TWI608837B - Method for stabilizing Chlorpheniramine or its salt - Google Patents
Method for stabilizing Chlorpheniramine or its salt Download PDFInfo
- Publication number
- TWI608837B TWI608837B TW103118783A TW103118783A TWI608837B TW I608837 B TWI608837 B TW I608837B TW 103118783 A TW103118783 A TW 103118783A TW 103118783 A TW103118783 A TW 103118783A TW I608837 B TWI608837 B TW I608837B
- Authority
- TW
- Taiwan
- Prior art keywords
- container
- chlorpheniramine
- liquid agent
- salt
- liquid
- Prior art date
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- 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 title claims description 94
- 229960003291 chlorphenamine Drugs 0.000 title claims description 93
- 150000003839 salts Chemical class 0.000 title claims description 79
- 238000000034 method Methods 0.000 title claims description 35
- 230000000087 stabilizing effect Effects 0.000 title claims description 11
- 239000007788 liquid Substances 0.000 claims description 131
- 238000002347 injection Methods 0.000 claims description 88
- 239000007924 injection Substances 0.000 claims description 88
- 239000003795 chemical substances by application Substances 0.000 claims description 75
- -1 polybutylene terephthalate Polymers 0.000 claims description 71
- 238000002360 preparation method Methods 0.000 claims description 42
- 229920001707 polybutylene terephthalate Polymers 0.000 claims description 36
- 229920005989 resin Polymers 0.000 claims description 34
- 239000011347 resin Substances 0.000 claims description 34
- 239000003889 eye drop Substances 0.000 claims description 24
- 230000006641 stabilisation Effects 0.000 claims description 15
- 238000011105 stabilization Methods 0.000 claims description 15
- 229920000139 polyethylene terephthalate Polymers 0.000 claims description 11
- 239000005020 polyethylene terephthalate Substances 0.000 claims description 9
- 239000011342 resin composition Substances 0.000 claims description 3
- 238000007599 discharging Methods 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 230000000903 blocking effect Effects 0.000 claims 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 29
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 29
- 239000003814 drug Substances 0.000 description 24
- 230000000144 pharmacologic effect Effects 0.000 description 21
- 238000001179 sorption measurement Methods 0.000 description 19
- 238000003860 storage Methods 0.000 description 17
- 239000004698 Polyethylene Substances 0.000 description 13
- 229920000573 polyethylene Polymers 0.000 description 12
- 229920003023 plastic Polymers 0.000 description 11
- 239000004033 plastic Substances 0.000 description 11
- 229940079593 drug Drugs 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 230000007423 decrease Effects 0.000 description 9
