JP2024040421A - Aqueous liquid preparation - Google Patents
Aqueous liquid preparation Download PDFInfo
- Publication number
- JP2024040421A JP2024040421A JP2024020182A JP2024020182A JP2024040421A JP 2024040421 A JP2024040421 A JP 2024040421A JP 2024020182 A JP2024020182 A JP 2024020182A JP 2024020182 A JP2024020182 A JP 2024020182A JP 2024040421 A JP2024040421 A JP 2024040421A
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- JP
- Japan
- Prior art keywords
- salt
- aqueous solution
- acid
- salts
- preservative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 239000007788 liquid Substances 0.000 title claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 121
- 239000003755 preservative agent Substances 0.000 claims abstract description 87
- 230000002335 preservative effect Effects 0.000 claims abstract description 81
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 claims abstract description 46
- 229960003679 brimonidine Drugs 0.000 claims abstract description 45
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229960001484 edetic acid Drugs 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000007864 aqueous solution Substances 0.000 claims description 93
- 239000000872 buffer Substances 0.000 claims description 40
- 230000007246 mechanism Effects 0.000 claims description 18
- 239000003889 eye drop Substances 0.000 claims description 15
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 15
- 239000008363 phosphate buffer Substances 0.000 claims description 13
- 239000007983 Tris buffer Substances 0.000 claims description 12
- IAVUPMFITXYVAF-XPUUQOCRSA-N dorzolamide Chemical compound CCN[C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-XPUUQOCRSA-N 0.000 claims description 7
- 229960003933 dorzolamide Drugs 0.000 claims description 7
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000003385 bacteriostatic effect Effects 0.000 abstract description 11
- 239000000203 mixture Substances 0.000 abstract description 10
- 238000009472 formulation Methods 0.000 abstract description 6
- 238000004321 preservation Methods 0.000 abstract description 3
- 239000006172 buffering agent Substances 0.000 abstract description 2
- 238000002156 mixing Methods 0.000 abstract description 2
- -1 sodium edetate dihydrate Chemical class 0.000 description 41
- 235000010338 boric acid Nutrition 0.000 description 33
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 32
- 229960002645 boric acid Drugs 0.000 description 31
- 239000004327 boric acid Substances 0.000 description 27
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 22
- 241000894006 Bacteria Species 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 238000012360 testing method Methods 0.000 description 16
- 229910052783 alkali metal Inorganic materials 0.000 description 14
- 238000010998 test method Methods 0.000 description 12
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 10
- 229910021538 borax Inorganic materials 0.000 description 10
- 239000004328 sodium tetraborate Substances 0.000 description 10
- 235000010339 sodium tetraborate Nutrition 0.000 description 10
- IWEGDQUCWQFKHS-UHFFFAOYSA-N 1-(1,3-dioxolan-2-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical group O1C(C)(C)C(C)(C)OB1C1=CN(CC2OCCO2)N=C1 IWEGDQUCWQFKHS-UHFFFAOYSA-N 0.000 description 9
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 9
- 229960001724 brimonidine tartrate Drugs 0.000 description 9
- 229940037001 sodium edetate Drugs 0.000 description 9
- 235000015165 citric acid Nutrition 0.000 description 8
- 241000233866 Fungi Species 0.000 description 7
- 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 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 229940012356 eye drops Drugs 0.000 description 7
- 159000000000 sodium salts Chemical class 0.000 description 7
- 239000011975 tartaric acid Substances 0.000 description 7
- 235000002906 tartaric acid Nutrition 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229920001817 Agar Polymers 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000008272 agar Substances 0.000 description 6
- 229940009662 edetate Drugs 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 230000000144 pharmacologic effect Effects 0.000 description 6
- 159000000001 potassium salts Chemical class 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- 229960000281 trometamol Drugs 0.000 description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 230000003204 osmotic effect Effects 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 159000000007 calcium salts Chemical class 0.000 description 4
- 238000011109 contamination Methods 0.000 description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 4
- 159000000003 magnesium salts Chemical class 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- 230000000813 microbial effect Effects 0.000 description 4
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 4
- 235000019799 monosodium phosphate Nutrition 0.000 description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 150000005846 sugar alcohols Polymers 0.000 description 4
- 239000002562 thickening agent Substances 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 3
- 230000003139 buffering effect Effects 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- XDVOLDOITVSJGL-UHFFFAOYSA-N 3,7-dihydroxy-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane Chemical compound O1B(O)OB2OB(O)OB1O2 XDVOLDOITVSJGL-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 240000006439 Aspergillus oryzae Species 0.000 description 2
- 235000002247 Aspergillus oryzae Nutrition 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010018307 Glaucoma and ocular hypertension Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 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
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 description 2
- 210000001742 aqueous humor Anatomy 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
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- 230000001580 bacterial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 229940097320 beta blocking agent Drugs 0.000 description 2
- 125000005619 boric acid group Chemical class 0.000 description 2
- 239000005018 casein Substances 0.000 description 2
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 2
- 235000021240 caseins Nutrition 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 239000002826 coolant Substances 0.000 description 2
- 229940124274 edetate disodium Drugs 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 230000036512 infertility Effects 0.000 description 2
- 230000004410 intraocular pressure Effects 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 229960002216 methylparaben Drugs 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
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- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
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- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
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- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 description 1
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- 208000010412 Glaucoma Diseases 0.000 description 1
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- OMCPLEZZPVJJIS-UHFFFAOYSA-N Hypadil (TN) Chemical compound C1C(O[N+]([O-])=O)COC2=C1C=CC=C2OCC(O)CNC(C)C OMCPLEZZPVJJIS-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
Description
本発明は、ブリモニジン及び／又はその塩を含み、少なくとも静菌作用が認められる水準以上の保存効力を備えた水性液剤に関する。 The present invention relates to an aqueous liquid preparation containing brimonidine and/or a salt thereof and having a preservative efficacy at least at a level at which bacteriostatic action is observed.
点眼液や洗眼液等の水性液剤には、微生物の繁殖を防止するために、通常、塩化ベンザルコニウム、メチルパラベン等の保存剤が配合されている。しかしながら、保存剤は、細菌の繁殖を防止できる一方、刺激性や細胞毒性を示すことがあることが知られている（非特許文献１参照）。 Aqueous solutions such as eye drops and eye washes usually contain preservatives such as benzalkonium chloride and methylparaben to prevent the growth of microorganisms. However, while preservatives can prevent the proliferation of bacteria, it is known that they can be irritating and cytotoxic (see Non-Patent Document 1).
従来、保存剤を含まない水性液剤において保存時の細菌の繁殖を防止するために、一旦外側に浸出した水性液剤の容器内への逆流を防止する機構、及び／又は異物（微生物等の）の容器内への侵入を防止する機構を有するマルチドーズ型容器（以下、「マルチドーズ型保存剤フリー容器」と表記することがある）に収容して使用されている（例えば、特許文献１～４等参照）。 Conventionally, in order to prevent bacterial growth during storage in aqueous solutions that do not contain preservatives, mechanisms have been developed to prevent the aqueous solutions that have leaked out from flowing back into the container, and/or to prevent foreign substances (such as microorganisms). It is used in a multi-dose container (hereinafter sometimes referred to as a "multi-dose preservative-free container") that has a mechanism to prevent intrusion into the container (for example, Patent Documents 1 to 4). etc.).
一方、ブリモニジン及びその塩は、アドレナリンα２受容体作動薬として知られており、眼房水産生抑制と共にぶどう膜強膜流出路を介した眼房水の流出を促進することによって、眼圧を低下させる作用があり、従来、緑内障や高眼圧症の治療に使用されている。 On the other hand, brimonidine and its salts are known as adrenergic α2 receptor agonists, and reduce intraocular pressure by suppressing aqueous humor production and promoting the outflow of aqueous humor through the uveoscleral outflow tract. It has been used to treat glaucoma and ocular hypertension.
本発明の目的は、ブリモニジン及び／又はその塩を含む水性液剤に関する製剤技術を提供することである。 An object of the present invention is to provide a formulation technique for an aqueous solution containing brimonidine and/or a salt thereof.
本発明者は、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含む水性液剤は、保存剤を実質的に含まなくても、少なくとも静菌作用が認められる水準以上の保存効力を備え得ることを見出した。本発明は、かかる知見に基づいて、更に検討を重ねることにより完成したものである。 The present inventor has determined that an aqueous solution containing brimonidine and/or its salt, edetic acid and/or its salt, and a buffer can exhibit at least a level of bacteriostatic action even if it does not substantially contain a preservative. It has been found that the above preservative effect can be achieved. The present invention was completed through further studies based on this knowledge.
