.000 claims description 11
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 9
- 230000001387 anti-histamine Effects 0.000 claims description 9
- 239000000739 antihistaminic agent Substances 0.000 claims description 9
- 229940068988 potassium aspartate Drugs 0.000 claims description 8
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims description 8
- PXGILEVFPBXLEB-UHFFFAOYSA-N 1,2-dimethyl-3-propan-2-ylazulene Chemical compound C1=CC=CC=C2C(C(C)C)=C(C)C(C)=C21 PXGILEVFPBXLEB-UHFFFAOYSA-N 0.000 claims description 7
- YEVNGPFKFOATCK-UHFFFAOYSA-N 1-ethyl-2,3-dimethylazulene Chemical compound C1=CC=CC=C2C(CC)=C(C)C(C)=C21 YEVNGPFKFOATCK-UHFFFAOYSA-N 0.000 claims description 7
- UFBURPRIIRCFJK-UHFFFAOYSA-N CCC1=CC=C(C)C2=C(S(O)(=O)=O)C=C(C)C2=C1 Chemical compound CCC1=CC=C(C)C2=C(S(O)(=O)=O)C=C(C)C2=C1 UFBURPRIIRCFJK-UHFFFAOYSA-N 0.000 claims description 7
- KKEMWYNNTBRYMR-UHFFFAOYSA-N azulene-1-sulfonic acid Chemical compound C1=CC=CC=C2C(S(=O)(=O)O)=CC=C21 KKEMWYNNTBRYMR-UHFFFAOYSA-N 0.000 claims description 7
- 239000006172 buffering agent Substances 0.000 claims description 7
- 229960000265 cromoglicic acid Drugs 0.000 claims description 7
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 claims description 7
- 229940024606 amino acid Drugs 0.000 claims description 6
- 150000001413 amino acids Chemical class 0.000 claims description 6
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 6
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims description 4
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 4
- 229960002684 aminocaproic acid Drugs 0.000 claims description 4
- YKZPPPNXRZHVGX-PXYKVGKMSA-L dipotassium;(2s)-2-aminobutanedioate;hydron;hydrate Chemical compound [H+].[H+].O.[K+].[K+].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O YKZPPPNXRZHVGX-PXYKVGKMSA-L 0.000 claims description 4
- SWHAQEYMVUEVNF-UHFFFAOYSA-N magnesium potassium Chemical compound [Mg].[K] SWHAQEYMVUEVNF-UHFFFAOYSA-N 0.000 claims description 4
- RXMQCXCANMAVIO-CEOVSRFSSA-L magnesium;(2s)-2-amino-4-hydroxy-4-oxobutanoate Chemical compound [H+].[H+].[Mg+2].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O RXMQCXCANMAVIO-CEOVSRFSSA-L 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 4
- 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 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 229960001983 magnesium aspartate Drugs 0.000 claims description 3
- 235000002639 sodium chloride Nutrition 0.000 description 88
- -1 fatty acid ester Chemical class 0.000 description 43
- 239000000126 substance Substances 0.000 description 23
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 19
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 15
- 229920005989 resin Polymers 0.000 description 13
- 239000011347 resin Substances 0.000 description 13
- 239000003889 eye drop Substances 0.000 description 12
- 239000004359 castor oil Substances 0.000 description 11
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 10
- 235000019438 castor oil Nutrition 0.000 description 10
- 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 10
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 9
- OJVABJMSSDUECT-UHFFFAOYSA-L berberin sulfate Chemical compound [O-]S([O-])(=O)=O.C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2.C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 OJVABJMSSDUECT-UHFFFAOYSA-L 0.000 description 9
- 239000004327 boric acid Substances 0.000 description 9
- 235000010338 boric acid Nutrition 0.000 description 9
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 9
- 229940012356 eye drops Drugs 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 230000000844 anti-bacterial effect Effects 0.000 description 8
- 150000001545 azulenes Chemical class 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 7
- 229920001225 polyester resin Polymers 0.000 description 7
- 239000004645 polyester resin Substances 0.000 description 7
- 229920000139 polyethylene terephthalate Polymers 0.000 description 7
- 239000005020 polyethylene terephthalate Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 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 6
- 239000004743 Polypropylene Substances 0.000 description 6
- 229920001214 Polysorbate 60 Polymers 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229920001155 polypropylene Polymers 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 229940083542 sodium Drugs 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000419 plant extract Substances 0.000 description 5
- GEYJUFBPCGDENK-UHFFFAOYSA-M sodium;3,8-dimethyl-5-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].CC(C)C1=CC=C(C)C2=C(S([O-])(=O)=O)C=C(C)C2=C1 GEYJUFBPCGDENK-UHFFFAOYSA-M 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- FWKQNCXZGNBPFD-UHFFFAOYSA-N Guaiazulene Chemical compound CC(C)C1=CC=C(C)C2=CC=C(C)C2=C1 FWKQNCXZGNBPFD-UHFFFAOYSA-N 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical compound C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 description 4
- 229920001400 block copolymer Polymers 0.000 description 4
- 239000002738 chelating agent Substances 0.000 description 4
- 239000002997 ophthalmic solution Substances 0.000 description 4
- 229940054534 ophthalmic solution Drugs 0.000 description 4
- 230000003204 osmotic effect Effects 0.000 description 4
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 4
- 229920005668 polycarbonate resin Polymers 0.000 description 4
- 239000004431 polycarbonate resin Substances 0.000 description 4
- 229920000573 polyethylene Polymers 0.000 description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 4
- 229940068968 polysorbate 80 Drugs 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- 241000723346 Cinnamomum camphora Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010015946 Eye irritation Diseases 0.000 description 3
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 239000003899 bactericide agent Substances 0.000 description 3
- 229930008380 camphor Natural products 0.000 description 3
- 229960000846 camphor Drugs 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000012611 container material Substances 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 239000000850 decongestant Substances 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 3
- 231100000013 eye irritation Toxicity 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000003589 local anesthetic agent Substances 0.000 description 3
- 239000007923 nasal drop Substances 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 239000011112 polyethylene naphthalate Substances 0.000 description 3
- 229920002959 polymer blend Polymers 0.000 description 3
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 229940068984 polyvinyl alcohol Drugs 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 239000002562 thickening agent Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- 229920003169 water-soluble polymer Polymers 0.000 description 3
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- VPWNQTHUCYMVMZ-UHFFFAOYSA-N 4,4'-sulfonyldiphenol Chemical class C1=CC(O)=CC=C1S(=O)(=O)C1=CC=C(O)C=C1 VPWNQTHUCYMVMZ-UHFFFAOYSA-N 0.000 description 2
- 229930185605 Bisphenol Natural products 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- GXGJIOMUZAGVEH-UHFFFAOYSA-N Chamazulene Chemical compound CCC1=CC=C(C)C2=CC=C(C)C2=C1 GXGJIOMUZAGVEH-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 241000207199 Citrus Species 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- DJDFFEBSKJCGHC-UHFFFAOYSA-N Naphazoline Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 DJDFFEBSKJCGHC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 241000218206 Ranunculus Species 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
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- 235000019172 retinyl palmitate Nutrition 0.000 description 1
- 239000011769 retinyl palmitate Substances 0.000 description 1
- 239000012487 rinsing solution Substances 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 235000019719 rose oil Nutrition 0.000 description 1
- 239000010666 rose oil Substances 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229960001516 silver nitrate Drugs 0.000 description 1
- GQTHJBOWLPZUOI-FJXQXJEOSA-M sodium D-pantothenate Chemical compound [Na+].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O GQTHJBOWLPZUOI-FJXQXJEOSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940068459 sodium pantothenate Drugs 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
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
- IDBYLPRJLWSMAI-UHFFFAOYSA-M sodium;1,2,3,3a,4,5,6,7,8,8a-decahydroazulene-1-sulfonate Chemical compound [Na+].C1CCCCC2C(S(=O)(=O)[O-])CCC21 IDBYLPRJLWSMAI-UHFFFAOYSA-M 0.000 description 1
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 235000011078 sorbitan tristearate Nutrition 0.000 description 1
- 239000001589 sorbitan tristearate Substances 0.000 description 1
- 229960004129 sorbitan tristearate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 235000019721 spearmint oil Nutrition 0.000 description 1
- 229960001294 spiramycin Drugs 0.000 description 1
- 235000019372 spiramycin Nutrition 0.000 description 1
- 229930191512 spiramycin Natural products 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229960002385 streptomycin sulfate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- YZMCKZRAOLZXAZ-UHFFFAOYSA-N sulfisomidine Chemical compound CC1=NC(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 YZMCKZRAOLZXAZ-UHFFFAOYSA-N 0.000 description 1
- FEPTXVIRMZIGFY-UHFFFAOYSA-N sulfisoxazole diolamine Chemical compound OCCNCCO.CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C FEPTXVIRMZIGFY-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229940127230 sympathomimetic drug Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 229960002494 tetracaine hydrochloride Drugs 0.000 description 1
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 1
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 1
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229940100613 topical solution Drugs 0.000 description 1
- 229960005342 tranilast Drugs 0.000 description 1
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 1
- 229960003962 trifluridine Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229960004791 tropicamide Drugs 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 238000005406 washing Methods 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
- 239000011576 zinc lactate Substances 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- 229940050168 zinc lactate Drugs 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、アズレン類、ベルベリン又はその塩、及びクロルフェニラミン又はその塩を含有する安定性に優れた水性液剤に関する。 The present invention relates to an aqueous liquid preparation having excellent stability containing azulene, berberine or a salt thereof, and chlorpheniramine or a salt thereof.
アズレン類とベルベリン又はその塩はいずれもそれ自体は水溶性の薬物であるが、これらを同時に配合すると結晶を生じるという問題があり、この問題を解消し経時的な結晶の発生を抑えたベルベリン類及びアズレンスルホン酸ナトリウム及びグリチルリチン酸二カリウムを含んでなることを特徴とする点眼剤組成物が知られている(特許文献1)。しかしながら、グリチルリチン酸二カリウムは、点眼投与や鼻腔投与時に不快な甘味を感じる場合があり官能面で問題があった。 Both azulene and berberine or their salts are water-soluble drugs themselves, but there is a problem that crystals are formed when they are blended at the same time, and berberine has solved this problem and suppressed the generation of crystals over time. An eye drop composition comprising sodium azulenesulfonate and dipotassium glycyrrhizinate is known (Patent Document 1). However, dipotassium glycyrrhizinate has a problem in sensory aspect because it may feel unpleasant sweetness when administered by eye drops or nasal administration.