- 229940012356 eye drops Drugs 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000000654 additive Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000739 antihistaminic agent Substances 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- DJDFFEBSKJCGHC-UHFFFAOYSA-N Naphazoline Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 DJDFFEBSKJCGHC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000004140 cleaning Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 4
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 4
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 4
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 4
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 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 3
- 230000004308 accommodation Effects 0.000 description 3
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- 239000000853 adhesive Substances 0.000 description 3
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- 239000003708 ampul Substances 0.000 description 3
- 230000001387 anti-histamine Effects 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- 239000002826 coolant Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
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- 229940097496 nasal spray Drugs 0.000 description 3
- 239000007922 nasal spray Substances 0.000 description 3
- 239000002736 nonionic surfactant Substances 0.000 description 3
- 229960003101 pranoprofen Drugs 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 229940124530 sulfonamide Drugs 0.000 description 3
- 150000003456 sulfonamides Chemical class 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- 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 2
- ZJVFLBOZORBYFE-UHFFFAOYSA-N Ibudilast Chemical compound C1=CC=CC2=C(C(=O)C(C)C)C(C(C)C)=NN21 ZJVFLBOZORBYFE-UHFFFAOYSA-N 0.000 description 2
- 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 2
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 2
- 229920003355 Novatec® Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002385 Sodium hyaluronate Polymers 0.000 description 2
- QKLSCPPJEVXONT-UHFFFAOYSA-N Sulfametomidine Chemical compound CC1=NC(OC)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 QKLSCPPJEVXONT-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940125715 antihistaminic agent Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical group CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 2
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- 235000020957 pantothenol Nutrition 0.000 description 1
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- 229960004811 pemirolast potassium Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
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- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
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- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
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- 238000006068 polycondensation reaction Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
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- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
