JPS6310730A - Stable aqueous solution - Google Patents
Stable aqueous solutionInfo
- Publication number
- JPS6310730A JPS6310730A JP8456886A JP8456886A JPS6310730A JP S6310730 A JPS6310730 A JP S6310730A JP 8456886 A JP8456886 A JP 8456886A JP 8456886 A JP8456886 A JP 8456886A JP S6310730 A JPS6310730 A JP S6310730A
- Authority
- JP
- Japan
- Prior art keywords
- aqueous solution
- sulfite
- sodium
- compound
- present
- 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
Links
- 239000007864 aqueous solution Substances 0.000 title abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229940049964 oleate Drugs 0.000 claims abstract description 6
- 239000007788 liquid Substances 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 11
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 35
- 239000003889 eye drop Substances 0.000 abstract description 13
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 abstract description 11
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 abstract description 10
- 229940079826 hydrogen sulfite Drugs 0.000 abstract description 10
- 239000007924 injection Substances 0.000 abstract description 6
- 238000002347 injection Methods 0.000 abstract description 6
- 230000001506 immunosuppresive effect Effects 0.000 abstract description 4
- BESWYMJGRRXSAL-UHFFFAOYSA-N O[SH2](O)=O Chemical compound O[SH2](O)=O BESWYMJGRRXSAL-UHFFFAOYSA-N 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- HZQDCMWJEBCWBR-UUOKFMHZSA-N Mizoribine Chemical compound OC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 HZQDCMWJEBCWBR-UUOKFMHZSA-N 0.000 description 18
- 229950000844 mizoribine Drugs 0.000 description 18
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 18
- 239000000243 solution Substances 0.000 description 12
- 229940012356 eye drops Drugs 0.000 description 9
- 235000010265 sodium sulphite Nutrition 0.000 description 9
- 238000009472 formulation Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- -1 alkali metal salts Chemical class 0.000 description 6
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 6
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 5
- 229940001584 sodium metabisulfite Drugs 0.000 description 5
- 235000010262 sodium metabisulphite Nutrition 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229960000686 benzalkonium chloride Drugs 0.000 description 4
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 4
- 229910000397 disodium phosphate Inorganic materials 0.000 description 4
- 235000019800 disodium phosphate Nutrition 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 4
- 229940033663 thimerosal Drugs 0.000 description 4
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 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
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-isoascorbic acid Chemical compound OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid 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
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000010350 erythorbic acid Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229940026239 isoascorbic acid Drugs 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- BHZRJJOHZFYXTO-UHFFFAOYSA-L potassium sulfite Chemical compound [K+].[K+].[O-]S([O-])=O BHZRJJOHZFYXTO-UHFFFAOYSA-L 0.000 description 2
- 235000019252 potassium sulphite Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 229940001482 sodium sulfite Drugs 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- AUHDWARTFSKSAC-HEIFUQTGSA-N (2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-2-(6-oxo-1H-purin-9-yl)oxolane-2-carboxylic acid Chemical compound [C@]1([C@H](O)[C@H](O)[C@@H](CO)O1)(N1C=NC=2C(O)=NC=NC12)C(=O)O AUHDWARTFSKSAC-HEIFUQTGSA-N 0.000 description 1
- WADQOGCINABPRT-UHFFFAOYSA-N 3-chloro-2-methylphenol Chemical compound CC1=C(O)C=CC=C1Cl WADQOGCINABPRT-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 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-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
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- GRSZFWQUAKGDAV-UHFFFAOYSA-N Inosinic acid Natural products OC1C(O)C(COP(O)(O)=O)OC1N1C(NC=NC2=O)=C2N=C1 GRSZFWQUAKGDAV-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- JWEBAGKDUWFYTO-UHFFFAOYSA-L disodium;hydrogen phosphate;decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O JWEBAGKDUWFYTO-UHFFFAOYSA-L 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 description 1
- 235000013928 guanylic acid Nutrition 0.000 description 1
- 239000004226 guanylic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 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
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 235000013902 inosinic acid Nutrition 0.000 description 1
- 239000004245 inosinic acid Substances 0.000 description 1
- 229940028843 inosinic acid Drugs 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical class C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000006825 purine synthesis Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229940037001 sodium edetate Drugs 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
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 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
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000002054 transplantation Methods 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
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、医薬として有用な化合物である４−カルバモ
イル−１−β−Ｄ−リボフラノシル−イミダゾリウム−
５−オレイトまたはその塩（以下、単に本化合物と称す
ることがある）の安定な水性？夜剤である。Detailed Description of the Invention [Industrial Field of Application] The present invention relates to 4-carbamoyl-1-β-D-ribofuranosyl-imidazolium- which is a compound useful as a pharmaceutical.