一方、口腔用組成物にミカン科植物抽出物及び/又はキンポウゲ科植物抽出物を配合し、これを長期間に亘り保存すると、当該植物抽出物の主要有効成分であるベルベリンの残存率が低下するという問題を生じ、このため、ミカン科植物抽出物及び/又はキンポウゲ科植物抽出物の口腔組成物への安定化配合が望まれていたところ、ある種の直鎖状ポリリン酸塩を特定の重量比で含有することによってベルベリンが経時的に安定な口腔用組成物が得られることが記載されている(特許文献2)。また、マレイン酸クロルフェミラミンは、水溶液中で不安定になる問題があるところ、キサンチン誘導体と共存させると、クロルフェニラミン又はその塩の安定性を改善し、長期間に亘り安定的に保持できること(特許文献3)、水性液状組成物中に、0.0003〜0.006重量%のクロルフェミラミン塩類に、ポリオキシエチレン−ポリオキシプロピレンブロックコポリマー又はポリオキシエチレンソルビタン脂肪酸エステル類、及びキレート剤を含有すると安定性が高まることが記載されている(特許文献4)。 On the other hand, when a citrus family plant extract and / or buttercup plant plant extract is blended in the oral composition and stored for a long period of time, the residual rate of berberine as the main active ingredient of the plant extract is reduced. For this reason, there has been a demand for a stabilized formulation of a citrus plant extract and / or buttercup plant extract into an oral composition, and certain linear polyphosphates have a specific weight. It is described that the composition for oral cavity in which berberine is stable over time can be obtained by inclusion in a ratio (Patent Document 2). In addition, chlorfemiramine maleate has a problem of becoming unstable in an aqueous solution. When coexisting with a xanthine derivative, the stability of chlorpheniramine or a salt thereof can be improved and stably maintained for a long period of time. (Patent Document 3), 0.0003 to 0.006% by weight of chlorfemiramine salt in an aqueous liquid composition, polyoxyethylene-polyoxypropylene block copolymer or polyoxyethylene sorbitan fatty acid ester, and chelating agent It has been described that the stability is increased by containing (Patent Document 4).
ところで、本発明者は、(A)アズレン類を含有する水性液剤に(B)ベルベリン又はその塩、および特定の化合物を配合すると、水溶液中でのアズレン類の光安定性が向上し、かつ不溶性物質の生成を抑制し、長期にわたり安定性が改善した水性液剤が得られること、さらにアズレン類およびベルベリン又はその塩の生体組織移行性が向上された水性液剤が得られることを見出している(特許文献5及び特許文献6)。 By the way, when the present inventor blends (B) berberine or a salt thereof and a specific compound with an aqueous solution containing (A) azulene, the photostability of the azulene in an aqueous solution is improved and insoluble. It has been found that an aqueous liquid preparation that suppresses the production of substances and has improved stability over a long period of time can be obtained, and further an aqueous liquid preparation that improves the ability of azulene and berberine or a salt thereof to migrate to a living tissue can be obtained (patent) Document 5 and Patent document 6).
本発明の目的は、水性液剤中におけるアズレン類とベルベリン又はその塩との併用で生じる不溶性物質の生成を抑制し、長期にわたり安定性に優れた水性液剤を提供することにある。本発明の別の目的は、ベルベリン又はその塩及びクロルフェミラミン又はその塩の安定性を改善することにある。 An object of the present invention is to provide an aqueous liquid agent that suppresses the production of insoluble substances produced by the combined use of azulenes and berberine or a salt thereof in an aqueous liquid agent and is excellent in stability over a long period of time. Another object of the present invention is to improve the stability of berberine or a salt thereof and chlorfemiramine or a salt thereof.
本発明は、(A)アズレン類、(B)ベルベリン又はその塩、(C)クロルフェニラミン又はその塩を含有する安定化された水性液剤に関する。 The present invention relates to a stabilized aqueous solution containing (A) azulene, (B) berberine or a salt thereof, and (C) chlorpheniramine or a salt thereof.
すなわち、本発明は下記に掲げる発明である。
(1)(A)ジメチルイソプロピルアズレン、アズレンスルホン酸、ジメチルエチルアズレン、1,4-ジメチル-7-エチルアズレン-3-スルホン酸、及びこれらの薬理学的又は生理学的に許容できる塩からなる群より選択される少なくとも1種、
(B)ベルベリン又はその塩、並びに
(C)クロルフェニラミン又はその塩
を含有することを特徴とする水性液剤(但し、コンドロイチン硫酸ナトリウム、消炎剤、クロモグリク酸ナトリウム、及び抗ヒスタミン剤を同時に配合する眼科用組成物を除く)、
(2)さらに、非イオン性界面活性剤を含有する(1)に記載の水性液剤、
(3)さらに、緩衝剤を含有する(1)又は(2)に記載の水性液剤、
(4)さらに、アミノエチルスルホン酸、イプシロン−アミノカプロン酸、アスパラギン酸カリウム、アスパラギン酸マグネシウム、アスパラギン酸マグネシウムカリウム混合物、ヒアルロン酸ナトリウム及びコンドロイチン硫酸ナトリウムからなる群から選択される1種又は2種以上のアミノ酸類を含有する(1)乃至(3)のいずれかに記載の水性液剤、
(5)(A)成分とベルベリン又はその塩の合計量1重量部に対して、クロルフェニラミン又はその塩を0.001〜50重量部で含有する(1)乃至(4)のいずれかに記載の水性液剤、
(6)(A)成分を0.0001〜0.1w/v%、ベルベリン又はその塩を0.0001〜0.5w/v%、クロルフェニラミン又はその塩を0.0001〜0.1w/v%で含有する(1)乃至(5)のいずれかに記載の水性液剤、
(7)pHが5.0〜9.0である(1)乃至(6)のいずれかに記載の水性液剤、
(8)眼科用液剤である(1)乃至(7)のいずれかに記載の水性液剤、
(9)(A)ジメチルイソプロピルアズレン、アズレンスルホン酸、ジメチルエチルアズレン、1,4-ジメチル-7-エチルアズレン-3-スルホン酸、及びこれらの薬理学的又は生理学的に許容できる塩からなる群より選択される少なくとも1種、及び
(B)ベルベリン又はその塩を含む水性液剤に、
(C)クロルフェニラミン又はその塩
を配合することを特徴とする水性液剤中における不溶性物質の生成抑制方法(但し、コンドロイチン硫酸ナトリウム、消炎剤、クロモグリク酸ナトリウム、及び抗ヒスタミン剤を同時に配合する場合を除く)、
(10)(A)ジメチルイソプロピルアズレン、アズレンスルホン酸、ジメチルエチルアズレン、1,4-ジメチル-7-エチルアズレン-3-スルホン酸、及びこれらの薬理学的又は生理学的に許容できる塩からなる群より選択される少なくとも1種、及び
(B)ベルベリン又はその塩を含む水性液剤に、
(C)クロルフェニラミン又はその塩
を配合することを特徴とする水性液剤中における前記(B)成分の安定性向上方法(但し、コンドロイチン硫酸ナトリウム、消炎剤、クロモグリク酸ナトリウム、及び抗ヒスタミン剤を同時に配合する場合を除く)。
That is, this invention is the invention hung up below.
(1) (A) Group consisting of dimethylisopropylazulene, azulenesulfonic acid, dimethylethylazulene, 1,4-dimethyl-7-ethylazulene-3-sulfonic acid, and pharmacologically or physiologically acceptable salts thereof At least one selected from
(B) Berberine or a salt thereof , and (C) Aqueous solution characterized by containing chlorpheniramine or a salt thereof (however, an ophthalmic mixture containing sodium chondroitin sulfate, anti-inflammatory agent, sodium cromoglycate, and an antihistamine at the same time) Except composition)
(2) The aqueous liquid according to (1), further comprising a nonionic surfactant,
(3) The aqueous liquid according to (1) or (2), further containing a buffer,
(4) Further, one or more selected from the group consisting of aminoethylsulfonic acid, epsilon-aminocaproic acid, potassium aspartate, magnesium aspartate, magnesium potassium aspartate, sodium hyaluronate and sodium chondroitin sulfate The aqueous liquid preparation according to any one of (1) to (3), which comprises amino acids;
(5) In any one of (1) to (4), 0.001 to 50 parts by weight of chlorpheniramine or a salt thereof is added to 1 part by weight of the total amount of component (A) and berberine or a salt thereof. The aqueous liquid according to the description,
(6) 0.0001-0.1 w / v% of component (A) , 0.0001-0.5 w / v% of berberine or a salt thereof, 0.0001-0.1 w / v of chlorpheniramine or a salt thereof The aqueous liquid preparation according to any one of (1) to (5), which is contained in v%,
(7) The aqueous liquid according to any one of (1) to (6), wherein the pH is 5.0 to 9.0,
(8) The aqueous liquid according to any one of (1) to (7), which is an ophthalmic liquid
(9) (A) Group consisting of dimethylisopropylazulene, azulenesulfonic acid, dimethylethylazulene, 1,4-dimethyl-7-ethylazulene-3-sulfonic acid, and pharmacologically or physiologically acceptable salts thereof at least one more selected, and (B) berberine or an aqueous solution containing a salt thereof,
(C) Chlorpheniramine or its salt
The method suppressing the formation of insolubles in aqueous solutions in which characterized in that Blend (but excluding sodium chondroitin sulfate, anti-inflammatory agents, cromolyn sodium, and the case of blending antihistamine simultaneously)
(10) (A) Group consisting of dimethylisopropylazulene, azulenesulfonic acid, dimethylethylazulene, 1,4-dimethyl-7-ethylazulene-3-sulfonic acid, and pharmacologically or physiologically acceptable salts thereof At least one selected from, and
(B) To an aqueous solution containing berberine or a salt thereof,
(C) Chlorpheniramine or its salt
A method for improving the stability of the component (B) in an aqueous liquid preparation (except for the case where sodium chondroitin sulfate, an anti-inflammatory agent, sodium cromoglycate, and an antihistamine are added at the same time) .