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- NMMVKSMGBDRONO-UHFFFAOYSA-N potassium;9-methyl-3-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound [K+].CC1=CC=CN(C2=O)C1=NC=C2C1=NN=N[N-]1 NMMVKSMGBDRONO-UHFFFAOYSA-N 0.000 description 1
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- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
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- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
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- 239000011769 retinyl palmitate Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- 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
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
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- 229940068459 sodium pantothenate Drugs 0.000 description 1
- 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 1
- 239000012453 solvate Substances 0.000 description 1
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- ZZORFUFYDOWNEF-UHFFFAOYSA-N sulfadimethoxine Chemical compound COC1=NC(OC)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ZZORFUFYDOWNEF-UHFFFAOYSA-N 0.000 description 1
- 229960000973 sulfadimethoxine Drugs 0.000 description 1
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- 229960004936 sulfamethoxypyridazine Drugs 0.000 description 1
- QWCJHSGMANYXCW-UHFFFAOYSA-N sulfaphenazole Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=NN1C1=CC=CC=C1 QWCJHSGMANYXCW-UHFFFAOYSA-N 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 229960000337 tetryzoline Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 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
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 description 1
- 229960005342 tranilast Drugs 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
- 229960004224 tyloxapol Drugs 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 229960001939 zinc chloride Drugs 0.000 description 1
- 239000011576 zinc lactate Substances 0.000 description 1
- 229940050168 zinc lactate Drugs 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D47/00—Closures with filling and discharging, or with discharging, devices
- B65D47/04—Closures with discharging devices other than pumps
- B65D47/06—Closures with discharging devices other than pumps with pouring spouts or tubes; with discharge nozzles or passages
- B65D47/18—Closures with discharging devices other than pumps with pouring spouts or tubes; with discharge nozzles or passages for discharging drops; Droppers
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- Medical Preparation Storing Or Oral Administration Devices (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本發明係有關於可穩定維持含氯苯那敏或其鹽、且pH為7.0以上之液劑的製品。再者,本發明係有關於含氯苯那敏或其鹽且pH為7.0以上之液劑的穩定化方法。
氯苯那敏或其鹽係已知有抗組織胺作用,被使用於點眼劑、點鼻劑、皮膚外用劑、內服劑等醫藥。以往,關於利用氯苯那敏或其鹽之製劑技術係出現過許多報告。例如,有報告提出在眼黏膜或鼻黏膜局部用水性液劑中藉由併用氯苯那敏或其鹽及普拉洛芬(pranoprofen)或其鹽,可獲得優良之消炎作用及止癢作用(專利文獻1),在外用劑組成物中藉由併用阿達巴林(adapalene)與馬來酸氯苯那敏,可提升阿達巴林對角質與皮膚的滲透性(專利文獻2),在感冒用組成物中,藉由併用氯苯那敏與假麻黃鹼,可獲得優良之黏膜發炎症狀(鼻塞等)之減輕‧除去作用(專利文獻3)等。
