JP2017186372A - Pharmaceutical composition containing dorzolamide, timolol, and surfactant - Google Patents
Pharmaceutical composition containing dorzolamide, timolol, and surfactant Download PDFInfo
- Publication number
- JP2017186372A JP2017186372A JP2017136330A JP2017136330A JP2017186372A JP 2017186372 A JP2017186372 A JP 2017186372A JP 2017136330 A JP2017136330 A JP 2017136330A JP 2017136330 A JP2017136330 A JP 2017136330A JP 2017186372 A JP2017186372 A JP 2017186372A
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- salt
- composition according
- surfactant
- timolol
- 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.)
- Granted
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 137
- 229960003933 dorzolamide Drugs 0.000 title claims abstract description 40
- 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 title claims abstract description 40
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 title claims abstract description 37
- 229960004605 timolol Drugs 0.000 title claims abstract description 37
- 239000004094 surface-active agent Substances 0.000 title claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 104
- -1 fatty acid ester Chemical class 0.000 claims abstract description 74
- 229960000686 benzalkonium chloride Drugs 0.000 claims abstract description 46
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims abstract description 46
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 36
- 239000004359 castor oil Substances 0.000 claims abstract description 27
- 235000019438 castor oil Nutrition 0.000 claims abstract description 25
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims abstract description 25
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 20
- 239000000194 fatty acid Substances 0.000 claims abstract description 20
- 229930195729 fatty acid Natural products 0.000 claims abstract description 20
- 229920001214 Polysorbate 60 Polymers 0.000 claims abstract description 12
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 6
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims abstract description 5
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960003260 chlorhexidine Drugs 0.000 claims abstract description 5
- 239000006196 drop Substances 0.000 claims description 48
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 39
- 239000003889 eye drop Substances 0.000 claims description 27
- 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 description 22
- 229960001484 edetic acid Drugs 0.000 claims description 16
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 14
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 14
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 14
- 239000002736 nonionic surfactant Substances 0.000 claims description 13
- 239000003093 cationic surfactant Substances 0.000 claims description 10
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 10
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 10
- 229920000053 polysorbate 80 Polymers 0.000 claims description 10
- 229940068968 polysorbate 80 Drugs 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 208000010412 Glaucoma Diseases 0.000 claims description 7
- 206010030043 Ocular hypertension Diseases 0.000 claims description 7
- OSRUSFPMRGDLAG-QMGYSKNISA-N dorzolamide hydrochloride Chemical compound [Cl-].CC[NH2+][C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 OSRUSFPMRGDLAG-QMGYSKNISA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 claims description 5
- 229960002506 dorzolamide hydrochloride Drugs 0.000 claims description 5
- WLRMANUAADYWEA-NWASOUNVSA-N (S)-timolol maleate Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 WLRMANUAADYWEA-NWASOUNVSA-N 0.000 claims description 4
- 229960005221 timolol maleate Drugs 0.000 claims description 4
- 239000002563 ionic surfactant Substances 0.000 claims 1
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 description 20
- 239000000203 mixture Substances 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 14
- 235000015165 citric acid Nutrition 0.000 description 12
- 238000009472 formulation Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 229920006158 high molecular weight polymer Polymers 0.000 description 10
- 239000003755 preservative agent Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 230000002335 preservative effect Effects 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- 239000003381 stabilizer Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000003963 antioxidant agent Substances 0.000 description 6
- 235000006708 antioxidants Nutrition 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000002997 ophthalmic solution Substances 0.000 description 5
- 229940054534 ophthalmic solution Drugs 0.000 description 5
- 229920001451 polypropylene glycol Polymers 0.000 description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000003945 anionic surfactant Substances 0.000 description 4
- 230000002421 anti-septic effect Effects 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 4
- 239000007951 isotonicity adjuster Substances 0.000 description 4
- 229920000573 polyethylene Polymers 0.000 description 4
- 238000006116 polymerization reaction Methods 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229920002675 Polyoxyl Polymers 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000003002 pH adjusting agent Substances 0.000 description 3
- 239000001509 sodium citrate Substances 0.000 description 3
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 3
- 235000011083 sodium citrates Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000012929 tonicity agent Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-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
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 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
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229940069275 cosopt Drugs 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 238000013461 design Methods 0.000 description 2
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- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 230000004410 intraocular pressure Effects 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229920000139 polyethylene terephthalate Polymers 0.000 description 2
- 239000005020 polyethylene terephthalate Substances 0.000 description 2
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- HLWRUJAIJJEZDL-UHFFFAOYSA-M sodium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC([O-])=O HLWRUJAIJJEZDL-UHFFFAOYSA-M 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 2
- 229940070756 timolol 5 mg Drugs 0.000 description 2
- 235000010384 tocopherol Nutrition 0.000 description 2
- 229930003799 tocopherol Natural products 0.000 description 2
- 229960001295 tocopherol Drugs 0.000 description 2
- 239000011732 tocopherol Substances 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- BLJRIMJGRPQVNF-JTQLQIEISA-N (S)-timolol (anhydrous) Chemical compound CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 BLJRIMJGRPQVNF-JTQLQIEISA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
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- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- 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
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
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- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229950004959 sorbitan oleate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000003813 thumb Anatomy 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
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- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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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- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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Abstract
Description
本発明は、ドルゾラミド又はその塩、チモロール又はその塩及び0.001〜5%(w/v)のベンザルコニウム塩化物以外の界面活性剤を含有し、ベンザルコニウム塩化物を含有しない医薬組成物に関する。 The present invention includes a pharmaceutical composition containing dorzolamide or a salt thereof, timolol or a salt thereof and a surfactant other than 0.001 to 5% (w / v) of benzalkonium chloride, and not containing benzalkonium chloride. Related to things.
炭酸脱水酵素阻害剤であるドルゾラミド及び受容体遮断薬であるチモロールは眼圧下降作用を示すことから緑内障又は高眼圧症の治療に有用である。そして、ドルゾラミドとチモロールの両方を含有する組成物は高眼圧の処置に特に有用であることが特許文献1に記載されており、ドルゾラミドとチモロールを含有する製剤がコソプト(登録商標)配合点眼液として販売されている。 Dorzolamide, which is a carbonic anhydrase inhibitor, and timolol, which is a receptor blocker, are useful for the treatment of glaucoma or ocular hypertension because they exhibit an intraocular pressure lowering action. Patent Document 1 describes that a composition containing both dorzolamide and timolol is particularly useful for the treatment of high intraocular pressure, and a preparation containing dorzolamide and timolol is a Cosopt (registered trademark) ophthalmic solution. It is sold as.
ところで、点眼液は、繰り返しの使用に伴う菌類等の繁殖を防止するため、一定以上の防腐効力が必要であり、上述のコソプト(登録商標)配合点眼液には防腐剤としてベンザルコニウム塩化物が配合されている。しかし、塩化ベンザルコニウムには細胞障害性があり、曝露量が増えると角膜上皮障害を引き起こす可能性がある(非特許文献1。従って、安全性や製造コスト等の観点から、ベンザルコニウム塩化物を含まない新たな点眼液が望まれている。 By the way, the ophthalmic solution needs to have a certain level of antiseptic effect in order to prevent the growth of fungi and the like associated with repeated use, and the above-mentioned Cosopt (registered trademark) ophthalmic solution contains benzalkonium chloride as a preservative. Is blended. However, benzalkonium chloride has cytotoxicity and may cause corneal epithelial damage when the exposure dose increases (Non-patent Document 1. Therefore, from the viewpoint of safety, manufacturing cost, etc., benzalkonium chloride is used. A new ophthalmic solution that does not contain substances is desired.
本発明者らは、ドルゾラミド又はその塩及びチモロール又はその塩を含有し、ベンザルコニウム塩化物を含有しない医薬組成物を研究する過程において、ドルゾラミド又はその塩及びチモロール又はその塩を含有する医薬組成物がベンザルコニウム塩化物を含有しない場合、ベンザルコニウム塩化物を含有する場合に比べて医薬組成物の一滴量が大幅に増加することを見出した。医薬組成物の一滴量の大幅な増加は、製品中の医薬組成物の総量を増加に繋がり、将来的な大きな製品設計の変更や製品製造プロセスの見直しの可能性を内在する。よって、新たな医薬組成物を開発するにあたり、医薬組成物の一滴量を既存の製品の一滴量と同等とすることは、従来の製品設計や製品製造プロセスを有効に活用でき、医薬の開発スピードや医薬の開発経済性の面で大きなメリットがあり好ましい。 In the course of studying a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof but not containing benzalkonium chloride, the present inventors have formulated a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof. It has been found that when the product does not contain benzalkonium chloride, the amount of one drop of the pharmaceutical composition is greatly increased compared to the case of containing benzalkonium chloride. A significant increase in the amount of one drop of the pharmaceutical composition leads to an increase in the total amount of the pharmaceutical composition in the product, which inherently has the potential for major future product design changes and product manufacturing process reviews. Therefore, when developing a new pharmaceutical composition, making the drop volume of a pharmaceutical composition equal to the drop volume of an existing product can effectively utilize the conventional product design and product manufacturing process, and the speed of drug development. It is preferable because of its great merit in terms of development economics and medicine.