Stable aqueous 5-oleate or its salt (hereinafter sometimes simply referred to as the present compound)? It is a night pill.
４−カルバモイル−１−β−Ｄ−リボフラノシル−イミ
ダゾリウム−５−オレイトはミゾリビンとも呼ばれ、糸
状菌オイペニシリウム・ブレフェルジアスム（Ｅｕｐｅ
ｎｉｃｉｌｌｉｕｍ ｂｒｅｆｅｌｄｉａｎｕ＊）培養
濾液中より発見されたイミダゾール系核酸関連化合物で
あり、免疫抑制作用を有する物質である。4-Carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate, also called mizoribine, is produced by the filamentous fungus Eupenicillium brefeldiasum (Eupe
It is an imidazole-based nucleic acid-related compound discovered in the culture filtrate of Nicilium brefeldianu*), and is a substance that has immunosuppressive effects.
その作用は、核酸のプリン合成系のイノシン酸からグア
ニル酸に至る経路を拮抗阻害し、リンパ球の増殖を選択
的に抑制すると考えられている。Its action is thought to competitively inhibit the pathway from inosinic acid to guanylic acid in the nucleic acid purine synthesis system, thereby selectively suppressing the proliferation of lymphocytes.
その強力な免疫抑制作用に着目して錠剤がすでに市販さ
れている。Tablets are already on the market for its powerful immunosuppressive effects.
ところで、本化合物は上述の如く、免疫抑制作用を有し
ているので、たとえばこれを中性付近において高濃度で
安定な水性液剤に調製することができれば、眼への投与
が可能となり、角膜移植手術時の拒絶反応抑制剤等とし
て使用しえ、また注射剤等としても使用可能となり、そ
の用途、投与形態の多様化を図ることが可能となる。By the way, as mentioned above, this compound has an immunosuppressive effect, so if it could be prepared into a highly concentrated and stable aqueous solution at around neutrality, it would be possible to administer it to the eye, and it would be useful for corneal transplantation. It can be used as a rejection inhibitor during surgery, and can also be used as an injection, making it possible to diversify its uses and administration forms.
このような観点から、本発明者らは本化合物の水性液剤
について種々研究を重ねてきたところ、本化合物は水溶
液状態では不安定であることを知った。From this point of view, the present inventors have conducted various studies on aqueous liquid preparations of the present compound, and have found that the present compound is unstable in an aqueous solution state.
従って、本発明の目的は本化合物□が安定に存在しうる
水性液剤を提供することであり、上述したことから明ら
かなように、本発明はそもそもその目的自体が新規な発
明である。Therefore, the object of the present invention is to provide an aqueous liquid preparation in which the present compound □ can be stably present, and as is clear from the above, the object of the present invention itself is a novel invention.
かかる新規目的を解決するために本発明者らは、水性溶
液中における本化合物の安定化について広範な検討を試
みてきた。In order to solve this new object, the present inventors have attempted extensive studies on stabilizing the present compound in an aqueous solution.
その結果、本発明者らは、驚くべきことに本化合物を含
有する水性液剤中に、亜硫酸塩、亜硫酸水素塩およびメ
タ重亜硫酸塩から選ばれる少なくとも一種を共存させる
ことにより、本化合物の水性溶液中での安定性が著しく
向上されるが、従来様々の水性液剤中で不安定な物質を
安定化するために用いられて来た所謂安定化剤と称され
る物質を添加しても、医薬として使用しうるに足るだけ
の安定化効果は得られないことを見出して本発明を完成
するに至った。即ち、従来各種化合物の安定化剤として
使用されているアスコルビン酸、イソアスコルビン酸、
炭酸ナトリウム、クエン酸ナトリウム、エデト酸二ナト
リウム、グリセリン、ポリビニルピロリドン、サイクロ
デキストリン（α−１β−およびγ−）、Ｎ−アセチル
システィン等は本化合物の水性溶液中での安定化には寄
与しないが、亜硫酸塩、亜硫酸水素塩およびメタ重亜硫
酸塩から選ばれる少なくとも一種を含有させた場合には
、本化合物またはその塩の水性溶液中での安定性が著し
く向上することを見出した。As a result, the present inventors surprisingly found that by coexisting at least one selected from sulfite, hydrogen sulfite, and metabisulfite in an aqueous solution containing the present compound, an aqueous solution of the present compound can be obtained. However, even if a so-called stabilizer, which has traditionally been used to stabilize unstable substances in various aqueous liquids, is added, the stability of the drug will be significantly improved. The present invention was completed based on the discovery that a sufficient stabilizing effect could not be obtained for use as an anti-oxidant compound. That is, ascorbic acid, isoascorbic acid, which has been conventionally used as a stabilizer for various compounds;
Sodium carbonate, sodium citrate, disodium edetate, glycerin, polyvinylpyrrolidone, cyclodextrin (α-1β- and γ-), N-acetylcysteine, etc. do not contribute to the stabilization of this compound in aqueous solution. It has been found that the stability of the present compound or its salt in an aqueous solution is significantly improved when at least one selected from , sulfite, hydrogen sulfite and metabisulfite is contained.