另一方面,收容醫藥之容器係被要求經時性穩定維持藥理成分或添加劑。尤其,在以液劑方式提供醫藥
的情況下,由於醫藥所含之藥理成分或添加劑處於經常接觸容器內壁的狀態,設計成醫藥所含之藥理成分或添加劑難以吸附至容器為重要。
至今,檢討過各種使藥理成分難以吸附至塑膠製容器的製劑技術。例如,在專利文獻4,報告有藉由將有機胺調配至含容易吸附至合成樹脂成形物之藥物的水性液劑,可抑制水性液劑中該藥物之對合成樹脂成形物的吸附。此外,在專利文獻5,報告有藉由將非離子性界面活性劑調配至含拉坦前列腺素(latanoprost)之點眼液組成物,可防止拉坦前列腺素之對塑膠容器的吸附。再者,在專利文獻6,報告有充填至使用1次後即丟棄類型之塑膠製容器的眼科用液劑組成物,其係含選自於抗組織胺劑、血管收縮劑及消炎、收斂劑所構成之群中至少1種的藥理成分,且不含防腐劑,並藉由將pH設定為p5~6,使該藥理成分難以吸附至塑膠製容器。
然而,關於在表示為中性至鹼性液劑中之氯苯那敏及/或其鹽所示之對塑膠容器的吸附特性並無報告提及,在以往技術中,於含氯苯那敏及/或其鹽,且表示為中性至鹼性的液劑,尚未確立關於用以將氯苯那敏及/或其鹽穩定維持在塑膠容器內的技術為現狀。
專利文獻1:日本特開2002-193805號公報
專利文獻2:日本特開2008-137936號公報
專利文獻3:日本特開2002-332229號公報
專利文獻4:日本特開2007-119422號公報
專利文獻5:國際公開第2008/96804號小冊子
專利文獻6:日本特開2002-249445號公報
在醫藥領域,作為收容液劑之容器,通常使用裝設聚乙烯製管嘴之塑膠製容器。在此,本發明人係在關於將含氯苯那敏及/或其鹽之液劑的pH進行各種改變,收容至通常使用之塑膠製容器,並評價氯苯那敏及/或其鹽的安全性時,面臨在將pH設定為7.0以上之液劑,氯苯那敏及/或其鹽會吸附至聚乙烯製管嘴,且使液劑中之氯苯那敏及/或其鹽之含量降低的特有課題。尤其,在點眼劑,由於氯苯那敏及/或其鹽係被設定為較低含有量,因此其含有量之降低,有使根據氯苯那敏或其鹽之藥理作用的降低變得顯著的傾向,前述課題之解決在點眼劑的領域可謂為特別重要。
在此,本發明之目的在於提供一種技術,為對於含氯苯那敏及/或其鹽且pH為7.0以上之液劑,可抑制氯苯那敏及/或其鹽吸附至容器並穩定維持的技術。
本發明人為了解決前述課題,進行努力檢討的結果,發現關於含氯苯那敏及/或其鹽、且pH為7.0以上之液劑,作為用以收容之容器,藉由採用含聚對苯二甲酸丁二
酯之樹脂作為構成其內壁面(注出部之內部空間壁面及/或蓋部之與注出部之注出口對向的壁面等)之樹脂,可抑制氯苯那敏及/或其鹽吸附至該內壁面,並可穩定維持液劑中之氯苯那敏及/或其鹽的含有量。本發明係根據如此發現而完成者。
亦即,本發明係提供下述所揭示態樣之含氯苯那敏或其鹽製品、及穩定化方法。
項1. 一種含氯苯那敏類製品,是由將含氯苯那敏及/或其藥學上所容許之鹽且pH為7.0以上之液劑收容於容器而成者,其特徵為:前述容器具備收容前述液劑的容器本體、具有注出收容於前述容器本體之液劑之注出口的注出部、及堵住前述注出口的蓋部,其中,前述注出部之內部空間壁面,及前述蓋部中與前述注出口對向之壁面之至少一方,為以含聚對苯二甲酸丁二酯之樹脂構成。
項2. 如項1所記載之含氯苯那敏類製品,其中前述注出部為將前述液劑以液滴狀注出之管嘴,該管嘴之內部空間壁面為以含聚對苯二甲酸丁二酯之樹脂構成。
項3. 如項1或2所記載之含氯苯那敏類製品,其中前述容器本體係以含聚對苯二甲酸乙二酯之樹脂構成。
項4. 如項1~3中任一項所記載之含氯苯那敏類製品,其中前述液劑之pH為7.5~9.0。
項5. 如項1~4中任一項所記載之含氯苯那敏類製品,其中
於前述液劑含有氯苯那敏及/或其藥學上所容許之鹽0.0006~0.2w/v%。
項6. 如請求項1~5中任一項之含氯苯那敏類製品,其中前述液劑為點眼劑。
項7. 一種穩定化方法,為含有氯苯那敏及/或其藥學上所容許之鹽且pH為7.0以上之液劑的穩定化方法,其特徵為:於構成容器內壁之至少一部分區域為以含聚對苯二甲酸丁二酯之樹脂構成的容器,收容含有氯苯那敏及/或其藥學上所容許之鹽的液劑。
項8. 如項7所記載之穩定化方法,其中前述容器係具備收容前述液劑的容器本體、具有注出收容於前述容器本體之液劑之注出口的注出部、及堵住前述注出口的蓋部;且前述注出部之內部空間壁面,及前述蓋部中與前述注出口對向之壁面的至少一方,為以含聚對苯二甲酸丁二酯之樹脂構成。
項9. 如項7或8所記載之穩定化方法,其中前述注出部為將前述液劑以液滴狀注出之管嘴,該管嘴之內部空間壁面為以含聚對苯二甲酸丁二酯之樹脂構成。
項10. 如項7~9中任一項所記載之穩定化方法,其中前述容器本體為以含聚對苯二甲酸乙二酯之樹脂構成。
項11. 如項7~10中任一項所記載之穩定化方法,其中前述液劑之pH為7.5~9.0。
項12. 如項7~11中任一項所之穩定化方法,其中於前述液劑含有氯苯那敏及/或其藥學上所容許之鹽
0.0006~0.2w/v%。
項13. 如項7~12中任一項所記載之穩定化方法,其中前述液劑為點眼劑。
根據本發明,在pH7.0以上之液劑含有氯苯那敏及/或其鹽的同時,可抑制氯苯那敏及/或其鹽吸附至收容之容器並經時性穩定維持。
此外,即使運用以往技術,在pH為7.0以上之液劑,亦無法避免氯苯那敏及/或其鹽吸附至收容之容器的內壁而使其含有量降低,尤其,在氯苯那敏及/或其鹽被設定為較低含量的點眼劑或點鼻劑,因保存而造成藥理作用之減低為不可迴避。對此,根據本發明,可克服如此之以往技術的缺點,即使以點眼劑或點鼻劑等方式提供,亦可抑制氯苯那敏及/或其鹽之含有量的降低,以穩定維持其藥理作用的狀態進行保存。
1‧‧‧容器本體
2‧‧‧注出部
3‧‧‧蓋部
4‧‧‧抽出部之內部空間
5‧‧‧抽出部之內部空間壁面
6‧‧‧蓋部之與注出部之注出口
對向的壁面
圖1為表示關於本發明所使用之點眼容器之一態樣例的剖面圖。
圖2為表示圖1所示之點眼容器的部分放大剖面圖。
圖3為表示關於本發明所使用之點眼容器之一態樣例的剖面圖。
圖4為表示關於本發明所使用之點眼容器之一態樣例的剖面圖。
圖5為表示圖4所示之點眼容器的部分放大剖面圖。
圖6為表示關於本發明所使用之洗眼容器之一態樣例的剖面圖。
在本說明書中,所謂氯苯那敏及/或其鹽之「穩定化」或「穩定性」,係指抑制液劑中之氯苯那敏或其鹽之含有量經時性降低,且穩定維持該含有量,或者指其特性。此外,在本說明書中,「含氯苯那敏類製品」,係指含氯苯那敏及/或其鹽之液劑處於被收容於容器之狀態者。此外,在本說明書中,所謂單位「w/v%」係指質量對體積百分率,與g/100mL同義,所謂「w/w%」係指質量百分率,與重量%同義。