このように、医薬組成物の一滴量が低減されることが望まれる一方で、上述のとおり、ベンザルコニウム塩化物を含まない新たな点眼液が望まれている。 Thus, while it is desired that the amount of one drop of the pharmaceutical composition is reduced, as described above, a new ophthalmic solution that does not contain benzalkonium chloride is desired.
したがって、ドルゾラミド又はその塩及びチモロール又はその塩を含有する医薬組成物において、ベンザルコニウム塩化物を含有しないにもかかわらず、その一滴量を低減させることが求められている。 Therefore, in a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, it is required to reduce the amount of one drop even though it does not contain benzalkonium chloride.
本発明の課題は、ドルゾラミド又はその塩及びチモロール又はその塩を含有する医薬組成物において、ベンザルコニウム塩化物を含有しないにもかかわらず、医薬組成物の一滴量を、ベンザルコニウム塩化物を含有するその医薬組成物の一滴量と同等の量に近づけるように制御することである。 An object of the present invention is to provide a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, while not containing benzalkonium chloride. The amount of the pharmaceutical composition to be contained is controlled so as to approach the amount equivalent to one drop.
本発明者らは、意外にも、ドルゾラミド又はその塩及びチモロール又はその塩を含有する医薬組成物において、ベンザルコニウム塩化物を含有しないにもかかわらず、0.001〜5%(w/v)のベンザルコニウム塩化物以外の界面活性剤を含有させることで、医薬組成物の一滴量が制御されることを見出し、本発明を完成した。具体的に、本発明は以下を提供する。 The present inventors have surprisingly found that in a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, 0.001 to 5% (w / v) although it does not contain benzalkonium chloride. It was found that the amount of one drop of the pharmaceutical composition can be controlled by containing a surfactant other than benzalkonium chloride in (1). Specifically, the present invention provides the following.
(1) ドルゾラミド又はその塩、チモロール又はその塩及び0.001〜5%(w/v)のベンザルコニウム塩化物以外の界面活性剤を含有し、ベンザルコニウム塩化物を含有しない医薬組成物。 (1) A pharmaceutical composition containing a surfactant other than dorzolamide or a salt thereof, timolol or a salt thereof and 0.001 to 5% (w / v) benzalkonium chloride, and not containing benzalkonium chloride .
(2) ドルゾラミド又はその塩がドルゾラミド塩酸塩である、(1)記載の医薬組成物。 (2) The pharmaceutical composition according to (1), wherein the dorzolamide or a salt thereof is dorzolamide hydrochloride.
(3) チモロール又はその塩が、チモロールマレイン酸塩である、(1)又は(2)に記載の医薬組成物。 (3) The pharmaceutical composition according to (1) or (2), wherein timolol or a salt thereof is timolol maleate.
(4) 界面活性剤が、非イオン性界面活性剤である、(1)〜(3)のいずれか一項に記載の医薬組成物。 (4) The pharmaceutical composition according to any one of (1) to (3), wherein the surfactant is a nonionic surfactant.
(5) 非イオン性界面活性剤が、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンヒマシ油及びモノステアリン酸ポリエチレングリコールからなる群より選択される少なくとも一つの非イオン性界面活性剤を含む、(4)記載の医薬組成物。 (5) At least the nonionic surfactant is selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and polyethylene glycol monostearate The pharmaceutical composition according to (4), comprising one nonionic surfactant.
(6) 非イオン性界面活性剤が、ポリオキシエチレンソルビタン脂肪酸エステルである、(4)記載の医薬組成物。 (6) The pharmaceutical composition according to (4), wherein the nonionic surfactant is a polyoxyethylene sorbitan fatty acid ester.
(7) 非イオン性界面活性剤が、ポリソルベート80、ポリオキシエチレン硬化ヒマシ油60又はポリオキシル35ヒマシ油である、(4)記載の医薬組成物。 (7) The pharmaceutical composition according to (4), wherein the nonionic surfactant is polysorbate 80, polyoxyethylene hydrogenated castor oil 60, or polyoxyl 35 castor oil.
(8) 界面活性剤が、カチオン性界面活性剤である、(1)〜(3)のいずれか一項に記載の医薬組成物。 (8) The pharmaceutical composition according to any one of (1) to (3), wherein the surfactant is a cationic surfactant.
(9) カチオン性界面活性剤が、クロルヘキシジン及びその塩からなる群より選択される少なくとも一つのカチオン性界面活性剤を含む、(8)記載の医薬組成物。 (9) The pharmaceutical composition according to (8), wherein the cationic surfactant comprises at least one cationic surfactant selected from the group consisting of chlorhexidine and a salt thereof.
(10) ドルゾラミド又はその塩の含有量が0.1〜5%(w/v)である、(1)〜(9)のいずれか一項に記載の医薬組成物。 (10) The pharmaceutical composition according to any one of (1) to (9), wherein the content of dorzolamide or a salt thereof is 0.1 to 5% (w / v).
(11) チモロール又はその塩の含有量が0.01−2%(w/v)である、(1)〜(10)のいずれか一項に記載の医薬組成物。 (11) The pharmaceutical composition according to any one of (1) to (10), wherein the content of timolol or a salt thereof is 0.01-2% (w / v).
(12) 界面活性剤の含有量が、0.03〜0.8%(w/v)である、(1)〜(11)のいずれか一項に記載の医薬組成物。 (12) The pharmaceutical composition according to any one of (1) to (11), wherein the surfactant content is 0.03 to 0.8% (w / v).
(13) 界面活性剤の含有量が、0.05〜0.5%(w/v)である、(1)〜(12)のいずれか一項に記載の医薬組成物。 (13) The pharmaceutical composition according to any one of (1) to (12), wherein the surfactant content is 0.05 to 0.5% (w / v).
(14) pHが3.0〜8.0である、(1)〜(13)のいずれか一項に記載の医薬組成物。 (14) The pharmaceutical composition according to any one of (1) to (13), wherein the pH is 3.0 to 8.0.
(15) ヒドロキシエチルセルロースをさらに含有する、(1)〜(14)のいずれか一項に記載の医薬組成物。 (15) The pharmaceutical composition according to any one of (1) to (14), further comprising hydroxyethylcellulose.
(16) エデト酸又はその塩をさらに含有する、(1)〜(15)のいずれか一項に記載の医薬組成物。 (16) The pharmaceutical composition according to any one of (1) to (15), further comprising edetic acid or a salt thereof.
(17) クエン酸又はその塩をさらに含有する、(1)〜(16)のいずれか一項に記載の医薬組成物。 (17) The pharmaceutical composition according to any one of (1) to (16), further containing citric acid or a salt thereof.
(18) 点眼容器に入れられた、(1)〜(17)のいずれか一項に記載の医薬組成物。 (18) The pharmaceutical composition according to any one of (1) to (17), which is placed in an eye drop container.
(19) 点眼容器の滴下口の外径が2.0〜4.5mmである、(18)記載の医薬組成物。 (19) The pharmaceutical composition according to (18), wherein the outer diameter of the dropping port of the eye drop container is 2.0 to 4.5 mm.
(20) 緑内障又は高眼圧症の治療に用いられる、(1)〜(19)のいずれか一項に記載の医薬組成物。 (20) The pharmaceutical composition according to any one of (1) to (19), which is used for the treatment of glaucoma or ocular hypertension.
(21) 緑内障又は高眼圧症を治療するための薬剤の製造における、(1)〜(20)のいずれか一項に記載の医薬組成物の使用。 (21) Use of the pharmaceutical composition according to any one of (1) to (20) in the manufacture of a medicament for treating glaucoma or ocular hypertension.
(22) ドルゾラミド又はその塩、及び、チモロール又はその塩を含有し、ベンザルコニウム塩化物を含有しない医薬組成物に、0.001〜5%(w/v)のベンザルコニウム塩化物以外の界面活性剤を含有させることによる、医薬組成物の一滴量を制御する方法。 (22) A pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof and not containing benzalkonium chloride, except 0.001 to 5% (w / v) of benzalkonium chloride A method for controlling a drop amount of a pharmaceutical composition by containing a surfactant.
なお、前記(1)から(22)の各構成は、任意に2以上を選択して組み合わせることができる。 Note that two or more of the configurations (1) to (22) can be arbitrarily selected and combined.
本発明によれば、ドルゾラミド又はその塩及びチモロール又はその塩を含有する医薬組成物において、ベンザルコニウム塩化物を含有しないにもかかわらず、0.001〜5%(w/v)のベンザルコニウム塩化物以外の界面活性剤を含有することにより、医薬組成物の一滴量が制御され、ベンザルコニウム塩化物を含有するその医薬組成物と同等の一滴量に近づけることができる。 According to the present invention, in a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof, 0.001 to 5% (w / v) benzalco, although it does not contain benzalkonium chloride. By containing a surfactant other than nium chloride, the amount of one drop of the pharmaceutical composition can be controlled, and it can be brought close to the same drop amount as that of the pharmaceutical composition containing benzalkonium chloride.
以下に、本発明について詳細に説明するが、本発明はこれに特に限定されない。 Hereinafter, the present invention will be described in detail, but the present invention is not particularly limited thereto.
