JPH0780760B2 - Stabilized phenylephrine liquid agent - Google Patents
Stabilized phenylephrine liquid agentInfo
- Publication number
- JPH0780760B2 JPH0780760B2 JP17717286A JP17717286A JPH0780760B2 JP H0780760 B2 JPH0780760 B2 JP H0780760B2 JP 17717286 A JP17717286 A JP 17717286A JP 17717286 A JP17717286 A JP 17717286A JP H0780760 B2 JPH0780760 B2 JP H0780760B2
- Authority
- JP
- Japan
- Prior art keywords
- phenylephrine
- salt
- examples
- acid
- liquid agent
- 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.)
- Expired - Fee Related
Links
- 229960001802 phenylephrine Drugs 0.000 title claims description 18
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 title claims description 17
- 239000007788 liquid Substances 0.000 title claims description 8
- 150000003839 salts Chemical class 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 9
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 9
- 239000004334 sorbic acid Substances 0.000 claims description 9
- 229940075582 sorbic acid Drugs 0.000 claims description 9
- 235000010199 sorbic acid Nutrition 0.000 claims description 9
- 150000001413 amino acids Chemical class 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000002845 discoloration Methods 0.000 description 9
- 229940024606 amino acid Drugs 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 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 description 6
- 239000003889 eye drop Substances 0.000 description 6
- 229940068988 potassium aspartate Drugs 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- -1 amino acid salt Chemical class 0.000 description 4
- 238000004040 coloring Methods 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
- 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 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 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 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 239000000872 buffer 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
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 2
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 229960001983 magnesium aspartate Drugs 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000007923 nasal drop Substances 0.000 description 2
- OSZNNLWOYWAHSS-UHFFFAOYSA-M neostigmine methyl sulfate Chemical compound COS([O-])(=O)=O.CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 OSZNNLWOYWAHSS-UHFFFAOYSA-M 0.000 description 2
- 229960002253 neostigmine methylsulfate Drugs 0.000 description 2
- 229960003733 phenylephrine hydrochloride Drugs 0.000 description 2
- OCYSGIYOVXAGKQ-FVGYRXGTSA-N phenylephrine hydrochloride Chemical compound [H+].[Cl-].CNC[C@H](O)C1=CC=CC(O)=C1 OCYSGIYOVXAGKQ-FVGYRXGTSA-N 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 230000003405 preventing effect Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RBCOYOYDYNXAFA-UHFFFAOYSA-L (5-hydroxy-4,6-dimethylpyridin-3-yl)methyl phosphate Chemical compound CC1=NC=C(COP([O-])([O-])=O)C(C)=C1O RBCOYOYDYNXAFA-UHFFFAOYSA-L 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- POJWUDADGALRAB-PVQJCKRUSA-N Allantoin Natural products NC(=O)N[C@@H]1NC(=O)NC1=O POJWUDADGALRAB-PVQJCKRUSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- 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 1
- 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 1
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl 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
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000006550 Mydriasis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 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 1
- 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 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 229960000458 allantoin Drugs 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 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 description 1
- FDJOLVPMNUYSCM-UVKKECPRSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2,7, Chemical compound [Co+3].N#[C-].C1([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)[N-]\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O FDJOLVPMNUYSCM-UVKKECPRSA-L 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- 229960003720 enoxolone Drugs 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 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 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 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 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 230000002911 mydriatic effect Effects 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229940100656 nasal solution Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 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
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 229940075554 sorbate Drugs 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-N sorbic acid group Chemical class C(\C=C\C=C\C)(=O)O WSWCOQWTEOXDQX-MQQKCMAXSA-N 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
【発明の詳細な説明】 〔技術分野〕 本発明は、点眼液あるいは点鼻液として有用な安定化さ
れたフェニレフリン系液剤に関する。TECHNICAL FIELD The present invention relates to a stabilized phenylephrine-based liquid agent useful as an eye drop or a nasal drop.
フェニレフリン系化合物は、強力な血管収縮作用および
散瞳作用を有することから、点眼液あるいは点鼻液とし
て繁用されている。Phenylephrine-based compounds have a strong vasoconstrictor action and mydriatic action, and are therefore commonly used as eye drops or nasal drops.