本發明之含氯苯那敏類製品,其特徵為含氯苯那敏及/或其鹽、且pH為7.0以上之收容於容器的液劑,被收容於注出部之內部空間壁面及/或蓋部之與注出部之注出口對向之壁面為以聚對苯二甲酸丁二酯所構成的容器。以下,詳述關於本發明之含氯苯那敏類製品。
液劑
本發明之含氯苯那敏類製品中,收容於容器之液劑,係含有氯苯那敏及/或其鹽。氯苯那敏亦被稱為3-(4-氯苯基)-N,N-二甲基-3-吡啶-2-基-丙烷-1-胺,作為抗組織胺為公知之化合物。
作為氯苯那敏之鹽,係只要以藥學上所容許為限度便無特別限制,例如可舉出馬來酸鹽、富馬酸鹽等有機酸鹽;鹽酸鹽、硫酸鹽等無機酸鹽。在此等氯苯那敏之鹽中,宜舉出馬來酸鹽。
此外,氯苯那敏及/或其鹽,係可為水合物等溶劑合物的形態,此外亦可為d體、dl體之任一者。
在本發明所使用之液劑,氯苯那敏及其鹽之中,可單獨使用1種,亦可將2種以上組合使用。在氯苯那敏及其鹽中,亦可舉出宜為氯苯那敏之鹽,更宜為氯苯那敏馬來酸鹽。
關於本發明所使用之液劑的氯苯那敏及/或其鹽的含有量,係無特別限制,只要因應該液劑之用途等適當設定即可,例如可舉出0.0006~0.2w/v%,宜舉出0.001~0.1w/v%,較宜舉出0.001~0.03w/v%,更宜舉出0.006~0.03w/v%。
本發明所使用之液劑,pH係設定為7.0以上。在以往的技術,若在含氯苯那敏及/或其鹽的液劑將pH設定為7.0以上,則對於以往通用之容器的壁面會表現出氯苯那敏及/或其鹽的吸附作用,但在本發明,即使將pH設定為7.0以上,亦可抑制氯苯那敏及/或其鹽對容器壁面之吸附,穩定維持其含有量。
此外,在含氯苯那敏及/或其鹽之液劑,已確認對於以往通用之容器的壁面,有pH越高則氯苯那敏及/或其鹽之吸附作用變得越顯著的傾向。對此,根據本發明,即
使將液劑之pH設定為適宜之7.5以上,或設定為更適宜之8.0以上,亦可充分抑制氯苯那敏及/或其鹽對容器壁面的吸附,並穩定維持氯苯那敏及/或其鹽。有鑑於如此之本發明效果,作為本發明所使用之液劑之pH的具體範圍,可舉出7.0~9.0,更宜為7.5~9.0,尤宜為8.0~9.0。
為了將本發明所使用之液劑調整為前述pH,例如,可藉由添加pH調整劑的方式進行。作為pH調整劑,例如可舉出氫氧化鈉、氫氧化鉀等鹼;醋酸、檸檬酸、鹽酸、磷酸、酒石酸等酸。此等之pH調整劑,可單獨使用1種,亦可將2種以上組合使用。
本發明所使用之液劑,係除了前述成分之外,可因應其用途,含有其他的藥理成分。關於所使用之藥理成分,並無特別限制,例如可自消炎藥、消炎止痛藥、化學療法藥、抗菌藥、抗病毒藥、賀爾蒙藥、維生素藥、抗白內障藥、血管新生抑制藥、免疫抑制藥、蛋白酶抑制藥、醛醣還原酵素抑制藥、抗組織胺劑、抗過敏劑、抗焦慮藥、抗精神病藥、抗生素、抗腫瘍藥、抗高血脂症藥、止咳.化痰藥、肌肉弛緩藥、抗癲癇藥、抗潰瘍藥、抗憂鬱藥、強心藥、心律不整治療藥、血管擴張藥、高壓利尿藥、糖尿病治療藥、抗結核病藥、麻醉藥拮抗藥、皮膚疾患用藥、齒科口腔用藥、診斷用藥、公眾衛生用藥等以往公知之藥理成分適當選擇使用。
在此等藥理成分中,作為在點眼劑、洗眼劑、點鼻劑、點耳劑等眼科或耳鼻喉科領域所使用之液劑的情況
下之具體例,係可舉出普拉洛芬、甘草酸二鉀、尿囊素、ε-胺己酸、溴芬酸、酮咯酸氨丁三醇、奈帕芬胺(nepafenac)、氯化小蘖鹼、硫酸小蘖鹼、薁磺酸鈉(sodium azulene sulfonate)、硫酸鋅、乳酸鋅、溶菌酶鹽酸鹽等消炎劑;雙苯羥基胺鹽酸鹽等抗組織胺劑;色苷酸鈉、酮替芬富馬酸鹽、阿札司特(acitazanolast)、氨來呫諾(amlexanox)、吡嘧司特鉀(pemirolast potassium)、曲尼司特(tranilast)、異丁司特(ibudilast)、左卡巴斯汀鹽酸鹽(levocabastine hydrochloride)、奧洛帕定鹽酸鹽(olopatadine hydrochloride)等抗過敏劑;諾氟沙星、氧氟沙星(ofloxacin)、洛美沙星(lomefloxacin)、左氟沙星(levofloxacin)、見大黴素、加替沙星(gatifloxacin)等抗菌劑;抗壞血酸、黃素腺嘌呤二核苷酸鈉、氰鈷胺、吡哆醇鹽酸鹽、醋酸生育酚酯、醋酸視黃醇酯、棕櫚酸視黃醇酯、泛醇(panthenol)、泛酸鈣、泛酸鈉等維生素類;天門冬酸、牛磺酸、軟骨素硫酸鈉等胺基酸類;新斯狄格明甲基硫酸鹽等膽鹼酯酶抑制劑;萘甲唑啉(naphazoline)、四氫唑啉(tetrahydrozoline)、腎上腺素、麻黃素、脫羥腎上腺素、dl-甲基麻黃素等血管收縮劑;玻尿酸鈉等角膜結膜上皮障礙治療藥;磺胺甲異噁唑、磺胺二[口井]、磺胺異噁唑、磺胺二甲嘧啶、磺胺二甲氧嘧啶、磺胺甲氧嗒[口井](sulfamethoxypyridazine)、球磺胺、磺胺託嘧啶(sulfamethomidine)、磺胺苯吡唑(sulfaphenazole)、磺胺胍、鄰苯二甲醯磺胺噻唑、琥珀醯磺胺噻唑等磺胺劑等。例示於此之化合物,係以藥學上所容許為限度,可為鹽之
形態,亦可為其他鹽之形態。此等之藥理成分,可單獨使用1種,亦可將2種以上組合使用。
關於此等之藥理成分的含有量,係因應藥理成分之種類或液劑的用途適當設定。
此外,在本發明所使用之液劑,除了前述成分之外,亦可因應必要,含有緩衝劑、張力劑、助溶劑、黏性基劑、鉗合劑、冷卻劑、防腐劑、穩定劑、界面活性劑等添加劑。
作為緩衝劑,係例如可舉出磷酸緩衝劑、硼酸緩衝劑、檸檬酸緩衝劑、酒石酸緩衝劑、醋酸緩衝劑、Tris緩衝劑、胺基酸等。此等之緩衝劑可單獨使用1種,亦可將2種以上組合使用。
作為張力劑,係可舉出山梨醇、葡萄糖、甘露糖醇等糖類;甘油、丙二醇等多元醇類;氯化鈉等鹽類;硼酸等。此等之張力劑可單獨使用1種,亦可將2種以上組合使用。
作為助溶劑,係例如可舉出聚氧乙烯山梨醇酐單油酸酯、聚氧乙烯氫化蓖麻油、泰洛沙伯(tyloxapol)、普流尼克(pluronic)等非離子性界面活性劑;甘油、聚乙烯二醇等多元醇等。此等之助溶劑可單獨使用1種,亦可將2種以上組合使用。
作為黏性基劑,係例如可舉出聚乙烯吡咯啶酮、聚乙二醇、聚乙烯醇、羧基乙烯聚合物、三仙膠、軟骨素硫酸鈉、玻尿酸鈉等水溶性高分子;羥丙甲纖維素、羥乙
基纖維素、甲基纖維素、羥丙基纖維素、羥丙基甲基纖維素、羧甲基纖維素鈉等纖維素類等。此等之黏性基劑可單獨使用1種,亦可將2種以上混合使用。
作為鉗合劑,係例如可舉出乙二胺四乙酸、檸檬酸、琥珀酸、抗壞血酸、三羥甲基胺基甲烷、氮三醋酸、1-羥乙烷-1,1-二膦酸、聚磷酸、偏磷酸、六偏磷酸、此等之藥學上所容許等。此等之鉗合劑可單獨使用1種,亦可將2種以上組合使用。
作為冷卻劑,係例如可舉出1-薄荷腦、龍腦、樟腦、尤加利樹油等。此等之冷卻劑可單獨使用1種,亦可將2種以上組合使用。