即ち、本発明は、下記に掲げる態様の発明を提供する。
項１． ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含み、保存剤を実質的に含まない、水性液剤。
項２． 緩衝剤が、ホウ酸緩衝剤、リン酸緩衝剤、及びトリス緩衝剤よりなる群から選択される少なくとも１種である、項１に記載の水性液剤。
項３． エデト酸及び／又はその塩の濃度が０．００５～０．５ｗ／ｖ％である、項１又は２に記載の水性液剤。
項４． ブリモニジン及び／又はその塩の濃度が０．０５～０．２ｗ／ｖ％である、項１～３のいずれかに記載の水性液剤。
項５． ｐＨが６～８である、項１～４のいずれかに記載の水性液剤。
項６． 点眼液である、項１～５のいずれかに記載の水性液剤。
項７． 一旦外側に浸出した水性液剤の容器内への逆流を防止する機構、及び／又は異物の容器内への混入を防止する機構を有するマルチドーズ型容器に収容されている、項１～６のいずれかに記載の水性液剤。
項８． ブリモニジン及び／又はその塩がブリモニジン酒石酸塩であり、
ブリモニジン及び／又はその塩の濃度が０．０５～０．２ｗ／ｖ％であり、
緩衝剤が、ホウ酸緩衝剤、リン酸緩衝剤、及びトリス緩衝剤よりなる群から選択される少なくとも１種であり、
エデト酸及び／又はその塩がエデト酸ナトリウム二水和物であり、
エデト酸及び／又はその塩の濃度が０．００５～０．５ｗ／ｖ％であり、
ｐＨが６～８であり、且つ
一旦外側に浸出した水性液剤の容器内への逆流を防止する機構、及び／又は異物の容器内への混入を防止する機構を有するマルチドーズ型容器に収容されている、水性液剤。
項９． ブリモニジン及び／又はその塩を含む水性液剤に保存効力を付与する方法であって、
保存剤を実質的に含まず、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤を含む水性液剤を調製する工程を含む、
保存効力の付与方法。
項１０． 緩衝剤が、ホウ酸緩衝剤、リン酸緩衝剤、及びトリス緩衝剤よりなる群から選択される少なくとも１種である、項９に記載の付与方法。
項１１． 水性液剤におけるエデト酸及び／又はその塩の濃度が０．００５～０．５ｗ／ｖ％である、項９又は１０に記載の付与方法。
項１２． ブリモニジン及び／又はその塩の濃度が０．０５～０．２ｗ／ｖ％である、項９～１１のいずれかに記載の付与方法。
項１３． 水性液剤のｐＨが６～８である、項９～１２のいずれかに記載の付与方法。
項１４． 水性液剤が点眼液である、項９～１３のいずれかに記載の付与方法。
項１５． 水性液剤が一旦外側に浸出した水性液剤の容器内への逆流を防止する機構、及び／又は異物の容器内への混入を防止する機構を有するマルチドーズ型容器に収容されている、項９～１４のいずれかに記載の付与方法。
項１６． 水性液剤におけるブリモニジン及び／又はその塩の濃度が０．０５～０．２ｗ／ｖ％であり、
緩衝剤が、ホウ酸緩衝剤、リン酸緩衝剤、及びトリス緩衝剤よりなる群から選択される少なくとも１種であり、
エデト酸及び／又はその塩がエデト酸ナトリウム二水和物であり、
水性液剤におけるエデト酸及び／又はその塩の濃度が０．００５～０．５ｗ／ｖ％であり、
水性液剤のｐＨが６～８であり、且つ
更に、調製した水性液剤を、一旦外側に浸出した水性液剤の容器内への逆流を防止する機構、及び／又は異物の容器内への混入を防止する機構を有するマルチドーズ型容器に収容する工程を含む、保存効力の付与方法。
項１７． ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含み、保存剤を実質的に含まない、水性液剤が、
一旦外側に浸出した水性液剤の容器内への逆流を防止する機構、及び／又は異物の容器内への混入を防止する機構を有するマルチドーズ型容器に収容されている、
ことを特徴とする、医薬製品。
That is, the present invention provides the inventions of the following aspects.
Item 1. An aqueous liquid preparation containing brimonidine and/or a salt thereof, edetic acid and/or a salt thereof, and a buffer, and substantially free of a preservative.
Item 2. Item 2. The aqueous solution according to Item 1, wherein the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, and Tris buffer.
Item 3. Item 3. The aqueous liquid preparation according to Item 1 or 2, wherein the concentration of edetic acid and/or its salt is 0.005 to 0.5 w/v%.
Item 4. Item 4. The aqueous liquid preparation according to any one of Items 1 to 3, wherein the concentration of brimonidine and/or its salt is 0.05 to 0.2 w/v%.
Item 5. Item 5. The aqueous liquid preparation according to any one of Items 1 to 4, which has a pH of 6 to 8.
Item 6. Item 6. The aqueous liquid preparation according to any one of Items 1 to 5, which is an eye drop.
Section 7. Any of Items 1 to 6, which is housed in a multi-dose type container that has a mechanism to prevent the aqueous solution once leached outside from flowing back into the container and/or a mechanism to prevent foreign matter from entering the container. An aqueous liquid preparation described in Crab.
Section 8. brimonidine and/or its salt is brimonidine tartrate;
The concentration of brimonidine and/or its salt is 0.05 to 0.2 w/v%,
The buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, and Tris buffer,
edetate and/or its salt is sodium edetate dihydrate,
The concentration of edetic acid and/or its salt is 0.005 to 0.5 w/v%,
It is housed in a multi-dose type container with a pH of 6 to 8 and which has a mechanism to prevent the aqueous solution once leached to the outside from flowing back into the container and/or a mechanism to prevent foreign matter from entering the container. Aqueous liquid formulation.
Item 9. A method for imparting preservative efficacy to an aqueous solution containing brimonidine and/or a salt thereof, the method comprising:
preparing an aqueous solution substantially free of preservatives and containing brimonidine and/or a salt thereof, edetic acid and/or a salt thereof, and a buffer;
Method of imparting preservative effect.
Item 10. 10. The method according to item 9, wherein the buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, and Tris buffer.
Item 11. Item 11. The method according to Item 9 or 10, wherein the concentration of edetic acid and/or its salt in the aqueous solution is 0.005 to 0.5 w/v%.
Item 12. Item 12. The method for applying according to any one of Items 9 to 11, wherein the concentration of brimonidine and/or its salt is 0.05 to 0.2 w/v%.
Item 13. Item 13. The method for applying according to any one of Items 9 to 12, wherein the pH of the aqueous solution is 6 to 8.
Section 14. Item 14. The application method according to any one of Items 9 to 13, wherein the aqueous solution is an eye drop.
Item 15. The aqueous solution is housed in a multi-dose container having a mechanism to prevent the aqueous solution from flowing back into the container once it has oozed out, and/or a mechanism to prevent foreign matter from entering the container. 14. The imparting method according to any one of 14.
Section 16. The concentration of brimonidine and/or its salt in the aqueous solution is 0.05 to 0.2 w/v%,
The buffer is at least one selected from the group consisting of borate buffer, phosphate buffer, and Tris buffer,
edetate and/or its salt is sodium edetate dihydrate,
The concentration of edetic acid and/or its salt in the aqueous solution is 0.005 to 0.5 w/v%,
The pH of the aqueous solution is 6 to 8, and the prepared aqueous solution is further provided with a mechanism that prevents the aqueous solution once leached outside from flowing back into the container and/or prevents foreign matter from entering the container. A method for imparting preservative efficacy, the method comprising the step of housing the container in a multi-dose container having a mechanism for imparting preservative efficacy.
Section 17. An aqueous liquid preparation containing brimonidine and/or a salt thereof, edetic acid and/or a salt thereof, and a buffer, and substantially free of a preservative,
Housed in a multi-dose container that has a mechanism to prevent the aqueous solution once leached to the outside from flowing back into the container and/or a mechanism to prevent foreign matter from entering the container.
A pharmaceutical product characterized by:
本発明の水性液剤によれば、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩との相乗作用によって、保存剤を実質的に含んでいなくても、少なくとも静菌作用が認められる水準以上の保存効力を備えることができる。そのため、本発明の水性液剤は、マルチドーズ型保存剤フリー容器に収容して使用しても、ノズルの外側表面での液残りによって生じ得る微生物汚染を防ぐことができ、点眼操作等によって投与される水性液剤の安全性をより高度に確保することができる。 According to the aqueous solution of the present invention, due to the synergistic action of brimonidine and/or its salt and edetic acid and/or its salt, at least bacteriostatic action is observed even if it does not substantially contain a preservative. It can have a preservative effect that exceeds the standard. Therefore, even when the aqueous liquid preparation of the present invention is stored in a multi-dose type preservative-free container and used, microbial contamination that may occur due to liquid residue on the outer surface of the nozzle can be prevented, and it can be administered by eye drop operation etc. The safety of aqueous liquid preparations can be ensured to a higher degree.
１．定義
本明細書において、「水性液剤」とは、水を基剤として含み液状を呈する製剤である。
1. Definition As used herein, the term "aqueous liquid preparation" refers to a preparation containing water as a base and exhibiting a liquid form.
本明細書において、「ブリモニジン」とは、アドレナリンα２受容体作動薬として公知の化合物であり、５－ブロモ－Ｎ－（４，５－ジヒドロ－１Ｈ－イミダゾール－２－イル）キノキサリン－６－アミンを指す。 As used herein, "brimonidine" is a compound known as an adrenergic α2 receptor agonist, and is 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine. refers to
本明細書において、「エデト酸」とは、別名エチレンジアミン四酢酸とも称される公知の化合物である。 In this specification, "edetic acid" is a known compound also called ethylenediaminetetraacetic acid.
本明細書において、「緩衝剤」とは、水性液剤の水素イオン濃度（ｐＨ）の変動を和らげる作用を持つ化合物又は混合物のことを指す。 As used herein, the term "buffer" refers to a compound or mixture that has the effect of moderating fluctuations in the hydrogen ion concentration (pH) of an aqueous solution.
本明細書において、「保存剤」とは、保存効力を有する成分であって、点眼剤で許容される濃度で該当の成分のみを含む水溶液にした場合、当該水溶液が第十七改正日本薬局方参考情報「保存効力試験法」においてカテゴリー「ＩＡ」で定められた判定基準に基づいて「適合」と判断されるものを指す。但し、本発明において、保存剤には、ホウ酸緩衝剤は包含されない。 As used herein, "preservative" refers to a component that has a preservative effect, and when an aqueous solution containing only the relevant component at an allowable concentration for eye drops, the aqueous solution is Refers to items that are judged to be ``conforming'' based on the criteria set forth in the category ``IA'' in the reference information ``Preservation efficacy testing method.'' However, in the present invention, the preservative does not include a boric acid buffer.
本明細書において、「保存剤を実質的に含まない」とは、保存剤の濃度が、保存剤のみでは保存効力を発揮し得ない濃度であることを指し、具体的には、保存剤のみを含む水溶液にした場合、当該水溶液が第十七改正日本薬局方 参考情報「保存効力試験法」においてカテゴリー「ＩＣ」で定められた基準に基づいて「適合」となる保存剤の最小濃度よりも少ないことを指す。 As used herein, the term "substantially free of preservatives" refers to a concentration of preservatives that is such that the preservatives alone cannot exert the preservative effect. When an aqueous solution containing a preservative is made, the concentration of the preservative is higher than the minimum concentration of the preservative that the aqueous solution meets the criteria specified in the category "IC" in the Reference Information "Preservative Efficacy Test Methods" of the 17th Edition of the Japanese Pharmacopoeia. Refers to less.