本発明の医薬組成物において、含有されるドルゾラミドは、化学名(4S, 6S)-4-Ethylamino-6-methyl-5, 6-dihydro-4H-thieno[2, 3-b]thiopyran-2-sulfonamide 7, 7-dioxideで表される化合物である。ドルゾラミドは、市販又は公知の製造方法により得られるものであれば、特に制限されない。 In the pharmaceutical composition of the present invention, the contained dorzolamide has the chemical name (4S, 6S) -4-Ethylamino-6-methyl-5,6-dihydro-4H-thieno [2,3-b] thiopyran-2- It is a compound represented by sulfonamide 7, 7-dioxide. Dorzolamide is not particularly limited as long as it is commercially available or can be obtained by a known production method.
本発明の医薬組成物において、含有されるチモロールは、化学名(2S)-1-[(1, 1-Dimethylethyl)amino]-3-(4-morpholin-4-yl-1, 2, 5-thiadiazol-3-yloxy)propan-2-olで表される化合物である。チモロールは、市販又は公知の製造方法により得られるものであれば、特に制限されない。 In the pharmaceutical composition of the present invention, timolol contained is represented by the chemical name (2S) -1-[(1, 1-Dimethylethyl) amino] -3- (4-morpholin-4-yl-1, 2, 5- thiadiazol-3-yloxy) propan-2-ol. Timolol is not particularly limited as long as it is commercially available or can be obtained by a known production method.
本発明の医薬組成物において、含有されるドルゾラミド及びチモロールは塩であってもよく、医薬として許容される塩であれば特に制限はない。塩としては無機酸との塩、有機酸との塩、四級アンモニウム塩、ハロゲンイオンとの塩、アルカリ金属との塩、アルカリ土類金属との塩、金属塩、有機アミンとの塩等が挙げられる。 In the pharmaceutical composition of the present invention, the contained dorzolamide and timolol may be salts, and are not particularly limited as long as they are pharmaceutically acceptable salts. Salts include inorganic acid salts, organic acid salts, quaternary ammonium salts, halogen ion salts, alkali metal salts, alkaline earth metal salts, metal salts, organic amine salts, etc. Can be mentioned.
無機酸との塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。 Examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
有機酸との塩としては、酢酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、クエン酸、酒石酸、アジピン酸、グルコン酸、グルコヘプト酸、グルクロン酸、テレフタル酸、メタンスルホン酸、アラニン、乳酸、馬尿酸、1,2−エタンジスルホン酸、イセチオン酸、ラクトビオン酸、オレイン酸、没食子酸、パモ酸、ポリガラクツロン酸、ステアリン酸、タンニン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸、硫酸ラウリル、硫酸メチル、ナフタレンスルホン酸、スルホサリチル酸等との塩が挙げられる。 Salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine , Lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid and the like.
四級アンモニウム塩としては、臭化メチル、ヨウ化メチル等との塩が挙げられる。 Examples of quaternary ammonium salts include salts with methyl bromide, methyl iodide and the like.
ハロゲンイオンとの塩としては、塩化物イオン、臭化物イオン、ヨウ化物イオン等との塩が挙げられる。 Examples of salts with halogen ions include salts with chloride ions, bromide ions, iodide ions and the like.
アルカリ金属との塩としては、リチウム、ナトリウム、カリウム等との塩が挙げられる。 Examples of the salt with an alkali metal include salts with lithium, sodium, potassium and the like.
アルカリ土類金属との塩としては、カルシウム、マグネシウム等との塩が挙げられる。 Examples of the salt with alkaline earth metal include salts with calcium, magnesium and the like.
金属塩としては、鉄、亜鉛等との塩が挙げられる。 Examples of the metal salt include salts with iron, zinc and the like.
有機アミンとの塩としては、トリエチレンジアミン、2−アミノエタノール、2,2−イミノビス(エタノール)、1−デオキシ−1−(メチルアミノ)−2−D−ソルビトール、2−アミノ−2−(ヒドロキシメチル)−1,3−プロパンジオール、プロカイン、N,N−ビス(フェニルメチル)−1,2−エタンジアミン等との塩が挙げられる。 Examples of salts with organic amines include triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxy And salts with methyl) -1,3-propanediol, procaine, N, N-bis (phenylmethyl) -1,2-ethanediamine and the like.
ドルゾラミドの塩としては、一塩酸塩(ドルゾラミド塩酸塩)が特に好ましく、チモロールの塩としては、一マレイン酸塩(チモロールマレイン酸塩)が特に好ましい。 As the salt of dorzolamide, monohydrochloride (dorzolamide hydrochloride) is particularly preferable, and as the salt of timolol, monomaleate (timolol maleate) is particularly preferable.
本発明の医薬組成物において、ドルゾラミド及びチモロール並びにそれらの塩は、水和物又は溶媒和物の形態をとってもよい。チモロールの水和物としては、ヘミハイドレートが好ましい。 In the pharmaceutical composition of the present invention, dorzolamide and timolol and their salts may take the form of hydrates or solvates. As the hydrate of timolol, hemihydrate is preferable.
本発明の医薬組成物において、ドルゾラミド又はその塩の含有量は、医薬として許容される量であれば、特に制限されないが、0.1〜5%(w/v)が好ましく、0.2〜4%(w/v)がより好ましく、0.3〜3%(w/v)がさらに好ましく、0.4〜2.5%(w/v)がもっと好ましく、0.5〜2%(w/v)が特に好ましく、0.5%(w/v)、1%(w/v)又は2%(w/v)が最も好ましい。なお、本発明の防腐剤が使用される医薬組成物においてドルゾラミドの塩が含有される場合、これらの値はフリーのドルゾラミドに換算した含有量である。なお、「%(w/v)」は、本発明の医薬組成物100mL中に含まれる対象成分(ここでは、ドルゾラミド)の質量(g)を意味する。以下、特に断りがない限り同様とする。また、本明細書中に記載の全ての%(w/v)は、%(w/w)と読み替えてもよい。「%(w/w)」は、本発明の医薬組成物100g中に含まれる対象成分(ここでは、ドルゾラミド)の質量(g)を意味する。 In the pharmaceutical composition of the present invention, the content of dorzolamide or a salt thereof is not particularly limited as long as it is a pharmaceutically acceptable amount, but is preferably 0.1 to 5% (w / v), preferably 0.2 to 4% (w / v) is more preferred, 0.3-3% (w / v) is more preferred, 0.4-2.5% (w / v) is more preferred, 0.5-2% ( w / v) is particularly preferred, with 0.5% (w / v), 1% (w / v) or 2% (w / v) being most preferred. In addition, when the salt of a dorzolamide contains in the pharmaceutical composition in which the preservative of this invention is used, these values are content converted into the free dorzolamide. Note that “% (w / v)” means the mass (g) of the target component (here, Dorzolamide) contained in 100 mL of the pharmaceutical composition of the present invention. The same applies hereinafter unless otherwise specified. Moreover, all% (w / v) described in this specification may be read as% (w / w). “% (W / w)” means the mass (g) of the target component (here, Dorzolamide) contained in 100 g of the pharmaceutical composition of the present invention.
本発明の医薬組成物において、含有されるチモロール又はその塩の含有量は、所望の薬効を奏するのに十分な量であれば特に制限されないが、0.01〜2%(w/v)が好ましく、0.05〜1%(w/v)がより好ましく、0.1〜0.8%(w/v)がさらに好ましく、0.2〜0.7%(w/v)がさらにより好ましく、0.5%(w/v)が特に好ましい。なお、本発明の医薬組成物においてチモロールの塩が含有される場合は、これらの値はフリーのチモロールに換算した含有量である。 In the pharmaceutical composition of the present invention, the content of timolol or a salt thereof is not particularly limited as long as it is an amount sufficient to achieve a desired drug effect, but 0.01 to 2% (w / v) is Preferably, 0.05 to 1% (w / v) is more preferable, 0.1 to 0.8% (w / v) is more preferable, and 0.2 to 0.7% (w / v) is even more preferable 0.5% (w / v) is particularly preferable. In addition, when the salt of timolol is contained in the pharmaceutical composition of the present invention, these values are contents converted to free timolol.
ドルゾラミド又はその塩の含有量は、治療効果及び防腐効果の観点から、チモロール又はその塩の含有量に対し、0.1〜10倍が好ましく、0.5〜8倍がより好ましく、1倍〜5倍であることがさらに好ましい。 The content of dorzolamide or a salt thereof is preferably from 0.1 to 10 times, more preferably from 0.5 to 8 times, more preferably from 1 time to the content of timolol or a salt thereof from the viewpoint of therapeutic effect and antiseptic effect. More preferably, it is 5 times.
本発明の医薬組成物において、0.001〜5%(w/v)のベンザルコニウム塩化物以外の界面活性剤を含むことで、ベンザルコニウム塩化物を含まないにもかかわらず、一滴量が低減される。その理由は、従来のベンザルコニウム塩化物を含む医薬組成物は、ベンザルコニウム塩化物が防腐効果を奏する一方で、医薬組成物の一滴量を低減させる効果を担っていたと考えられるが、本発明においては界面活性剤がベンザルコニウム塩化物の代わりの役割を担うためと推測される。 In the pharmaceutical composition of the present invention, by containing a surfactant other than 0.001 to 5% (w / v) benzalkonium chloride, the amount of one drop is not included even though benzalkonium chloride is not contained. Is reduced. The reason for this is considered that the conventional pharmaceutical composition containing benzalkonium chloride was responsible for the effect of reducing the amount of one drop of the pharmaceutical composition while benzalkonium chloride exerted an antiseptic effect. In the invention, it is assumed that the surfactant plays a role instead of benzalkonium chloride.