作為防腐劑,係例如可舉出山梨酸或其鹽、安息香酸或其鹽、對羥苯甲酸甲酯、對羥苯甲酸乙酯、對羥苯甲酸丙酯、氯丁醇、洛赫西定葡萄糖酸鹽、硼酸、去氫醋酸或其鹽、氯化芐烷銨、氯化芐乙氧銨(benzethonium chloride)、苯甲醇、氯化鋅、對氯間二甲苯酚(para chloro meta xylenol)、氯甲酚、苯乙醇、泊利氯銨(polidronium chloride)、硫柳汞、二丁基羥甲苯、鹽酸聚己雙胍(polihexanide HCl)等。此等之防腐劑可單獨使用1種,亦可將2種以上組合使用。
作為穩定劑,係例如可舉出聚乙烯吡咯啶酮、亞硫酸鹽、單乙醇胺、甘油、丙二醇、環糊精、葡聚醣(dextran)、抗壞血酸、乙二胺四乙酸鹽、牛磺酸、生育酚、二丁基羥甲苯等。此等之穩定劑可單獨使用1種,亦可將2種以上組
合使用。
作為界面活性劑,係例如可舉出泰洛沙伯、聚氧乙烯氫化蓖麻油、聚氧乙烯聚氧丙稀嵌段共聚物、聚氧乙烯山梨醇酐脂肪酸酯、辛苯聚醇(octoxynol)等非離子性界面活性劑;烷基二胺基乙甘胺酸、月桂基二甲基胺基醋酸甜菜鹼等兩性界面活性劑;烷基硫酸鹽、N-醯基牛磺酸鹽、聚氧乙烯烷基醚磷酸鹽、聚氧乙烯烷基醚硫酸鹽等陰離子界面活性劑;烷基吡啶陽離子鹽、烷基胺鹽等陽離子界面活性劑等。此等之界面活性劑可單獨使用1種,亦可將2種以上組合使用。
關於此等之添加劑的濃度,係可因應添加劑的種類或液劑的用途適當設定。
本發明所使用之液劑的形態,係只要為含有水作為基劑者即可,例如可舉出可為水溶液狀、懸濁液狀、乳液狀等任一者,宜為水溶液狀。
關於本發明所使用之液劑的用途,係無特別限制,例如可舉出醫藥、隱形眼鏡清潔用品等。作為醫藥,具體而言可舉出點眼劑(包含配戴隱形眼鏡時亦可點眼之隱形眼鏡用點眼劑)、洗眼劑等眼科用劑;點鼻劑、點耳劑等耳鼻喉科用液劑;內服劑、注射劑、外用劑等。此外,作為隱形眼鏡清潔用品,具體而言可舉出隱形眼鏡配戴液、隱形眼鏡用多用途溶液等。
在此等之液劑的用途中,眼科用液劑、耳鼻喉科液劑、及隱形眼鏡清潔用品,尤其在點眼劑,多將氯苯那
敏及/或其鹽設定為較低含量,而有氯苯那敏及/或其鹽的含有量稍微降低,便會對其藥理作用產生很大影響之特有的問題點。對此,根據本發明,在穩定維持氯苯那敏及/或其鹽之含有量的效果優良,即使為將氯苯那敏及/或其鹽設定為較低含量之液劑,亦可經時性穩定維持其藥理作用。有鑑於如此之本發明的效果,作為本發明所使用之適當例,可舉出眼科用液劑、耳鼻喉科用液劑、及隱形眼鏡清潔用品,尤宜舉出點眼劑。
此外,本發明所使用之液劑,係可為充填有複數次分之使用量,重複使用之多次劑量(multi dose)型,此外亦可為充填有單次分之使用量,1次用畢之單一劑量(unit dose)型。
本發明所使用之液劑,係可因應其形態或用途等,依照公知之調製法製造,例如,在為醫藥的情況下,可使用第十六改正日本藥局方 製劑總則所記載之方法製造。
容器
在本發明之含氯苯那敏類製品,係為了收容前述液劑,使用具備容器本體、注出部、蓋部,其中前述注出部之內部空間壁面及/或蓋部之與注出部之注出口對向的壁面為以含聚對苯二甲酸丁二酯之樹脂構成的容器。
<容器之構造>
構成前述容器之容器本體,為收容前述液劑的部位。關於該容器本體的形狀、大小並無特別限制,可因應收容
之液劑種類適當設定。
所謂構成前述容器之注出部,係具有連通容器本體與容器本體外部之間的內部空間,並具備將收容於容器本體之液劑注出的注出口,其中前述注出口為以與容器本體之開口部連通的方式設置,將收容於該容器本體之液劑,透過該內部空間自該注出口注出(排出)至容器外部的部位。該注出部,只要為以可將收容於容器本體之液劑自注出口注出至容器本體外的方式構成,關於其構造便無特別限制,例如,可為使液劑以液滴狀注出的方式構成,此外亦可為使液劑以非液滴狀流出的方式構成。從能夠更有效發揮本發明之效果的觀點,以前述注出部為使液劑以液滴狀注出之方式構成的管嘴為佳。此外,在該注出部,例如,亦可設置如內栓管嘴或開孔內栓的內栓。
前述注出部之一部或全部,係可為與容器本體微一體成形者。此外,前述注出部,亦可為插入至容器本體之開口部的內腔或者為裝設於外側者。
此外,構成前述容器之蓋部,為堵住前述注出口的部位。該蓋部只要具備與容器本體及/或注出口嵌合的構造即可。更具體而言,在本發明之含氯苯那敏類製品為多次劑量型的情況下,只要為與容器本體及/或注出口以可裝卸方式嵌合之構造即可,此外在本發明之含氯苯那敏類製品為單一劑量型的情況下,只要為與容器本體及/或注出口以可分離方式嵌合之構造即可。與容器本體及/或注出口以可裝卸方式嵌合之構造的適當例,可舉出相對於容器本體
及/或注出部,以藉由螺旋嵌合而可裝卸方式安裝之蓋部。在藉由螺旋嵌合,將蓋部與容器本體及/或注出部以可裝卸方式安裝的情況下,只要於蓋部設置有與容器本體及/或注出部之螺旋部螺合的螺旋部即可。
前述容器的形狀,係可因應收容之含氯苯那敏類製品的用途適當設定。具體而言,可舉出點眼容器、洗眼容器、點鼻容器等。
將在本發明所使用之容器之具體態樣的例表示於圖1~6。
圖1為點眼容器之一態樣例的剖面圖。圖2為圖1所示之點眼容器的部分放大剖面圖。在圖1所示的點眼容器,於容器本體1之開口部的內腔,插入有可將前述液劑以液滴狀注出的注出部2,再者蓋部3以藉由螺旋嵌合而可裝卸方式安裝於容器本體1,堵住注出部2的注出口。在該點眼容器,收容於容器本體1之液劑,係透過注出部2之內部空間4自注出口注出至容器外。圖1所示之點眼容器,雖可使用於單一劑量型之液劑的收容,但適合使用於多次劑量性之液劑的收容。
圖3為點眼容器之一態樣的剖面圖。在圖3所示之點眼容器,容器本體1與注出部2,不使用黏著或機械性接合,以同一素材一體成形,可透過注出部2之內部空間4自注出口至容器外將前述液劑以液滴狀注出。在圖3省略蓋部,為方便而插入假設線(虛線)。在圖3所示之點眼容器,位於假設線下方的容器構件相當於容器本體1,位於假設線
上方的容器構件相當於注出部2。圖3所示之點眼容器,雖可使用於單一劑量型之液劑的收容,但適合使用於多次劑量型之液劑的收容。
圖4為點眼容器之一態樣的剖面圖,圖5為圖4所示之點眼容器的部分放大剖面圖。在圖4所示之點眼劑,容器本體1、注出部2、及蓋部3為一體成形。雖然注出部2與蓋部3為已連結狀態,但使用時藉由將此等分離,收容於容器本體1之前述液劑,可透過注出部2之內部空間4自注出口注出至容器外。在圖4及圖5,為方便而插入假設線(虛線)。在圖4及圖5中,2條假設線間之容器構件相當於注出部2,2條假設線間之空間為注出部2之內部空間4。圖4所示之點眼容器,適合使用於單一劑量型之液劑的收容。
圖6為洗眼容器的剖面圖。在圖6所示之洗眼容器,容器本體1與注出部2的一部分為一體成形。在該洗眼容器,收容於容器本體1之前述液劑,係透過注出部2織內部空間4自注出口注出至容器外。在圖6,為方便而插入假設線(虛線)。
在圖1~6,雖舉出點眼容器及洗眼容器之具體態樣,但在本發明,非為受此等之構造或形狀所限定者,此外,即使為點眼容器及洗眼容器以外的容器,只要具備預定之特徵便可使用。
<容器之構成素材>
前述容器中,前述注出部之內部空間壁面,及前述蓋部之與前述注出口對向之壁面中至少一方,為以含聚對苯
