JP4700291B2 - Injectable composition - Google Patents
Injectable composition Download PDFInfo
- Publication number
- JP4700291B2 JP4700291B2 JP2004130348A JP2004130348A JP4700291B2 JP 4700291 B2 JP4700291 B2 JP 4700291B2 JP 2004130348 A JP2004130348 A JP 2004130348A JP 2004130348 A JP2004130348 A JP 2004130348A JP 4700291 B2 JP4700291 B2 JP 4700291B2
- Authority
- JP
- Japan
- Prior art keywords
- injectable composition
- composition according
- vial
- pharmaceutical compound
- acidic pharmaceutical
- 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.)
- Expired - Lifetime
Links
- 239000007972 injectable composition Substances 0.000 title claims description 64
- 150000001875 compounds Chemical class 0.000 claims description 85
- 230000002378 acidificating effect Effects 0.000 claims description 68
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 50
- 229960004700 cefotiam hydrochloride Drugs 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 26
- 239000007924 injection Substances 0.000 claims description 25
- 238000002347 injection Methods 0.000 claims description 25
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 25
- 239000007787 solid Substances 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 22
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 16
- 239000003125 aqueous solvent Substances 0.000 claims description 15
- 229960003791 cefmenoxime Drugs 0.000 claims description 12
- -1 organic acid salt Chemical class 0.000 claims description 10
- 150000007524 organic acids Chemical class 0.000 claims description 9
- 239000002504 physiological saline solution Substances 0.000 claims description 9
- 239000004475 Arginine Substances 0.000 claims description 8
- QYQDKDWGWDOFFU-IUODEOHRSA-N Cefotiam Chemical compound CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 QYQDKDWGWDOFFU-IUODEOHRSA-N 0.000 claims description 8
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 8
- 239000001569 carbon dioxide Substances 0.000 claims description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 8
- HJJDBAOLQAWBMH-YCRCPZNHSA-N cefmenoxime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NN=NN1C HJJDBAOLQAWBMH-YCRCPZNHSA-N 0.000 claims description 8
- 229960001242 cefotiam Drugs 0.000 claims description 8
- 150000007522 mineralic acids Chemical class 0.000 claims description 7
- NTJHUKMPVIFDNY-XFDPNJHTSA-N (6r,7r)-7-[[(2z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetyl]amino]-3-(imidazo[1,2-b]pyridazin-4-ium-1-ylmethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;chloride Chemical compound [Cl-].N([C@@H]1C(N2C(=C(CN3C4=CC=CN=[N+]4C=C3)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=NSC(N)=N1 NTJHUKMPVIFDNY-XFDPNJHTSA-N 0.000 claims description 6
- 229960002642 cefozopran Drugs 0.000 claims description 6
- QDUIJCOKQCCXQY-WHJQOFBOSA-N cefozopran Chemical compound N([C@@H]1C(N2C(=C(CN3C4=CC=CN=[N+]4C=C3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=NSC(N)=N1 QDUIJCOKQCCXQY-WHJQOFBOSA-N 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 238000007710 freezing Methods 0.000 claims description 3
- 230000008014 freezing Effects 0.000 claims description 3
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims 4
- BWRRTAXZCKVRON-DGPOFWGLSA-N cefotiam dihydrochloride Chemical compound Cl.Cl.CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 BWRRTAXZCKVRON-DGPOFWGLSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 43
- SVSFIELZISOJDT-XRZFDKQNSA-N (6r,7r)-7-[[2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-3-[[1-[2-(dimethylamino)ethyl]tetrazol-5-yl]sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrochloride Chemical compound Cl.CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 SVSFIELZISOJDT-XRZFDKQNSA-N 0.000 description 32
- 150000007514 bases Chemical class 0.000 description 28
- 238000000034 method Methods 0.000 description 20
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 16
- 229930064664 L-arginine Natural products 0.000 description 16
- 235000014852 L-arginine Nutrition 0.000 description 16
- 238000001802 infusion Methods 0.000 description 15
- 238000002156 mixing Methods 0.000 description 15
- 239000002245 particle Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000011812 mixed powder Substances 0.000 description 11
- 229920001971 elastomer Polymers 0.000 description 10
- 239000011521 glass Substances 0.000 description 10
- 239000008213 purified water Substances 0.000 description 10
- 150000001782 cephems Chemical class 0.000 description 9
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 8
- 239000003242 anti bacterial agent Substances 0.000 description 7
- 229940088710 antibiotic agent Drugs 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000013329 compounding Methods 0.000 description 6
- 238000009826 distribution Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000001488 sodium phosphate Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 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 4