本発明の医薬組成物において、含有される界面活性剤は、医薬品の添加物として使用可能な界面活性剤であれば特に制限はない。そのような界面活性剤としては、非イオン性界面活性剤、カチオン性界面活性剤、アニオン性界面活性剤が挙げられる。 The surfactant contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is a surfactant that can be used as a pharmaceutical additive. Examples of such surfactants include nonionic surfactants, cationic surfactants, and anionic surfactants.
非イオン性界面活性剤の例としては、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンヒマシ油、ポリオキシエチレンポリオキシプロピレングリコール、モノステアリン酸ポリエチレングリコール、ショ糖脂肪酸エステル、ビタミンE TPGS等が挙げられ、これらのうち、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンヒマシ油及びモノステアリン酸ポリエチレングリコールからなる群より選択される少なくとも一つを含むことが好ましく、ポリオキシエチレンソルビタン脂肪酸エステルが特に好ましく、ポリオキシエチレンソルビタン脂肪酸エステルのうち、ポリソルベート80(ポリオキシエチレン(20)ソルビタンオレイン酸エステル)が最も好ましい。 Examples of nonionic surfactants include polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, polyethylene glycol monostearate , Sucrose fatty acid ester, vitamin E TPGS, etc. Among these, from polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil and polyethylene glycol monostearate It is preferable to include at least one selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters. Of Le, polysorbate 80 (polyoxyethylene (20) sorbitan oleate) are most preferred.
ポリオキシエチレンソルビタン脂肪酸エステルとしては、ポリソルベート80、ポリソルベート65、ポリソルベート60、ポリソルベート40、ポリオキシエチレンソルビタンモノラウレート、ポリオキシエチレンソルビタントリオレート等が挙げられる。 Examples of the polyoxyethylene sorbitan fatty acid ester include polysorbate 80, polysorbate 65, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and the like.
ポリオキシエチレン脂肪酸エステルとしては、ステアリン酸ポリオキシル40等が挙げられる。 Examples of polyoxyethylene fatty acid esters include polyoxyl 40 stearate.
ポリオキシエチレン硬化ヒマシ油としては、酸化エチレンの重合数の異なる種々のポリオキシエチレン硬化ヒマシ油を用いることができ、酸化エチレンの重合数は10〜100が好ましく、20〜80がより好ましく、40〜70が特に好ましく、60が最も好ましい。ポリオキシエチレン硬化ヒマシ油の具体例としては、ポリオキシエチレン硬化ヒマシ油10、ポリオキシエチレン硬化ヒマシ油40、ポリオキシエチレン硬化ヒマシ油50、ポリオキシエチレン硬化ヒマシ油60等が挙げられ、ポリオキシエチレン硬化ヒマシ油60が好ましい。 As the polyoxyethylene hydrogenated castor oil, various polyoxyethylene hydrogenated castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 10 to 100, more preferably 20 to 80, and 40 ~ 70 is particularly preferred and 60 is most preferred. Specific examples of the polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, and the like. Ethylene hydrogenated castor oil 60 is preferred.
ポリオキシエチレンヒマシ油としては、酸化エチレンの重合数の異なる種々のポリオキシエチレンヒマシ油を用いることができ、酸化エチレンの重合数は5〜100が好ましく、20〜50がより好ましく、30〜40が特に好ましく、35が最も好ましい。ポリオキシエチレンヒマシ油の具体例としては、ポリオキシル5ヒマシ油、ポリオキシル9ヒマシ油、ポリオキシル15ヒマシ油、ポリオキシル35ヒマシ油、ポリオキシル40ヒマシ油等が挙げられ、ポリオキシル35ヒマシ油が好ましい。 As polyoxyethylene castor oil, various polyoxyethylene castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 5 to 100, more preferably 20 to 50, and 30 to 40. Is particularly preferred and 35 is most preferred. Specific examples of polyoxyethylene castor oil include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil and the like, and polyoxyl 35 castor oil is preferred.
ポリオキシエチレンポリオキシプロピレングリコールとしては、ポリオキシエチレン(160)ポリオキシプロピレン(30)グリコール、ポリオキシエチレン(42)ポリオキシプロピレン(67)グリコール、ポリオキシエチレン(54)ポリオキシプロピレン(39)グリコール、ポリオキシエチレン(196)ポリオキシプロピレン(67)グリコール、ポリオキシエチレン(20)ポリオキシプロピレン(20)グリコール等が挙げられる。 As polyoxyethylene polyoxypropylene glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) And glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol and the like.
ショ糖脂肪酸エステルとしては、ショ糖ステアリン酸エステル等が挙げられる。 Examples of the sucrose fatty acid ester include sucrose stearate ester.
ビタミンE TPGSは、トコフェロールポリエチレングリコール1000コハク酸エステルともいう。 Vitamin E TPGS is also referred to as tocopherol polyethylene glycol 1000 succinate.
本発明の医薬組成物に非イオン性界面活性剤を配合する場合の非イオン性界面活性剤の含有量は、0.001〜5(w/v)が好ましく、0.01〜2%(w/v)がより好ましく、0.03〜0.8%(w/v)がさらに好ましく、0.04〜0.6%(w/v)がもっと好ましく、0.05〜0.5%(w/v)が一層好ましく、0.07〜0.4%(w/v)がことさら好ましく、0.09〜0.3%(w/v)が特に好ましく、0.1〜0.2%(w/v)が最も好ましい。 The content of the nonionic surfactant when the nonionic surfactant is blended with the pharmaceutical composition of the present invention is preferably 0.001 to 5 (w / v), and 0.01 to 2% (w / V) is more preferable, 0.03 to 0.8% (w / v) is more preferable, 0.04 to 0.6% (w / v) is more preferable, and 0.05 to 0.5% ( w / v) is more preferable, 0.07 to 0.4% (w / v) is more preferable, 0.09 to 0.3% (w / v) is particularly preferable, and 0.1 to 0.2%. (W / v) is most preferred.
カチオン性界面活性剤の例としては、アルキルアミン塩、アルキルアミンポリオキシエチレン付加物、脂肪酸トリエタノールアミンモノエステル塩、アシルアミノエチルジエチルアミン塩、脂肪酸ポリアミン縮合物、アルキルイミダゾリン、1−アシルアミノエチル−2−アルキルイミダゾリン、1−ヒドロキシルエチル−2−アルキルイミダゾリン、クロルヘキシジン又はそれらの塩等が挙げられ、クロルヘキシジン又はその塩が好ましく、クロルヘキシジングルコン酸塩が最も好ましい。 Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl- Examples thereof include 2-alkylimidazoline, 1-hydroxylethyl-2-alkylimidazoline, chlorhexidine or a salt thereof, chlorhexidine or a salt thereof is preferable, and chlorhexidine gluconate is most preferable.
本発明の医薬組成物にカチオン性界面活性剤を配合する場合のカチオン性界面活性剤の含有量は、0.001〜5(w/v)が好ましく、0.001〜1%(w/v)がより好ましく、0.001〜0.1%(w/v)がさらに好ましく、0.001〜0.01%(w/v)が特に好ましく、0.001〜0.005%(w/v)が最も好ましい。 When the cationic surfactant is added to the pharmaceutical composition of the present invention, the content of the cationic surfactant is preferably 0.001 to 5 (w / v), and 0.001 to 1% (w / v). ) Is more preferable, 0.001 to 0.1% (w / v) is more preferable, 0.001 to 0.01% (w / v) is particularly preferable, and 0.001 to 0.005% (w / v) v) is most preferred.
アニオン性界面活性剤の例としては、リン脂質等が挙げられ、リン脂質としてはレシチン等が挙げられる。 Examples of anionic surfactants include phospholipids, and examples of phospholipids include lecithin.
本発明の医薬組成物にアニオン性界面活性剤を配合する場合のアニオン性界面活性剤の含有量は、0.001〜5(w/v)が好ましく、0.005〜2%(w/v)がより好ましく、0.01〜1%(w/v)がさらに好ましく、0.005〜0.01%(w/v)が特に好ましい。 The content of the anionic surfactant when the anionic surfactant is blended with the pharmaceutical composition of the present invention is preferably 0.001 to 5 (w / v), and 0.005 to 2% (w / v). ) Is more preferable, 0.01 to 1% (w / v) is more preferable, and 0.005 to 0.01% (w / v) is particularly preferable.
本発明の医薬組成物には、必要に応じて添加剤を用いることができ、添加剤としては、高分子量重合体、緩衝剤、等張化剤、安定化剤、抗酸化剤、防腐剤、pH調整剤等を加えることができる。 In the pharmaceutical composition of the present invention, additives can be used as necessary. Examples of the additives include high molecular weight polymers, buffers, isotonic agents, stabilizers, antioxidants, preservatives, A pH adjuster or the like can be added.