即ち、本発明は本化合物と、亜硫酸塩、亜硫酸水素塩お
よびメタ重亜硫酸塩から選ばれる少なくとも一種を含有
せしめてなる水性液剤である。That is, the present invention is an aqueous liquid preparation containing the present compound and at least one selected from sulfites, hydrogen sulfites, and metabisulfites.
本願発明における安定化の対象は、ミゾリビンまたはそ
の塩であり、塩としては本化合物と塩を形成し得る非毒
性の無機酸あるいは有機酸または非毒性の有機塩基また
は無機塩基が例示される。The object to be stabilized in the present invention is mizoribine or a salt thereof, and examples of the salt include non-toxic inorganic acids or organic acids, or non-toxic organic bases or inorganic bases that can form a salt with the present compound.
本発明の水性液剤においては、本化合物を含有する水性
溶液中に亜硫酸塩、亜硫酸水素塩およびメタ重亜硫酸塩
から選ばれる少なくとも一種が含有せしめられる。亜硫
酸塩、亜硫酸水素塩およびメタ重亜硫酸塩における塩と
しては、たとえばナトリウム塩、カリウム塩等のアルカ
リ金属塩、カルシウム塩等のアルカリ土類金属塩、アン
モニウム塩等の有機塩基塩等が例示される。In the aqueous solution of the present invention, at least one selected from sulfites, hydrogen sulfites and metabisulfites is contained in the aqueous solution containing the present compound. Examples of the salts in sulfite, hydrogen sulfite and metabisulfite include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, and organic base salts such as ammonium salts. .
本発明の水性液剤は、本化合物が水中に溶解された態様
であれば特に制限されるものではなく、たとえば点眼剤
、注射剤等のｆＩＥ、様が例示される。The aqueous liquid preparation of the present invention is not particularly limited as long as the present compound is dissolved in water, and examples include fIE forms such as eye drops and injections.
水としては、たとえば注射用蒸留水、滅菌精製水等が例
示される。Examples of water include distilled water for injection, sterilized purified water, and the like.
本化合物１重量部に対する亜硫酸塩、亜硫酸水素塩およ
びメタ重亜硫酸塩の配合割合は、これらの総量として通
常ｏ、ｏｏｓ〜５０重量部、好ましくは０．０５〜２重
量部である。The blending ratio of sulfite, hydrogen sulfite and metabisulfite to 1 part by weight of the present compound is usually o, oos to 50 parts by weight, preferably 0.05 to 2 parts by weight as a total amount thereof.
・本発明の水性液剤は、本化合物、並びに亜硫酸塩、亜
硫酸水素塩およびメタ重亜硫酸塩から選ばれる少なくと
も一種を水に熔解させることによって製造することが出
来、本化合物の水性液剤中における濃度は水に対して、
０．１〜２０ｗ／ｖ％、好ましくは１〜１０ｗ／ｖ％程
度であり、極めて高濃度にまで水溶化せしめ得るもので
ある。- The aqueous liquid preparation of the present invention can be produced by dissolving the present compound and at least one selected from sulfite, hydrogen sulfite, and metabisulfite in water, and the concentration of the present compound in the aqueous liquid preparation is against the water,
It is about 0.1 to 20 w/v%, preferably about 1 to 10 w/v%, and can be water-soluble to extremely high concentrations.
