JP2007063265A - Method for preventing degradation of thermally unstable medicament - Google Patents
Method for preventing degradation of thermally unstable medicament Download PDFInfo
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- JP2007063265A JP2007063265A JP2006210644A JP2006210644A JP2007063265A JP 2007063265 A JP2007063265 A JP 2007063265A JP 2006210644 A JP2006210644 A JP 2006210644A JP 2006210644 A JP2006210644 A JP 2006210644A JP 2007063265 A JP2007063265 A JP 2007063265A
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- ophthalmic solution
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- 239000003814 drug Substances 0.000 title claims abstract description 61
- 230000015556 catabolic process Effects 0.000 title claims abstract description 5
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 5
- 238000000034 method Methods 0.000 title claims description 24
- 150000001412 amines Chemical class 0.000 claims abstract description 31
- 229940079593 drug Drugs 0.000 claims description 56
- 239000002997 ophthalmic solution Substances 0.000 claims description 51
- 229940054534 ophthalmic solution Drugs 0.000 claims description 51
- 229960001160 latanoprost Drugs 0.000 claims description 23
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical group CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 19
- 238000000354 decomposition reaction Methods 0.000 claims description 15
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 14
- 229960000281 trometamol Drugs 0.000 claims description 14
- 150000003180 prostaglandins Chemical class 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 8
- XXUPXHKCPIKWLR-JHUOEJJVSA-N isopropyl unoprostone Chemical compound CCCCCCCC(=O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(=O)OC(C)C XXUPXHKCPIKWLR-JHUOEJJVSA-N 0.000 claims description 7
- 229960002368 travoprost Drugs 0.000 claims description 7
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 claims description 7
- 229950008081 unoprostone isopropyl Drugs 0.000 claims description 7
- 229960004458 tafluprost Drugs 0.000 claims description 6
- WSNODXPBBALQOF-VEJSHDCNSA-N tafluprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\C(F)(F)COC1=CC=CC=C1 WSNODXPBBALQOF-VEJSHDCNSA-N 0.000 claims description 6
- 239000006210 lotion Substances 0.000 abstract 5
- 239000003889 eye drop Substances 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229940012356 eye drops Drugs 0.000 description 5
- 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
- 239000008213 purified water Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- -1 amine compound Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 3
- 235000019799 monosodium phosphate Nutrition 0.000 description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- LRJOMUJRLNCICJ-JZYPGELDSA-N Prednisolone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O LRJOMUJRLNCICJ-JZYPGELDSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 229960003194 meglumine Drugs 0.000 description 2
- 229960000334 methylprednisolone sodium succinate Drugs 0.000 description 2
- IMBXEJJVJRTNOW-XYMSELFBSA-N methylprednisolone succinate Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC(O)=O)CC[C@H]21 IMBXEJJVJRTNOW-XYMSELFBSA-N 0.000 description 2
- 229960004811 pemirolast potassium Drugs 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- NMMVKSMGBDRONO-UHFFFAOYSA-N potassium;9-methyl-3-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound [K+].CC1=CC=CN(C2=O)C1=NC=C2C1=NN=N[N-]1 NMMVKSMGBDRONO-UHFFFAOYSA-N 0.000 description 2
- 229960002800 prednisolone acetate Drugs 0.000 description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
- 229960004919 procaine Drugs 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000002562 thickening agent Substances 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
- 238000010792 warming Methods 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- UMYAMXGXQKNONL-UHFFFAOYSA-M C(CC(O)(C(=O)O)CC(=O)O)(=O)[O-].B(O)(O)O.[K+] Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)[O-].B(O)(O)O.[K+] UMYAMXGXQKNONL-UHFFFAOYSA-M 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 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 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 229940124342 antiallergic ophthalmic agent Drugs 0.000 description 1
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 1
- 229960005274 benzocaine Drugs 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 239000002526 disodium citrate Substances 0.000 description 1
- 235000019262 disodium citrate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 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
- 229960004418 trolamine Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、熱的に不安定な薬物を含有する点眼液に有機アミンを配合することにより、点眼液中の熱的に不安定な薬物の分解を抑制する方法、および熱的に不安定な薬物を含有する点眼液に有機アミンを配合することにより、点眼液中の熱的に不安定な薬物の分解が抑制された点眼液組成物に関する。 The present invention relates to a method for inhibiting the decomposition of a thermally unstable drug in eye drops by blending an organic amine with an eye drop containing a thermally unstable drug, and a thermally unstable The present invention relates to an ophthalmic solution composition in which decomposition of a thermally unstable drug in an ophthalmic solution is suppressed by adding an organic amine to the ophthalmic solution containing the drug.