本発明では、(A)アズレン類、(B)ベルベリン又はその塩及び(C)クロルフェニラミン又はその塩を含有させて、水性液剤中における不溶性物質の生成が抑制され長期にわたり安定な水性液剤が得られる。また、本発明の水性液剤では、ベルベリン又はその塩、クロルフェニラミン又はその塩の長期安定性が顕著に改善できる。すなわち、アズレン類及びベルベリン又はその塩を併用すると不溶性物質が生成するが、クロルフェニラミン又はその塩をともに配合することで不溶性物質の生成が抑制できる。また、かかる3成分を含有する水性液剤中では、ベルベリン又はその塩、クロルフェニラミン又はその塩の安定性が改善されており、特に非イオン性界面活性剤存在下における安定性の改善に顕著な効果が発揮される。 In the present invention, (A) azulenes, (B) berberine or a salt thereof, and (C) chlorpheniramine or a salt thereof are contained, and the formation of insoluble substances in the aqueous liquid is suppressed, and an aqueous liquid that is stable for a long time is obtained. can get. In the aqueous liquid preparation of the present invention, the long-term stability of berberine or a salt thereof, chlorpheniramine or a salt thereof can be remarkably improved. That is, when azulenes and berberine or a salt thereof are used in combination, an insoluble substance is generated, but by adding chlorpheniramine or a salt thereof together, the generation of an insoluble substance can be suppressed. Further, in the aqueous liquid preparation containing these three components, the stability of berberine or a salt thereof, chlorpheniramine or a salt thereof is improved, and is particularly remarkable in the improvement of the stability in the presence of a nonionic surfactant. The effect is demonstrated.
本発明の水性液剤におけるアズレン類としては、例えば、ジメチルイソプロピルアズレン(グアイアズレン、1,4-ジメチル-7-イソプロピルアズレンともいう)、アズレンスルホン酸(水溶性アズレン、グアイアズレンスルホン酸、1,4-ジメチル-7-イソプロピルアズレン-3-スルホン酸ともいう)、ジメチルエチルアズレン(カマズレン、1,4-ジメチル-7-エチルアズレンともいう)、1,4-ジメチル-7-エチルアズレン-3-スルホン酸(カマズレンスルホン酸ともいう)、およびこれらの薬理学的又は生理学的に許容できる塩などが使用できる。これらのアズレン類は、単独で又は二種以上組み合わせて使用できる。
これらの薬理学的又は生理学的に許容できる塩としては、例えば、有機酸塩(例えば、乳酸塩、酢酸塩、酪酸、トリフルオロ酢酸塩、フマル酸塩、マレイン酸塩、酒石酸塩、クエン酸塩、コハク酸塩、マロン酸塩、メタンスルホン酸塩、トルエンスルホン酸塩、トシル酸塩、パルミチン酸塩、ステアリン酸塩など)、無機酸塩(例えば、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、リン酸塩など)、有機塩基との塩(例えば、メチルアミン、トリエチルアミン、トリエタノールアミン、モルホリン、ピペラジン、ピロリジン、アミノ酸、トリピリジン、ピコリンなどの有機アミンとの塩など)、無機塩基との塩(例えばアンモニウム塩、ナトリウム、カリウムなどのアルカリ金属、カルシウム、マグネシウムなどのアルカリ土類金属、アルミニウムなどの金属との塩など)などが例示できる。特に水性液剤においてはアズレンスルホン酸ナトリウムが用いられる。
Examples of the azulene in the aqueous liquid preparation of the present invention include dimethylisopropylazulene (also referred to as guaiazulene, 1,4-dimethyl-7-isopropylazulene), azulenesulfonic acid (water-soluble azulene, guaiazulenesulfonic acid, 1,4-dimethyl). -7-isopropylazulene-3-sulfonic acid), dimethylethylazulene (also called camazulene, 1,4-dimethyl-7-ethylazulene), 1,4-dimethyl-7-ethylazulene-3-sulfonic acid ( And also pharmacologically or physiologically acceptable salts thereof. These azulenes can be used alone or in combination of two or more.
These pharmacologically or physiologically acceptable salts include, for example, organic acid salts (for example, lactate, acetate, butyric acid, trifluoroacetate, fumarate, maleate, tartrate, citrate , Succinate, malonate, methanesulfonate, toluenesulfonate, tosylate, palmitate, stearate, etc., inorganic acid salt (eg hydrochloride, sulfate, nitrate, hydrogen bromide) Acid salts, phosphates, etc.), salts with organic bases (eg salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, amino acids, tripyridine, picoline, etc.), inorganic bases Salts (for example, ammonium salts, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum And salts with metals such as beam), and others. In particular, azulene sodium sulfonate is used in an aqueous solution.
本発明の水性液剤におけるアズレン類の含有量は、使用する化合物やその塩の種類等によって異なるが、0.0001〜0.1W/V%(以下、特に言及しない限り「W/V%」を単に「%」で示す)、好ましくは、0.001〜0.1%程度であり、例えば、眼科用液剤である場合、通常、0.0004〜0.05%、好ましくは、0.001〜0.03%、さらに好ましくは0.004〜0.02%程度である。 The content of azulene in the aqueous liquid preparation of the present invention varies depending on the compound used and the type of salt thereof, but is 0.0001 to 0.1 W / V% (hereinafter referred to as “W / V%” unless otherwise specified). Simply indicated by “%”), preferably about 0.001 to 0.1%. For example, in the case of an ophthalmic solution, it is usually 0.0004 to 0.05%, preferably 0.001 to It is about 0.03%, more preferably about 0.004 to 0.02%.
本発明の水性液剤におけるベルベリン又はその塩としては、例えば、硫酸ベルベリンや塩化ベルベリンなどの塩酸塩や硫酸塩などが例示でき、オウバクやオウレンといったベルベリン又はその塩を含有する生薬のエキス等を用いてもよい。また、ベルベリン又はその塩は、単独で又は二種以上組み合わせて使用できる。 Examples of berberine or a salt thereof in the aqueous liquid preparation of the present invention include, for example, hydrochlorides and sulfates such as berberine sulfate and berberine chloride, and an extract of a herbal medicine containing berberine or a salt thereof such as buckwheat or auren. Also good. Moreover, berberine or its salt can be used individually or in combination of 2 or more types.
本発明の水性液剤中におけるベルベリン又はその塩の含有量は、通常、0.0001〜0.5%、好ましくは、0.001〜0.1%程度であり、例えば、眼科用液剤である場合、ベルベリン又はその塩の組成物中の含有量は、通常、0.0001〜0.1%、より好ましくは、0.0005〜0.05%、特に好ましくは0.005〜0.025%程度である。オウバク・オウレンのエキス等を用いる場合も、組成物中のベルベリン又はその塩の含有量が前記濃度となるように調製して使用することができる。 The content of berberine or a salt thereof in the aqueous liquid preparation of the present invention is usually 0.0001 to 0.5%, preferably about 0.001 to 0.1%, for example, an ophthalmic liquid preparation. The content of berberine or a salt thereof in the composition is usually 0.0001 to 0.1%, more preferably 0.0005 to 0.05%, particularly preferably about 0.005 to 0.025%. It is. In the case of using an extract of Acer aurium or the like, it can be prepared and used so that the content of berberine or a salt thereof in the composition becomes the above-mentioned concentration.
本発明の水性液剤におけるアズレン類に対するベルベリン又はその塩の割合は、通常、アズレン類1重量部に対して、ベルベリン又はその塩0.1〜50重量部、好ましくは0.2〜10重量部、さらに好ましくは0.25〜7重量部程度の範囲から選択できる。なお、この範囲を著しく外れると、本発明により得られる不溶性物質生成抑制効果は低減する傾向にある。 The ratio of berberine or a salt thereof to azulene in the aqueous liquid preparation of the present invention is usually 0.1 to 50 parts by weight, preferably 0.2 to 10 parts by weight of berberine or a salt thereof relative to 1 part by weight of azulene. More preferably, it can select from the range of about 0.25-7 weight part. In addition, if it deviates significantly from this range, the insoluble substance production inhibitory effect obtained by the present invention tends to be reduced.
本発明の水性液剤におけるクロルフェニラミン又はその塩としては、代表的にはマレイン酸クロルフェミラミンが挙げられる。本発明の水性液剤中におけるクロルフェニラミン又はその塩の含有量は、通常、0.0001〜0.1%、好ましくは0.0003〜0.05%、より好ましくは0.0006〜0.03%程度である。 A typical example of chlorpheniramine or a salt thereof in the aqueous liquid preparation of the present invention is chlorpheniramine maleate. The content of chlorpheniramine or a salt thereof in the aqueous liquid preparation of the present invention is usually 0.0001 to 0.1%, preferably 0.0003 to 0.05%, more preferably 0.0006 to 0.03. %.
本発明の水性液剤におけるアズレン類とベルベリン又はその塩に対するクロルフェニラミン又はその塩の割合は、アズレン類とベルベリン又はその塩の合計量1重量部に対して、クロルフェニラミン又はその塩は、通常0.001〜50重量部、好ましくは0.01〜20重量部、さらに好ましくは0.05〜10重量部程度の範囲から選択できる。なお、上限範囲を著しく外れると、眼刺激性が生じ、また、下限範囲を著しく外れると、本発明により得られる不溶性物質生成抑制効果は低減する傾向にある。
また、アズレン類1重量部に対して、クロルフェニラミン又はその塩は、通常0.002〜100重量部、好ましくは0.02〜40重量部、さらに好ましくは0.1〜20重量部程度の範囲から選択できる。なお、上限範囲を著しく外れると、眼刺激性が生じ、また、下限範囲を著しく外れると、本発明により得られる不溶性物質生成抑制効果は低減する傾向にある。
さらに、ベルベリン又はその塩1重量部に対して、クロルフェニラミン又はその塩は、通常0.002〜100重量部、好ましくは0.02〜40重量部、さらに好ましくは0.1〜20重量部程度の範囲から選択できる。なお、上限範囲を著しく外れると、眼刺激性が生じ、また下限範囲を著しく外れると、本発明により得られる不溶性物質生成抑制効果は低減する傾向にある。
The ratio of chlorpheniramine or a salt thereof to azulene and berberine or a salt thereof in the aqueous liquid preparation of the present invention is usually chlorpheniramine or a salt thereof relative to 1 part by weight of the total amount of azulene and berberine or a salt thereof. It can be selected from the range of 0.001 to 50 parts by weight, preferably 0.01 to 20 parts by weight, more preferably 0.05 to 10 parts by weight. If the upper limit is significantly deviated, eye irritation occurs, and if the lower limit is deviated significantly, the insoluble substance production inhibitory effect obtained by the present invention tends to be reduced.
In addition, chlorpheniramine or a salt thereof is usually 0.002 to 100 parts by weight, preferably 0.02 to 40 parts by weight, and more preferably about 0.1 to 20 parts by weight with respect to 1 part by weight of azulene. You can select from a range. If the upper limit is significantly deviated, eye irritation occurs, and if the lower limit is deviated significantly, the insoluble substance production inhibitory effect obtained by the present invention tends to be reduced.
Furthermore, chlorpheniramine or a salt thereof is usually 0.002 to 100 parts by weight, preferably 0.02 to 40 parts by weight, and more preferably 0.1 to 20 parts by weight with respect to 1 part by weight of berberine or a salt thereof. You can choose from a range of degrees. In addition, when the upper limit range is significantly deviated, eye irritation occurs, and when the lower limit range is deviated significantly, the insoluble substance production inhibitory effect obtained by the present invention tends to be reduced.