本発明の医薬組成物には、医薬品の添加物として使用可能な高分子量重合体を適宜配合することができる。高分子量重合体の例としては、メチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース、ポリビニルピロリドン、ポリビニルアルコール、カルボキシビニルポリマー、ポリエチレングリコール等が挙げられ、ヒドロキシエチルセルロースが好ましい。 In the pharmaceutical composition of the present invention, a high molecular weight polymer that can be used as a pharmaceutical additive can be appropriately blended. Examples of high molecular weight polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, Examples thereof include carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxy vinyl polymer, polyethylene glycol and the like, and hydroxyethyl cellulose is preferred.
本発明の医薬組成物において、高分子量重合体は、1%(w/v)水溶液としたときの粘度(特にヒドロキシエチルセルロースの粘度)が、25℃において、50〜100000(mPa・s)であるものが好ましく100〜30000(mPa・s)であるものがより好ましく、500〜10000(mPa・s)であるものがさらに好ましく、1000〜5000(mPa・s)であるものが特に好ましく、2000〜4000(mPa・s)であるものが最も好ましい。高分子量重合体の粘度は、高分子量重合体のみを含む1%(w/v)水溶液について、25℃においてオスワルド型粘度計を用いた毛細管粘度計法により測定する。 In the pharmaceutical composition of the present invention, the high molecular weight polymer has a viscosity (particularly the viscosity of hydroxyethyl cellulose) in a 1% (w / v) aqueous solution of 50 to 100,000 (mPa · s) at 25 ° C. Those having 100 to 30000 (mPa · s) are more preferred, those having 500 to 10000 (mPa · s) are more preferred, those having 1000 to 5000 (mPa · s) are particularly preferred, and 2000 to The most preferable is 4000 (mPa · s). The viscosity of the high molecular weight polymer is measured for a 1% (w / v) aqueous solution containing only the high molecular weight polymer by a capillary viscometer method using an Oswald viscometer at 25 ° C.
本発明の医薬組成物に高分子量重合体を配合する場合の高分子量重合体の含有量は、高分子量重合体の種類等により適宜調整することができるが、0.001〜5%(w/v)が好ましく、0.01〜3%(w/v)がより好ましく、0.1〜2%(w/v)がさらに好ましく、0.2〜1%(w/v)が最も好ましい。 The content of the high molecular weight polymer when the high molecular weight polymer is blended with the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the high molecular weight polymer, etc., but is 0.001 to 5% (w / v) is preferred, 0.01 to 3% (w / v) is more preferred, 0.1 to 2% (w / v) is more preferred, and 0.2 to 1% (w / v) is most preferred.
本発明の医薬組成物には、医薬品の添加物として使用可能な緩衝剤を配合することができる。緩衝剤の例としては、リン酸又はその塩、クエン酸又はその塩、酢酸又はその塩、炭酸又はその塩、酒石酸又はその塩、ε−アミノカプロン酸、トロメタモール等が挙げられる。 The pharmaceutical composition of the present invention may contain a buffering agent that can be used as a pharmaceutical additive. Examples of the buffer include phosphoric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ε-aminocaproic acid, trometamol, and the like.
リン酸塩としては、リン酸ナトリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸カリウム、リン酸二水素カリウム、リン酸水素二カリウム等が挙げられ、クエン酸塩としては、クエン酸ナトリウム、クエン酸二ナトリウム等が挙げられ、酢酸塩としては、酢酸ナトリウム、酢酸カリウム等が挙げられ、炭酸塩としては、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられ、酒石酸塩としては、酒石酸ナトリウム、酒石酸カリウム等が挙げられる。クエン酸又はその塩が好ましく、クエン酸ナトリウムが特に好ましい。 Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and the citrate includes citric acid. Sodium, disodium citrate and the like can be mentioned. Examples of the acetate include sodium acetate and potassium acetate. Examples of the carbonate include sodium carbonate and sodium bicarbonate. Examples of the tartrate include sodium tartrate, Examples include potassium tartrate. Citric acid or a salt thereof is preferred, and sodium citrate is particularly preferred.
本発明の医薬組成物に緩衝剤を配合する場合の緩衝剤の含有量は、緩衝剤の種類等により適宜調整することができるが、0.001〜10%(w/v)が好ましく、0.01〜5%(w/v)がより好ましく、0.1〜3%(w/v)がさらに好ましく、0.2〜2%(w/v)が最も好ましい。 The content of the buffer when blending the buffer with the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the buffer, etc., but is preferably 0.001 to 10% (w / v). 0.01 to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is more preferable, and 0.2 to 2% (w / v) is most preferable.
本発明の医薬組成物には、医薬品の添加物として使用可能な等張化剤を適宜配合することができる。等張化剤の例としては、イオン性等張化剤や非イオン性等張化剤等が挙げられる。イオン性等張化剤としては、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム等が挙げられ、塩化ナトリウムが好ましい。非イオン性等張化剤としてはグリセリン、プロピレングリコール、ソルビトール、マンニトール等が挙げられ、マンニトールが好ましい。本発明の医薬組成物に等張化剤を配合する場合の等張化剤の含有量は、等張化剤の種類等により適宜調整することができるが、0.01〜10%(w/v)が好ましく、0.02〜7%(w/v)がより好ましく、0.1〜5%(w/v)がさらに好ましく、0.5〜4%(w/v)が特に好ましく、0.8〜3%(w/v)が最も好ましい。 In the pharmaceutical composition of the present invention, an isotonic agent that can be used as a pharmaceutical additive can be appropriately blended. Examples of isotonic agents include ionic and nonionic tonicity agents. Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and sodium chloride is preferable. Nonionic tonicity agents include glycerin, propylene glycol, sorbitol, mannitol and the like, with mannitol being preferred. The content of the tonicity agent when blended with the isotonic agent in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of tonicity agent and the like, but is 0.01 to 10% (w / v) is preferred, 0.02 to 7% (w / v) is more preferred, 0.1 to 5% (w / v) is more preferred, 0.5 to 4% (w / v) is particularly preferred, Most preferred is 0.8-3% (w / v).
本発明の医薬組成物には、医薬品の添加物として使用可能な安定化剤を適宜配合することができる。安定化剤の例としては、エデト酸、エデト酸一ナトリウム、エデト酸二ナトリウム、エデト酸四ナトリウム、クエン酸ナトリウム等が挙げられ、エデト酸二ナトリウムが好ましく、エデト酸二ナトリウム二水和物が特に好ましい。 In the pharmaceutical composition of the present invention, a stabilizer that can be used as a pharmaceutical additive can be appropriately blended. Examples of stabilizers include edetic acid, monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate and the like, disodium edetate is preferred, and disodium edetate dihydrate is Particularly preferred.
本発明の医薬組成物に安定化剤を配合する場合の安定化剤の含有量は、安定化剤の種類等により適宜調整することができるが、0.0001〜0.5%(w/v)が好ましく、0.0005〜0.3%(w/v)がより好ましく、0.001〜0.1%(w/v)がさらに好ましく、0.002〜0.08%(w/v)がもっと好ましく、0.003〜0.05%(w/v)が一層好ましく、0.005〜0.03%(w/v)が特に好ましく、0.007〜0.01%(w/v)が最も好ましい。なお、本発明の医薬組成物においてエデト酸の塩又はその水和物が含有される場合、これらの値はエデト酸の塩又はその水和物の質量を基に計算された含有量である。 The content of the stabilizer when the stabilizer is added to the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the stabilizer, etc., but is 0.0001 to 0.5% (w / v ) Is preferable, 0.0005 to 0.3% (w / v) is more preferable, 0.001 to 0.1% (w / v) is more preferable, and 0.002 to 0.08% (w / v) ) Is more preferable, 0.003 to 0.05% (w / v) is more preferable, 0.005 to 0.03% (w / v) is particularly preferable, and 0.007 to 0.01% (w / v) v) is most preferred. In addition, when the salt of edetic acid or its hydrate is contained in the pharmaceutical composition of this invention, these values are content calculated based on the mass of the salt of edetic acid or its hydrate.
本発明の医薬組成物には、医薬品の添加物として使用可能な抗酸化剤を適宜配合することができる。抗酸化剤の例としては、アスコルビン酸、トコフェロール、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、エリソルビン酸ナトリウム、没食子酸プロピル、亜硫酸ナトリウム等が挙げられる。 The pharmaceutical composition of the present invention can be appropriately blended with an antioxidant that can be used as a pharmaceutical additive. Examples of antioxidants include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like.
本発明の医薬組成物に抗酸化剤を配合する場合の抗酸化剤の含有量は、抗酸化剤の種類等により適宜調整することができるが、0.0001〜1%(w/v)が好ましく、0.0005〜0.1%(w/v)がより好ましく、0.001〜0.02%(w/v)がさらに好ましく、0.005〜0.010%(w/v)が最も好ましい。 The content of the antioxidant when the antioxidant is blended with the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the antioxidant, etc., but is 0.0001 to 1% (w / v). Preferably, 0.0005 to 0.1% (w / v) is more preferable, 0.001 to 0.02% (w / v) is more preferable, and 0.005 to 0.010% (w / v) is more preferable. Most preferred.