点眼液には、例えばラタノプロスト、イソプロピルウノプロストン、タフルプロスト、トラボプロスト等のプロスタグランジン誘導体、コハク酸メチルプレドニゾロンナトリウム、酢酸プレドニゾロン等のエステル化されたステロイド、パラオキシ安息香酸エチル、アミノ安息香酸エチル、プロカイン、アスピリン等のカルボン酸エステルなど熱に不安定な薬物を配合することがある。 Eye drops include, for example, prostaglandin derivatives such as latanoprost, isopropyl unoprostone, tafluprost, travoprost, esterified steroids such as methylprednisolone sodium succinate, prednisolone acetate, ethyl paraoxybenzoate, ethyl aminobenzoate, Sometimes heat-labile drugs such as carboxylic acid esters such as procaine and aspirin are added.
しかし、流通過程や貯蔵過程で、点眼液の保管温度が上昇することがあり、点眼液に熱的に不安定な薬物が含まれている場合には、保管温度が上昇して該薬物が分解すると所望の薬効が発揮されず、さらに、浮遊物が発生したり、点眼液が白濁することもある。冷所で保管すれば、熱に不安定な薬物の分解を効果的に抑制できるが、点眼液は様々な環境に晒されるので、冷所での保管以外の方法で該薬物の分解を抑制する必要がある。 However, the storage temperature of eye drops may increase during the distribution process or storage process. If the eye drops contain a thermally unstable drug, the storage temperature increases and the drug decomposes. As a result, the desired medicinal effect is not exhibited, and suspended matter may be generated, or the ophthalmic solution may become cloudy. If stored in a cool place, the decomposition of heat-labile drugs can be effectively suppressed, but the ophthalmic solution is exposed to various environments, so that the decomposition of the drug is suppressed by a method other than storage in a cold place. There is a need.
ところで、点眼液には、水溶性の有機アミンを緩衝剤として添加するのが一般的であるが、それ以外の目的で水溶性の有機アミンを配合することもある。 By the way, it is common to add a water-soluble organic amine as a buffering agent to the ophthalmic solution, but a water-soluble organic amine may be blended for other purposes.
特許文献１は、抗アレルギー眼科用剤に関する発明を開示したものであり、ペミロラストカリウム（薬物）に有機アミンを配合することによって、ペミロラストカリウムの結晶析出を防止できることが記載されている。また、特許文献２は、テトラゾール誘導体を含有する点眼剤に関する発明を開示したものであり、塩基性アミン化合物を配合すればカチオン系防腐剤の防腐効果を増強できることが記載されている。 Patent Document 1 discloses an invention related to an antiallergic ophthalmic agent, and describes that it is possible to prevent crystal precipitation of pemirolast potassium by blending an organic amine with pemirolast potassium (drug). . Patent Document 2 discloses an invention relating to eye drops containing a tetrazole derivative, and describes that the antiseptic effect of a cationic preservative can be enhanced by adding a basic amine compound.
しかしながら、熱的に不安定な薬物を含有する点眼液に有機アミンを配合することによって、該薬物を安定化し、その分解を抑制する報告はない。
流通過程や貯蔵過程で点眼液の保管温度が上昇しても、点眼液に含まれる熱的に不安定な薬物の分解を抑制し、該点眼液を安定化することが望まれている。 Even when the storage temperature of the eye drop increases during the distribution process or the storage process, it is desired to suppress the decomposition of the thermally unstable drug contained in the eye drop and stabilize the eye drop.
本発明者らは、熱的に不安定な薬物の分解を抑制するために鋭意研究したところ、熱的に不安定な薬物を含有する点眼液に有機アミンを配合すれば、点眼液中の該薬物の分解を効果的に抑制でき、点眼液を安定に保存できることを見出した。 The present inventors have intensively studied to suppress the decomposition of a thermally unstable drug. When an organic amine is added to an ophthalmic solution containing a thermally unstable drug, the It was found that the decomposition of the drug can be effectively suppressed and the ophthalmic solution can be stored stably.