本発明の水性液剤においては、アズレン類及びベルベリン又はその塩の併用によって生じる不溶性物質の生成が抑制されるが、水性液剤に、さらに非イオン性界面活性剤を含有することによって不溶性物質生成抑制効果がさらに高まる。また、本発明の水性液剤においては、ベルベリン又はその塩、及びクロルフェニラミン又はその塩の安定性が改善されている。特に非イオン性界面活性剤の存在化において、ベルベリン又はその塩、及びクロルフェニラミン又はその塩は不安定となる傾向があるが、アズレン類及びベルベリン又はその塩、及びクロルフェニラミン又はその塩の3成分を含有する本発明の水性液剤では分解が抑制され長期にわたり安定に保持できる。 In the aqueous liquid preparation of the present invention, the production of insoluble substances generated by the combined use of azulenes and berberine or a salt thereof is suppressed. However, the aqueous liquid preparation further contains a nonionic surfactant to suppress the production of insoluble substances. Is further increased. Moreover, in the aqueous liquid preparation of this invention, the stability of berberine or its salt, and chlorpheniramine or its salt is improved. In particular, in the presence of a nonionic surfactant, berberine or a salt thereof and chlorpheniramine or a salt thereof tend to be unstable, but azulene and berberine or a salt thereof, and chlorpheniramine or a salt thereof In the aqueous liquid preparation of the present invention containing three components, decomposition is suppressed and can be stably maintained for a long time.
かかる非イオン性界面活性剤としては、通常当業者が水性液剤に利用しうるものを用いることができ、例えば、非イオン性界面活性剤であるポリオキシエチレン(以下、POEともいう。)−ポリオキシプロピレン(以下、POPともいう。)ブロックコポリマー (例えば、ポロクサマー407 、ポロクサマー235 、ポロクサマー188 など) ;ポロキサミンなどのエチレンジアミンのPOE-POPブロックコポリマー付加物;モノラウリル酸POE(20)ソルビタン(ポリソルベート20) ,モノオレイン酸POE(20)ソルビタン (ポリソルベート80) ,POEソルビタンモノステアレート(ポリソルベート60),POEソルビタントリステアレート(ポリソルベート65) などのPOEソルビタン脂肪酸エステル類;POE硬化ヒマシ油5 ,POE硬化ヒマシ油10 ,POE硬化ヒマシ油20 ,POE硬化ヒマシ油40 ,POE硬化ヒマシ油50、POE硬化ヒマシ油60 ,POE硬化ヒマシ油100などのPOE硬化ヒマシ油類;POE(9) ラウリルエーテルなどのPOEアルキルエーテル類;POE(20)POP(4) セチルエーテルなどのPOE・POPアルキルエーテル類;POE(10)ノニルフェニルエーテルなどのPOEアルキルフェニルエーテル類などが挙げられる。なお、括弧内の数字は付加モル数を示す。なかでも好ましくは、ポリオキシエチレン−ポリオキシプロピレンブロックコポリマー、POEソルビタン脂肪酸エステル類又はPOE硬化ヒマシ油類から選ばれる非イオン性界面活性剤であり、特に好ましくは、ポリオキシエチレン−ポリオキシプロピレンブロックコポリマー、ポリソルベート80、ポリオキシエチレン硬化ヒマシ油60である。 As such nonionic surfactants, those that can be used by those skilled in the art for aqueous liquids can be used. For example, polyoxyethylene (hereinafter also referred to as POE) -poly, which is a nonionic surfactant. Oxypropylene (hereinafter also referred to as POP) block copolymer (for example, poloxamer 407, poloxamer 235, poloxamer 188, etc.); POE-POP block copolymer adduct of ethylenediamine such as poloxamine; POE (20) sorbitan monolauryl acid (polysorbate 20) ), POE sorbitan fatty acid esters such as POE (20) sorbitan monooleate (polysorbate 80), POE sorbitan monostearate (polysorbate 60), POE sorbitan tristearate (polysorbate 65); POE cured castor oil 5, POE cured Castor oil 1 0, POE hydrogenated castor oil 20, POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, POE hydrogenated castor oil such as POE hydrogenated castor oil 100; POE alkyl ethers such as POE (9) lauryl ether POE (20) POP (4) POE-POP alkyl ethers such as cetyl ether; POE alkyl phenyl ethers such as POE (10) nonyl phenyl ether. The numbers in parentheses indicate the number of added moles. Among them, nonionic surfactants selected from polyoxyethylene-polyoxypropylene block copolymers, POE sorbitan fatty acid esters or POE hydrogenated castor oils are preferable, and polyoxyethylene-polyoxypropylene blocks are particularly preferable. Copolymer, polysorbate 80, polyoxyethylene hydrogenated castor oil 60.
本発明の水性液剤における非イオン性界面活性剤の含有量は、界面活性剤の種類などによって異なるので一概に規定できないが、通常、0.0001〜5%、好ましくは0.001〜3%、さらに好ましくは0.005〜2%、特に好ましくは0.01〜1.5%、より特に好ましくは0.05〜1%程度で用いられる。 The content of the nonionic surfactant in the aqueous liquid preparation of the present invention varies depending on the type of surfactant and the like, and thus cannot be specified unconditionally, but is usually 0.0001 to 5%, preferably 0.001 to 3%, More preferably, it is used in an amount of about 0.005 to 2%, particularly preferably about 0.01 to 1.5%, and more preferably about 0.05 to 1%.
本発明の水性液剤においては、アズレン類及びベルベリン又はその塩の併用によって生じる不溶性物質の生成が抑制されるが、水性液剤中に更に緩衝剤を含有することによって不溶性物質生成抑制効果がさらに高まる。 In the aqueous liquid preparation of the present invention, the production of insoluble substances caused by the combined use of azulene and berberine or a salt thereof is suppressed, but the effect of inhibiting the production of insoluble substances is further enhanced by further containing a buffer in the aqueous liquid preparation.
かかる緩衝剤としては、通常当業者が水性液剤に利用しうる緩衝作用があるものであれば特に制限されることなく使用することができる。具体的には、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤、クエン酸緩衝剤、酢酸緩衝剤などが例示される。好ましくは、ホウ酸緩衝剤、リン酸緩衝剤、クエン酸緩衝剤、炭酸緩衝剤であり、特に好ましくはホウ酸緩衝剤である。ここで、ホウ酸緩衝剤としては、ホウ酸、ホウ酸のアルカリ金属塩又はホウ酸のアルカリ土類金属塩などのホウ酸塩、ホウ酸とホウ酸塩との組み合わせなどを挙げることができる。リン酸緩衝剤としては、リン酸、リン酸のアルカリ金属塩又はリン酸のアルカリ土類金属塩などのリン酸塩、リン酸とリン酸塩との組み合わせなどを挙げることができる。クエン酸緩衝剤としては、クエン酸、クエン酸のアルカリ金属塩又はクエン酸のアルカリ土類金属塩などのクエン酸塩、クエン酸とクエン酸塩との組み合わせなどを挙げることができる。炭酸緩衝剤としては、炭酸、炭酸のアルカリ金属塩又は炭酸のアルカリ土類金属塩などの炭酸塩、炭酸と炭酸塩との組み合わせなどを挙げることができる。なお、緩衝剤は1種単独で使用されても、2種以上を組み合わせて使用することもできる。 Such a buffering agent can be used without particular limitation as long as it has a buffering action that can be used by an ordinary person skilled in the art for aqueous solutions. Specific examples include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, and acetate buffer. Preferred are borate buffer, phosphate buffer, citrate buffer, and carbonate buffer, and particularly preferred is borate buffer. Examples of the boric acid buffer include boric acid, boric acid such as boric acid, alkali metal salt of boric acid or alkaline earth metal salt of boric acid, and a combination of boric acid and boric acid salt. Examples of the phosphate buffer include phosphates such as phosphoric acid, alkali metal salts of phosphoric acid or alkaline earth metal salts of phosphoric acid, and combinations of phosphoric acid and phosphate. Examples of the citrate buffer include citrates such as citric acid, alkali metal salts of citric acid or alkaline earth metal salts of citric acid, and combinations of citric acid and citrate. Examples of the carbonic acid buffer include carbonates such as carbonic acid, alkali metal carbonates or alkaline earth metal carbonates, and combinations of carbonic acid and carbonates. In addition, even if a buffering agent is used individually by 1 type, it can also be used in combination of 2 or more type.
本発明の水性液剤における緩衝剤の含有量は、緩衝剤の種類などによって異なるので一概に規定できないが、通常、0.0001〜10%、好ましくは0.001〜5%、さらに好ましくは0.01〜5%、特に好ましくは0.1〜3%程度で用いられる。 The content of the buffering agent in the aqueous liquid preparation of the present invention varies depending on the type of the buffering agent and cannot be defined unconditionally, but is usually 0.0001 to 10%, preferably 0.001 to 5%, more preferably 0.00. It is used at 01 to 5%, particularly preferably about 0.1 to 3%.
本発明の水性液剤においては、ベルベリン又はその塩、及びクロルフェニラミン又はその塩の安定性が改善されているが、さらに特定のアミノ酸類を水性液剤に含有することによってこれらの成分の安定性が高まることから好ましい。 In the aqueous liquid preparation of the present invention, the stability of berberine or a salt thereof, and chlorpheniramine or a salt thereof is improved, but the stability of these components can be improved by further containing specific amino acids in the aqueous liquid preparation. It is preferable because it increases.
かかるアミノ酸類としては、アミノエチルスルホン酸(タウリン)、イプシロン−アミノカプロン酸、アスパラギン酸カリウム、アスパラギン酸マグネシウム、アスパラギン酸マグネシウムカリウム混合物、ヒアルロン酸ナトリウム及びコンドロイチン硫酸ナトリウムからなる群から選択される少なくとも1種又は2種以上を組み合わせて使用する。 Such amino acids include at least one selected from the group consisting of aminoethylsulfonic acid (taurine), epsilon-aminocaproic acid, potassium aspartate, magnesium aspartate, magnesium potassium aspartate, sodium hyaluronate and sodium chondroitin sulfate. Or two or more types are used in combination.