本発明の医薬組成物には、医薬品の添加物として使用可能な防腐剤を適宜配合することができる。防腐剤の例としては、ベンザルコニウム臭化物、ベンゼトニウム塩化物、ソルビン酸、ソルビン酸カリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル、クロロブタノール、エデト酸又はその塩等が挙げられる。エデト酸の塩の例としては、エデト酸一ナトリウム、エデト酸二ナトリウム、エデト酸四ナトリウム、クエン酸ナトリウム等が挙げられ、エデト酸二ナトリウムが好ましく、エデト酸二ナトリウム二水和物が特に好ましい。 In the pharmaceutical composition of the present invention, a preservative that can be used as a pharmaceutical additive can be appropriately blended. Examples of preservatives include benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, edetic acid, and salts thereof. Examples of salts of edetic acid include monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate and the like, disodium edetate is preferred, and disodium edetate is particularly preferred. .
本発明の医薬組成物に防腐剤を配合する場合の防腐剤の含有量は、防腐剤の種類等により適宜調整することができるが、0.0001〜3%(w/v)が好ましく、0.0005〜1%(w/v)がより好ましく、0.001〜0.5%(w/v)がさらに好ましく、0.005〜0.1%(w/v)が最も好ましい。なお、エデト酸又はその塩は安定化剤として医薬組成物に添加されることもあり、本発明の医薬組成物にエデト酸又はその塩を含む場合は、0.0001〜0.5%(w/v)が好ましく、0.0005〜0.3%(w/v)がより好ましく、0.001〜0.1%(w/v)がさらに好ましく、0.002〜0.08%(w/v)がもっと好ましく、0.003〜0.05%(w/v)が一層好ましく、0.005〜0.03%(w/v)が特に好ましく、0.007〜0.01%(w/v)が最も好ましい。これらの値は本発明の医薬組成物に含まれるエデト酸及びその塩の総量としてその値であり、エデト酸の塩又はその水和物の質量を基に計算される。 The content of the preservative when the preservative is blended with the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the preservative, but is preferably 0.0001 to 3% (w / v), 0 .0005 to 1% (w / v) is more preferable, 0.001 to 0.5% (w / v) is more preferable, and 0.005 to 0.1% (w / v) is most preferable. In addition, edetic acid or a salt thereof may be added to a pharmaceutical composition as a stabilizer. When edetic acid or a salt thereof is included in the pharmaceutical composition of the present invention, 0.0001 to 0.5% (w / V) is preferable, 0.0005 to 0.3% (w / v) is more preferable, 0.001 to 0.1% (w / v) is further preferable, and 0.002 to 0.08% (w / V) is more preferable, 0.003 to 0.05% (w / v) is more preferable, 0.005 to 0.03% (w / v) is particularly preferable, and 0.007 to 0.01% ( w / v) is most preferred. These values are those values as the total amount of edetic acid and its salt contained in the pharmaceutical composition of the present invention, and are calculated based on the mass of the salt of edetic acid or its hydrate.
本発明の医薬組成物には、医薬品の添加物として使用可能なpH調整剤を適宜配合することができる。pH調整剤の例としては、塩酸、リン酸、クエン酸、酢酸、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられ、クエン酸が好ましい。 The pharmaceutical composition of the present invention can be appropriately mixed with a pH adjuster that can be used as an additive for pharmaceuticals. Examples of the pH adjuster include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like, and citric acid is preferable.
本発明の医薬組成物は、高分子量重合体としてヒドロキシエチルセルロースを、緩衝剤としてクエン酸又はその塩を、防腐剤としてエデト酸又はその塩をそれぞれ組み合わせて含むことが特に好ましい。この場合において、それぞれの成分の含有量は、ヒドロキシエチルセルロースが0.001〜5%(w/v)、クエン酸又はその塩が0.001〜10%(w/v)、エデト酸又はその塩が0.0001〜0.5%(w/v)であることが好ましく、ヒドロキシエチルセルロースが0.01〜3%(w/v)、クエン酸又はその塩が0.01〜5%(w/v)、エデト酸又はその塩が0.001〜0.1%(w/v)であることがより好ましく、ヒドロキシエチルセルロースが0.1〜2%(w/v)、クエン酸又はその塩が0.1〜3%(w/v)、エデト酸又はその塩が0.003〜0.05%(w/v)であることがさらに好ましく、ヒドロキシエチルセルロースが0.2〜1%(w/v)、クエン酸又はその塩が0.2〜2%(w/v)、エデト酸又はその塩が0.007〜0.01%(w/v)であることが最も好ましい。 The pharmaceutical composition of the present invention particularly preferably contains hydroxyethyl cellulose as a high molecular weight polymer, citric acid or a salt thereof as a buffer, and edetic acid or a salt thereof as a preservative. In this case, the content of each component is 0.001 to 5% (w / v) for hydroxyethyl cellulose, 0.001 to 10% (w / v) for citric acid or a salt thereof, edetic acid or a salt thereof. Is preferably 0.0001 to 0.5% (w / v), 0.01 to 3% (w / v) of hydroxyethyl cellulose, 0.01 to 5% (w / v) of citric acid or a salt thereof. v), edetic acid or a salt thereof is more preferably 0.001 to 0.1% (w / v), hydroxyethyl cellulose is 0.1 to 2% (w / v), citric acid or a salt thereof More preferably, 0.1 to 3% (w / v), edetic acid or a salt thereof is 0.003 to 0.05% (w / v), and hydroxyethyl cellulose is 0.2 to 1% (w / v). v) 0.2 to 2% citric acid or salt thereof (w / ), And most preferably edetic acid or a salt thereof is 0.007~0.01% (w / v).
本発明の医薬組成物のpHは、医薬として許容されるpHであれば特に制限はなく、3.0〜8.0が好ましく、ドルゾラミドの安定性の観点から、3.0〜6.0がより好ましく、4.0〜6.0がさらに好ましく、5.0〜6.0がもっと好ましく、5.5〜6.0が特に好ましく、5.5〜5.8が最も好ましい。 The pH of the pharmaceutical composition of the present invention is not particularly limited as long as it is a pharmaceutically acceptable pH, preferably 3.0 to 8.0, and from the viewpoint of the stability of dorzolamide, 3.0 to 6.0. More preferably, 4.0 to 6.0 is more preferable, 5.0 to 6.0 is more preferable, 5.5 to 6.0 is particularly preferable, and 5.5 to 5.8 is most preferable.
本発明の医薬組成物の浸透圧比(生理食塩液に対する)は、適宜調整することができるが、0.1−2.4が好ましく、0.7〜2.1がより好ましく、0.9〜1.1が特に好ましく、約1が最も好ましい。 The osmotic pressure ratio (with respect to physiological saline) of the pharmaceutical composition of the present invention can be adjusted as appropriate, but is preferably 0.1 to 2.4, more preferably 0.7 to 2.1, and 0.9 to 1.1 is particularly preferred and about 1 is most preferred.
本発明の医薬組成物の粘度は、適宜調整することができるが、オスワルド型粘度計を用いた毛細管粘度計法、25℃において、50〜700(mPa・s)であることが好ましく、55〜500(mPa・s)であることがより好ましく、60〜300(mPa・s)であることがさらに好ましく、65〜200(mPa・s)であることが特に好ましく、65〜170(mPa・s)であることが最も好ましい。 The viscosity of the pharmaceutical composition of the present invention can be adjusted as appropriate, but is preferably 50 to 700 (mPa · s) at 25 ° C. using a capillary viscometer method using an Oswald viscometer. More preferably, it is 500 (mPa · s), more preferably 60 to 300 (mPa · s), particularly preferably 65 to 200 (mPa · s), and 65 to 170 (mPa · s). ) Is most preferred.
本発明の医薬組成物は、無色澄明、わずかに粘稠性のある無菌水性の医薬組成物であることが望ましく、特に点眼用組成物(点眼剤)であることが特に好ましい。 The pharmaceutical composition of the present invention is desirably a colorless and clear, slightly viscous, sterile aqueous pharmaceutical composition, and particularly preferably an eye drop composition (eye drop).
本発明の医薬組成物は、ユニットドーズ型点眼容器やマルチドーズ型点眼容器に入れることができ、マルチドーズ型点眼容器に入れられることが好ましい。ユニットドーズ型点眼容器とは一回使い切りの点眼容器であり、マルチドーズ型点眼容器とは複数回使用することを目的にキャップ等の開閉を自由に行えるようにした点眼容器である。逆流防止機能等の防腐効果を発揮するための特別な構造を有するPFMD(Preservative Free Multi Dose)点眼容器に入れてもよい。点眼容器の素材に特に制限はなく、例えば、ポリエチレン(PE)製、ポリプロピレン(PP)製、ポリエチレンテレフタレート(PET)製等の点眼容器を用いることができる。点眼容器の滴下口の外径は、2.0〜4.5mmが好ましく、2.5〜4.0mmがより好ましく、3.0〜3.6mmが最も好ましい。 The pharmaceutical composition of the present invention can be placed in a unit dose type eye drop container or a multi dose type eye drop container, and is preferably placed in a multi dose type eye drop container. A unit dose type eye drop container is an eye drop container that can be used once, and a multi dose type eye drop container is an eye drop container that can be freely opened and closed for the purpose of using it multiple times. You may put in the PFMD (Preservative Free Multi Dose) eye drop container which has a special structure for exhibiting antiseptic effects, such as a backflow prevention function. There is no restriction | limiting in particular in the raw material of an eye drop container, For example, eye drop containers made from a product made from polyethylene (PE), a product made from polypropylene (PP), a product made from polyethylene terephthalate (PET), etc. can be used. The outer diameter of the dropping port of the eye drop container is preferably 2.0 to 4.5 mm, more preferably 2.5 to 4.0 mm, and most preferably 3.0 to 3.6 mm.