本明細書において、「マルチドーズ型容器」とは、複数回分の使用量の水性液剤が充填され、繰返し使用される容器を指す。マルチドーズ型容器には、一旦外側に浸出した水性液剤の容器内への逆流を防止する機構又は異物の容器内への混入を防止する機構を有するマルチドーズ型容器（即ち、マルチドーズ型保存剤フリー容器）と、当該機構を有していないマルチドーズ型容器がある。マルチドーズ型保存剤フリー容器は、一旦外側に浸出した水性液剤の容器内への逆流を防止する機構又は異物の容器内への混入を防止する機構として、通常、逆流防止弁、マイクロフィルター、特殊な二重構造ボトル等の構造を有している（例えば、特許文献１～４）。 As used herein, the term "multi-dose container" refers to a container that is filled with an aqueous solution for multiple uses and is used repeatedly. Multi-dose containers (i.e., multi-dose preservatives) have a mechanism to prevent aqueous liquids that have once oozed out from flowing back into the container or to prevent foreign matter from entering the container. There are two types of containers: free containers) and multi-dose containers that do not have this mechanism. Multi-dose preservative-free containers usually have a backflow prevention valve, microfilter, special It has a structure such as a double-walled bottle (for example, Patent Documents 1 to 4).
本明細書において、「ユニットドーズ型容器」とは、単回分の使用量の水性液剤が充填され、１回の点眼で使い終わる容器を指す。 As used herein, the term "unit-dose container" refers to a container that is filled with a single dose of aqueous liquid and used after one eye drop.
本明細書において、「医薬製品」とは、水性液剤が任意の容器に収容されている状態にある製品を指す。 As used herein, the term "pharmaceutical product" refers to a product containing an aqueous solution contained in any container.
本明細書において、「保存効力を付与する方法」とは、第十七改正日本薬局方 参考情報「保存効力試験法」においてカテゴリー「ＩＣ」で定められた基準に基づいて「適合」とならない水性液剤に、同試験においてカテゴリー「ＩＣ」で定められた基準に基づいて「適合」となる水性液剤にする方法を意味する。また、「ＩＣ」で定められた基準に基づいて「適合」と判断された効力のことを「日局ＩＣ適合保存効力」と表記することがある。 In this specification, "a method of imparting preservative efficacy" refers to an aqueous product that does not "conform" based on the criteria specified in the category "IC" in the reference information "Preservative efficacy test method" of the 17th edition of the Japanese Pharmacopoeia. Refers to a method of making an aqueous solution into an aqueous solution that is ``compliant'' based on the criteria established in the category ``IC'' in the same test. In addition, the effect determined to be ``conforming'' based on the standards established by the ``IC'' is sometimes referred to as the ``Japanese Bureau IC Conformity Preservation Effect.''
本明細書において、「静菌作用」とは、第十七改正日本薬局方 参考情報「保存効力試験法」に基づく試験において、細菌又は真菌の生菌数を減少させないが、少なくとも増加もさせない程度の作用である。また、「少なくとも静菌作用が認められる水準以上の保存効力を備える」とは、前記の「ＩＣ」で定められた基準に基づいて「適合」と判断されることと同義である。 In this specification, "bacteriostatic action" refers to the extent to which the number of viable bacteria or fungi does not decrease, or at least does not increase, in a test based on the Reference Information "Preservative Efficacy Test Method" of the 17th Edition of the Japanese Pharmacopoeia. This is the effect of In addition, "having a preservative efficacy at least at a level at which bacteriostatic action is recognized" has the same meaning as being judged as "conforming" based on the criteria set by the above-mentioned "IC".
２．水性液剤
従来、マルチドーズ型保存剤フリー容器には該当しない通常のマルチドーズ型容器に収容する点眼液については、第十七改正日本薬局方 参考情報「保存効力試験法」においてカテゴリー「ＩＡ」で定められた判定基準に基づいて「適合」とされる保存効力を有していることが必要とされているが、マルチドーズ型保存剤フリー容器に収容する点眼液では、同判定基準を満たす保存効力は必要とされていない。しかしながら、水性液剤をマルチドーズ型保存剤フリー容器に収容して頻回使用すると、ノズルの外側表面に水性液剤が付着したまま残存することがある。ノズルの外側表面に残存した水性液剤は、微生物に汚染される場合があり、このような状態で頻回使用すると、点眼操作等によって投与される水性液剤の無菌状態を確保できなくなる。そのため、マルチドーズ型保存剤フリー容器に収容する水性製剤では、保存剤を配合していなくても、少なくとも静菌作用が認められる水準以上の保存効力を有していることが望ましい。
2. Aqueous solutions Conventionally, ophthalmic solutions stored in ordinary multi-dose containers, which do not fall under multi-dose preservative-free containers, have been classified as category "IA" in the Reference Information "Preservative Efficacy Test Methods" of the 17th edition of the Japanese Pharmacopoeia. Eye drops that are stored in multi-dose preservative-free containers must have a preservative effect that meets the criteria. No efficacy is required. However, when an aqueous solution is stored in a multi-dose preservative-free container and used frequently, the aqueous solution may remain attached to the outer surface of the nozzle. The aqueous solution remaining on the outer surface of the nozzle may be contaminated with microorganisms, and if it is used frequently in this condition, it will no longer be possible to ensure the sterility of the aqueous solution administered by eyedropping or the like. Therefore, it is desirable that an aqueous preparation stored in a multi-dose preservative-free container has a preservative efficacy that is at least at a level at which bacteriostatic action is observed, even if no preservative is added.
しかしながら、従来、ブリモニジン及び／又はその塩を含む水性液剤において、保存剤を配合することなく保存効力を高める製剤技術については報告されておらず、従来技術では、マルチドーズ型保存剤フリー容器に収容した際にノズルの外側表面に水性液剤が残存することによって生じる微生物汚染の懸念を払拭できていない。 However, to date, there has been no report on formulation technology that increases the preservative efficacy of aqueous liquid preparations containing brimonidine and/or its salts without adding preservatives. Concerns about microbial contamination caused by aqueous liquid remaining on the outer surface of the nozzle have not been eliminated.
これに対して、本発明者は、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含み、保存剤を実質的に含まない水性液剤は、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩との相乗作用により保存効力が向上し、保存剤を使用しなくても、第十七改正日本薬局方 参考情報「保存効力試験法」においてカテゴリー「ＩＣ」で定められた判定基準に基づいて「適合」とされる保存効力を有することを見出した。 On the other hand, the present inventor has proposed that an aqueous solution containing brimonidine and/or its salt, edetic acid and/or its salt, and a buffer and substantially free of a preservative is brimonidine and/or its salt. The synergistic effect of the salt and edetic acid and/or its salts improves preservative efficacy, and even without the use of preservatives, it is classified as category "IC" in the reference information "Preservative efficacy test method" of the 17th revised Japanese Pharmacopoeia. It was found that it has a preservative effect that is considered to be ``conforming'' based on the criteria set forth in .
１つの態様において、本発明は、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含み、保存剤を実質的に含まない、水性液剤を提供する。 In one embodiment, the present invention provides an aqueous solution comprising brimonidine and/or a salt thereof, edetic acid and/or a salt thereof, a buffer, and is substantially free of preservatives.
本発明で使用されるブリモニジンの塩としては、薬学的に許容されることを限度として特に制限されないが、具体的には、酒石酸塩、酢酸塩等の有機酸塩；塩酸塩等の無機酸塩等が挙げられる。また、ブリモニジン又はその塩は、水和物等の溶媒和物の形態であってもよい。ブリモニジン又はその塩の中でも、好ましくはブリモニジン酒石酸塩が挙げられる。
本発明の水性液剤において、ブリモニジン又はその塩のいずれか一方を単独で使用してもよく、またこれらを組み合わせて使用してもよい。
The salts of brimonidine used in the present invention are not particularly limited as long as they are pharmaceutically acceptable, but specifically include organic acid salts such as tartrate and acetate; inorganic acid salts such as hydrochloride. etc. Further, brimonidine or a salt thereof may be in the form of a solvate such as a hydrate. Among brimonidine or its salts, brimonidine tartrate is preferred.
In the aqueous solution of the present invention, either brimonidine or its salt may be used alone or in combination.
本発明の水性液剤において、ブリモニジン又はその塩の濃度は、特に制限されず、水性液剤の用途、適用対象となる患者の症状の程度、１回当たりの適用量等に応じて適宜設定すればよいが、例えば０．０５～０．２ｗ/ｖ％、好ましくは０．１～０．２ｗ/ｖ％、特に好ましくは０．１ｗ/ｖ％が挙げられる。本明細書において、ブリモニジン又はその塩の濃度は、ブリモニジン酒石酸塩に換算された濃度である。 In the aqueous solution of the present invention, the concentration of brimonidine or its salt is not particularly limited, and may be appropriately set depending on the use of the aqueous solution, the degree of symptoms of the patient to whom it is applied, the amount applied per time, etc. is, for example, 0.05 to 0.2 w/v%, preferably 0.1 to 0.2 w/v%, particularly preferably 0.1 w/v%. In this specification, the concentration of brimonidine or its salt is the concentration converted to brimonidine tartrate.
本発明で使用されるエデト酸の塩としては、薬学的に許容されることを限度として特に制限されないが、例えば、エデト酸一ナトリウム、エデト酸二ナトリウム（ＥＤＴＡ）、エデト酸四ナトリウム等のエデト酸ナトリウム塩が挙げられる。また、エデト酸の塩は、水和物等の溶媒和物の形態であってもよい。また、エデト酸又はその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。エデト酸又はその塩の中でも、より一層優れた保存効力を備えさせるという観点から、好ましくはエデト酸ナトリウム二水和物が挙げられる。 The salt of edetate used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, but examples include edetate monosodium, edetate disodium (EDTA), and edetate tetrasodium. acid sodium salts. Moreover, the salt of edetic acid may be in the form of a solvate such as a hydrate. Moreover, one type may be selected from edetic acid or its salt and used alone, or two or more types may be used in combination. Among edetate or its salts, sodium edetate dihydrate is preferred from the viewpoint of providing even better preservative efficacy.