二甲酸丁二酯(PBT)之樹脂構成。在此,所謂「在蓋部之與前述注出口對向之壁面」,相當於在將蓋部安裝於容器本體及/或注出部時覆蓋注出口之蓋部的內壁部分。具體而言,若舉出圖2、5、及6為例,則元件符號5所示之面部分相當於「注出部之內部空間壁面」,元件符號6所示之面部分相當於「在蓋部之與前述注出口對向之壁面」。
如此利用含聚對苯二甲酸丁二酯之樹脂,構成注出部之內部空間壁面及/或在蓋部之與注出部之注出口對向之壁面,可有效抑制氯苯那敏及/或其鹽對該注出部及/或蓋部的吸附、積蓄,而穩定維持液劑中之氯苯那敏及/或其鹽的含有量。
構成前述注出部之內部空間壁面及/或前述蓋部之與注出部之注出口對向之壁面的樹脂,係亦可為聚對苯二甲酸丁二酯單獨構成者,此外亦可為聚對苯二甲酸丁二酯與其他聚合物的摻聚物所構成者。作為構成前述注出部之壁面及/或前述蓋部之與注出部之注出口對向之壁面的樹脂,在使用聚對苯二甲酸丁二酯與其他聚合物之摻聚物的情況下,以發揮本發明之效果為限,關於此等之混合比例並無特別限制,相對於該摻聚物之總量,期望聚對苯二甲酸丁二酯佔50w/w%以上,宜為佔70w/w%以上,更宜為佔90w/w%以上。
在前述容器,只要注出部之內部空間壁面,及蓋部之與注出部之注出口對向之壁面的至少一方,含聚對苯二甲酸丁二酯即可。例如,在採用以液滴狀注出液劑之注
出部(例如,使液劑以液滴狀滴下之方式構成的管嘴)的情況下,從有效抑制氯苯那敏及/或其鹽之含有量降低的觀點,至少,以注出部之內部空間壁面為以含聚對苯二甲酸丁二酯之樹脂構成為佳,以注出部之內部空間壁面及蓋部之與注出部之注出口對向之壁面兩者皆以含聚對苯二甲酸丁二酯之樹脂構成為更佳。此外,例如,在採用以非液滴狀注出液劑之注出部的情況下,從有效抑制氯苯那敏及/或其鹽之含有量降低的觀點,至少,以蓋部之與注出部之注出口對向之壁面為以含聚對苯二甲酸丁二酯之樹脂構成為佳,以注出部之內部空間壁面及蓋部之與注出部之注出口對向之壁面兩者皆以含聚對苯二甲酸丁二酯之樹脂構成為更佳。
注出部之內部空間壁面及/或蓋部之與注出部之注出口對向之壁面,係只要為由含聚對苯二甲酸丁二酯之樹脂構成,關於此等之壁面以外部位的構成素材便無特別限制。例如,此等之壁面以外部位可為以含聚對苯二甲酸丁二酯之樹脂構成,或者亦可為以聚對苯二甲酸丁二酯以外的素材構成。
前述容器,在容器本體與注出部為一體成形的情況下,容器本體係由與注出部相同之樹脂構成。
此外,前述容器,在將前述注出部插入前述容器本體開口部之內腔進行安裝的情況下,容器本體係可舉出為玻璃製或塑膠製之任一者,宜舉出為塑膠製。在如此態樣之容器,在將容器本體為塑膠製的情況下,關於形成容
器本體之樹脂種類並無特別限制,例如可舉出聚對苯二甲酸乙二酯、聚對苯二甲酸丁二酯、聚苯乙烯、丙烯腈丁二烯苯乙烯等。在此等中,由於聚對苯二甲酸乙二酯在具備優良之成形性的同時,可抑制氯苯那敏及/或其鹽之吸附,因此適合使用作為形成容器本體的樹脂。
本發明之穩定化方法,為含氯苯那敏及/或其藥學上所容許之鹽且pH為7.0以上之液劑的穩定化方法,其特徵為將該液劑,收容至構成容器內壁之區域的至少一部分為以含聚對苯二甲酸丁二酯之樹脂構成的容器者。
關於在本發明之穩定化方法所使用之「含氯苯那敏及/或其藥學上所容許之鹽且pH為7.0以上之液劑」,與在前述含氯苯那敏類製品中所使用之液劑為相同。
此外,在本發明之穩定化方法所使用之容器,為構成容器內壁之區域的至少一部分,為以含聚對苯二甲酸丁二酯之樹脂構成的容器。所謂構成容器內壁之區域,為形成收容液劑之容器之內部空間的壁面區域,具體而言,由容器本體之內壁面、注出部之內壁面、及蓋部之內壁面形成。亦即,本發明之穩定化方法所使用之容器,只要容器本體之內壁面、注出部之內壁面、及蓋部之內壁面中至少一部分,為以含對苯二甲酸丁二酯之樹脂構成即可。所謂注出部之內壁面,為注出部之內部空間的壁面部分。此外,所謂蓋部之內壁面,為與前述注出部之注出口對向的
蓋部之壁面區域。關於容器本體、注出部、及蓋部之構造上的構成,如前述「1.含氯苯那敏類製品」之「容器」欄的記載。
在本發明之穩定化方法所使用之容器,只要構成容器內壁之區域的至少一部分為以含前述聚合物之樹脂構成即可,宜舉出在前述含氯苯那敏類製品所使用之容器。
本發明之穩定化方法,係在含氯苯那敏及/或其藥學上所容許之鹽且pH為7.0以上之液劑中,由於可有效抑制氯苯那敏及/或其鹽之含量降低,提升氯苯那敏及/或其鹽之保存穩定性,因此亦可作為該液劑之保存方法實施。
以下,舉出實施例具體說明本發明,但本發明非受此等之任何限制者。另外,在以下的試驗例中,氯苯那敏馬來酸鹽,係使用日局馬來酸氯苯那敏(金剛化學股份有限公司製)。
試驗例1:氯苯那敏馬來酸鹽之吸附性評價(檢討pH造成的影響)
調製表2及表3所示之液劑測定在收容至各種容器進行保存時之氯苯那敏馬來酸鹽含有量的經時變化。具體而言,依照通常方法調製表2及表3所示之液劑,收容至表1所示之各容器,並藉由以密封狀態在50℃之溫度條件下靜置8週進行保存。此時,在容器1及3的情況下液劑之收容量設為10mL,在容器2的情況下液劑之收容量設為5mL。此外,在容器1及容器3的情況下,保存中以使蓋部在下方,容器
本體之底部在上方,將容器倒立的狀態靜置。在開始保存前,自保存開始2週後及8週後,對容器中之液劑進行取樣,藉由以HPLC測定液劑中之氯苯那敏馬來酸鹽的含有量,算出保存後之氯苯那敏馬來酸鹽的殘存率(%)。另外,容器3為以往通用之點眼容器的例。此外,已知玻璃一般而言不會確認有藥物之吸附,容器2為氯苯那敏馬來酸鹽難以吸附之容器的例。
#1 10mL容積之聚對苯二甲酸乙二酯製的點眼容器。
#2 聚對苯二甲酸丁二酯製管嘴(點眼容器用之管嘴,商品名「NOVADURAN(登錄商標)5010R5X」,Mitsubishi Engineering-Plastics股份有限公司製)。
#3 聚乙烯製管嘴(低密度聚乙烯樹脂製之點眼容器用管嘴,商品名「NOVATEC(登錄商標)LD LJ808」,日本聚乙烯股份有限公司製)。
#4 聚丙烯製之蓋。
將所獲得之結果表示於表2及3。根據此結果,在收容至安裝聚乙烯製管嘴之容器3的液劑,雖然在pH為6.5以下,不會確認氯苯那敏馬來酸鹽之含有量降低而可穩定
維持,但若pH為7.0以上,則氯苯那敏馬來酸鹽之含有量會降低,尤其在pH8.0以上的情況下,其含有量之降低變為顯著。相對於此,收容至安裝聚對苯二甲酸丁二酯製管嘴之容器1的液劑,即使pH為7.0以上,亦可充分抑制氯苯那敏馬來酸鹽之含有量的降低。此外,根據在為玻璃製安瓿之容器2即使pH為7.0以上亦沒有確認到氯苯那敏馬來酸鹽之含有量降低,可判明收容至容器3之液劑的氯苯那敏馬來酸鹽之含有量的降低,係起因於對聚乙烯製管嘴的吸附。
亦即,根據此結果,在含氯苯那敏馬來酸鹽之液劑,若為pH7.0以上,氯苯那敏馬來酸鹽會吸附至聚乙烯製管嘴,使液劑中之氯苯那敏馬來酸鹽之含有量降低,但若使用聚對苯二甲酸丁二酯製管嘴,則確認到即使為pH7.0以上,氯苯那敏馬來酸鹽之對該管嘴的吸附亦受到抑制,穩定維持液劑中之氯苯那敏的含有量。
[表2]
試驗例2:氯苯那敏馬來酸鹽之吸附性評價(檢討其他含有成分造成的影響)