本医薬組成物の一滴量は、点眼容器の滴下口の口径等により変わりうるが、28〜36μLであることが好ましく、29〜35μLであることがより好ましく、30〜34μLであることが最も好ましい。或いは、28〜36mgであることが好ましく、29〜35mgであることがより好ましく、30〜34mgであることが最も好ましい。本医薬組成物の一滴量は、容器胴部を通常の点眼剤の使用と同様に押す等して一滴滴下した後、天秤で質量を測定すること等により測定することができる。例えば、室温で、点眼容器を上向きにし、キャップをはずした後、点眼容器を真下に向けて、容器胴部をできるだけゆっくり(例えば、2〜5秒、好ましくは3秒程度)と押し、天秤に置いた受け皿に一滴滴下する。一滴滴下後は、容器を下向きに保持したまま、容器胴部に加えている力を緩める。天秤で一滴量の質量を測定することにより、本発明組成物の一滴の質量を測定することができる。また、測定された本発明組成物の一滴量の質量と本医薬組成物の比重から、本発明組成物の一滴量の体積も容易に計算することができる。なお、異なる医薬組成物のそれぞれ一滴量同士を比較するときは、それぞれを同条件(例えば、同様の温度、同様の点眼容器、同様の滴下条件(例えば、滴下時の点眼容器の傾ける角度、容器胴部に加える力及び時間)、同様の一滴量の質量の測定方法)で一滴量を算出したもの同士を比較して行う。 The amount of one drop of the pharmaceutical composition may vary depending on the diameter of the dropping port of the eye drop container, but is preferably 28 to 36 μL, more preferably 29 to 35 μL, and most preferably 30 to 34 μL. . Alternatively, it is preferably 28 to 36 mg, more preferably 29 to 35 mg, and most preferably 30 to 34 mg. The amount of one drop of the present pharmaceutical composition can be measured by, for example, pressing the container body in the same manner as using normal eye drops and dropping one drop, and then measuring the mass with a balance. For example, at room temperature, the eye drop container is turned upward, the cap is removed, the eye drop container is pointed directly down, the container body is pushed as slowly as possible (for example, about 2 to 5 seconds, preferably about 3 seconds), and the balance is Drop a drop on the saucer. After dropping one drop, the force applied to the container body is relaxed while holding the container downward. By measuring the mass of one drop with a balance, the mass of one drop of the composition of the present invention can be measured. Moreover, the volume of the drop amount of the composition of the present invention can be easily calculated from the measured mass of the drop amount of the composition of the present invention and the specific gravity of the pharmaceutical composition. In addition, when comparing each drop amount of different pharmaceutical compositions, the same conditions (for example, the same temperature, the same eye drop container, the same dropping condition (for example, the angle of inclination of the eye drop container at the time of dropping, the container The force and time applied to the body part, and the same method for measuring the mass of a single drop) are compared with each other.
本発明の医薬組成物の剤形は、医薬品として使用可能なものであれば特に制限されないが、特に点眼剤が好ましく、当該技術分野における通常の方法に従って製造することができる。 The dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a pharmaceutical product, but an eye drop is particularly preferable and can be produced according to a usual method in the technical field.
本発明の医薬組成物は、緑内障又は高眼圧症の治療剤として有用である。 The pharmaceutical composition of the present invention is useful as a therapeutic agent for glaucoma or ocular hypertension.
本発明の医薬組成物を投与する場合、所望の薬効を奏するのに十分であれば用法用量に特に制限はないが、1回1〜3滴、1日1〜5回点眼するのが好ましく、1回1〜2滴、1日2〜4回点眼するのがより好ましく、1回1滴、1日3回点眼するのが最も好ましい。 When administering the pharmaceutical composition of the present invention, there is no particular limitation on the dosage as long as it is sufficient to achieve the desired drug effect, but it is preferable to instill 1 to 3 drops, 1 to 5 times a day, More preferably, 1 to 2 drops per day, 2 to 4 times per day, most preferably 1 drop per day, 3 times per day.
本発明の医薬組成物は、コンタクトレンズ(装着者)用として有用である。適用されるコンタクトレンズの種類に特に制限はなく、具体的には、ハードコンタクトレンズ、ソフトコンタクトレンズ等が挙げられ、酸素透過性コンタクトレンズでもよい。ソフトコンタクトレンズとしては、含水ソフトコンタクトレンズ、非含水ソフトコンタクトレンズ、(非イオン性)シリコーンハイドロゲルソフトコンタクトレンズ等が挙げられる。 The pharmaceutical composition of the present invention is useful for contact lenses (wearers). The type of contact lens to be applied is not particularly limited, and specific examples include hard contact lenses, soft contact lenses, and the like, and oxygen permeable contact lenses may be used. Examples of the soft contact lens include a hydrous soft contact lens, a non-hydrous soft contact lens, and a (nonionic) silicone hydrogel soft contact lens.
上記の本発明の医薬組成物の詳細な説明は、緑内障又は高眼圧症を治療するための薬剤の製造における本発明の医薬組成物の使用、及び、本発明の医薬組成物の一滴量を制御する方法にも適用される。 The above detailed description of the pharmaceutical composition of the present invention controls the use of the pharmaceutical composition of the present invention in the manufacture of a medicament for the treatment of glaucoma or ocular hypertension and the amount of one drop of the pharmaceutical composition of the present invention. It is also applied to the method.
本発明の医薬組成物の一滴量を制御する方法は、ドルゾラミド又はその塩及びチモロール又はその塩を含有し、ベンザルコニウム塩化物を含有しない医薬組成物に、0.001〜5%(w/v)のベンザルコニウム塩化物以外の界面活性剤を含有させることを含む。 The method for controlling the amount of one drop of the pharmaceutical composition of the present invention includes 0.001 to 5% (w / w) of a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof and not containing benzalkonium chloride. v) containing a surfactant other than benzalkonium chloride.
本発明の医薬組成物の一滴量を制御する方法によれば、ドルゾラミド又はその塩及びチモロール又はその塩を含有し、ベンザルコニウム塩化物を含有しない医薬組成物の一滴量を制御することができ、ベンザルコニウム塩化物を含有する医薬組成物の一滴量と同等に近づけるように制御することができる。つまり、ドルゾラミド又はその塩、チモロール又はその塩及びベンザルコニウム塩化物を含有する医薬組成物において、ベンザルコニウム塩化物を含有しない医薬組成物とすると一滴量は増加してしまうが、このベンザルコニウム塩化物を含有しない医薬組成物に0.001〜5%(w/v)のベンザルコニウム塩化物以外の界面活性剤を含有させることにより医薬組成物の一滴量は減少し、ベンザルコニウム塩化物を含有する医薬組成物の一滴量と同等に近づけるように制御することができる。なお、「医薬組成物の一滴量の制御」とは、医薬組成物の一滴量を下方方向に制御すること(つまり、医薬組成物の一滴量を減少させる方向への制御)を意味する。 According to the method for controlling the drop amount of the pharmaceutical composition of the present invention, the drop amount of the pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof and not containing benzalkonium chloride can be controlled. The pharmaceutical composition containing benzalkonium chloride can be controlled to be close to the amount of one drop. In other words, in a pharmaceutical composition containing dorzolamide or a salt thereof, timolol or a salt thereof and benzalkonium chloride, the amount of one drop increases when the pharmaceutical composition does not contain benzalkonium chloride. By including 0.001 to 5% (w / v) of a surfactant other than benzalkonium chloride in a pharmaceutical composition not containing nium chloride, the amount of one drop of the pharmaceutical composition is reduced, and benzalkonium is reduced. It can be controlled to be close to the drop amount of a pharmaceutical composition containing chloride. Note that “control of the drop amount of the pharmaceutical composition” means that the drop amount of the pharmaceutical composition is controlled in the downward direction (that is, control in the direction of decreasing the drop amount of the pharmaceutical composition).
以下に製剤例及び粘度測定試験の結果を示すが、これらは本発明をより良く理解するためのものであり、本発明の範囲を限定するものではない。 Although the example of a formulation and the result of a viscosity measurement test are shown below, these are for understanding this invention better and do not limit the scope of the present invention.
製剤例
以下に本発明の代表的な製剤例を示す。なお、下記製剤例において各成分の配合量は製剤1mL中の含量である。
Formulation Example A typical formulation example of the present invention is shown below. In the following formulation examples, the amount of each component is the content in 1 mL of the formulation.