本発明の水性液剤において、エデト酸又はその塩のいずれか一方を単独で使用してもよく、またこれらを組み合わせて使用してもよい。 In the aqueous solution of the present invention, either edetic acid or its salt may be used alone or in combination.
本発明の水性液剤において、エデト酸又はその塩の濃度としては、より一層優れた保存効力を備えさせるという観点から、通常０．００１～０．５ｗ/ｖ％、好ましくは０．００５～０．０５ｗ/ｖ％、更に好ましくは０．００３～０．０２ｗ/ｖ％、特に好ましくは０．００５～０．０１ｗ/ｖ％が挙げられる。本明細書において、エデト酸又はその塩の濃度は、エデト酸二ナトリウム二水和物に換算された濃度である。 In the aqueous solution of the present invention, the concentration of edetic acid or its salt is usually 0.001 to 0.5 w/v%, preferably 0.005 to 0.00%, from the viewpoint of providing even better preservative efficacy. 0.05 w/v%, more preferably 0.003 to 0.02 w/v%, particularly preferably 0.005 to 0.01 w/v%. In this specification, the concentration of edetate or its salt is the concentration converted to edetate disodium dihydrate.
本発明で使用される緩衝剤としては、薬学的に許容されることを限度として特に制限されないが、例えば、ホウ酸緩衝剤、リン酸緩衝剤、トリス緩衝剤、クエン酸緩衝剤、酒石酸緩衝剤、酢酸緩衝剤、アミノ酸緩衝剤等が挙げられる。 Buffers used in the present invention are not particularly limited as long as they are pharmaceutically acceptable, but examples include borate buffers, phosphate buffers, Tris buffers, citrate buffers, and tartrate buffers. , acetate buffer, amino acid buffer, and the like.
ホウ酸緩衝剤としては、具体的には、ホウ酸及び／又はその塩が挙げられる。ホウ酸としては、薬学的に許容されることを限度として特に制限されないが、例えば、オルトホウ酸、メタホウ酸、テトラホウ酸等が挙げられる。これらのホウ酸の中でも、好ましくはオルトホウ酸及びテトラホウ酸が挙げられる。これらのホウ酸は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。ホウ酸の塩としては、薬学的に許容されることを限度として、特に制限されないが、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；アルミニウム塩；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、ピロリジン等の有機アミン塩等が挙げられる。また、ホウ酸／又はその塩は、ホウ砂等のように、水和物の形態であってもよい。 Specific examples of the boric acid buffer include boric acid and/or its salts. The boric acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include orthoboric acid, metaboric acid, tetraboric acid, and the like. Among these boric acids, orthoboric acid and tetraboric acid are preferred. These boric acids may be used alone or in combination of two or more. Examples of boric acid salts include, but are not particularly limited to, as long as they are pharmaceutically acceptable; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; Examples include organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, and pyrrolidine. Further, boric acid/or its salt may be in the form of a hydrate, such as borax.
ホウ酸緩衝剤として、ホウ酸及びその塩の中から、１種を選択して単独で使用してもよく、２種以上を組み合わせて使用してもよい。ホウ酸及びその塩の中でも、より優れた保存効力を備えさせるという観点から、好ましくはホウ酸及びホウ砂の少なくとも１種、更に好ましくはオルトホウ酸及びホウ砂の少なくとも１種が挙げられる。 As the boric acid buffer, one type may be selected from boric acid and its salts and used alone, or two or more types may be used in combination. Among boric acid and its salts, preferably at least one of boric acid and borax, and more preferably at least one of orthoboric acid and borax, from the viewpoint of providing better preservative efficacy.
また、ホウ酸緩衝剤の好適な一態様として、ホウ酸とホウ砂を組み合わせが挙げられる。このようにホウ酸とホウ砂を組み合わせて使用することによって、より一層優れた保存効力を備えさせることが可能になる。ホウ酸とホウ砂を組み合わせて使用する場合、これらの比率については、特に制限されないが、例えば、ホウ酸１００質量部当たり、ホウ砂が０～１００質量部、好ましく２０～８０質量部、更に好ましくは４０～６０質量部が挙げられる。 Further, a preferred embodiment of the boric acid buffer includes a combination of boric acid and borax. By using boric acid and borax in combination in this way, it becomes possible to provide even better preservative efficacy. When boric acid and borax are used in combination, their ratio is not particularly limited, but for example, borax is preferably 0 to 100 parts by mass, preferably 20 to 80 parts by mass, and more preferably 20 to 80 parts by mass, per 100 parts by mass of boric acid. is 40 to 60 parts by mass.
ホウ酸緩衝剤の使用量については、緩衝作用の観点から、ホウ酸又はその塩の濃度として、通常０．１～２ｗ/ｖ％、更に好ましくは０．５～１．５ｗ/ｖ％、更に好ましくは０．７～１．０ｗ/ｖ％、特に好ましくは０．４～０．６ｗ/ｖ％が挙げられる。本明細書において、ホウ酸又はその塩の濃度は、ホウ酸に換算された濃度である。 Regarding the amount of boric acid buffer to be used, from the viewpoint of buffering effect, the concentration of boric acid or its salt is usually 0.1 to 2 w/v%, more preferably 0.5 to 1.5 w/v%, and more preferably 0.5 to 1.5 w/v%. Preferably it is 0.7 to 1.0 w/v%, particularly preferably 0.4 to 0.6 w/v%. In this specification, the concentration of boric acid or its salt is a concentration converted to boric acid.
リン酸緩衝剤としては、具体的には、リン酸及び／又はその塩が挙げられる。リン酸の塩としては、薬学的に許容されることを限度として特に制限されないが、例えば、リン酸水素二ナトリウム、リン酸水素二カリウム等のリン酸水素二アルカリ金属塩；リン酸二水素ナトリウム、リン酸二水素カリウム等のリン酸二水素アルカリ金属塩；リン酸三ナトリウム、リン酸三カリウム等のリン酸三アルカリ金属塩等が挙げられる。また、リン酸の塩は、水和物等の溶媒和物の形態であってもよく、例えば、リン酸水素二ナトリウムの場合であれば十二水和物の形態、リン酸二水素ナトリウムの場合であれば二水和物の形態等であってもよい。 Specific examples of the phosphate buffer include phosphoric acid and/or its salts. Phosphoric acid salts are not particularly limited as long as they are pharmaceutically acceptable, but examples include dialkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; sodium dihydrogen phosphate; , alkali metal salts of dihydrogen phosphate such as potassium dihydrogen phosphate; and trialkali metal salts of phosphate such as trisodium phosphate and tripotassium phosphate. In addition, the salt of phosphoric acid may be in the form of a solvate such as a hydrate; for example, in the case of disodium hydrogen phosphate, it is in the form of a dodecahydrate; If necessary, it may be in the form of a dihydrate.
リン酸緩衝剤として、リン酸及びその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。リン酸及びその塩の中でも、より優れた保存効力を備えさせるという観点から、好ましくはリン酸塩、更に好ましくはリン酸水素二アルカリ金属塩及びリン酸二水素アルカリ金属塩の少なくとも１種、特に好ましくはリン酸水素二ナトリウム及びリン酸二水素ナトリウムの少なくとも１種が挙げられる。 As the phosphate buffer, one type may be selected from phosphoric acid and its salts and used alone, or two or more types may be used in combination. Among phosphoric acid and its salts, from the viewpoint of providing better preservative efficacy, phosphates are preferred, and more preferably at least one of dialkali metal hydrogen phosphate and alkali metal dihydrogen phosphate, especially Preferably, at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate is used.
また、リン酸緩衝剤の好適な一態様として、リン酸水素二アルカリ金属塩とリン酸二水素アルカリ金属塩を組み合わせが挙げられる。このようにリン酸水素二アルカリ金属塩とリン酸二水素アルカリ金属塩を組み合わせて使用することによって、より一層優れた保存効力を備えさせることが可能になる。リン酸水素二アルカリ金属塩とリン酸二水素アルカリ金属塩を組み合わせて使用する場合、これらの比率については、特に制限されないが、例えば、リン酸水素二アルカリ金属塩１００質量部当たり、リン酸二水素アルカリ金属塩が１～１２０質量部、好ましく５～８０質量部、更に好ましくは１０～４０質量部が挙げられる。 Further, a preferred embodiment of the phosphate buffer includes a combination of a dialkali metal hydrogen phosphate salt and an alkali metal dihydrogen phosphate salt. By using the dialkali metal hydrogen phosphate and the alkali metal dihydrogen phosphate in combination in this way, it becomes possible to provide the product with even better preservative efficacy. When using a combination of a di-alkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate, the ratio is not particularly limited; The hydrogen alkali metal salt may be used in an amount of 1 to 120 parts by weight, preferably 5 to 80 parts by weight, and more preferably 10 to 40 parts by weight.
リン酸緩衝剤の使用量については、緩衝作用の観点から、リン酸又はその塩の濃度が、通常０．１～５ｗ/ｖ％、好ましくは１～３ｗ/ｖ％、更に好ましくは１．５～２．０ｗ/ｖ％が挙げられる。本明細書において、リン酸緩衝剤の濃度は、リン酸に換算された濃度である。 Regarding the amount of phosphate buffer to be used, from the viewpoint of buffering effect, the concentration of phosphoric acid or its salt is usually 0.1 to 5 w/v%, preferably 1 to 3 w/v%, and more preferably 1.5%. ~2.0w/v% is mentioned. As used herein, the concentration of phosphate buffer is the concentration converted to phosphoric acid.
トリス緩衝剤としては、具体的には、トロメタモール及び／又はその塩が挙げられる。トロメタモールの塩としては、薬学的に許容されることを限度として特に制限されないが、例えば、酢酸塩等の有機酸塩；塩酸塩、スルホン酸塩等の有機酸塩が挙げられる。 Specific examples of the Tris buffer include trometamol and/or its salts. Salts of trometamol are not particularly limited as long as they are pharmaceutically acceptable, and include, for example, organic acid salts such as acetate; organic acid salts such as hydrochloride and sulfonate.