本発明水性液剤における亜硫酸塩、亜硫酸水素塩および
メタ重亜硫酸塩の添加量は、これらの総量として通常、
０．１〜５ｗ／ｖ％、好ましくは０，５〜２−／ｖ％程
度である。The amount of sulfite, hydrogen sulfite and metabisulfite added in the aqueous solution of the present invention is usually as follows:
It is about 0.1 to 5 w/v%, preferably about 0.5 to 2-/v%.
さらに本発明者らは次の知見を得た。即ち、本化合物は
、実験例１において明らかにしたように、あらゆるｐ）
Ｉの水性溶液中において不安定であり、比較的安定なρ
１１２およびｐＨ７付近においてもこれを医薬として実
用化するには未だ不十分であることを見出し、かつ本発
明の水性液剤は、後記実験例３において明らかにしたよ
うに、ｐＨ６〜１０程度において格段に安定であること
を見出した。従って、本発明の水性液剤は、−ａにｐｉ
（６〜１０、好ましくはｐ１１７〜９、さらに好ましく
はｐＨ８程度に３周整するのがよい。Furthermore, the present inventors obtained the following knowledge. That is, the present compound, as revealed in Experimental Example 1, contains all p)
I is unstable in aqueous solution of I, and relatively stable ρ
112 and around pH 7, it was found that this was still insufficient for practical use as a medicine, and as clarified in Experimental Example 3 below, the aqueous liquid preparation of the present invention was significantly effective at a pH of about 6 to 10. It was found to be stable. Therefore, the aqueous solution of the present invention has pi in -a.
(It is good to adjust the pH to about 6 to 10, preferably 117 to 9, and more preferably about 8 for three times.
本発明の水性液剤には、本発明の目的に反しない限り、
通常水性液剤に用いられる添加剤、たとえばｐＨ調整用
の緩衝剤（リン酸緩衝液、ホウ酸緩衝液、クエン酸緩衝
液、酒石酸緩衝液、酢酸緩衝液等）、等張化剤（ソルビ
トール、グリセリン、ポリエチレングリコール、プロピ
レングリコール、グルコース、塩化ナトリウム等）、防
腐殺菌剤（塩化ベンザルコニウム、パラオキシ安息香酸
エステル類、ベンジルアルコール、パラクロルメタキシ
ノール、クロルクレゾール、フェネチルアルコール、ソ
ルビン酸またはその塩、チメロサール、クロロブタノー
ル等）、キレート剤（エデト酸ナトリウム、クエン酸ナ
トリウム、縮合リン酸ナトリウム等）、粘稠剤（ポリビ
ニルピロリドン、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セルロース
、ポリビニルアルコール、ポリアクリｊし酸ナトリウム
等）等を通常使用される添加量で配合することができる
。The aqueous liquid preparation of the present invention includes, as long as it does not contradict the purpose of the present invention,
Additives normally used in aqueous solutions, such as buffers for pH adjustment (phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer, etc.), tonicity agents (sorbitol, glycerin, etc.) , polyethylene glycol, propylene glycol, glucose, sodium chloride, etc.), preservatives and disinfectants (benzalkonium chloride, paraoxybenzoic acid esters, benzyl alcohol, parachlormetaxinol, chlorcresol, phenethyl alcohol, sorbic acid or its salts, Thimerosal, chlorobutanol, etc.), chelating agents (sodium edetate, sodium citrate, condensed sodium phosphate, etc.), thickening agents (polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, sodium polyacrylate) etc.) can be added in the commonly used amounts.
本発明の水性液剤には、本発明の目的に反しない限り本
化合物以外の薬効成分を配合することができる。The aqueous liquid preparation of the present invention may contain medicinal ingredients other than the present compound as long as they do not contradict the purpose of the present invention.
本発明の水性液剤を調製するにあたっては、液剤のｇｔ
類に応じて、自体既知の手段を採用することができる。In preparing the aqueous solution of the present invention, the gt of the solution is
Depending on the type, per se known means can be adopted.
実験例１
ミゾリビン１０ｇに水２０−を加え、加温して溶かす、
６０ｍ１のアセトンを加え、５℃で２４時間放置した後
濾過し、冷アセトンで洗浄し、減圧下で２４時間乾燥す
る。この操作を２回繰り返した後、１００−のメタノー
ルを加えて懸濁液を調製し、約３時間還流して濾過し、
冷メタノールで洗浄する。これを減圧下３０℃で４８時
間乾燥したものを標準品とした（含１９９．５％：非水
滴定法）、当該標準品の各ｐＨに対する分解速度定数（
−１ｏｇ ｋ）をプロットした結果を第１図に示す。Experimental Example 1 Add 20 g of water to 10 g of mizoribine and dissolve by heating.