依照通常方法調製表4及表5所示之液劑,並以與前述試驗例1同樣的方法,測定在收容至表1所示之各種容器進行保存時之氯苯那敏馬來酸鹽的殘存率。另外,在本試驗中,於50℃之保存期間設定為4週。
將所獲得之結果表示於表4及5。根據此結果,在含氯苯那敏馬來酸鹽,pH為7.0以上之液性,變更緩衝劑的種類,或添加鉗合劑,在收容至安裝聚對苯二甲酸丁二酯製管嘴之容器1的情況下,確認到可充分抑制氯苯那敏馬來酸鹽之含有量降低的事實。
[表4]
試驗例3:氯苯那敏馬來酸鹽之吸附性評價(檢討其他含有成分、氯苯那敏馬來酸鹽之含有量造成的影響)
依照通常方法調製表6所示之液劑,並以與前述試驗例1同樣的方法,測定在收容至表1所示之各種容器進行保存時之氯苯那敏馬來酸鹽的殘存率。另外,在本試驗中,於50℃之保存期間設定為4週。
將所獲得之結果表示於表6。根據此結果,在含氯苯那敏馬來酸鹽,pH為7.0以上之液性,添加普拉洛芬,或將氯苯那敏馬來酸鹽從低含有量變動為高含有量,在收容至安裝聚對苯二甲酸丁二酯製管嘴之容器1的情況下,亦確認到可充分抑制氯苯那敏馬來酸鹽之含有量降低的事實。
[表6]
參考試驗例1:氯苯那敏馬來酸鹽以外之藥理成分之吸附性評價
依照通常方法調製表7所示之液劑,並以與前述試驗例1同樣的方法,收容至表1所示之各種容器進行保存,並藉由HPLC測定各藥理成分(待布卡因鹽酸鹽、萘甲唑啉鹽酸鹽、吡哆醇鹽酸鹽)之含有量的經時變化。另外,在本試驗中,於50℃之保存期間設定為2週。
將所獲得之結果表示於表7。在含待布卡因鹽酸鹽之液劑,若調整為pH8.5,則待布卡因鹽酸鹽不會溶解而成為白濁狀態。此外,在含萘甲唑啉鹽酸鹽之液劑,不論收容至任一者之容器,萘甲唑啉鹽酸鹽之殘存率皆顯著降低。另一方面,在含吡哆醇鹽酸鹽之液劑,不論收容至認一者之容器,吡哆醇鹽酸鹽之殘存率皆維持很高,不確認有對容器之吸附的課題。
從以上的結果,確認到pH7.0以上之液劑的藥理成分,會吸附至安裝聚乙烯製管嘴之容器,卻不會吸附至安裝聚對苯二甲酸丁二酯製管嘴之容器的特性,是在氯苯那敏馬來酸鹽確認到之特有的特性。
[表7]
參考試驗例2:脂溶性抗氧化劑的評價
調製表8所示之液劑,並對與該液劑為接觸狀態下之聚乙烯或聚對苯二甲酸丁二酯進行關於脂溶性抗氧化劑(丁羥甲氧苯)之吸附性的評價。具體而言,於收容6mL之液劑的玻璃製安瓿容器,放入1個聚乙烯製管嘴(低密度聚乙烯樹脂製之點眼容器用管嘴,商品名「NOVATEC(登錄商標)LD LJ808」,日本聚乙烯股份有限公司製)或者放入1個聚對苯二甲酸丁二酯製管嘴(點眼容器用之管嘴,商品名「NOVADURAN(登錄商標)5010R5X」,Mitsubishi Engineering-Plastics股份有限公司製),藉由將安瓿容器之開口部熔封的方式進行密封。以管嘴浸漬在液劑中的狀態於50℃之溫度條件靜置2週。接著,將密封之玻璃製安瓿容器開封,藉由以HPLC測定液劑中之脂溶性抗氧化劑含有量,算出保存後之脂溶性抗氧化劑的殘存率(%)。此外,為了比較,以與上述同樣的方法不放入管嘴進行試驗。
將結果表示於表8。從參考例4-1~4-3的結果可明顯看出,丁羥甲氧苯即使在浸漬有聚乙烯製或聚對苯二甲酸丁二酯製之任一管嘴的情況下,液劑中的含量亦幾乎沒有變化,穩定維持,可確認對聚乙烯製管嘴之吸附,為在氯苯那敏馬來酸鹽確認到之特有的問題。
[表8]
PBT:聚對苯二甲酸丁二酯。
PE:聚乙烯。
1‧‧‧容器本體
2‧‧‧注出部
3‧‧‧蓋部
Claims (13)
- 一種含氯苯那敏類製品,是由將含氯苯那敏及/或其藥學上所容許之鹽且pH為7.0以上之液劑收容於容器而成者,其特徵為:前述容器具備收容前述液劑的容器本體、具有注出收容於前述容器本體之液劑之注出口的注出部、及堵住前述注出口的蓋部,其中,前述注出部之內部空間壁面,及前述蓋部中與前述注出口對向之壁面之至少一方,為以含聚對苯二甲酸丁二酯之樹脂構成。
- 如請求項1之含氯苯那敏類製品,其中前述注出部為將前述液劑以液滴狀注出之管嘴,該管嘴之內部空間壁面為以含聚對苯二甲酸丁二酯之樹脂構成。
- 如請求項1或2之含氯苯那敏類製品,其中前述容器本體係以含聚對苯二甲酸乙二酯之樹脂構成。
- 如請求項1或2之含氯苯那敏類製品,其中前述液劑之pH為7.5~9.0。
- 如請求項1或2之含氯苯那敏類製品,其中於前述液劑含氯苯那敏及/或其藥學上所容許之鹽0.0006~0.2w/v%。
- 如請求項1或2之含氯苯那敏類製品,其中前述液劑為點眼劑。
- 一種穩定化方法,為含氯苯那敏及/或其藥學上所容許之鹽且pH為7.0以上之液劑的穩定化方法,其特徵為: 於構成容器內壁之至少一部分區域為以含聚對苯二甲酸丁二酯之樹脂構成的容器,收容含氯苯那敏及/或其藥學上所容許之鹽的液劑。
- 如請求項7之穩定化方法,其中前述容器具備收容前述液劑的容器本體、具有注出收容於前述容器本體之液劑之注出口的注出部、及堵住前述注出口的蓋部;且前述注出部之內部空間壁面,及前述蓋部中與前述注出口對向之壁面的至少一方,為以含聚對苯二甲酸丁二酯之樹脂構成。
- 如請求項7或8之穩定化方法,其中前述注出部為將前述液劑以液滴狀注出之管嘴,該管嘴之內部空間壁面為以含聚對苯二甲酸丁二酯之樹脂構成。
- 如請求項7或8之穩定化方法,其中前述容器本體為以含聚對苯二甲酸乙二酯之樹脂構成。
- 如請求項7或8之穩定化方法,其中前述液劑之pH為7.5~9.0。
- 如請求項7或8之穩定化方法,其中於前述液劑含氯苯那敏及/或其藥學上所容許之鹽0.0006~0.2w/v%。
- 如請求項7或8之穩定化方法,其中前述液劑為點眼劑。
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WO2017043488A1 (ja) * | 2015-09-08 | 2017-03-16 | ロート製薬株式会社 | 眼科組成物 |
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JPH05261139A (ja) * | 1992-03-19 | 1993-10-12 | Eisai Co Ltd | 医薬品の分包剤 |
US5725874A (en) * | 1993-05-19 | 1998-03-10 | Hisamitsu Pharmaceutical Co., Inc. | Solubilizer and external preparations containing the same |
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FR2770495B1 (fr) * | 1997-11-04 | 1999-12-24 | Transphyto Sa | Dispositif de conditionnement pour liquide a distribuer goutte a goutte |
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