トリス酸緩衝剤として、トロメタモール及びその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。トロメタモール及びその塩の中でも、より優れた保存効力を備えさせるという観点から、好ましくはトロメタモールが挙げられる。 As the tris acid buffer, one type may be selected from trometamol and its salts and used alone, or two or more types may be used in combination. Among trometamol and its salts, trometamol is preferred from the viewpoint of providing better preservative efficacy.
トリス緩衝剤の使用量については、緩衝作用の観点から、通常０．１～２ｗ/ｖ％、好ましくは０．３～１．７５ｗ/ｖ％、更に好ましくは０．５～１．５ｗ/ｖ％が挙げられる。本明細書において、トリス緩衝剤の濃度は、トロメタモールに換算された濃度である。 The amount of Tris buffer to be used is usually 0.1 to 2 w/v%, preferably 0.3 to 1.75 w/v%, more preferably 0.5 to 1.5 w/v from the viewpoint of buffering effect. % is mentioned. As used herein, the concentration of Tris buffer is the concentration in terms of trometamol.
クエン酸緩衝剤としては、具体的には、クエン酸及び／又はその塩が挙げられる。クエン酸の塩としては、薬学的に許容されることを限度として特に制限されないが、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩等が挙げられる。また、クエン酸の塩は、水和物等の溶媒和物の形態であってもよい。クエン酸緩衝剤として、クエン酸及びその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Specific examples of the citric acid buffer include citric acid and/or its salts. Salts of citric acid are not particularly limited as long as they are pharmaceutically acceptable, but examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. It will be done. Further, the salt of citric acid may be in the form of a solvate such as a hydrate. As the citric acid buffer, one type may be selected from citric acid and its salts and used alone, or two or more types may be used in combination.
酒石酸緩衝剤としては、具体的には、酒石酸及び／又はその塩が挙げられる。酒石酸の塩としては、薬学的に許容されることを限度として特に制限されないが、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩等が挙げられる。また、酒石酸の塩は、水和物等の溶媒和物の形態であってもよい。酒石酸緩衝剤として、酒石酸及びその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Specific examples of the tartaric acid buffer include tartaric acid and/or its salts. Salts of tartaric acid are not particularly limited as long as they are pharmaceutically acceptable, and include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. . Moreover, the salt of tartaric acid may be in the form of a solvate such as a hydrate. As the tartaric acid buffer, one type may be selected from tartaric acid and its salts and used alone, or two or more types may be used in combination.
酢酸緩衝剤としては、具体的には、酢酸及び／又はその塩が挙げられる。酢酸の塩としては、薬学的に許容されることを限度として特に制限されないが、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；アンモニウム塩等が挙げられる。また、酢酸の塩は、水和物等の溶媒和物の形態であってもよい。酢酸緩衝剤として、酢酸及びその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Specific examples of the acetate buffer include acetic acid and/or its salts. Salts of acetic acid are not particularly limited as long as they are pharmaceutically acceptable, but include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts, etc. can be mentioned. Further, the acetic acid salt may be in the form of a solvate such as a hydrate. As the acetic acid buffer, one type may be selected from acetic acid and its salts and used alone, or two or more types may be used in combination.
アミノ酸緩衝剤としては、具体的には、酸性アミノ酸及び／又はそれらの塩が挙げられる。酸性アミノ酸としては、具体的には、アスパラギン酸、グルタミン酸が挙げられる。酸性アミノ酸の塩としては、薬学的に許容されることを限度として特に制限されないが、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩等が挙げられる。アミノ酸緩衝剤として、酸性アミノ酸及びその塩の中から１種を選択して単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Specific examples of the amino acid buffer include acidic amino acids and/or salts thereof. Specific examples of acidic amino acids include aspartic acid and glutamic acid. Salts of acidic amino acids are not particularly limited as long as they are pharmaceutically acceptable, and include, for example, alkali metal salts such as sodium salts and potassium salts. As the amino acid buffer, one type may be selected from acidic amino acids and their salts and used alone, or two or more types may be used in combination.
これらの緩衝剤は、１種単独で使用してもよく、２種以上を組み合わせて使用してもよい。 These buffers may be used alone or in combination of two or more.
これらの緩衝剤の中でも、より一層優れた保存効力を備えさせるという観点から、好ましくはホウ酸緩衝剤、リン酸緩衝剤、トリス緩衝剤が挙げられる。 Among these buffers, boric acid buffers, phosphate buffers, and Tris buffers are preferred from the viewpoint of providing even better preservative efficacy.
本発明の水性液剤では、保存剤を実質的に含まないが、保存剤のみを含む水溶液にした場合に、当該水溶液が第十七改正日本薬局方 参考情報「保存効力試験法」においてカテゴリー「ＩＣ」で定められた基準に基づいて「適合」となる保存剤の最小濃度よりも少ない程度の量の保存剤を含んでいてもよい。 Although the aqueous solution of the present invention does not substantially contain a preservative, if it is made into an aqueous solution containing only a preservative, the aqueous solution is categorized as may contain an amount of preservative that is less than the minimum concentration of preservative that would be ``acceptable'' based on the criteria set forth in ``Conformity.''
保存剤としては、具体的には、亜塩素酸ナトリウム等の亜塩素酸塩；塩化ベンザルコニウム、塩化ベンゼトニウム等の第四級アンモニウム塩；ソルビン酸、ソルビン酸カリウム等のソルビン酸及びその塩；メチルパラベン、パラオキシ安息香酸プロピル等のパラオキシ安息香酸エステル；安息香酸及びその塩；クロルクレゾール、フェネチルアルコール、塩化ポリドロニウム、チメロサール、クロロブタノール、クロルヘキシジン、ポリヘキサニド等が該当する。 Preservatives include, specifically, chlorites such as sodium chlorite; quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride; sorbic acid and its salts such as sorbic acid and potassium sorbate; Paraoxybenzoic acid esters such as methylparaben and propyl paraoxybenzoate; benzoic acid and its salts; chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, chlorobutanol, chlorhexidine, polyhexanide, and the like.
本発明の水性液剤において許容される保存剤の濃度については、保存の種類等に応じて異なるが、具体的には、０．００１ｗ/ｖ％未満、好ましくは０．０００５ｗ/ｖ％以下、更に好ましくは０．０００１ｗ/ｖ％以下、特に好ましくは０ｗ/ｖ％が挙げられる。 The concentration of the preservative allowed in the aqueous solution of the present invention varies depending on the type of storage, etc., but specifically, it is less than 0.001 w/v%, preferably less than 0.0005 w/v%, and Preferably it is 0.0001 w/v% or less, particularly preferably 0 w/v%.
本発明の水性液剤では、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含むことによって、少なくとも静菌作用が認められる水準以上の保存効力を備えることが可能になっている。そのため、本発明の水性液剤では、前記成分以外に、ブリモニジン及び／又はその塩との共存下で保存効力を向上させる成分については、実質的に含んでなくてもよい。 By containing brimonidine and/or its salt, edetic acid and/or its salt, and a buffer, the aqueous solution of the present invention can have preservative efficacy at least at a level at which bacteriostatic action is recognized. It has become. Therefore, the aqueous solution of the present invention does not need to contain substantially any component that improves the preservative efficacy in coexistence with brimonidine and/or its salt, in addition to the above-mentioned components.
例えば、ドルゾラミド及び／又はその塩は、ｐＨが６．０以上の水性液剤においてブリモニジン及び／又はその塩と共存すると、保存効力を向上させ得ることが知られているので、本発明の水性液剤の一態様として、ドルゾラミド及び／又はその塩を実質的に含まないことが挙げられる。ドルゾラミドの塩としては、具体的には、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等の無機酸との塩；酢酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、クエン酸、酒石酸等の有機酸との塩；アルカリ金属との塩、アルカリ土類金属との塩、有機アミンとの塩、ハロゲン化物等が該当する。また、「ドルゾラミド及び／又はその塩を実質的に含まない」とは、具体的には、ドルゾラミド及び／又はその塩の濃度が、０．１ｗ/ｖ％未満、好ましくは０．０５ｗ/ｖ％以下、更に好ましくは０．０１ｗ/ｖ％以下、特に好ましくは０ｗ/ｖ％が挙げられる。 For example, it is known that when dorzolamide and/or its salt coexists with brimonidine and/or its salt in an aqueous solution with a pH of 6.0 or more, it can improve the preservative efficacy. In one embodiment, it does not substantially contain dorzolamide and/or its salt. Examples of salts of dorzolamide include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; acetic acid, oxalic acid, fumaric acid, maleic acid, and succinic acid. , salts with organic acids such as malic acid, citric acid, and tartaric acid; salts with alkali metals, salts with alkaline earth metals, salts with organic amines, and halides. Furthermore, "substantially free of dorzolamide and/or its salt" specifically means that the concentration of dorzolamide and/or its salt is less than 0.1 w/v%, preferably 0.05 w/v%. The following is more preferable: 0.01 w/v% or less, particularly preferably 0 w/v%.
本発明の水性液剤には、前記成分の他に、必要に応じて、等張化剤、多価アルコール、界面活性剤、粘稠剤、キレート剤（エデト酸及びその塩以外）、清涼化剤、安定化剤、ｐＨ調整剤等の添加剤を含有してもよい。 In addition to the above-mentioned components, the aqueous liquid preparation of the present invention may optionally include an isotonic agent, a polyhydric alcohol, a surfactant, a thickening agent, a chelating agent (other than edetic acid and its salts), and a cooling agent. , stabilizers, pH adjusters, and other additives.