製剤例1
ドルゾラミド 10mg
チモロール 5mg
ポリソルベート80 0.1mg
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
pH 5.65
Formulation Example 1
Dorzolamide 10mg
Timolol 5mg
Polysorbate 80 0.1mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 5.65
製剤例2
ドルゾラミド 20mg
チモロール 5mg
ポリソルベート80 0.1mg
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
pH 5.65
Formulation Example 2
Dorzolamide 20mg
Timolol 5mg
Polysorbate 80 0.1mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 5.65
なお、前記製剤例1及び2におけるドルゾラミド、チモロール及び界面活性剤の種類や配合量、並びに、pHを適宜調整し所望の組成物を得ることができる。 In addition, the desired composition can be obtained by appropriately adjusting the types and blending amounts of dorzolamide, timolol and surfactant in Formulation Examples 1 and 2 and the pH.
粘度測定試験
1.被験製剤の調製
<ベンザルコニウム塩化物を含有する製剤(BAK含有製剤)の調製>
ヒドロキシエチルセルロース(0.95g)を滅菌精製水に溶解し、高圧蒸気滅菌(121℃、30分)し、0.95%(w/w)ヒドロキシエチルセルロース溶液とした。また、ドルゾラミド塩酸塩(2.7825g)、チモロールマレイン酸塩(1.7075g)、クエン酸ナトリウム水和物(0.735g)、D−マンニトール(7.5g)を滅菌精製水に溶解し、2.5倍濃厚液Aとした。そして、10%(w/v)ベンザルコニウム塩化物溶液を滅菌精製水で希釈し0.5%ベンザルコニウム塩化物溶液とした。2.5倍濃厚液A12mLに0.5%(w/v)ベンザルコニウム塩化物溶液0.3mLを投入し、さらに0.95%(w/w)ヒドロキシエチルセルロース溶液15gを投入し、撹拌した。そして1N水酸化ナトリウムを添加し、pH5.65に調整した。滅菌精製水を加え全量30gに調整することにより、BAK(ベンザルコニウム塩化物)を含有する溶液を調製した。調製した溶液(5mL)をポリエチレン製の点眼容器(ノズル先端の外径;3.2mm)に入れてBAK含有製剤1を調製した。BAK含有製剤1の調製方法と同様の方法にてBAK含有製剤2を調製した。
Viscosity measurement test Preparation of test preparation <Preparation of preparation containing benzalkonium chloride (BAK-containing preparation)>
Hydroxyethyl cellulose (0.95 g) was dissolved in sterilized purified water and autoclaved (121 ° C., 30 minutes) to give a 0.95% (w / w) hydroxyethyl cellulose solution. Also, dorzolamide hydrochloride (2.7825 g), timolol maleate (1.77075 g), sodium citrate hydrate (0.735 g) and D-mannitol (7.5 g) were dissolved in sterilized purified water. A 5 times concentrated liquid A was obtained. A 10% (w / v) benzalkonium chloride solution was diluted with sterilized purified water to obtain a 0.5% benzalkonium chloride solution. To 12 mL of 2.5-fold concentrated solution A, 0.3 mL of 0.5% (w / v) benzalkonium chloride solution was added, and further 15 g of 0.95% (w / w) hydroxyethyl cellulose solution was added and stirred. . Then, 1N sodium hydroxide was added to adjust the pH to 5.65. A solution containing BAK (benzalkonium chloride) was prepared by adding sterilized purified water to adjust the total amount to 30 g. The prepared solution (5 mL) was put in a polyethylene eye drop container (outer diameter of nozzle tip; 3.2 mm) to prepare BAK-containing preparation 1. BAK-containing preparation 2 was prepared in the same manner as the preparation method for BAK-containing preparation 1.
<実施例及び比較例の製剤の調製>
ポリソルベート80を0.015g秤量し、上記<ベンザルコニウム塩化物を含有する製剤(BAK含有製剤)の調製>における方法と同様に調製した2.5倍濃厚液A12mLに0.95%(w/w)ヒドロキシエチルセルロース溶液15gを投入し、撹拌後1N水酸化ナトリウムを添加し、pH5.65に調整し、滅菌精製水を加え全量30gに調整することにより、BAKを含有しない溶液を調製した。調製した溶液(5mL)をポリエチレン製の点眼容器に入れて実施例1の製剤を調製した。配合成分・配合量を表1及び表2に示すとおりに変更した点以外は、実施例1の調製方法と同様の方法にて実施例2〜9、比較例1及び比較例2の製剤を調製した。
<Preparation of formulations of Examples and Comparative Examples>
0.015 g of polysorbate 80 was weighed, and 0.95% (w / w) A solution containing no BAK was prepared by adding 15 g of a hydroxyethylcellulose solution, adding 1N sodium hydroxide after stirring, adjusting the pH to 5.65, and adding sterilized purified water to a total amount of 30 g. The prepared solution (5 mL) was placed in a polyethylene eye dropper to prepare the formulation of Example 1. Preparations of Examples 2 to 9, Comparative Example 1 and Comparative Example 2 were prepared in the same manner as the preparation method of Example 1, except that the ingredients and amounts were changed as shown in Table 1 and Table 2. did.
2.試験方法
室温で、各製剤の点眼容器を上向きにし、キャップをはずした後、点眼容器を真下に向けて、容器胴部を親指と人差し指で約3秒かけてゆっくりと押し、セミミクロ天秤に置いた受け皿に一滴滴下した。一滴滴下後は、容器を下向きに保持したまま、容器胴部に加えている力を緩めた。セミミクロ天秤で質量を測定することにより、各製剤の一滴量を測定した。各製剤についての試験は、全て同じ条件で行った。
2. Test method At room temperature, the eye drop container of each preparation was turned upward, the cap was removed, the eye drop container was pointed directly down, the container body was slowly pushed with the thumb and forefinger for about 3 seconds, and placed on a semi-micro balance. A drop was dropped on the saucer. After dropping one drop, the force applied to the container body was loosened while holding the container downward. The amount of each drop was measured by measuring the mass with a semi-micro balance. All tests for each formulation were performed under the same conditions.
3.試験結果及び考察
試験結果を表1及び表2に示す。
3. Test results and discussion The test results are shown in Tables 1 and 2.
表1及び表2に示されるように、界面活性剤(ポリソルベート80)及びベンザルコニウム塩化物を含まない比較例1及び比較例2の製剤の一滴量は、界面活性剤を含まないがベンザルコニウム塩化物を含有するBAK含有製剤1及びBAK含有製剤2の一滴量のおよそ1.4倍であった。一方、本発明にあたる、ドルゾラミド塩酸塩、チモロールマレイン酸及び0.05〜0.5%(w/w)の界面活性剤(ポリソルベート80、ポリオキシエチレン硬化ヒマシ油60、又はポリオキシル35ヒマシ油)を含有し、ベンザルコニウム塩化物を含有しない実施例1〜9の製剤の一滴量は、BAK含有製剤1及びBAK含有製剤2の一滴量と同程度であった。この結果から、ドルゾラミド又はその塩及びチモロール又はその塩を含有する医薬組成物において、ベンザルコニウム塩化物を含有しなくても、界面活性剤を含む事で、医薬組成物の一滴量をベンザルコニウム塩化物を含有する医薬組成物の一滴量と同等の量に近づけることができることがわかった。また、実施例4、5、8及び9の比較から、界面活性剤としては、特に、ポリソルベート80が優れることがわかった。 As shown in Tables 1 and 2, one drop of the preparations of Comparative Example 1 and Comparative Example 2 containing no surfactant (polysorbate 80) and benzalkonium chloride contains no surfactant but benzalkco It was approximately 1.4 times the amount of one drop of BAK-containing preparation 1 and BAK-containing preparation 2 containing nium chloride. On the other hand, dorzolamide hydrochloride, timolol maleic acid and 0.05 to 0.5% (w / w) surfactant (polysorbate 80, polyoxyethylene hydrogenated castor oil 60, or polyoxyl 35 castor oil) according to the present invention are used. The amount of one drop of the preparations of Examples 1 to 9 that contained and did not contain benzalkonium chloride was the same as that of the BAK-containing preparation 1 and the BAK-containing preparation 2. From this result, it is found that a pharmaceutical composition containing dorzolamide or a salt thereof and timolol or a salt thereof does not contain benzalkonium chloride, so that a drop of the pharmaceutical composition can be reduced by including a surfactant. It has been found that it can approach an amount equivalent to a drop amount of a pharmaceutical composition containing nium chloride. In addition, from the comparison of Examples 4, 5, 8 and 9, it was found that polysorbate 80 was particularly excellent as the surfactant.
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WO2022173043A1 (en) * | 2021-02-15 | 2022-08-18 | 参天製薬株式会社 | Water-based pharmaceutical composition containing ursodeoxycholic acid or salt thereof |
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US20190134051A1 (en) * | 2017-11-06 | 2019-05-09 | Rheostasis, Llc | Composition for treating ocular disorders such as macular degeneration, retinopathy and glaucoma |
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WO2019112030A1 (en) * | 2017-12-08 | 2019-06-13 | 千寿製薬株式会社 | Aqueous liquid agent including water-soluble polymer |
JP2019104727A (en) * | 2017-12-08 | 2019-06-27 | 千寿製薬株式会社 | Aqueous solution containing water-soluble polymer |
WO2022173043A1 (en) * | 2021-02-15 | 2022-08-18 | 参天製薬株式会社 | Water-based pharmaceutical composition containing ursodeoxycholic acid or salt thereof |
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JP2017165707A (en) | 2017-09-21 |
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JP6886878B2 (en) | 2021-06-16 |
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