60 ml of acetone are added and after standing at 5° C. for 24 hours it is filtered, washed with cold acetone and dried under reduced pressure for 24 hours. After repeating this operation twice, 100-methanol was added to prepare a suspension, which was refluxed for about 3 hours and filtered.
Wash with cold methanol. This was dried at 30°C under reduced pressure for 48 hours and used as a standard product (containing 199.5%: non-aqueous titration method).The decomposition rate constant for each pH of the standard product (
-1og k) is shown in FIG. 1.
第１図から明らかなように、ｐＨ２および７付近の水性
溶液中で本化合物は最も安定かことがわかる。As is clear from FIG. 1, this compound is most stable in aqueous solutions around pH 2 and 7.
実験例２
ミゾリビンに亜硫塩酸、亜硫酸水素塩およびメタ重亜硫
酸塩から選ばれる少なくとも一種を配合した場合におけ
るミゾリビンの安定性向上効果を明らかにするために、
亜硫酸ナトリウム、亜硫酸水素ナトリウムおよびメタ重
亜硫酸ナトリウム並びに対照として通常水性溶液中で不
安定な物質の安定化に用いられる安定化剤を用いて安定
化試験を行った。対照として用いた安定化剤は、アスコ
ルビン酸、イソアスコルビン酸（以上酸化防止剤）、炭
酸ナトリウム（以上着色防止剤）ならびにクエン酸ナト
リウム、エデト酸二ナトリウム、グリセリン（以上分解
防止剤）及びホウ酸、ポリビニルピロリドン、サイクロ
デキストリン（α−１β−およびγ−）、Ｎ−アセチル
ラスティンである。Experimental Example 2 In order to clarify the stability improvement effect of mizoribine when at least one selected from sulfite, hydrogen sulfite, and metabisulfite is blended with mizoribine,
Stabilization tests were carried out using sodium sulfite, sodium hydrogen sulfite and sodium metabisulfite and as a control stabilizers commonly used to stabilize substances that are unstable in aqueous solutions. The stabilizers used as controls were ascorbic acid, isoascorbic acid (antioxidant), sodium carbonate (anticoloring agent), sodium citrate, disodium edetate, glycerin (decomposition inhibitor), and boric acid. , polyvinylpyrrolidone, cyclodextrin (α-1β- and γ-), and N-acetyl lastine.
ミゾリビンの濃度を３％、各種安定化剤の濃度は０．２
．０．５．１．０％とし、ｐＨ７，４０℃、７日間保存
の後、その色調の変化を観察した結果、亜硫酸ナトリウ
ム、亜硫酸水素ナトリウム、メタ′重亜硫酸ナトリウム
を添加した群では視覚的に認められる着色は全くみられ
なかったが、対照群ではすべてに着色が明らかに認めら
れた。The concentration of mizoribine was 3%, and the concentration of various stabilizers was 0.2.
．． 0.5.1.0%, and after storage at pH 7 and 40°C for 7 days, changes in color were observed. As a result, the groups to which sodium sulfite, sodium hydrogen sulfite, and sodium metabisulfite were added visually showed There was no appreciable coloration, whereas coloration was clearly observed in all of the control group.
実験例３
’０．１’Ｍリン酸緩衝液−に、ミゾリビン３％および
亜硫酸ナトリウムを０．２％の濃度で加えた７８液を調
製した。Experimental Example 3 78 solutions were prepared by adding 3% mizoribine and 0.2% sodium sulfite to 0.1M phosphate buffer.
この溶液を第１表に記載の各種ｐＨとし、これらを４０
℃゛で７日間保存した後、ミゾリビンの残存率（％）を
高速液体クロマトグラフ法により調べた。This solution was adjusted to various pH values listed in Table 1, and these were adjusted to 40%
After storage at ℃ for 7 days, the residual rate (%) of mizoribine was examined by high performance liquid chromatography.
なお、対照として０．１ Ｍリン酸緩衝液にミゾリビン
を３％の濃度で加えた溶液を使用した。As a control, a solution prepared by adding mizoribine at a concentration of 3% to 0.1 M phosphate buffer was used.