本発明の水性液剤における特定のアミノ酸類の含有量は、アミノエチルスルホン酸(タウリン)、アスパラギン酸カリウム、アスパラギン酸マグネシウム及びアスパラギン酸マグネシウムカリウム混合物からなる群から選択されるものを使用する場合には、総量として、好ましくは0.0001〜10%、より好ましくは0.001〜7%、特に好ましくは0.01〜2%程度で用いられる。ヒアルロン酸ナトリウム及びコンドロイチン硫酸ナトリウムからなる群から選択されるものを使用する場合には、総量として、好ましくは0.0001〜10%、より好ましくは0.001〜5%、特に好ましくは0.005〜2%程度で用いられる。 When the content of the specific amino acids in the aqueous liquid preparation of the present invention is selected from the group consisting of aminoethylsulfonic acid (taurine), potassium aspartate, magnesium aspartate and magnesium potassium aspartate, The total amount is preferably 0.0001 to 10%, more preferably 0.001 to 7%, and particularly preferably about 0.01 to 2%. When using one selected from the group consisting of sodium hyaluronate and sodium chondroitin sulfate, the total amount is preferably 0.0001 to 10%, more preferably 0.001 to 5%, and particularly preferably 0.005. Used at about ~ 2%.
本発明の水性液剤は、目的に応じて内服あるいは外用のいずれの形態でも使用することができる。内服の形態としては、内科用等、外用の形態としては、眼科用、歯科用、耳鼻科用、皮膚科用等、様々な用途の局所投与液剤として提供することができるが、不溶性物質の生成も抑制されることから、異物の発生が特に問題とされる製剤に適しており、特に眼科用液剤として有用である。なお、眼科用液剤としては医薬用の製剤に限らず、コンタクトレンズ用剤などの非医薬用の製剤としても利用できる。例えば、点眼薬(点眼剤とも言う、コンタクトレンズ装用中にも使用できる点眼薬を含む)、洗眼薬(洗眼剤とも言う、コンタクトレンズ装用中にも使用できる洗眼薬を含む)、コンタクトレンズ装着液、コンタクトレンズ用剤(洗浄液、保存液、すすぎ液、消毒液、マルチパーパスソリューションなど)などが挙げられる。なお、本明細書において、コンタクトレンズとは、ハードコンタクトレンズ(酸素透過性ハードコンタクトレンズも含む)、ソフト、カラーコンタクトレンズなどのあらゆるタイプのコンタクトレンズを包含する。 The aqueous liquid preparation of the present invention can be used in any form for internal use or external use depending on the purpose. As an internal form, it can be provided as a topical solution for various uses such as ophthalmology, dental, otolaryngology, dermatology, etc. Therefore, it is suitable for preparations in which the generation of foreign substances is particularly problematic, and is particularly useful as an ophthalmic solution. The ophthalmic solution is not limited to a pharmaceutical preparation, and can be used as a non-pharmaceutical preparation such as a contact lens preparation. For example, eye drops (also referred to as eye drops, including eye drops that can also be used while wearing contact lenses), eye wash (also referred to as eye wash, including eye drops that can also be used while wearing contact lenses), contact lens mounting solutions And contact lens agents (cleaning solution, preserving solution, rinsing solution, disinfecting solution, multipurpose solution, etc.). In this specification, contact lenses include all types of contact lenses such as hard contact lenses (including oxygen permeable hard contact lenses), soft, and color contact lenses.
本発明の水性液剤は、安定性に優れているので複数回に亘り投与する形態で包装され、かつ使用者が継続的に使用するマルチドーズの水性液剤、例えば、点眼薬、洗眼薬、鼻洗浄液、口腔用薬(口腔咽頭薬、含嗽用薬等)、点耳薬、点鼻薬、液状内服薬(液状胃腸薬、液状風邪薬等)、皮膚外用薬などとしても有用である。また、水性液剤の投与量又は適用量は、患者の体重、症状、投与回数、投与方法等によって増減できることは言うまでもない。 Since the aqueous liquid preparation of the present invention is excellent in stability, it is packaged in a form to be administered multiple times and is continuously used by the user, such as multi-dose aqueous liquid preparations such as eye drops, eye wash, nasal wash It is also useful as an oral medicine (oropharyngeal medicine, gargle medicine, etc.), ear drops, nasal drops, liquid internal medicine (liquid gastrointestinal medicine, liquid cold medicine, etc.), skin external medicine and the like. Needless to say, the dose or application amount of the aqueous liquid can be increased or decreased depending on the patient's weight, symptoms, frequency of administration, administration method, and the like.
本発明では、本発明の水性液剤は、pHを3.5〜9.0程度の範囲で製剤形態や用途にあわせて適宜選択することができる。成分安定性を向上させて不溶性物質の生成を抑制する面から、好ましくは5.0〜9.0、より好ましくはpH5.5〜9.0、さらに好ましくはpH6.0〜8.5、特に好ましくは6.5〜8.2である。 In the present invention, the aqueous liquid preparation of the present invention can be appropriately selected in accordance with the preparation form and application within the pH range of about 3.5 to 9.0. From the aspect of improving the component stability and suppressing the generation of insoluble substances, it is preferably 5.0 to 9.0, more preferably pH 5.5 to 9.0, still more preferably pH 6.0 to 8.5, Preferably it is 6.5-8.2.
本発明の水性液剤は、本発明の効果を妨げない限り、アズレン類、ベルベリン又はその塩、クロルフェニラミン又はその塩の他に、種々の成分(薬理活性成分や生理活性成分を含む)を組み合わせて含有してもよい。このような成分の種類は特に制限されず、例えば、充血除去成分、眼調節薬成分、抗炎症薬成分または収斂薬成分、抗ヒスタミン薬成分又は抗アレルギー薬成分、ビタミン類、抗菌薬成分、殺菌薬成分、糖類、セルロース又はその誘導体又はそれらの塩、前述以外の水溶性高分子、局所麻酔薬成分、ステロイド成分などが例示できる。本発明において好適な成分としては、例えば、次のような成分が挙げられる。 The aqueous liquid preparation of the present invention is a combination of various components (including pharmacologically active ingredients and physiologically active ingredients) in addition to azulenes, berberine or a salt thereof, chlorpheniramine or a salt thereof, as long as the effects of the present invention are not hindered. May be contained. The type of such components is not particularly limited, and examples thereof include, for example, a decongestant component, an eye regulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, antibacterial component, and bactericidal component. Examples thereof include drug components, saccharides, cellulose or derivatives thereof or salts thereof, water-soluble polymers other than those described above, local anesthetic components, steroid components, and the like. Examples of suitable components in the present invention include the following components.
充血除去成分:例えば、α−アドレナリン作動薬、具体的にはエピネフリン、塩酸エピネフリン、塩酸エフェドリン、塩酸オキシメタゾリン、塩酸テトラヒドロゾリン、塩酸ナファゾリン、塩酸フェニレフリン、塩酸メチルエフェドリン、酒石酸水素エピネフリン、硝酸ナファゾリンなど。これらはd体、l体又はdl体のいずれでもよい。 Decongestant: For example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, naphazoline nitrate. These may be d-form, l-form or dl-form.
眼筋調節薬成分:例えば、アセチルコリンと類似した活性中心を有するコリンエステラーゼ阻害剤、具体的にはメチル硫酸ネオスチグミン、トロピカミド、ヘレニエン硫酸アトロピンなど。 Eye muscle modulator component: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, atropine sulfate helenien, and the like.
抗炎症薬成分または収斂薬成分:例えば、グリチルリチン酸類(グリチルリチン酸二カリウム、グリチルリチン酸モノアンモニウム等)、硫酸亜鉛、乳酸亜鉛、アラントイン、イプシロン−アミノカプロン酸、インドメタシン、塩化リゾチーム、硝酸銀、プラノプロフェン、ジクロフェナクナトリウム、ブロムフェナクナトリウムなど。 Anti-inflammatory component or astringent component: for example, glycyrrhizic acids (dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, pranoprofen, Diclofenac sodium, bromfenac sodium, etc.
抗ヒスタミン薬成分又は抗アレルギー薬成分:例えば、アシタザノラスト、アンレキサノクス、イブジラスト、トラニラスト、塩酸ジフェンヒドラミン、塩酸レボカバスチン、フマル酸ケトチフェン、クロモグリク酸ナトリウム、ペミロラストカリウムなど。 Antihistamine component or antiallergic agent component: for example, acitazanolast, amlexanox, ibudilast, tranilast, diphenhydramine hydrochloride, levocabastine hydrochloride, ketotifen fumarate, sodium cromoglycate, pemirolast potassium and the like.
ビタミン類:例えば、酢酸レチノール、パルミチン酸レチノール、塩酸ピリドキシン、フラビンアデニンジヌクレオチドナトリウム、リン酸ピリドキサール、シアノコバラミン、パンテノール、パントテン酸カルシウム、パントテン酸ナトリウム、アスコルビン酸、酢酸トコフェロールなど。 Vitamins: for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid, tocopherol acetate and the like.
抗菌薬成分または殺菌薬成分:例えば、硫酸アミノデオキシカナマイシン、硫酸カナマイシン、硫酸ゲンタマイシン、硫酸シソマイシン、硫酸ストレプトマイシン、トブラマイシン、硫酸ミクロノマイシン、アルキルポリアミノエチルグリシン、クロラムフェニコール、スルファメトキサゾール、スルフイソキサゾール、スルファメトキサゾールナトリウム、スルフイソキサゾールジエタノールアミン、スルフイソキサゾールモノエタノールアミン、スルフイソメゾールナトリウム、スルフイソミジンナトリウム、塩酸テトラサイクリン、塩酸オキシテトラサイクリン、オフロキサシン、ノルフロキサシン、レボフロキサシン、塩酸ロメフロキサシン、スルベニシンナトリウム、塩酸セフメノキシム、ベンジルペニシリンカリウム、コリスチンメタスルホン酸ナトリウム、エリスロマイシン、ラクトビオン酸エリスロマイシン、キタサマイシン、スピラマイシン、硫酸フラジオマイシン、硫酸ポリミキシン、ジベカシン、アミカシン、硫酸アミカシン、アシクロビル、イオドデオキシサイチジン、イドクスウリジン、シクロサイチジン、シトシンアラビノシド、トリフルオロチミジン、ブロモデオキシウリジン、ポリビニルアルコールヨウ素、ヨウ素、アムホテリシンB、イソコナゾール、エコナゾール、クロトリマゾール、ナイスタチン、ピマリシン、フルオロシトシン、ミコナゾールなど。 Antibacterial or bactericidal component: for example, aminodeoxykanamycin sulfate, kanamycin sulfate, gentamicin sulfate, sisomycin sulfate, streptomycin sulfate, tobramycin, micronomycin sulfate, alkylpolyaminoethylglycine, chloramphenicol, sulfamethoxazole, Sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfisomethazole sodium, sulfisomidine sodium, tetracycline hydrochloride, oxytetracycline hydrochloride, ofloxacin, Norfloxacin, levofloxacin, lomefloxacin hydrochloride, sulbenicin sodium, cefmenoxime hydrochloride, benzylpenicillin potassium, colitis Sodium metasulfonate, erythromycin, erythromycin lactobionate, kitasamycin, spiramycin, fradiomycin sulfate, polymyxin sulfate, dibekacin, amikacin, amikacin sulfate, acyclovir, iododeoxycytidine, idoxuridine, cyclocytidine, cytosine arabinoside, Trifluorothymidine, bromodeoxyuridine, polyvinyl alcohol iodine, iodine, amphotericin B, isoconazole, econazole, clotrimazole, nystatin, pimaricin, fluorocytosine, miconazole and the like.