等張化剤としては、薬学的に許容されることを限度として特に制限されないが、例えば、グリセリン、プロピレングリコール、ブチレングリコール、ポリエチレングリコール等の多価アルコール；塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、酢酸ナトリウム、酢酸カリウム、亜硫酸水素ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、リン酸水素二ナトリウム、リン酸二水素ナトリウム等の金属塩等が挙げられる。これらの等張化剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The tonicity agent is not particularly limited as long as it is pharmaceutically acceptable, but examples include polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol; sodium chloride, potassium chloride, calcium chloride, and chloride. Examples include metal salts such as magnesium, sodium acetate, potassium acetate, sodium hydrogen sulfite, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. These tonicity agents may be used alone or in combination of two or more.
多価アルコールとしては、薬学的に許容されることを限度として特に制限されないが、例えば、プロピレングリコール、ブチレングリコール、ポリエチレングリコール、グリセリン等が挙げられる。これらの多価アルコールは、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include propylene glycol, butylene glycol, polyethylene glycol, glycerin, and the like. These polyhydric alcohols may be used alone or in combination of two or more.
界面活性剤としては、薬学的に許容されることを限度として特に制限されないが、例えば、チロキサポール、ポリオキシエチレン硬化ヒマシ油、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、ポリオキシエチレンソルビタン脂肪酸エステル、オクトキシノール等の非イオン性界面活性剤；アルキルジアミノエチルグリシン、ラウリルジメチルアミノ酢酸ベタイン等の両性界面活性剤；アルキル硫酸塩、Ｎ－アシルタウリン塩、ポリオキシエチレンアルキルエーテルリン酸塩、ポリオキシエチレンアルキルエーテル硫酸塩等の陰イオン界面活性剤；アルキルピリジニウム塩、アルキルアミン塩等の陽イオン界面活性剤等が挙げられる。これらの界面活性剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The surfactant is not particularly limited as long as it is pharmaceutically acceptable, but examples include tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxy Non-ionic surfactants such as alcohol; amphoteric surfactants such as alkyldiaminoethylglycine, lauryldimethylaminoacetic acid betaine; alkyl sulfates, N-acyl taurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl Examples include anionic surfactants such as ether sulfates; cationic surfactants such as alkylpyridinium salts and alkylamine salts. These surfactants may be used alone or in combination of two or more.
粘稠剤としては、薬学的に許容されることを限度として特に制限されないが、例えば、カルボキシビニルポリマー、ポリビニルピロリドン、ポリエチレングリコール、ポリビニルアルコール、キサンタンガム、コンドロイチン硫酸ナトリウム、ヒアルロン酸ナトリウム等の水溶性高分子；ヒドロキシエチルセルロース、メチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム等のセルロース類等が挙げられる。これらの粘稠剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The thickening agent is not particularly limited as long as it is pharmaceutically acceptable, but examples include highly water-soluble thickeners such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate. Molecules: Examples include celluloses such as hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose. These thickeners may be used alone or in combination of two or more.
キレート剤（エデト酸及びその塩以外）としては、薬学的に許容されることを限度として特に制限されないが、例えば、クエン酸、コハク酸、アスコルビン酸、トリヒドロキシメチルアミノメタン、ニトリロトリ酢酸、１－ヒドロキシエタン－１，１－ジホスホン酸、ポリリン酸、メタリン酸、ヘキサメタリン酸、これら塩等が挙げられる。塩の形態としては、薬学的に許容されることを限度として特に制限されないが、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩等が挙げられる。これらのキレート剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Chelating agents (other than edetic acid and its salts) are not particularly limited as long as they are pharmaceutically acceptable, but examples include citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1- Examples include hydroxyethane-1,1-diphosphonic acid, polyphosphoric acid, metaphosphoric acid, hexametaphosphoric acid, and salts thereof. The form of the salt is not particularly limited as long as it is pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts. These chelating agents may be used alone or in combination of two or more.
清涼化剤としては、薬学的に許容されることを限度として特に制限されないが、例えば、l－メントール、ボルネオール、カンフル、ユーカリ油等が挙げられる。これらの清涼化剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The cooling agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include l-menthol, borneol, camphor, eucalyptus oil, and the like. These refreshing agents may be used alone or in combination of two or more.
安定化剤としては、薬学的に許容されることを限度として特に制限されないが、例えば、ポリビニルピロリドン、亜硫酸塩、モノエタノールアミン、シクロデキストリン、デキストラン、アスコルビン酸、タウリン、トコフェロール、ジブチルヒドロキシトルエン等が挙げられる。これらの安定化剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Stabilizers are not particularly limited as long as they are pharmaceutically acceptable, but examples include polyvinylpyrrolidone, sulfites, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, dibutylhydroxytoluene, and the like. Can be mentioned. These stabilizers may be used alone or in combination of two or more.
ｐＨ調整剤としては、薬学的に許容されることを限度として特に制限されないが、例えば、塩酸、酢酸、ホウ酸、アミノエチルスルホン酸、イプシロン－アミノカプロン酸等の酸；水酸化ナトリウム、水酸化カリウム、ホウ砂、トリエタノールアミン、モノエタノールアミン、炭酸水素ナトリウム、炭酸ナトリウム等のアルカリが挙げられる。これらのｐＨ調整剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Examples of pH adjusters include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid; sodium hydroxide, potassium hydroxide, etc., but are not particularly limited as long as they are pharmaceutically acceptable. , borax, triethanolamine, monoethanolamine, sodium bicarbonate, sodium carbonate, and other alkalis. These pH adjusters may be used alone or in combination of two or more.
これらの添加剤の濃度は、使用する添加剤の種類や水性液剤に付与すべき特性等に応じて適宜設定すればよい。 The concentration of these additives may be appropriately set depending on the type of additive used, the characteristics to be imparted to the aqueous liquid, and the like.
更に、本発明の水性液剤には、ブリモニジン及び／又はその塩以外に、本発明の効果を妨げない範囲で、必要に応じて、緑内障や高眼圧症に対して治療効果を示す薬理成分が含まれていてもよい。 Furthermore, the aqueous liquid preparation of the present invention may optionally contain pharmacological ingredients that exhibit therapeutic effects on glaucoma and ocular hypertension, in addition to brimonidine and/or its salts, to the extent that they do not interfere with the effects of the present invention. It may be
このような薬理成分としては、例えば、タフルプロスト、ラタノプロスト、イソプロピルウノプロストン等のプロスタグランジン類；ピロカルピン塩酸塩等の副交感神経刺激薬；ジスチグミン臭化物等の抗コリンエステラーゼ薬；ジピベフリン塩酸塩等の交感神経刺激薬；ベタキソロール塩酸塩等のβ1遮断薬；チモロールマレイン酸塩等のβ遮断薬；ニプラジロール、レボブノロール塩酸塩等のα1・β遮断薬；ブナゾシン塩酸塩等のα1遮断薬等が挙げられる。これらの薬理成分は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 Such pharmacological ingredients include, for example, prostaglandins such as tafluprost, latanoprost, and isopropyl unoprostone; parasympathomimetic agents such as pilocarpine hydrochloride; anticholinesterase agents such as distigmine bromide; and sympathetic nerve agents such as dipivefrin hydrochloride. Stimulants; β 1 blockers such as betaxolol hydrochloride; β blockers such as timolol maleate; α 1 and β blockers such as nipradilol and levobunolol hydrochloride; α 1 blockers such as bunazosin hydrochloride, etc. . These pharmacological ingredients may be used alone or in combination of two or more.
これらの薬理成分の濃度は、使用する薬理成分の種類や付与すべき薬効等に応じて適宜設定すればよい。 The concentration of these pharmacological components may be appropriately set depending on the type of pharmacological component used, the medicinal effect to be imparted, and the like.
本発明の水性液剤のｐＨについては、特に制限されないが、例えば、ｐＨ６～８が挙げられる。本発明の水性液剤のｐＨとして、より一層優れた保存効力を備えさせるという観点から、好ましくはｐＨ７～８、更に好ましくはｐＨ７が挙げられる。 The pH of the aqueous solution of the present invention is not particularly limited, but includes, for example, pH 6 to 8. The pH of the aqueous solution of the present invention is preferably pH 7 to 8, more preferably pH 7, from the viewpoint of providing even better preservative efficacy.
本発明の水性液剤の浸透圧比については、特に制限されないが、例えば、０．５～４、好ましくは０．７～１．３、更に好ましくは０．９～１．１が挙げられる。当該浸透圧比は、０．９ｗ／ｖ％塩化ナトリウム水溶液の浸透圧に対する比率であり、浸透圧は第十七改正日本薬局方に規定されている「浸透圧法（オスモル濃度測定法）」に準じて測定される。 The osmotic pressure ratio of the aqueous solution of the present invention is not particularly limited, but may be, for example, 0.5 to 4, preferably 0.7 to 1.3, and more preferably 0.9 to 1.1. The osmotic pressure ratio is the ratio to the osmotic pressure of a 0.9 w/v% sodium chloride aqueous solution, and the osmotic pressure is determined according to the "osmotic pressure method (osmolality measurement method)" specified in the 17th edition of the Japanese Pharmacopoeia. be measured.
本発明の水性液剤は、前述する成分を含むことにより、少なくとも静菌作用が認められる水準以上の保存効力を有することが可能になっている。本発明の水性製剤が有する保存効力として、具体的には、第十七改正日本薬局方 参考情報「保存効力試験法」においてカテゴリー「ＩＣ」で定められた基準に基づいて「適合」と判断されるものである。日局ＩＣ適合保存効力は、第十七改正日本薬局方 参考情報「保存効力試験法」に準拠した試験方法で判定でき、具体的な試験方法は後述する試験例の欄に示す通りである。 By containing the above-mentioned components, the aqueous solution of the present invention can have a preservative efficacy that is at least at a level at which bacteriostatic action is recognized. Specifically, the preservative efficacy of the aqueous preparation of the present invention is determined to be ``conforming'' based on the criteria specified in the category ``IC'' in the reference information ``Preservative efficacy test method'' of the 17th edition of the Japanese Pharmacopoeia. It is something that The Japan Pharmacopoeia IC compatible preservative efficacy can be determined by a test method based on the reference information "Preservative efficacy test method" of the 17th edition of the Japanese Pharmacopoeia, and the specific test method is as shown in the test example section below.