すなわち、本発明は、
（１）熱的に不安定な薬物を含有する点眼液に有機アミンを配合することにより、点眼液中の熱的に不安定な薬物の分解を抑制する方法、
（２）熱的に不安定な薬物が、熱的に分解しやすい薬物である前（１）記載の方法、
（３）熱的に分解しやすい薬物が、熱的に加水分解しやすい薬物である前（２）記載の方法、
（４）熱的に不安定な薬物が、プロスタグランジン誘導体である前（１）記載の方法、
（５）プロスタグランジン誘導体が、ラタノプロスト、イソプロピルウノプロストン、タフルプロストまたはトラボプロストである前（４）記載の方法、
（６）有機アミンが、水酸基を有する有機アミンである前（１）記載の方法、
（７）水酸基を有する有機アミンが、トロメタモールである前（６）記載の方法、
（８）ラタノプロストを含有する点眼液にトロメタモールを配合することにより、点眼液中のラタノプロストの分解を抑制する方法、
（９）熱的に不安定な薬物を含有する点眼液に有機アミンを配合することにより、点眼液中の熱的に不安定な薬物の分解が抑制された点眼液組成物、
（１０）熱的に不安定な薬物が、熱的に分解しやすい薬物である前（９）記載の点眼液組成物、
（１１）熱的に分解しやすい薬物が、熱的に加水分解しやすい薬物である前（１０）記載の点眼液組成物、
（１２）熱的に不安定な薬物が、プロスタグランジン誘導体である前（９）記載の点眼液組成物、
（１３）プロスタグランジン誘導体が、ラタノプロスト、イソプロピルウノプロストン、タフルプロストまたはトラボプロストである前（１２）記載の点眼液組成物、
（１４）有機アミンが、水酸基を有する有機アミンである前（９）記載の点眼液組成物、
（１５）水酸基を有する有機アミンが、トロメタモールである前（１４）記載の点眼液組成物、および
（１６）ラタノプロストを含有する点眼液にトロメタモールを配合することにより、点眼液中のラタノプロストの分解が抑制された点眼液組成物、である。
That is, the present invention
(1) A method for suppressing decomposition of a thermally unstable drug in an eye drop by blending an organic amine with an eye drop containing a thermally unstable drug,
(2) The method according to (1), wherein the thermally unstable drug is a drug that is easily thermally decomposed,
(3) The method according to (2) above, wherein the thermally decomposable drug is a thermally hydrolyzable drug,
(4) The method according to (1), wherein the thermally unstable drug is a prostaglandin derivative,
(5) The method according to (4) above, wherein the prostaglandin derivative is latanoprost, isopropyl unoprostone, tafluprost or travoprost,
(6) The method according to (1), wherein the organic amine is an organic amine having a hydroxyl group,
(7) The method according to (6), wherein the organic amine having a hydroxyl group is trometamol,
(8) A method for suppressing degradation of latanoprost in ophthalmic solution by blending trometamol with ophthalmic solution containing latanoprost,
(9) An ophthalmic solution composition in which decomposition of a thermally unstable drug in the ophthalmic solution is suppressed by adding an organic amine to the ophthalmic solution containing a thermally unstable drug,
(10) The ophthalmic solution composition according to (9), wherein the thermally unstable drug is a drug that is easily thermally decomposed,
(11) The ophthalmic solution composition described in (10) above, wherein the thermally decomposable drug is a thermally hydrolyzable drug,
(12) The ophthalmic solution composition according to (9), wherein the thermally unstable drug is a prostaglandin derivative,
(13) The ophthalmic solution composition according to the above (12), wherein the prostaglandin derivative is latanoprost, isopropyl unoprostone, tafluprost or travoprost,
(14) The ophthalmic solution composition according to (9), wherein the organic amine is an organic amine having a hydroxyl group,
(15) When the organic amine having a hydroxyl group is trometamol, the ophthalmic solution composition described in (14) above, and (16) the ophthalmic solution containing latanoprost, trometamol is added, whereby latanoprost in the ophthalmic solution is decomposed. A suppressed ophthalmic solution composition.