このフェニレフリン系化合物の力価は中性ないし弱酸性
で安定であるが、この水溶液は長時間保存すると不安定
になり溶液が着色又は変色するという欠点があり、特に
新陳代謝促進剤や抗プラスミン剤としてアスパラギン酸
カリウム等のアミノ酸あるいはアミノ酸塩が配合された
水溶液の場合は、その着色又は変色劣化が著しい。The potency of this phenylephrine-based compound is neutral or weakly acidic and stable, but this aqueous solution has the drawback that it becomes unstable when stored for a long time and the solution becomes discolored or discolored, especially as a metabolism promoter or antiplasmin agent. In the case of an aqueous solution containing an amino acid such as potassium aspartate or an amino acid salt, its coloration or discoloration deterioration is remarkable.
従来、このようなフェニレフリン系化合物の安定化方法
としては、pHを１付近に保つ方法、酸素を遮断する方
法、エデト酸塩根のキレート試薬を添加する方法あるい
はメタ重亜硫酸塩等の抗酸化剤を添加する方法の種々の
方法が提案されているが、いずれも満足すべきものでは
なかった。Conventionally, as a method for stabilizing such a phenylephrine-based compound, a method of maintaining the pH at around 1, a method of blocking oxygen, a method of adding a chelating agent for edetate root, or an antioxidant such as metabisulfite Various methods have been proposed as a method of adding a compound, but none of them was satisfactory.
例えば、pHが１付近に保たれたフェニレフリン系点眼液
あるいは点鼻液は、生体に使用した場合の刺激性に問題
があり、また他の方法も着色又は変色防止効果が不充分
でありその商品価値が劣るものであった。For example, a phenylephrine type ophthalmic solution or a nasal solution whose pH is kept around 1 has a problem of irritation when used in a living body, and other methods have insufficient coloring or discoloration preventing effect, so that the product It was inferior in value.
〔目的〕 本発明は、経日あるいは日光曝露によっても着色又は変
色を生じることがなく、しかも使用感に優れたフェニレ
フリン系液剤を提供することを目的とする。[Purpose] It is an object of the present invention to provide a phenylephrine-based liquid preparation which is free from discoloration or discoloration even with the passage of time or exposure to sunlight and which is excellent in usability.
本発明によれば、フェニレフリン系化合物及びアミノ酸
もしくはその塩を配合した液剤であって、更にソルビン
酸又はその塩を0.005〜0.1W/V％含有させたことを特徴
とする安定化されたフェニレフリン系液剤が提供され
る。According to the present invention, a stabilized phenylephrine-based compound comprising a phenylephrine-based compound and an amino acid or a salt thereof, further comprising sorbic acid or a salt thereof in an amount of 0.005 to 0.1 W / V%. A liquid formulation is provided.
本発明のフェニレフリン液剤は、安定化剤としてソルビ
ン酸又はその塩を0.005〜0.1W/V％含有させたことか
ら、アミノ酸もしはその塩が配合されているにも拘ら
ず、経日によっても安定であり、また長期間日光等に曝
露されても着色又は変色を生じることがないため、プラ
スチック容器やガラス容器に入れて保存することがで
き、しかもその保存pHも通常の点眼剤として好ましい値
である５以上にすることが可能であるため、その使用感
にも優れたものである。Since the phenylephrine solution of the present invention contains sorbic acid or a salt thereof as a stabilizer in an amount of 0.005 to 0.1 W / V%, it is stable even with the passage of time despite the fact that an amino acid or a salt thereof is blended. Moreover, since it does not cause coloration or discoloration even when exposed to sunlight for a long period of time, it can be stored in a plastic container or a glass container, and its storage pH is at a preferable value as a normal eye drop. Since it can be set to 5 or more, it is excellent in the feeling of use.
つぎに、本発明をさらに詳細に説明する。Next, the present invention will be described in more detail.
本発明は、安定化剤としてソルビン酸又はその塩を用い
る。The present invention uses sorbic acid or a salt thereof as a stabilizer.