本発明の水性液剤の製剤形態については、特に制限されず、水溶液状、懸濁液状、乳液状等のいずれであってもよいが、好ましくは水溶液状が挙げられる。 The formulation form of the aqueous solution of the present invention is not particularly limited, and may be in the form of an aqueous solution, suspension, emulsion, etc., but preferably an aqueous solution.
本発明の水性液剤は、点眼液、洗眼液等の眼科用製剤等として使用することができる。特に、本発明の水性液剤は、ブリモニジン及び／又はその塩の作用によって、眼房水の産生を抑制して、眼圧を低下させることができるので、点眼液として提供され、緑内障又は高眼圧症の治療するための水性液剤として好適に使用できる。 The aqueous solution of the present invention can be used as ophthalmic preparations such as eye drops and eye washes. In particular, the aqueous solution of the present invention can suppress the production of aqueous humor and lower intraocular pressure through the action of brimonidine and/or its salt, so it can be provided as an eye drop and used to treat glaucoma or ocular hypertension. It can be suitably used as an aqueous solution for the treatment of.
本発明の水性液剤は、その用途に応じて、公知の調製法に従って製造すればよく、例えば、第十七改正日本薬局方 製剤総則に記載された方法を用いて製造することができる。 The aqueous liquid preparation of the present invention may be manufactured according to a known preparation method depending on its intended use, and for example, it can be manufactured using the method described in the 17th edition of the Japanese Pharmacopoeia, General Rules for Preparations.
本発明の水性液剤を収容する容器については、当該水性製剤の用途に応じて、点眼容器、洗眼容器等を使用すればよい。 As for the container containing the aqueous liquid preparation of the present invention, an eye drop container, an eye wash container, etc. may be used depending on the use of the aqueous preparation.
本発明の水性液剤は、マルチドーズ型容器であってもよく、ユニットドーズ型容器であってもよい。 The aqueous liquid preparation of the present invention may be in a multi-dose type container or a unit-dose type container.
また、マルチドーズ型容器の場合、保存中に収容されている水性液剤の無菌状態を維持するために、マルチドーズ型保存剤フリー容器を使用することが特に好ましい。保存剤を含まない従来の水性液剤では、マルチドーズ型保存剤フリー容器を使用しても、ノズルの外側表面に残存した水性液剤の微生物汚染が懸念されるが、本発明の水性液剤では、少なくとも静菌作用が認められる水準以上の保存効力を備えているので、マルチドーズ型保存剤フリー容器のノズルの外側表面に残存しても、前記微生物汚染を抑制することができる。 Furthermore, in the case of a multi-dose type container, it is particularly preferable to use a multi-dose type preservative-free container in order to maintain the sterility of the aqueous solution contained therein during storage. With conventional aqueous solutions that do not contain preservatives, even if a multi-dose preservative-free container is used, there is a concern about microbial contamination of the aqueous solution remaining on the outer surface of the nozzle, but with the aqueous solution of the present invention, at least Since it has a preservative effect higher than the level at which bacteriostatic action is recognized, the microbial contamination can be suppressed even if it remains on the outer surface of the nozzle of a multi-dose preservative-free container.
３．保存効力の付与方法
本発明は、ブリモニジン及び／又はその塩を含む水性液剤に保存効力を付与する方法であって、水性液剤において、保存剤を実質的に含まず、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含む水性液剤を調製する工程を含むことを特徴とする、保存効力の付与方法を提供する。
3. Method for imparting preservative efficacy The present invention is a method for imparting preservative efficacy to an aqueous solution containing brimonidine and/or a salt thereof, the aqueous solution containing substantially no preservative and containing brimonidine and/or a salt thereof. Provided is a method for imparting preservative efficacy, which comprises the step of preparing an aqueous solution containing edetic acid and/or its salt, and a buffer.
本発明の保存効力の付与方法によれば、ブリモニジン及び／又はその塩を含む水性液剤に日局ＩＣ適合保存効力を付与することが可能になる。 According to the method for imparting preservative efficacy of the present invention, it is possible to impart preservative efficacy compatible with the Japanese Pharmacopoeia IC to an aqueous solution containing brimonidine and/or a salt thereof.
本発明の保存効力の付与方法において、使用するブリモニジン及び／又はその塩の種類や濃度、エデト酸及び／又はその塩の種類や濃度、緩衝剤の種類や濃度、水性液剤に配合される他の添加剤や薬理成分の種類、水性液剤のｐＨ、製剤形態、用途等については、前記「１．水性液剤」の欄に記載の通りである。 In the method for imparting preservative effect of the present invention, the type and concentration of brimonidine and/or its salt, the type and concentration of edetic acid and/or its salt, the type and concentration of the buffering agent, and other ingredients added to the aqueous solution. The types of additives and pharmacological ingredients, the pH of the aqueous solution, the formulation form, the use, etc. are as described in the column of "1. Aqueous solution" above.
以下に、実施例を挙げて、本発明を具体的に説明するが、本発明はこれらによって何ら限定されるものではない。なお、以下の試験例において、ホウ酸は、全てオルトホウ酸を使用した。 EXAMPLES The present invention will be specifically described below with reference to Examples, but the present invention is not limited to these in any way. In addition, in the following test examples, orthoboric acid was used as the boric acid.
試験例１：保存効力の評価
第十七改正日本薬局方 参考情報「保存効力試験法」に準拠して、表１に示す組成の点眼液の保存効力の評価を行った。具体的な試験方法等は以下に示す通りである。
Test Example 1: Evaluation of Preservative Efficacy The preservative efficacy of eye drops having the composition shown in Table 1 was evaluated in accordance with the reference information "Preservative Efficacy Test Method" of the 17th edition of the Japanese Pharmacopoeia. The specific test method etc. are as shown below.
１．試験材料及び試験方法
１－１．検体の調製
表１～３に示す組成の水性液剤（点眼液）を調製し、０．２２μｍフィルターでろ過したものを検体とした。なお、実施例１のホウ酸及びホウ砂の総量は、ホウ酸に換算した量として０．７２ｇ（濃度として０．７２ｗ／ｖ％）であり、実施例２のリン酸水素二ナトリウム水和物及びリン酸二水素ナトリウムの総量は、リン酸に換算した量として１．８ｇ（濃度として１．８ｗ／ｖ％）である。
1. Test materials and test methods
1-1. Preparation of Specimen Aqueous solutions (eye drops) having the compositions shown in Tables 1 to 3 were prepared and filtered through a 0.22 μm filter to serve as the specimen. The total amount of boric acid and borax in Example 1 was 0.72 g (concentration: 0.72 w/v%) in terms of boric acid; The total amount of sodium dihydrogen phosphate was 1.8 g (concentration: 1.8 w/v%) in terms of phosphoric acid.
１－２．試験菌
以下に示す３種の細菌及び２種の真菌を使用した。
（細菌）
・黄色ブドウ球菌（Staphylococcus aureus、S.aureus / ATCC 6538）
・大腸菌（Escherichia coli、E.coli / ATCC 8739）
・緑膿菌（Pseudomonas aeruginosa、P.aeruginosa / ATCC 9027）
（真菌）
・カンジタ菌（Candida albicans、C.albicans / ATCC 10231）
・黒麹かび（Aspergillus brasiliensis、A.brasiliensis / ATCC 16404）
1-2. Test Bacteria Three types of bacteria and two types of fungi shown below were used.
(bacteria)
・Staphylococcus aureus (S. aureus / ATCC 6538)
・Escherichia coli (E.coli / ATCC 8739)
・Pseudomonas aeruginosa (Pseudomonas aeruginosa, P.aeruginosa / ATCC 9027)
(fungus)
・Candida albicans (C.albicans / ATCC 10231)
・Black koji mold (Aspergillus brasiliensis, A.brasiliensis / ATCC 16404)
１－３．前培養
前記試験菌をそれぞれカンテン斜面培地の表面に接種して前培養した。前培養用のカンテン培地としては、細菌の場合はソイビーン・カゼイン・ダイジェストカンテン培地を、真菌の場合はサブロー・ブドウ糖カンテン培地を用いた。前培養は、細菌の場合は３０～３５℃で１８～２４時間、カンジタ菌は２０～２５℃で４４～５２時間、黒麹かびは２０～２５℃で６～１０日間培養した。
1-3. Preculture The above test bacteria were inoculated onto the surface of an agar slant medium and precultured. As the agar medium for preculture, soy bean casein digest agar medium was used for bacteria, and Sabouraud glucose agar medium was used for fungi. Preculture was performed at 30-35°C for 18-24 hours for bacteria, 44-52 hours at 20-25°C for Candida, and 6-10 days at 20-25°C for Aspergillus oryzae.
１－４．混合試料の調製及び菌数測定
前記検体を１０ｍＬずつ５本の滅菌済みの共栓付試験管に分注し、前培養した各試験菌を１×１０5～１×１０6ＣＦＵ／ｍＬとなるよう接種し、これらを混合試料とした。混合試料を２０～２５℃、遮光保存した。なお、各試験菌は混合せず、菌種毎にそれぞれ単独に検体に接種して混合試料を調製した。
1-4. Preparation of mixed sample and measurement of bacterial count Dispense 10 mL of the above sample into five sterilized stoppered test tubes, and pre-culture each test bacteria to a concentration of 1 x 10 5 to 1 x 10 6 CFU/mL. These were used as a mixed sample. The mixed sample was stored at 20-25°C, protected from light. Note that the test bacteria were not mixed, but each type of bacteria was individually inoculated into the specimen to prepare a mixed sample.