本発明において、熱的に不安定な薬物は、常温（２５℃）よりも温度が高くなると点眼液中で分解する傾向のある薬物であれば特に限定されず、このような熱的に不安定な薬物としては例えば、ラタノプロスト、イソプロピルウノプロストン、タフルプロスト、トラボプロスト等のプロスタグランジン誘導体をはじめ、コハク酸メチルプレドニゾロンナトリウム、酢酸プレドニゾロン等のエステル化されたステロイド、パラオキシ安息香酸エチル、アミノ安息香酸エチル、プロカイン、アスピリン等のカルボン酸エステルなどのエステル結合を有する熱的に加水分解する傾向のある薬物が挙げられ、特に好ましくはラタノプロスト、イソプロピルウノプロストン、トラボプロストなどのプロスタグランジン誘導体である。 In the present invention, the thermally unstable drug is not particularly limited as long as it is a drug that tends to decompose in ophthalmic solution when the temperature is higher than normal temperature (25 ° C.), and such a thermally unstable drug is used. Examples of such drugs include prostaglandin derivatives such as latanoprost, isopropyl unoprostone, tafluprost, and travoprost, esterified steroids such as methylprednisolone sodium succinate and prednisolone acetate, ethyl paraoxybenzoate, and aminobenzoic acid. Drugs having an ester bond such as carboxylic acid esters such as ethyl, procaine, and aspirin and having a tendency to thermally hydrolyze may be mentioned. Particularly preferred are prostaglandin derivatives such as latanoprost, isopropyl unoprostone, and travoprost. .
点眼液中の熱的に不安定な薬物の濃度は、該薬物が所望の薬効を奏する濃度であれば特に制限されないが、例えば０．００００１〜１０％（Ｗ／Ｖ）である。 The concentration of the thermally unstable drug in the ophthalmic solution is not particularly limited as long as the drug has a desired drug effect, and is, for example, 0.00001 to 10% (W / V).
有機アミンは、水溶性の有機アミンであれば特に限定されず、水溶性の有機アミンとしては例えば、モノエタノールアミン、ジエタノールアミン、トリエタノールアミン、トロメタモール、メグルミンなどの水酸基を有する有機アミンが挙げられ、より好ましくはトロメタモール、メグルミンである。 The organic amine is not particularly limited as long as it is a water-soluble organic amine, and examples of the water-soluble organic amine include organic amines having a hydroxyl group such as monoethanolamine, diethanolamine, triethanolamine, trometamol, and meglumine. More preferred are trometamol and meglumine.
点眼液中の有機アミンの濃度は特に制限されないが、例えばトロメタモールであれば０．００１〜５％（Ｗ／Ｖ）が好ましく、より好ましくは０．００５〜３％（Ｗ／Ｖ）である。 The concentration of the organic amine in the ophthalmic solution is not particularly limited. For example, in the case of trometamol, 0.001 to 5% (W / V) is preferable, and 0.005 to 3% (W / V) is more preferable.
本発明の点眼液は汎用されている方法によって調製することができ、必要に応じて等張化剤、緩衝剤、ｐＨ調節剤、可溶化剤、増粘剤等を添加することができる。 The ophthalmic solution of the present invention can be prepared by a widely used method, and an isotonic agent, a buffer, a pH adjuster, a solubilizer, a thickener, etc. can be added as necessary.
等張化剤としては、例えばグリセリン、プロピレングリコール、ポリエチレングリコール、トリハロース、シュクロース、ソルビトール、マンニトール、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム等を挙げることができる。 Examples of the isotonizing agent include glycerin, propylene glycol, polyethylene glycol, trihalose, sucrose, sorbitol, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
緩衝剤としては、例えばリン酸ナトリウム、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のリン酸塩；ホウ酸ナトリウム、ホウ酸カリウム等のホウ酸塩；クエン酸ナトリウム、クエン酸二ナトリウム等のクエン酸塩；酢酸ナトリウム、酢酸カリウム等の酢酸塩、炭酸ナトリウム、炭酸水素ナトリウム等の炭酸塩等を挙げることができる。 Examples of the buffer include phosphates such as sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate; sodium borate, potassium borate Citrates such as sodium citrate and disodium citrate; acetates such as sodium acetate and potassium acetate; carbonates such as sodium carbonate and sodium hydrogencarbonate;
ｐＨ調節剤としては、例えば塩酸、クエン酸、リン酸、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を挙げることができる。 Examples of the pH regulator include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.
可溶化剤としては、例えばポリソルベート８０、ポリエキシエチレン硬化ヒマシ油６０、マクロゴール４０００等を挙げることができる。 Examples of the solubilizer include polysorbate 80, polyethylene ethylene hardened castor oil 60, macrogol 4000, and the like.
増粘剤としては、例えばヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルアルコール、カルボキシビニルポリマー、ポリビニルピロリドン等を挙げることができる。 Examples of the thickener include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, carboxyvinyl polymer, polyvinylpyrrolidone and the like.
本発明の点眼液のｐＨは３〜９、特に４〜８とするのが好ましい。 The pH of the ophthalmic solution of the present invention is preferably 3 to 9, particularly 4 to 8.