ソルビン酸の塩としては、ナトリウム、カリウム等のア
ルカリ金属塩が好ましく用いられる。ソルビン酸又はそ
の塩の配合量は全液剤溶量に対し、0.005〜0.1W/V％、
好ましくは0.01〜0.05W/V％である。ソルビン酸の配合
量が、0.1W/V％を超えると粘膜刺激作用が強過ぎ、点眼
剤への応用に難点を生じ、またソルビン酸塩の配分量が
0.1W/V％を超えると、液剤の安定性が逆に悪くなる。ま
た0.005W/V％未満では着色又は変色防止効果が不充分と
なる。As the sorbic acid salt, alkali metal salts such as sodium and potassium are preferably used. The compounding amount of sorbic acid or its salt is 0.005 to 0.1 W / V% with respect to the total amount of solution dissolved,
It is preferably 0.01 to 0.05 W / V%. If the blending amount of sorbic acid exceeds 0.1 W / V%, the mucous membrane stimulating effect is too strong, causing difficulty in application to eye drops, and the amount of sorbate distributed is too high.
When it exceeds 0.1 W / V%, the stability of the liquid agent is deteriorated. If it is less than 0.005 W / V%, the effect of preventing coloring or discoloration becomes insufficient.
本発明で用いるフェニレフリン系化合物は、下記一般式
で表わされるフェニレフリンの他その無機塩又は有機塩
が包含される。The phenylephrine-based compound used in the present invention includes phenylephrine represented by the following general formula and inorganic salts or organic salts thereof.
無機塩としては、塩酸塩、リン酸塩、硫酸塩、硝酸塩が
挙げられるが、塩酸塩が好ましく用いられる。 Examples of the inorganic salt include hydrochlorides, phosphates, sulfates and nitrates, and hydrochlorides are preferably used.
有機塩としては、酒石酸塩、タンニン酸塩、クエン酸
塩、サリチル酸塩、グルタミン酸塩が挙げられるが、酒
石酸を用いることが望ましい。Examples of the organic salt include tartrate, tannate, citrate, salicylate and glutamate, and it is preferable to use tartaric acid.
本発明においては、フェニレフリン系化合物の使用量は
全液剤溶量に対して、0.01〜0.1W/V％、好ましくは0.03
〜0.08W/V％である。0.1W/V％を超えると、一般用薬と
して好ましくない散瞳作用が出現することとなり、また
0.01W/V％未満では効果が不充分となるので望ましくな
い。In the present invention, the amount of the phenylephrine-based compound used is 0.01 to 0.1 W / V%, preferably 0.03% based on the total amount of the solution dissolved.
~ 0.08W / V%. If it exceeds 0.1 W / V%, mydriasis, which is unfavorable as an over-the-counter drug, will appear.
If it is less than 0.01 W / V%, the effect is insufficient, which is not desirable.
本発明においては、前記フェニレフリン系化合物と共に
新陳代謝促進剤あるいは抗プラスミン剤としてアミノ酸
もしくはその塩を用いる。アミノ酸もしくはその塩とし
ては、例えば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、アミノエチルスルホン酸、ε−アミノカプロン酸が
例示されるが、有効性の点からみて、アスパラギン酸カ
リウムを用いることが適当である。アミノ酸もしくはそ
の塩の使用量は、全液剤溶量に対して、0.1〜5W/V％、
好ましくは0.5〜1W/V％である。5W/V％を超えると、副
作用が出現することとなり、0.1W/V％未満では効果が不
充分となるので望ましくない。In the present invention, an amino acid or a salt thereof is used as a metabolism promoter or an antiplasmin agent together with the phenylephrine compound. Examples of amino acids or salts thereof include potassium aspartate, magnesium aspartate, magnesium / potassium aspartate, aminoethylsulfonic acid, and ε-aminocaproic acid, but from the viewpoint of effectiveness, use potassium aspartate. Is appropriate. The amount of amino acid or its salt used is 0.1 to 5 W / V%, based on the total amount of the solution dissolved.
It is preferably 0.5 to 1 W / V%. If it exceeds 5 W / V%, side effects will appear, and if it is less than 0.1 W / V%, the effect will be insufficient, which is not desirable.