その結果を後記第１表に示す。The results are shown in Table 1 below.
実験例４
亜硫酸ナトリウムの濃度を０．５％とする以外は実験例
３に準じて処理してミゾリビンの残存率を調べた。その
結果は後記第２表の通りである。Experimental Example 4 The procedure of Experimental Example 3 was followed except that the concentration of sodium sulfite was 0.5%, and the residual rate of mizoribine was investigated. The results are shown in Table 2 below.
実験例５
亜硫酸ナトリウムの濃度を１．０％とする以外は実験例
３に準じて処理してミゾリビンの残存率を調べた。その
結果は後記第３表の通りである。Experimental Example 5 The procedure of Experimental Example 3 was followed except that the concentration of sodium sulfite was 1.0%, and the residual rate of mizoribine was investigated. The results are shown in Table 3 below.
実験例６
実験例３〜５における亜硫酸ナトリウムの代わりに亜硫
酸水素ナトリウムを使用する以外は、実験例３〜５に準
じて処理し、後記第４〜６表記載の通りの結果を得た。Experimental Example 6 The procedure of Experimental Examples 3 to 5 was followed except that sodium bisulfite was used instead of sodium sulfite in Experimental Examples 3 to 5, and the results shown in Tables 4 to 6 below were obtained.
実験例７
実験例３〜５における亜硫酸ナトリウムの代わりにメタ
重亜硫酸塩を使用する以外は、実験例３〜５に準じて処
理しても実験例３〜５と同様のミゾリビンの残存率が得
られる。Experimental Example 7 The same residual rate of mizoribine as in Experimental Examples 3 to 5 was obtained even if the treatment was performed according to Experimental Examples 3 to 5 except that metabisulfite was used instead of sodium sulfite in Experimental Examples 3 to 5. It will be done.
製剤例１ （点眼剤）
本化合物 ３．０ｇ亜硫酸ナ
トリウム １．０ｇリン酸酸水素ナ
ナトリウム ０．５ｇ塩化ベンザルコニウム
０．０１ｇ水酸化ナトリウム 適量
（ｐＨ８，０）滅菌精製水 全ｆｆｉ
１００ｍ滅菌精製水約８０ｍＦに亜硫酸ナトリウム１
．０ｇ、リン酸水素二ナトリウム・１２水塩０．５ｇお
よび本化合物３．０ｇを順次加えて溶かす、この液に塩
化ベンザルコニウム０．０１ｇを加えて溶かし、さらに
水酸化ナトリウムを加えてｐＨを約８に調整し、滅菌精
製水を加えて全１ｉ１００−とする、この液をろ過滅菌
（０，４５μｒｒｔ） したのち点眼用プラスチック瓶
に無菌的に充填して点眼剤を得た。Formulation Example 1 (Eye drops) This compound 3.0g Sodium sulfite 1.0g Sodium hydrogen phosphate 0.5g Benzalkonium chloride
0.01g Sodium hydroxide Appropriate amount (pH 8,0) Sterile purified water All ffi
Sodium sulfite 1 in 100 m sterile purified water approximately 80 mF
．． 0g, disodium hydrogen phosphate 12 hydrate, 0.5g, and 3.0g of this compound were sequentially added and dissolved. To this solution, 0.01g of benzalkonium chloride was added and dissolved, and sodium hydroxide was further added to adjust the pH. The solution was adjusted to about 8 and sterilized purified water was added to make a total of 1i100-. This solution was sterilized by filtration (0.45 μrrt) and then aseptically filled into a plastic bottle for eye drops to obtain an eye drop.
製剤例２（注射剤）
本化合物 １．０ｇ亜硫酸カ
リウム ０．５ｇリン酸酸水素ナナ
トリウム ０．５ｇ塩化ナトリウム
０．３ｇ水酸化ナトリウム 適量（
ｐＨ７，４）滅菌精製水 全量 １０〇
−滅菌精製水約８０−に亜硫酸カリウム０．５ｇ。Formulation Example 2 (injection) This compound 1.0g Potassium sulfite 0.5g Sodium hydrogen phosphate 0.5g Sodium chloride
0.3g sodium hydroxide appropriate amount (
pH 7,4) Sterile purified water Total amount: 100 - Sterile purified water about 80 - and potassium sulfite 0.5 g.