糖類:例えば単糖類、二糖類、具体的にはグルコース、トレハロースなど。 Sugars: for example, monosaccharides, disaccharides, specifically glucose, trehalose and the like.
セルロース又はその誘導体又はそれらの塩:例えば、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロースなど。 Cellulose or a derivative thereof or a salt thereof: for example, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose and the like.
前述以外の水溶性高分子:ポリビニルアルコール(完全又は部分ケン化物)、ポリビニルピロリドンなど。 Water-soluble polymers other than those described above: polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, and the like.
局所麻酔薬成分:例えば、塩酸オキシブプロカイン、塩酸コカイン、塩酸コルネカイン、塩酸ジブカイン、塩酸テトラカイン、塩酸パラブチルアミノ安息香酸ジエチルアミノエチル、塩酸ピペロカイン、塩酸プロカイン、塩酸プロパラカイン、塩酸ヘキソチオカイン、塩酸リドカインなど。 Local anesthetic components: for example, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, lidocaine hydrochloride, etc.
ステロイド成分:例えば、デキサメタゾン、ヒドロコルチゾン、フルオロメトロン、プレドニゾロン、メチルプレドニゾロン、ヒドロキシメステロン(hydroxymesterone)、カプロン酸ヒドロコルチゾン、カプロン酸プレドニゾロン、酢酸コルチゾン、酢酸ヒドロコルチゾン、酢酸プレドニゾロン、デキサメタゾンメタスルホベンゾエートナトリウム、デキサメタゾン硫酸ナトリウム、デキサメタゾンリン酸ナトリウム、トリアムシノロンアセトニド、ベタメタゾンリン酸ナトリウム、メタスルホ安息香酸デキサメタゾンナトリウム、メチルプレドニゾロンなど。 Steroid component: for example, dexamethasone, hydrocortisone, fluorometholone, prednisolone, methylprednisolone, hydroxymesterone, hydrocortisone caproate, prednisolone caproate, cortisone acetate, hydrocortisone acetate, prednisolone acetate, sodium dexamethasone metasulfobenzoate, sodium dexamethasone sulfate Dexamethasone sodium phosphate, triamcinolone acetonide, betamethasone sodium phosphate, dexamethasone sodium metasulfobenzoate, methylprednisolone and the like.
水性液剤中のこれらの成分の配合量は製剤の種類、活性成分の種類などに応じて適宜選択され、水性液剤としての各種成分の配合量は当該技術分野で既知である。例えば、製剤全体に対して0.0001〜30%、好ましくは、0.001〜10%程度の範囲から選択できる。
より具体的には,水性液剤中の各成分の含有量は、例えば、以下の通りである。
The compounding amounts of these components in the aqueous liquid are appropriately selected according to the type of the preparation, the type of the active ingredient, and the like, and the compounding amounts of the various components as the aqueous liquid are known in the art. For example, it can be selected from the range of about 0.0001 to 30%, preferably about 0.001 to 10% with respect to the whole preparation.
More specifically, the content of each component in the aqueous liquid preparation is, for example, as follows.
充血除去成分(血管収縮薬又は交感神経興奮薬):例えば、0.0001〜0.5%、好ましくは、0.0005〜0.3%、さらに好ましくは0.001〜0.1%。
眼筋調節薬成分:例えば、0.0001〜0.5%、好ましくは、0.0005〜0.1%、さらに好ましくは0.0005〜0.01%。
抗炎症薬成分または収斂薬成分:例えば、0.0001〜10%、好ましくは0.0001〜5%。
抗ヒスタミン薬成分または抗アレルギー薬成分:例えば、0.0001〜10%、好ましくは0.001〜5%。
ビタミン類:例えば、0.0001〜1%、好ましくは、0.0001〜0.5%。
抗菌薬成分または殺菌薬成分:例えば、0.00001〜10%、好ましくは、0.0001〜10%。
糖類:例えば、0.0001〜5%、好ましくは0.001〜5%、さらに好ましくは0.01〜2%。
セルロース又はその誘導体又はそれらの塩:例えば、0.001〜5%、好ましくは0.01〜1%。
前述以外の水溶性高分子:例えば、0.001〜10%、好ましくは0.001〜5%、さらに好ましくは0.01〜3%。
局所麻酔薬成分:例えば、0.001〜1%、好ましくは0.01〜1%。
ステロイド成分:例えば、0.001〜1%、好ましくは0.01〜1%。
Decongestant component (vasoconstrictor or sympathomimetic drug): For example, 0.0001 to 0.5%, preferably 0.0005 to 0.3%, more preferably 0.001 to 0.1%.
Eye muscle modulator component: For example, 0.0001 to 0.5%, preferably 0.0005 to 0.1%, more preferably 0.0005 to 0.01%.
Anti-inflammatory component or astringent component: for example, 0.0001-10%, preferably 0.0001-5%.
Antihistamine component or antiallergic agent component: for example, 0.0001 to 10%, preferably 0.001 to 5%.
Vitamins: For example, 0.0001 to 1%, preferably 0.0001 to 0.5%.
Antibacterial component or bactericidal component: For example, 0.00001 to 10%, preferably 0.0001 to 10%.
Saccharides: For example, 0.0001 to 5%, preferably 0.001 to 5%, more preferably 0.01 to 2%.
Cellulose or a derivative thereof or a salt thereof: For example, 0.001 to 5%, preferably 0.01 to 1%.
Water-soluble polymers other than those described above: For example, 0.001 to 10%, preferably 0.001 to 5%, more preferably 0.01 to 3%.
Local anesthetic component: For example, 0.001-1%, preferably 0.01-1%.
Steroid component: For example, 0.001 to 1%, preferably 0.01 to 1%.
また、本発明の水性液剤には、発明の効果を損なわない範囲であれば、その用途や形態に応じて、常法に従い、様々な成分や添加物を適宜選択し、一種またはそれ以上を併用して含有させてもよい。それらの成分または添加物として、例えば、半固形剤や液剤などの調製に一般的に使用される担体(水、水性溶媒、水性または油性基剤など)、増粘剤、糖類、防腐剤、殺菌剤又は抗菌剤、pH調節剤、等張化剤、香料または清涼化剤、キレート剤などの各種添加剤を挙げることができる。 Further, in the aqueous liquid preparation of the present invention, as long as the effects of the invention are not impaired, various components and additives are appropriately selected according to the usage and form according to conventional methods, and one or more are used in combination. And may be contained. As those components or additives, for example, carriers (water, aqueous solvents, aqueous or oily bases, etc.) commonly used in the preparation of semi-solids and liquids, thickeners, sugars, preservatives, bactericides Various additives such as agents or antibacterial agents, pH regulators, tonicity agents, fragrances or refreshing agents, chelating agents and the like can be mentioned.
以下に本発明の水性液剤に使用される代表的な成分を例示するが、これらに限定されない。 Although the typical component used for the aqueous liquid preparation of this invention is illustrated below, it is not limited to these.
増粘剤:例えば、カルボキシビニルポリマー、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、アルギン酸、ポリビニルアルコール(完全、又は部分ケン化物)、マクロゴール、ポリビニルピロリドンなど。 Thickeners: for example, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, polyvinyl alcohol (completely or partially saponified), macrogol, polyvinylpyrrolidone and the like.
糖アルコール類:例えば、キシリトール、ソルビトール、マンニトールなど。なお、これらはd体、l体又はdl体のいずれでもよい。 Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.
防腐剤、殺菌剤又は抗菌剤:例えば、塩酸アルキルジアミノエチルグリシン、安息香酸ナトリウム、エタノール、塩化ベンザルコニウム、塩化ベンゼトニウム、グルコン酸クロルヘキシジン、クロロブタノール、ソルビン酸、ソルビン酸カリウム、デヒドロ酢酸ナトリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル、硫酸オキシキノリン、フェネチルアルコール、ベンジルアルコール、ビグアニド化合物(具体的には、ポリヘキサメチレンビグアニドなど)、グローキル(ローディア社製 商品名)など。 Preservatives, bactericides or antibacterial agents: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glow Kill (manufactured by Rhodia) Name) etc.
pH調整剤:例えば、塩酸、水酸化ナトリウム、トリエタノールアミン、モノエタノールアミンなど。 pH adjuster: for example, hydrochloric acid, sodium hydroxide, triethanolamine, monoethanolamine and the like.
等張化剤:例えば、亜硫酸水素ナトリウム、亜硫酸ナトリウム、塩化カリウム、塩化カルシウム、塩化ナトリウム、塩化マグネシウム、酢酸カリウム、酢酸ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、チオ硫酸ナトリウム、硫酸マグネシウム、リン酸水素二ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウム、グリセリン、プロピレングリコールなど。 Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol and the like.
香料又は清涼化剤:例えば、カンフル、ゲラニオール、ボルネオール、メントール、リュウノウ、ショウノウ、ウイキョウ油、クールミント油、スペアミント油、ハッカ水、ハッカ油、ペパーミント油、ベルガモット油、ユーカリ油、ローズ油など。これらはd体、l体又はdl体のいずれでもよい。 Perfume or refreshing agent: For example, camphor, geraniol, borneol, menthol, camphor, camphor, fennel oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil and the like. These may be d-form, l-form or dl-form.
キレート剤:例えば、アスコルビン酸、エデト酸四ナトリウム、エデト酸ナトリウム(日本薬局方)、クエン酸など。 Chelating agents: for example, ascorbic acid, tetrasodium edetate, sodium edetate (Japanese Pharmacopoeia), citric acid, etc.
安定剤:ジブチルヒドロキシトルエン、トロメタモール、ナトリウムホルムアルデヒドスルホキシレート(ロンガリット)、トコフェロール、ピロ亜硫酸ナトリウム、モノエタノールアミン、モノステアリン酸アルミニウムなど。 Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, etc.