本発明においては、上記必須成分の他にこの種液剤に通
常使用されている補助成分、例えば、メチル硫酸ネオス
チグミン、抗ヒスタミン剤、抗炎症剤、ビタミン、緩衝
剤、等張化剤及び増粘剤等を配合することもできる。こ
の場合、抗ヒスタミン剤としては、マレイン酸クロルフ
ェニラミン、塩酸ジフェンヒドラミンが、抗炎症剤とし
ては、グリチルリチン酸ニカリウム、グリチルレチン酸
が、ビタミンとしては、ビタミンＡ、ビタミンB2、ビタ
ミンB6、ビタミンB12、ビタミンＥが、緩衝剤として
は、ホウ酸、ホウ砂、クエン酸、クエン酸ナトリウムを
挙げることができる。また、等張化剤としては、塩化カ
リムウ、塩化カルシウム、塩化ナトリウムが、増粘剤と
しては、コンドロイチン硫酸ナトリウム、ポリビニルア
ルコール、ポリビニルピロリドン、ヒドロキシエチルセ
ルロースが例示される。In the present invention, in addition to the above-mentioned essential components, auxiliary components usually used in this liquid preparation, for example, neostigmine methyl sulfate, antihistamines, anti-inflammatory agents, vitamins, buffers, isotonic agents and thickeners, etc. It can also be blended. In this case, as an antihistamine, chlorpheniramine maleate, diphenhydramine hydrochloride, as an anti-inflammatory agent, dipotassium glycyrrhizinate, glycyrrhetinic acid, as vitamins, vitamin A, vitamin B 2 , vitamin B 6 , vitamin B 12 , Examples of the buffer agent containing vitamin E include boric acid, borax, citric acid, and sodium citrate. Examples of the isotonicity agent include kalimu chloride, calcium chloride, and sodium chloride, and examples of the thickening agent include sodium chondroitin sulfate, polyvinyl alcohol, polyvinylpyrrolidone, and hydroxyethyl cellulose.
本発明のフェニレフリン液剤は、安定化剤としてソルビ
ン酸又はその塩を0.005〜0.1W/V％含有させたことか
ら、アミノ酸もしくはその塩が配合されているにも拘ら
ず、経日によっても安定であり、また長期間日光等に曝
露されても着色又は変色を生じることがないため、プラ
スチチク容器やガラス容器に入れて保存することがで
き、しかもその容器pHも通常の点眼剤として好ましい値
である５以上にすることが可能であるため、その使用感
にも優れたものである。The phenylephrine solution of the present invention contains sorbic acid or a salt thereof as a stabilizer in an amount of 0.005 to 0.1 W / V%, and thus is stable even with the passage of time despite the fact that an amino acid or a salt thereof is blended. In addition, since it does not cause coloring or discoloration even when exposed to sunlight for a long period of time, it can be stored in a plastic container or a glass container, and the container pH is also a preferable value as an ordinary eye drop. Since it can be 5 or more, it is excellent in the feeling of use.
つぎに、実施例により本発明を更に詳細に説明する。な
お、以下に示す％はいずれもW/V％である。Next, the present invention will be described in more detail by way of examples. All the percentages shown below are W / V%.
実施例１〜10、比較例１〜６ 表−Ｉに示す配合組成を有する液剤を調製した。つぎ
に、得られた各液剤を無色のガラスアンプルに入れ、日
光爆射下で２週間、並びに恒温槽中（暗所）に40℃及び
50℃で１ケ月保存した後の着色又は変色の程度を調べ
た。その結果を表−Ｉに示す。Examples 1 to 10 and Comparative Examples 1 to 6 Liquid preparations having the composition shown in Table-I were prepared. Next, each of the obtained liquid agents was placed in a colorless glass ampoule, exposed to sunlight for 2 weeks, and kept in a thermostat (dark place) at 40 ° C and
The degree of coloration or discoloration after storage at 50 ° C for 1 month was examined. The results are shown in Table-I.
実施11〜12 下記に示す配合組成のフェニレフリン液剤100mlを実施
例１〜10と同様な方法で調製し、点眼用容器に保存した
後、前記各実施例と同様な試験に供したところ、実施例
１〜10と同様に、着色又は変色がなく使用感にも優れた
ものであることが判った。 Examples 11 to 12 100 ml of phenylephrine solution having the composition shown below was prepared in the same manner as in Examples 1 to 10 and stored in an eyedrop container, and then subjected to the same tests as those in each of the Examples. Similar to Nos. 1 to 10, it was found that there was no coloring or discoloration, and the usability was excellent.