リン酸水素二ナトリウム・１２水塩０．５ｇおよび本化
合物１．０ｇを順次加えて溶かす、この液に水酸化ナト
リウムを加えてＰＨを７．４に調整し、滅菌精製水を加
えて全量１００−とする、この液をろ過滅菌（０，２２
μｍ）したのちアンプルに無菌的に充填して注射剤を得
た。Add and dissolve 0.5 g of disodium hydrogen phosphate decahydrate and 1.0 g of this compound in sequence. Add sodium hydroxide to this solution to adjust the pH to 7.4, and add sterile purified water to make a total volume of 100 g. - This solution is sterilized by filtration (0,22
μm) and then aseptically filled into ampoules to obtain an injection.
製剤例３（点眼剤）
本化合物 ３．０ｇメタ重亜
硫酸ナトリウム １．０ｇリン酸酸水素ナナ
トリウム ０．５ｇ塩化ベンザルコニウム
０．０１ｇ水酸化ナトリウム 適量（
ｐＨ８，０）滅菌精製水 全量 １０〇
−以上の処方を使用し、製剤例１に準じて処理して点眼
剤を得た。Formulation example 3 (eye drops) This compound 3.0g Sodium metabisulfite 1.0g Sodium hydrogen phosphate 0.5g Benzalkonium chloride
0.01g sodium hydroxide appropriate amount (
Using a formulation with a pH of 8.0) sterile purified water (total amount: 100 - or higher), the eye drops were obtained by processing according to Formulation Example 1.
製剤例４（点眼剤）
本化合物 ５．０ｇメタ重亜
硫酸ナトリウム １．０ｇホウ酸
０．５ｇパラオキシ安息香酸メチル
０．０２６ｇパラオキシ安患香安息香酸ル ０
．０１４ｇ水酸化ナトリウム 適量（ｐＨ８，
０）滅菌精製水 全１ １０（ｌａｊ滅
菌精製水約８０１１１に、パラオキシ安息香酸メチル０
．０２６ ｇおよびバラオキシ安息香酸プロピル０．０
１４ｇを加え加温しながら溶かす、この液に冷却しなか
らメタ重亜硫酸ナトリウム１．ｏｇ。Formulation example 4 (eye drops) This compound 5.0g Sodium metabisulfite 1.0g Boric acid
0.5g Methyl paraoxybenzoate 0.026g Methyl paraoxybenzoate 0
．． 014g Sodium hydroxide appropriate amount (pH 8,
0) Sterile purified water total 1 10 (laj Sterilized purified water approximately 80111, methyl paraoxybenzoate 0
．． 026 g and propyl roseoxybenzoate 0.0
Add 14 g of sodium metabisulfite and dissolve while heating. To this solution, add 1. og.
ホウ酸０．５ｇおよび本化合物５．０ｇを順次加えて溶
かし、さらに水酸化ナトリウムを加えてρ■を約８．０
に調整し、滅菌精製水を加えて全量１０〇−とする、こ
の液をろ過滅菌（０，４５μｆｆ１） したのち点眼用
プラスチック瓶に無菌的に充填して点眼剤を得た。Add 0.5 g of boric acid and 5.0 g of this compound one after another to dissolve, and then add sodium hydroxide to bring the ρ■ to about 8.0.
Sterilized purified water was added to bring the total volume to 100. This solution was sterilized by filtration (0.45 μff1) and then aseptically filled into a plastic bottle for eye drops to obtain an eye drop.
製剤例５（点眼剤）
本化合物 １０．０ ｇチオ硫
酸ナトリウム １．０ｇリン酸酸水素ナ
ナトリウム ０．５ｇチメロサール
０．０ Ｏ５ｇ水酸化ナトリウム 適
量（ｐＨ８，０）滅菌精製水 全量 １
０〇−滅菌精製水約８０−にチオ硫酸ナトリウム１．０
ｇ、リン酸水素二ナトリウム０．５ｇおよび本化合物１
０．０ ｇを順次加えて溶かす、かくして得られた液に
チメロサールＯ，ＯＯ５ｇを加えて溶かし、さらに水酸
化ナトリウムを加えてｐＨを約８．０に調整し、滅菌精
製水を加えて全１ｔｉｏｏ献とする。Formulation example 5 (eye drops) This compound 10.0 g Sodium thiosulfate 1.0 g Sodium hydrogen phosphate 0.5 g Thimerosal
0.0 O5g Sodium hydroxide Appropriate amount (pH 8,0) Sterile purified water Total amount 1
0〇-About 80% of sterile purified water and 1.0% of sodium thiosulfate
g, 0.5 g of disodium hydrogen phosphate and this compound 1
Add 0.0 g of thimerosal in sequence and dissolve. Add 5 g of thimerosal O, OO to the thus obtained solution and dissolve. Add sodium hydroxide to adjust the pH to approximately 8.0, and add sterile purified water to make a total of 1 tioo. I will dedicate it to you.