溶解剤、基剤:オクチルドデカノール、オリーブ油、ゴマ油、酸化チタン、臭化カリウム、ダイズ油、ツバキ油、トウモロコシ油、ナタネ油、パラフィン、ヒマシ油、プラスチベース、ラッカセイ油、ラノリン、ワセリンなど。 Solubilizer, base: octyldodecanol, olive oil, sesame oil, titanium oxide, potassium bromide, soybean oil, camellia oil, corn oil, rapeseed oil, paraffin, castor oil, plastibase, peanut oil, lanolin, petrolatum and the like.
増粘剤:例えば、0.0005〜50%、好ましくは、0.001〜10%
防腐剤、殺菌剤又は抗菌剤:例えば、0.00001〜5%、好ましくは、0.0001〜2%
pH調節剤:例えば、0.00001〜5%、好ましくは、0.0001〜2%
等張化剤:例えば、0.001〜10%、好ましくは、0.01〜5%
香料または清涼化剤:例えば、0.00001〜5%、好ましくは、0.0001〜2%
キレート剤:例えば、0.00001〜5%、好ましくは、0.0001〜2%。
Thickener: for example 0.0005-50%, preferably 0.001-10%
Preservative, bactericidal agent or antibacterial agent: for example, 0.00001-5%, preferably 0.0001-2%
pH regulator: for example, 0.00001-5%, preferably 0.0001-2%
Isotonizing agent: for example 0.001 to 10%, preferably 0.01 to 5%
Perfume or refreshing agent: for example, 0.00001-5%, preferably 0.0001-2%
Chelating agent: for example, 0.00001-5%, preferably 0.0001-2%.
本発明の水性液剤は、必要に応じて、生体に許容される範囲内の浸透圧比に調節する必要がある。生理食塩液に対する浸透圧比は、通常、0.3〜4.1、好ましくは0.3〜2.1、特に好ましくは0.5〜1.4程度である。浸透圧の調節は、前記等張化剤、塩類などを用いて行うことができる。 The aqueous liquid preparation of the present invention needs to be adjusted to an osmotic pressure ratio within a range that is acceptable to a living body, if necessary. The osmotic pressure ratio with respect to physiological saline is usually 0.3 to 4.1, preferably 0.3 to 2.1, and particularly preferably about 0.5 to 1.4. The osmotic pressure can be adjusted using the isotonic agent, salts and the like.
本発明の水性液剤は、公知の方法により製造できるが、前述のように、アズレン類、ベルベリン又はその塩をある特定の割合や濃度で含有させることにより、不溶性物質を生成することがあるため、必要に応じて水性液剤への各成分の配合順序を考慮するとよい。具体的には ベルベリン又はその塩と、クロルフェニラミンまたはその塩を溶解した後に、アズレン類を加えて調製することが好ましい。また、眼科用液剤が点眼剤、洗眼剤などの場合は、各成分を混合し、必要により、ろ過滅菌処理し、容器に充填することにより調製できる。より具体的には、組成物が点眼剤であれば、例えば、蒸留水又は精製水及び添加剤を用いて、ベルベリン又はその塩、クロルフェニラミンまたはその塩とを溶解させ、さらにアズレン類を溶解させ、所定の浸透圧比及びpHに調整し、無菌環境下、ろ過滅菌処理し、洗浄滅菌済みの容器に無菌充填することにより製造できる。 The aqueous liquid preparation of the present invention can be produced by a known method, but as described above, by containing azulenes, berberine or a salt thereof in a specific ratio or concentration, an insoluble substance may be generated. It is advisable to consider the blending order of each component in the aqueous liquid as necessary. Specifically, it is preferable to prepare by adding azulene after dissolving berberine or a salt thereof and chlorpheniramine or a salt thereof. Further, when the ophthalmic solution is an eye drop, an eye wash, etc., it can be prepared by mixing each component, if necessary, filter sterilizing, and filling the container. More specifically, if the composition is eye drops, for example, using distilled water or purified water and additives, berberine or a salt thereof, chlorpheniramine or a salt thereof is dissolved, and further azulenes are dissolved. And adjusted to a predetermined osmotic pressure ratio and pH, sterilized by filtration in an aseptic environment, and aseptically filled into a container that has been sterilized by washing.
本発明の水性液剤は、例えば繰り返し使用する場合、プラスチック製容器などに収容すると、スクイズ性及び携帯性に優れ、扱いが容易である。さらに、本発明の水性液剤は、不溶性物質の生成が抑制されており、製造工程管理及び品質管理上、ろ過滅菌や異物確認試験が要求される眼科用水性液剤として好適に用いられる。 For example, when the aqueous liquid preparation of the present invention is used repeatedly, it is excellent in squeeze property and portability when stored in a plastic container or the like and is easy to handle. Furthermore, the aqueous liquid preparation of the present invention is suitably used as an ophthalmic aqueous liquid preparation that suppresses the production of insoluble substances and requires filtration sterilization and a foreign matter confirmation test in production process control and quality control.
前記水性液剤を収容できるプラスチック製容器の樹脂としては、例えば、オレフィン系樹脂(ポリエチレン、ポリプロピレンなど)、ポリエステル系樹脂、ポリフェニレンエーテル系樹脂、ポリカーボネート系樹脂、ポリスルホン系樹脂、ポリアミド系樹脂、硬質塩化ビニル樹脂、スチレン系樹脂(ポリスチレン、アクリロニトリル−スチレン共重合体(AS樹脂)など)、セルロースアセテート類などが例示できる。好ましい樹脂は、ポリエチレン、ポリプロピレン、ポリエステル系樹脂、ポリカーボネート系樹脂であり、特に好ましい樹脂は、ポリエステル系樹脂である。 Examples of the plastic container resin that can contain the aqueous liquid include olefin resins (polyethylene, polypropylene, etc.), polyester resins, polyphenylene ether resins, polycarbonate resins, polysulfone resins, polyamide resins, and hard vinyl chloride. Examples thereof include resins, styrene resins (polystyrene, acrylonitrile-styrene copolymers (AS resins), etc.), cellulose acetates, and the like. Preferred resins are polyethylene, polypropylene, polyester resins, and polycarbonate resins, and particularly preferred resins are polyester resins.
ポリエステル系樹脂としては、ジカルボン酸成分(フタル酸、テレフタル酸、ナフタレンジカルボン酸などの芳香族ジカルボン酸成分など)とジオール成分とで構成された樹脂が使用できる。具体的には、芳香族ポリエステル系樹脂、例えば、ポリアルキレンテレフタレート[ポリエチレンテレフタレート(PET)、ポリブチレンテレフタレート(PBT)などのポリC2-4アルキレンテレフタレートなど]、ポリアルキレンナフタレート[ポリエチレンナフタレート(PEN)、ポリブチレンナフタレートなどのポリC2-4アルキレンナフタレートなど]、ポリシクロアルキレンテレフタレート[ポリ(1,4−シクロヘキシレンジメチレンテレフタレート)(PCT)など]、ポリアリレート類(ビスフェノール類(ビスフェノール−Aなど)とフタル酸類(フタル酸、テレフタル酸)とで構成された樹脂など)などのホモポリエステルが挙げられる。また、ポリエステル系樹脂には、前記ホモポリエステル単位を主成分(例えば、50重量%以上)として含むコポリエステル、前記ホモポリエステルの共重合体(PETとPCTとの共重合体など)なども含まれる。なかでも、オレフィン系樹脂(ポリエチレンなど)、芳香族ポリエステル系樹脂(ポリエチレンテレフタレート、ポリエチレンナフタレート、ポリアリレートなど)、ポリカーボネート系樹脂が好ましい。ポリカーボネート系樹脂は、例えば、ビスフェノール類(ビスフェノール−Aなど)をベースとする芳香族ポリカーボネートである。 As the polyester resin, a resin composed of a dicarboxylic acid component (such as an aromatic dicarboxylic acid component such as phthalic acid, terephthalic acid, or naphthalenedicarboxylic acid) and a diol component can be used. Specifically, aromatic polyester resins such as polyalkylene terephthalate [poly C 2-4 alkylene terephthalate such as polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)], polyalkylene naphthalate [polyethylene naphthalate ( PEN), poly C 2-4 alkylene naphthalate such as polybutylene naphthalate, etc.], polycycloalkylene terephthalate [poly (1,4-cyclohexylene dimethylene terephthalate) (PCT) etc.], polyarylates (bisphenols ( Homopolyesters such as bisphenol-A) and phthalic acids (resins composed of phthalic acid and terephthalic acid). The polyester resin also includes a copolyester containing the homopolyester unit as a main component (for example, 50% by weight or more), a copolymer of the homopolyester (such as a copolymer of PET and PCT), and the like. . Of these, olefin resins (such as polyethylene), aromatic polyester resins (polyethylene terephthalate, polyethylene naphthalate, polyarylate, etc.) and polycarbonate resins are preferred. The polycarbonate resin is, for example, an aromatic polycarbonate based on bisphenols (such as bisphenol-A).
本発明においてプラスチック製容器は、強度、光透過性、ガス又は水蒸気バリア性(透湿性)等の品質面への影響とコストパフォーマンス等を考慮した上で、ポリマーアロイ(ポリマーブレンドなど)であってもよい。好ましいポリマーアロイには、複数の合成樹脂のポリマーブレンド(PETとPENとのポリマーブレンドなど)が含まれる。また、樹脂は、スクイズ性が良好で、繰り返しの押圧に対して耐久性を有する樹脂、透明性または半透明性の樹脂であることが好ましく、必要に応じて着色してもよい。 In the present invention, the plastic container is a polymer alloy (polymer blend or the like) in consideration of the influence on quality such as strength, light transmission, gas or water vapor barrier properties (moisture permeability) and cost performance. Also good. Preferred polymer alloys include polymer blends of a plurality of synthetic resins (such as polymer blends of PET and PEN). The resin is preferably a resin having good squeeze properties and durability against repeated pressing, and a transparent or translucent resin, and may be colored as necessary.
以下に、試験例、実施例に基づいて本発明をより詳細に説明するが、本発明はこれらの試験例、実施例によって限定されるものではない。 Hereinafter, the present invention will be described in more detail based on test examples and examples, but the present invention is not limited to these test examples and examples.