熱的に不安定な薬物を含有する点眼液に有機アミンを配合すれば、点眼液中の該薬物の分解を効果的に抑制できるので、安定な点眼液を提供することができる。 When an organic amine is added to an ophthalmic solution containing a thermally unstable drug, decomposition of the drug in the ophthalmic solution can be effectively suppressed, so that a stable ophthalmic solution can be provided.
［熱安定性試験］
熱的に不安定な薬物として、ラタノプロスト（化学名：イソプロピル−（Ｚ）−７［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）３，５−ジヒドロキシ−２−［（３Ｒ）−３−ヒドロキシ−５−フェニルペンチル］シクロペンチル］−５−ヘプタノエート）を用いて、熱安定性試験を行った。
[Thermal stability test]
As a thermally unstable drug, latanoprost (chemical name: isopropyl- (Z) -7 [(1R, 2R, 3R, 5S) 3,5-dihydroxy-2-[(3R) -3-hydroxy-5- Phenylpentyl] cyclopentyl] -5-heptanoate) was used to conduct a thermal stability test.
（１）試料調製
処方１
トロメタモール１ｇを精製水約８０ｍＬに溶解し、希塩酸でｐＨを７．０に調整し、精製水で全量１００ｍＬとし、基剤とした。ラタノプロスト５ｍｇに基剤１００ｍＬを加え、約８０℃の水浴中で加温しながら撹拌し、ラタノプロストを溶解させた。これを室温に戻した後ｐＨが７．０であることを確認した。
(1) Sample preparation formula 1
1 g of trometamol was dissolved in about 80 mL of purified water, the pH was adjusted to 7.0 with dilute hydrochloric acid, and the total volume was made up to 100 mL with purified water, which was used as a base. 100 mL of the base was added to 5 mg of latanoprost, and the mixture was stirred while warming in a water bath at about 80 ° C. to dissolve latanoprost. After returning this to room temperature, it was confirmed that the pH was 7.0.
比較処方１
リン酸二水素ナトリウム（緩衝剤）１ｇを精製水約８０ｍＬに溶解し、１Ｎ水酸化ナトリウムでｐＨを７．０に調整し、精製水で全量１００ｍＬとし、基剤とした。ラタノプロスト５ｍｇに基剤１００ｍＬを加え、約８０℃の水浴中で加温しながら撹拌し、ラタノプロストを溶解させた。これを室温に戻した後ｐＨが７．０であることを確認した。
Comparative prescription 1
1 g of sodium dihydrogen phosphate (buffering agent) was dissolved in about 80 mL of purified water, the pH was adjusted to 7.0 with 1N sodium hydroxide, and the total volume was made up to 100 mL with purified water. 100 mL of the base was added to 5 mg of latanoprost, and the mixture was stirred while warming in a water bath at about 80 ° C. to dissolve latanoprost. After returning this to room temperature, it was confirmed that the pH was 7.0.
（２）試験方法及び結果
処方１および比較処方１を５ｍLずつガラスアンプルに充填し、それぞれについて８０℃で４週間および５０℃で８週間保存した後、ラタノプロストの含有量を高速液体クロマトグラフィー（ＨＰＬＣ）を用いて定量し、残存率を求めた。試験結果を表１に示す。
（３）考察
表１から明らかなように、トロメタモールを配合した点眼液（試料１）のラタノプロストの残存率は、リン酸二水素ナトリウムを配合した点眼液（比較試料１）の残存率よりも大きい。したがって、熱的に不安定な薬物（ラタノプロスト）を含有する点眼液に有機アミン（トロメタモール）を配合すれば、点眼液中の熱的に不安定な薬物の分解を効果的に抑制し、安定に保存できる。
(3) Discussion As is apparent from Table 1, the residual rate of latanoprost in the ophthalmic solution containing trometamol (sample 1) is larger than the residual rate of the ophthalmic solution containing sodium dihydrogen phosphate (comparative sample 1). . Therefore, if an organic amine (trometamol) is added to an ophthalmic solution containing a thermally unstable drug (latanoprost), the decomposition of the thermally unstable drug in the ophthalmic solution is effectively suppressed and stabilized. Can be saved.
Claims (16)
The ophthalmic solution composition according to claim 14, wherein the organic amine having a hydroxyl group is trometamol.
An ophthalmic solution composition in which decomposition of latanoprost in an ophthalmic solution is suppressed by blending trometamol with an ophthalmic solution containing latanoprost.
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