この液をろ退域１１ｔ（０，４５μｉｎ） したのち点
眼用プラスチック瓶に無菌的に充填して点眼剤を得た。This liquid was filtered through 11t (0.45 μin) and then filled aseptically into a plastic bottle for eye drops to obtain an eye drop.
本発明で使用される亜硫酸塩、亜硫酸水素塩およびメタ
重亜硫酸塩は、本化合物またはその塩の水溶液中での安
定性を改善する作用を有するものであり、かかる亜硫酸
塩、亜硫酸水素塩およびメタ重亜硫酸塩から選ばれる少
なくとも一種を配合した本発明の水性液剤においては長
期間本化合物およびその塩が安定に存在しうるという効
果を有するとともに、高濃度においても安定で、また中
性付近で使用する場合においても安定な水性液剤が得ら
れるものである。The sulfite, hydrogen sulfite and metabisulfite used in the present invention have the effect of improving the stability of the present compound or its salt in an aqueous solution. The aqueous solution of the present invention containing at least one selected from bisulfites has the effect that the present compound and its salt can exist stably for a long period of time, is stable even at high concentrations, and can be used near neutrality. A stable aqueous solution can be obtained even when
（以下余白）
第１表 ミゾリビンの残存率（％）
表中、Ｎａはナトリウム塩であることを意味する（以下
、同様）。(The following is a blank space) Table 1 Residual rate of mizoribine (%) In the table, Na means sodium salt (the same applies hereinafter).
第２表 ミゾリビンの残存率（％） 第３表 ミゾリビンの残存率（％） 第４表 ミゾリビンの残存率（％） 第５表 ミゾリビンの残存率（％） 第６表 ミゾリビンの残存率（％）Table 2 Mizoribine residual rate (%) Table 3: Mizoribine residual rate (%) Table 4: Mizoribine residual rate (%) Table 5: Mizoribine residual rate (%) Table 6: Mizoribine residual rate (%)
第１図は、４−カルバモイル−１−β−Ｄ−リボフラノ
シル−イミダゾリウム−５−オレイトの水溶液中におけ
る安定性のｐｎプロフィールを示すグラフである。FIG. 1 is a graph showing the pn profile of the stability of 4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate in an aqueous solution.
Claims (2)
−イミダゾリウム−５−オレイトまたはその塩と、亜硫
酸塩、亜硫酸水素塩およびメタ重亜硫酸塩から選ばれる
少なくとも一種を含有せしめてなる水性液剤。(1) An aqueous liquid preparation containing 4-carbamoyl-1-β-D-ribofuranosyl-imidazolium-5-oleate or a salt thereof, and at least one selected from sulfites, hydrogen sulfites, and metabisulfites.
記載の水性液剤。(2) The aqueous liquid preparation according to claim (1), which has a pH of 6 to 10.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6946986 | 1986-03-27 | ||
| JP61-69469 | 1986-03-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6310730A true JPS6310730A (en) | 1988-01-18 |
| JPH06700B2 JPH06700B2 (en) | 1994-01-05 |
Family
ID=13403557
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8456886A Expired - Lifetime JPH06700B2 (en) | 1986-03-27 | 1986-04-11 | Stable aqueous solution |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06700B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004075690A (en) * | 1994-08-24 | 2004-03-11 | Merck & Co Inc | Alendronate composition for intravenous infusion |
| JP2006028028A (en) * | 2004-07-12 | 2006-02-02 | Teikoku Medix Kk | Oral medicinal composition |
-
1986
- 1986-04-11 JP JP8456886A patent/JPH06700B2/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004075690A (en) * | 1994-08-24 | 2004-03-11 | Merck & Co Inc | Alendronate composition for intravenous infusion |
| JP2006028028A (en) * | 2004-07-12 | 2006-02-02 | Teikoku Medix Kk | Oral medicinal composition |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06700B2 (en) | 1994-01-05 |
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