試験例1
下記表1に記載の組成に従い水性液剤を調製した。具体的には、精製水に、硫酸ベルベリン、マレイン酸クロルフェニラミン、ホウ酸、ホウ砂、ポリソルベート80を溶解し、そこにアズレンスルホン酸ナトリウムを加え、比較例1及び2と実施例1〜3について水酸化ナトリウム及び/または塩酸でpH5.4またはpH7.1に調整して全量を100mlとした。それぞれの水性液剤を無色透明のガラス瓶に充填し密封し遮光した。
各水性液剤について不溶性物質の生成の有無を目視により観察した。各水性液剤における結果を表1に示す。なお、不溶性物質の生成の有無に関して、不溶性物質の生成を認めなかった場合は○、不溶性物質の生成を認めた場合は×と表中に示した。
Test example 1
An aqueous solution was prepared according to the composition described in Table 1 below. Specifically, berberine sulfate, chlorpheniramine maleate, boric acid, borax, and polysorbate 80 are dissolved in purified water, and sodium azulene sulfonate is added thereto, and Comparative Examples 1 and 2 and Examples 1 to 3 are added. Was adjusted to pH 5.4 or pH 7.1 with sodium hydroxide and / or hydrochloric acid to make a total volume of 100 ml. Each aqueous solution was filled in a colorless and transparent glass bottle, sealed and shielded from light.
The presence or absence of the generation of insoluble substances in each aqueous liquid was visually observed. The results for each aqueous liquid are shown in Table 1. Regarding the presence / absence of the generation of insoluble substances, the table shows ◯ when no insoluble substances were generated and x when the generation of insoluble substances was observed.
表1から明らかなように、硫酸ベルベリンとアズレンスルホン酸ナトリウムにより生じた不溶性物質は非イオン性界面活性剤を含有した比較例では十分に抑制することができなかったが、マレイン酸クロルフェニラミンを用いた実施例では、不溶性物質の生成に対して高い抑制効果を発揮した。また、かかる効果は、非イオン性界面活性剤や緩衝剤の存在下においても認められ、緩衝剤や非イオン性界面活性剤の存在下ではさらに優れた抑制効果が認められた。 As is apparent from Table 1, the insoluble material produced by berberine sulfate and sodium azulene sulfonate could not be sufficiently suppressed in the comparative example containing a nonionic surfactant, but chlorpheniramine maleate was not suppressed. In the Example used, the high inhibitory effect with respect to the production | generation of an insoluble substance was exhibited. Further, such an effect was recognized even in the presence of a nonionic surfactant or a buffering agent, and a further excellent inhibitory effect was observed in the presence of a buffering agent or a nonionic surfactant.
試験例2
下記表2に記載の組成に従い水性液剤を調製した。具体的には、精製水に、ホウ酸、ホウ砂、硫酸ベルベリン、マレイン酸クロルフェニラミン、ポリソルベート80又はコンドロイチン硫酸ナトリウムを溶解し、そこにアズレンスルホン酸ナトリウムを加えて全量を100mlとした。それぞれの水性液剤を無色透明のガラス瓶に充填し密封し遮光して50℃又は60℃の恒温室内で保管した。
各水性液剤について、マレイン酸クロルフェニラミンと硫酸ベルベリンの残存率を求めた。製造直後及び2週間保管後の水性液剤について、マレイン酸クロルフェニラミン又は硫酸ベルベリン濃度を高速液体クロマトグラフィーにより測定した。測定した各水性液剤中の各成分の濃度から、式(残存率(%)=2週間保管後濃度×100/製造直後濃度)に従って各成分の残存率(%)を算出した。
Test example 2
An aqueous solution was prepared according to the composition described in Table 2 below. Specifically, boric acid, borax, berberine sulfate, chlorpheniramine maleate, polysorbate 80 or sodium chondroitin sulfate was dissolved in purified water, and sodium azulenesulfonate was added thereto to make a total volume of 100 ml. Each aqueous solution was filled in a colorless and transparent glass bottle, sealed, shielded from light, and stored in a thermostatic chamber at 50 ° C or 60 ° C.
For each aqueous solution, the residual ratio of chlorpheniramine maleate and berberine sulfate was determined. The concentration of chlorpheniramine maleate or berberine sulfate was measured by high performance liquid chromatography for aqueous solutions immediately after production and after storage for 2 weeks. From the measured concentration of each component in each aqueous liquid, the remaining rate (%) of each component was calculated according to the formula (residual rate (%) = concentration after storage for 2 weeks × 100 / concentration immediately after production).
水性液剤中ではマレイン酸クロルフェニラミン及び硫酸ベルベリンの安定性が低下する。特に非イオン性界面活性剤の存在下での低下が著しい。本発明の水性液剤では、アズレンスルホン酸ナトリウムとともに、マレイン酸クロルフェニラミン及び硫酸ベルベリンを含有することによって、マレイン酸クロルフェニラミン、硫酸ベルベリンの分解が抑制され安定性が改善されることが示された。なお、表には示さないが、いずれの実施例においても不溶性物質の生成が認められなかった。 In aqueous solutions, the stability of chlorpheniramine maleate and berberine sulfate is reduced. In particular, the decrease in the presence of a nonionic surfactant is remarkable. In the aqueous liquid preparation of the present invention, by containing chlorpheniramine maleate and berberine sulfate together with sodium azulenesulfonate, it is shown that the degradation of chlorpheniramine maleate and berberine sulfate is suppressed and the stability is improved. It was. Although not shown in the table, the generation of insoluble substances was not observed in any of the examples.
下記表3〜6に示す処方に従い、常法により、点眼液、洗眼液、点鼻液を調製し、無菌環境下でろ過滅菌し、滅菌済みの点眼用容器(容量15mL 容器材質 本体:ポリエチレンテレフタレート、ノズル:ポリエチレン、キャップ:ポリプロピレン)、洗眼用容器(容量300mL 容器材質 本体:ポリエチレンテレフタレート、キャップ:ポリプロピレン)、点鼻用容器(容量30mL 容器材質 本体:ポリプロピレン、ノズル:ポリプロピレン、エチレンキャップ:ポリプロピレン)に充填し、点眼剤又は洗眼剤、点鼻剤を製した。 In accordance with the formulations shown in Tables 3 to 6 below, eye drops, eye washes, and nasal drops are prepared by a conventional method, sterilized by filtration in a sterile environment, and sterilized eye drops containers (capacity 15 mL container material: main body: polyethylene terephthalate , Nozzle: Polyethylene, Cap: Polypropylene), Eyewash container (Capacity: 300 mL, Container material: Main body: Polyethylene terephthalate, Cap: Polypropylene), Nasal container (Capacity: 30 mL, Container material: Main body: Polypropylene, Nozzle: Polypropylene, Ethylene cap: Polypropylene) The eye drop, eye wash, and nasal drop were prepared.
Claims (10)
(B)ベルベリン又はその塩、並びに
(C)クロルフェニラミン又はその塩
を含有することを特徴とする水性液剤(但し、コンドロイチン硫酸ナトリウム、消炎剤、クロモグリク酸ナトリウム、及び抗ヒスタミン剤を同時に配合する眼科用組成物を除く)。 (A) selected from the group consisting of dimethylisopropylazulene, azulenesulfonic acid, dimethylethylazulene, 1,4-dimethyl-7-ethylazulene-3-sulfonic acid, and pharmacologically or physiologically acceptable salts thereof. At least one
(B) Berberine or a salt thereof , and (C) Aqueous solution characterized by containing chlorpheniramine or a salt thereof (however, an ophthalmic mixture containing sodium chondroitin sulfate, anti-inflammatory agent, sodium cromoglycate, and an antihistamine at the same time) Except composition) .
(B)ベルベリン又はその塩を含む水性液剤に、
(C)クロルフェニラミン又はその塩
を配合することを特徴とする水性液剤中における不溶性物質の生成抑制方法(但し、コンドロイチン硫酸ナトリウム、消炎剤、クロモグリク酸ナトリウム、及び抗ヒスタミン剤を同時に配合する場合を除く)。 (A) selected from the group consisting of dimethylisopropylazulene, azulenesulfonic acid, dimethylethylazulene, 1,4-dimethyl-7-ethylazulene-3-sulfonic acid, and pharmacologically or physiologically acceptable salts thereof. An aqueous solution containing at least one of (B) and berberine or a salt thereof,
(C) Chlorpheniramine or its salt
The method suppressing the formation of insolubles in aqueous solutions in which characterized in that Blend (but excluding sodium chondroitin sulfate, anti-inflammatory agents, cromolyn sodium, and the case of blending antihistamine simultaneously).
(B)ベルベリン又はその塩を含む水性液剤に、(B) To an aqueous solution containing berberine or a salt thereof,
(C)クロルフェニラミン又はその塩(C) Chlorpheniramine or its salt
を配合することを特徴とする水性液剤中における前記(B)成分の安定性向上方法(但し、コンドロイチン硫酸ナトリウム、消炎剤、クロモグリク酸ナトリウム、及び抗ヒスタミン剤を同時に配合する場合を除く)。A method for improving the stability of the component (B) in the aqueous liquid preparation (except for the case where sodium chondroitin sulfate, an anti-inflammatory agent, sodium cromoglycate, and an antihistamine are added at the same time).
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JP5616621B2 (en) * | 2008-12-10 | 2014-10-29 | ロート製薬株式会社 | Eye drops for silicone hydrogel contact lenses |
JP5632589B2 (en) * | 2009-02-19 | 2014-11-26 | ロート製薬株式会社 | Eye drops for silicone hydrogel contact lenses |
JP5419518B2 (en) * | 2009-03-31 | 2014-02-19 | 小林製薬株式会社 | Azulene derivative-containing liquid |
JP2011093891A (en) * | 2009-09-30 | 2011-05-12 | Rohto Pharmaceutical Co Ltd | Composition for ophthalmology |
JP5616619B2 (en) * | 2009-12-02 | 2014-10-29 | ロート製薬株式会社 | Ophthalmic composition for silicone hydrogel contact lens |
JP5977919B2 (en) * | 2010-03-31 | 2016-08-24 | 小林製薬株式会社 | Pharmaceutical composition |
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JP5686454B1 (en) * | 2013-12-12 | 2015-03-18 | 株式会社メニコン | Contact lens mounting liquid and method for improving refractive index of contact lens using the same |
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JP2015078236A (en) * | 2015-01-26 | 2015-04-23 | ロート製薬株式会社 | Ophthalmic composition for silicone hydrogel contact lens |
JP2015098490A (en) * | 2015-02-25 | 2015-05-28 | 小林製薬株式会社 | Pharmaceutical composition |
JP2017132764A (en) * | 2016-01-27 | 2017-08-03 | ロート製薬株式会社 | Ophthalmic composition for silicone hydrogel color contact lenses |
JP2016222728A (en) * | 2016-10-03 | 2016-12-28 | ロート製薬株式会社 | Ophthalmic composition for silicone hydrogel contact lenses |
JP2018197272A (en) * | 2018-09-19 | 2018-12-13 | ロート製薬株式会社 | Ophthalmic composition for silicone hydrogel contact lenses |
CN114761022B (en) * | 2019-11-29 | 2024-02-13 | 千寿制药株式会社 | pharmaceutical composition |
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