試験開始時、並びに試験開始から７、１４、及び２８日目に、各混合試料から１ｍＬをサンプリングし、その液を生理食塩水９ｍＬで希釈した。必要に応じ、さらに同様の希釈を２～３回行い、各希釈液１ｍＬを滅菌シャーレに分注した。次に、細菌の場合は０．１％レシチン及び０．７％ポリソルベート８０を添加したソイビーン・カゼイン・ダイジェストカンテン培地を、真菌の場合は０．１％レシチン及び０．７％ポリソルベート８０を添加したサブロー・ブドウ糖カンテン培地を加えて混釈した。そして、細菌の場合は３０～３５℃で３～５日間、真菌の場合は２０～２５℃で５～７日間培養した後に、生成コロニー数を測定し、混合試料１ｍＬ当たりの生菌数（cfu/mL）及び生菌数の対数減少値（log）を算出した。
１－５．保存効力の判定
各試験液の保存効力を、第十七改正日本薬局方 参考情報「保存効力試験法」の「４．
判定」の「表３ 製剤区分別判定基準」に記載されたカテゴリー１Ｃの基準に従って評価した。具体的には、（１）３種全ての細菌において、対数減少値（log）が１４日後に接種菌数に比べ１．０log以上、且つ２８日後の生菌数が１４日後から増加せず、且つ（２）２種全ての真菌において、１４日後及び２８日後の生菌数が接種菌数から増加しない、を全て満たした場合を「適合」と判定し、それ以外を「不適合」と判定した。
1-5. Judgment of preservative efficacy The preservative efficacy of each test solution was determined as described in “4.
Evaluation was made according to the criteria for Category 1C listed in "Table 3 Judgment Criteria by Formulation Category" in "Judgment". Specifically, (1) for all three types of bacteria, the logarithmic reduction value (log) is 1.0 log or more compared to the number of inoculated bacteria after 14 days, and the number of viable bacteria after 28 days does not increase after 14 days, and (2) for all two types of fungi, the number of viable bacteria after 14 days and 28 days does not increase from the number of inoculated bacteria. Cases that were satisfied were judged to be ``conforming'', and other cases were judged to be ``non-conforming''. .
２．試験結果
得られた結果を表１～３に示す。ブリモニジン酒石酸塩及びエデト酸ナトリウム二水和物を含まず、且つホウ酸緩衝剤（ホウ酸及びホウ砂）を含む水性液剤（参考例１）では、日局ＩＣ適合保存効力を有していたが、ホウ酸緩衝剤と共にブリモニジン酒石酸塩又はエデト酸ナトリウム二水和物を配合した水性液剤では（比較例１及び２）では、保存効力が低下し、日局ＩＣ適合保存効力を具備できていなかった。これに対して、ホウ酸緩衝剤と共に、ブリモニジン酒石酸塩及びエデト酸ナトリウム二水和物を配合した水性液剤（実施例１）では、保存効力が向上し、日局ＩＣ適合保存効力を有していた。また、リン酸緩衝剤及びトリス緩衝剤を使用した場合であっても、ブリモニジン酒石酸塩及びエデト酸ナトリウム二水和物を配合した水性液剤では、保存効力が向上し、日局ＩＣ適合保存効力を具備できていた。
2. Test results The results obtained are shown in Tables 1 to 3. An aqueous solution (Reference Example 1) that did not contain brimonidine tartrate and sodium edetate dihydrate and also contained a boric acid buffer (boric acid and borax) had a preservative efficacy that complied with the Japanese Pharmacopoeia IC. In aqueous solutions containing brimonidine tartrate or sodium edetate dihydrate together with a boric acid buffer (Comparative Examples 1 and 2), the preservative efficacy decreased and the preservative efficacy complied with the Japanese Pharmacopoeia IC was not achieved. . On the other hand, the aqueous solution containing brimonidine tartrate and sodium edetate dihydrate (Example 1) with a boric acid buffer improved the preservative efficacy and had a preservative efficacy that complied with the Japanese Pharmacopoeia IC. Ta. Furthermore, even when phosphate buffer and Tris buffer are used, the preservative efficacy of an aqueous solution containing brimonidine tartrate and sodium edetate dihydrate is improved, and the preservative efficacy is compliant with the Japanese Pharmacopoeia IC. It was equipped.
試験例２：熱安定性の評価
表５に示す組成の水性液剤（点眼液）を調製した。０．２２μｍフィルターでろ過した後に、各水性液剤５ｍＬを５ｍＬ容の無色ガラスアンプルに充填した。これらを卓上恒温恒湿器（NST-80、ナガノサイエンス株式会社）に入れ、遮光条件下、６０℃で４週間保管した。保管前後のブリモニジン酒石酸塩含量を、高速液体クロマトグラフシステム（株式会社島津製作所）を用いて下記の条件に従い測定した。
Test Example 2: Evaluation of Thermal Stability An aqueous solution (eye drop) having the composition shown in Table 5 was prepared. After filtering through a 0.22 μm filter, 5 mL of each aqueous solution was filled into a 5 mL colorless glass ampoule. These were placed in a tabletop constant temperature and humidity chamber (NST-80, Nagano Science Co., Ltd.) and stored at 60° C. for 4 weeks under light-shielded conditions. Brimonidine tartrate content before and after storage was measured using a high performance liquid chromatography system (Shimadzu Corporation) under the following conditions.
＜測定条件＞
検出器：紫外吸光光度計（測定波長：230 nm）
カラム： Symmetry C18, 4.6mm I.D.×150mm, 3.5μm, Waters
カラム温度：40℃温付近の一定温度
移動相A：4.3 mMリン酸水溶液/メタノール/アセトニトリル（容量比：84/8/8）混液
移動相B：4.3 mMリン酸水溶液/メタノール/アセトニトリル（容量比：40/30/30）混液
流量：1.0 mL/min
オートサンプラ内温度：5℃
移動相の送液：移動相A及び移動相Bの混合比率を表４に示すように変えて直線濃度勾配制御した。
<Measurement conditions>
Detector: Ultraviolet absorption photometer (measurement wavelength: 230 nm)
Column: Symmetry C18, 4.6mm ID×150mm, 3.5μm, Waters
Column temperature: Constant temperature around 40℃ Mobile phase A: 4.3 mM phosphoric acid aqueous solution/methanol/acetonitrile (volume ratio: 84/8/8) Mobile phase B: 4.3 mM phosphoric acid aqueous solution/methanol/acetonitrile (volume ratio) :40/30/30) Mixed liquid flow rate: 1.0 mL/min
Autosampler internal temperature: 5℃
Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 4 to control the linear concentration gradient.
次の算出式に従い、水性液剤中のブリモニジンの残存率を算出した。
得られた結果を表５に示す。エデト酸ナトリウム二水和物を配合していない場合では、保存剤を含まない水性液剤（比較例９）は、点眼液に一般的に配合される保存剤を含む水性液剤（比較例７及び８）に比べてブリモニジンの残存率が低下していた。亜硫酸水素ナトリウム及びベンザルコニウム塩化物といった保存剤を配合することでブリモニジンの安定性を向上することができる。しかしながら、保存剤を配合しなくとも、エデト酸ナトリウム二水和物を配合した水性液剤では、ブリモニジン酒石酸塩の安定性が更に向上していた。即ち、本結果から、保存剤を実質的に含まず、ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩とを含む水性液剤は、ブリモニジン及び／又はその塩の安定性の点でも優れていることが明らかとなった。 The results obtained are shown in Table 5. In the case where sodium edetate dihydrate is not blended, the aqueous solution containing no preservative (Comparative Example 9) is different from the aqueous solution containing a preservative commonly used in eye drops (Comparative Examples 7 and 8). ), the residual rate of brimonidine was lower than that of The stability of brimonidine can be improved by incorporating preservatives such as sodium bisulfite and benzalkonium chloride. However, even without the addition of a preservative, the stability of brimonidine tartrate was further improved in the aqueous solution containing sodium edetate dihydrate. In other words, from this result, an aqueous solution containing brimonidine and/or its salt and edetic acid and/or its salt, which is substantially free of preservatives, is also superior in terms of the stability of brimonidine and/or its salt. It became clear that
Claims (7)
一旦外側に浸出した水性液剤の容器内への逆流を防止する機構、及び／又は異物の容器内への混入を防止する機構を有するマルチドーズ型容器に収容されている、
水性液剤。 Contains brimonidine and/or a salt thereof, edetic acid and/or a salt thereof, and a buffer, substantially does not contain a preservative, and does not contain dorzolamide and/or a salt thereof,
Housed in a multi-dose container that has a mechanism to prevent the aqueous solution once leached outside from flowing back into the container and/or a mechanism to prevent foreign matter from entering the container.
Aqueous liquid.
水性液剤は保存剤を実質的に含まず、且つドルゾラミド及び／又はその塩を含まず、
ブリモニジン及び／又はその塩と、エデト酸及び／又はその塩と、緩衝剤とを含む水性液剤を調製する工程を含む、
保存効力の付与方法。 Containing brimonidine and/or its salt, it is housed in a multi-dose type container that has a mechanism to prevent the aqueous solution once leached to the outside from flowing back into the container and/or a mechanism to prevent foreign matter from entering the container. A method for imparting preservative efficacy to an aqueous solution, comprising:
The aqueous solution is substantially free of preservatives and free of dorzolamide and/or its salts;
A step of preparing an aqueous solution containing brimonidine and/or a salt thereof, edetic acid and/or a salt thereof, and a buffer,
Method of imparting preservative effect.
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| BR9914813A (en) * | 1998-10-27 | 2001-07-03 | Alcon Lab Inc | Preservative system for topically administrable pharmaceutical compositions |
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| US20120312840A1 (en) * | 2011-05-13 | 2012-12-13 | Ayako Hasegawa | Container closure system with integral antimicrobial additives |
| JP6567648B2 (en) * | 2014-07-28 | 2019-08-28 | サン、ファーマ、アドバンスト、リサーチ、カンパニー、リミテッドＳｕｎ Ｐｈａｒｍａ Ａｄｖａｎｃｅｄ Ｒｅｓｅａｒｃｈ Ｃｏｍｐａｎｙ Ｌｉｍｉｔｅｄ | Method for increasing bioavailability of a drug and / or sustaining ocular action |
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| JP7120789B2 (en) * | 2017-09-29 | 2022-08-17 | 積水化学工業株式会社 | Aqueous polyvinyl acetal resin composition |
| WO2019189720A1 (en) * | 2018-03-30 | 2019-10-03 | 千寿製薬株式会社 | Aqueous liquid formulation |
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| JP2020193233A (en) | 2020-12-03 |
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