実施例11 メチル硫酸ネオスチグミン 0.002W/V％ アスパラギン酸カリウム 1.0 マレイン酸クロルフェニラミン 0.02 塩酸フェニレフリン 0.1 塩化ベンザルコニウム 0.01 ホウ酸 １ ソルビン酸 0.03 精製水 適量 実施例12 ビタミンＥアセテート 0.015W/V％ アラントイン 0.1 アスパラギン酸カリウム 1.0 塩酸フェニレフリン 0.05 グリチルリチン酸ジカリウム 0.1 エデト酸ナトリウム 0.002 クロロブタノール 0.3 塩化ベンザルコニウム 0.01 ソルビン酸 0.01 硬化ヒマシ油ポリオキシエチレン（60）エーテル0.15
塩化ナトリウム 0.6 塩化カリウム 0.3 精製水 適量Example 11 Neostigmine methylsulfate 0.002W / V% Potassium aspartate 1.0 Chlorpheniramine maleate 0.02 Phenylephrine hydrochloride 0.1 Benzalkonium chloride 0.01 Boric acid 1 Sorbic acid 0.03 Purified water qs. Example 12 Vitamin E acetate 0.015W / V% Allantoin 0.1 potassium aspartate 1.0 phenylephrine hydrochloride 0.05 dipotassium glycyrrhizinate 0.1 sodium edetate 0.002 chlorobutanol 0.3 benzalkonium chloride 0.01 sorbic acid 0.01 hardened castor oil polyoxyethylene (60) ether 0.15
Sodium chloride 0.6 Potassium chloride 0.3 Purified water Suitable amount
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 (Ａ６１Ｋ 31/135 31:195 31:19） ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification number Office reference number FI technical display location (A61K 31/135 31: 195 31:19)
Claims (1)
くはその塩を配合した液剤であって、更にソルビン酸又
はその塩を0.005〜0.1W/V％含有させたことを特徴とす
る安定化されたフェニレフリン系液剤。1. A stabilized phenylephrine-based liquid preparation comprising a phenylephrine-based compound and an amino acid or a salt thereof, which further contains 0.005 to 0.1 W / V% of sorbic acid or a salt thereof. .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17717286A JPH0780760B2 (en) | 1986-07-28 | 1986-07-28 | Stabilized phenylephrine liquid agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17717286A JPH0780760B2 (en) | 1986-07-28 | 1986-07-28 | Stabilized phenylephrine liquid agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6333327A JPS6333327A (en) | 1988-02-13 |
| JPH0780760B2 true JPH0780760B2 (en) | 1995-08-30 |
Family
ID=16026442
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17717286A Expired - Fee Related JPH0780760B2 (en) | 1986-07-28 | 1986-07-28 | Stabilized phenylephrine liquid agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0780760B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007122581A3 (en) * | 2006-04-21 | 2009-07-02 | Procter & Gamble | Compositions and kits of phenylephrine |
| US10022339B2 (en) | 2006-04-21 | 2018-07-17 | The Procter & Gamble Company | Compositions and methods useful for treatment of respiratory illness |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59229907A (en) * | 1983-05-13 | 1984-12-24 | Rohm Co Ltd | Detecting circuit |
| JPH0641409B2 (en) * | 1987-08-08 | 1994-06-01 | 大正製薬株式会社 | Ophthalmic solution |
| WO1997007794A1 (en) * | 1995-08-28 | 1997-03-06 | Showa Yakuhin Kako Co., Ltd. | Composition for local anesthesia |
| FR2882930B1 (en) * | 2005-03-09 | 2009-03-27 | Walid Katib | NOVEL OPHTHALMOLOGICAL COMPOSITIONS AND THEIR USE |
| JP4979258B2 (en) * | 2005-04-08 | 2012-07-18 | ロート製薬株式会社 | Acitazanolast-containing aqueous composition |
| KR20090042956A (en) * | 2006-08-28 | 2009-05-04 | 센주 세이야꾸 가부시키가이샤 | Ophthalmic percutaneous absorption type preparation |
| JP7459508B2 (en) * | 2019-12-26 | 2024-04-02 | ライオン株式会社 | Mucin degeneration inhibitor and ophthalmic composition |
| JP7618968B2 (en) * | 2020-06-05 | 2025-01-22 | ライオン株式会社 | Ophthalmic composition, method for photostabilization, and method for inhibiting discoloration |
-
1986
- 1986-07-28 JP JP17717286A patent/JPH0780760B2/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007122581A3 (en) * | 2006-04-21 | 2009-07-02 | Procter & Gamble | Compositions and kits of phenylephrine |
| US10022339B2 (en) | 2006-04-21 | 2018-07-17 | The Procter & Gamble Company | Compositions and methods useful for treatment of respiratory illness |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6333327A (en) | 1988-02-13 |
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