- MPTNDTIREFCQLK-UNVJPQNDSA-N cefmenoxime hydrochloride Chemical compound [H+].[Cl-].S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NN=NN1C.S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NN=NN1C MPTNDTIREFCQLK-UNVJPQNDSA-N 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 235000010265 sodium sulphite Nutrition 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- ORFOPKXBNMVMKC-CEZXYXJGSA-N (6S,7S)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetyl]amino]-8-oxo-3-(pyridin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound CC(C)(O\N=C(/C(=O)N[C@@H]1[C@@H]2SCC(C[n+]3ccccc3)=C(N2C1=O)C([O-])=O)c1csc(N)n1)C(O)=O ORFOPKXBNMVMKC-CEZXYXJGSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 235000009697 arginine Nutrition 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 229960000484 ceftazidime Drugs 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
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 229940102223 injectable solution Drugs 0.000 description 3
- 238000005192 partition Methods 0.000 description 3
- 238000010298 pulverizing process Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- 235000019801 trisodium phosphate Nutrition 0.000 description 3
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 239000003708 ampul 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
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229960003194 meglumine Drugs 0.000 description 2
- RETIMRUQNCDCQB-UHFFFAOYSA-N mepivacaine hydrochloride Chemical compound Cl.CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C RETIMRUQNCDCQB-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-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
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 0 CC(C1)*1*(N(C([C@]1*(NC=S)=CC)SC2)C1=O)=C2S Chemical compound CC(C1)*1*(N(C([C@]1*(NC=S)=CC)SC2)C1=O)=C2S 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 241000892865 Heros Species 0.000 description 1
- 206010022086 Injection site pain Diseases 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 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 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- HVFLCNVBZFFHBT-ZKDACBOMSA-N cefepime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-N 0.000 description 1
- 229960002100 cefepime Drugs 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960002660 mepivacaine hydrochloride Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229960001309 procaine hydrochloride Drugs 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
Description
本発明は、注射用組成物に関する。詳細には、酸性医薬化合物および塩基性物質を含有する注射用組成物に関する。 The present invention relates to an injectable composition. Specifically, it relates to an injectable composition containing an acidic pharmaceutical compound and a basic substance.
セフェム系抗生物質では安定性や製造面で利点がある酸性物質の塩または付加物を原薬としていることがある。その例としては、たとえば臨床上有用に使用されている、塩酸セフォチアム（ｃｅｆｏｔｉａｍ ｈｙｄｒｏｃｈｌｏｒｉｄｅ：ＣＴＭ）、塩酸セフメノキシム（ｃｅｆｍｅｎｏｘｉｍｅ ｈｅｍｉｈｙｄｒｏｃｈｌｏｒｉｄｅ：ＣＭＸ）および塩酸セフォゾプラン（ｃｅｆｏｚｏｐｒａｎ ｈｙｄｒｏｃｈｌｏｒｉｄｅ：ＣＺＯＰ）等が挙げられる。
また、近年臨床上問題となっているＭＲＳＡ（ｍｅｔｈｉｃｉｌｌｉｎ ｒｅｓｉｓｔａｎｔ Ｓ． ａｕｒｅｕｓ：メチシリン耐性黄色ブドウ球菌）に有効な次式：
Cephem antibiotics may be based on a salt or adduct of an acidic substance that has advantages in terms of stability and manufacturing. Examples thereof include cefothia hydrochloride (CTM), cefmenoxime hydrochloride (CMX), and cefozopran hydrochloride (CefozopranHlOCl), which are used clinically, for example.
Further, the following effective formula for MRSA (methicillin resist S. aureus), which has been a clinical problem in recent years:
で表される化合物もまた、有機酸または無機酸の塩または付加物として使用される。 Are also used as salts or adducts of organic or inorganic acids.
このような酸性セフェム系抗生物質等の酸性医薬化合物は、注射時に患者に疼痛を感じさせる等の好ましくない性質も有している。この問題を解決する技術として、特開昭５３−２９９３６号公報（特許文献１）の実施例１には、塩酸セフォチアムと炭酸ナトリウムとを約１：１当量の量比で含有する組成物が開示されている。この特許文献１には、炭酸ナトリウムを配合することによりＣＴＭの溶解速度が向上する優れた利点も有することが記載されている。
一般に注射剤を溶解する場合、通常想定されないような好ましくない条件下(急激な温度上昇)で使用された場合、バイアル内で圧力上昇が起こり、注射器内への溶解液吸入時に刺針部分より液漏れを生じる場合がある。特許文献１に記載される、炭酸ナトリウムが配合された製剤でも、通常想定されないような好ましくない使用条件下（急激な温度上昇）で使用された場合においてはバイアル製剤にした場合、溶解時にバイアル内気圧の過度の上昇が起こり、注射器内への溶解液吸入時に刺針部分より液漏れを生じる場合があり、改善の余地があった。
In general, when dissolving an injection, if it is used under unfavorable conditions (rapid increase in temperature) that would not normally be expected, a pressure increase will occur in the vial, causing liquid leakage from the puncture part when the solution is inhaled into the syringe. May occur. Even when a preparation containing sodium carbonate described in Patent Document 1 is used under unfavorable use conditions (rapid increase in temperature) that are not normally assumed, when it is made into a vial preparation, There was room for improvement because an excessive increase in atmospheric pressure occurred and liquid leakage occurred from the puncture needle portion when the solution was inhaled into the syringe.
上記の問題に鑑み、本発明は、通常想定されないような好ましくない使用条件下(急激な温度上昇)で使用された場合でも注射器内への溶解液吸入時に刺針部分より液漏れを生じない注射用組成物を提供することを課題とする。 In view of the above problems, the present invention is for injection that does not cause liquid leakage from the puncture portion when inhaling the solution into the syringe even when used under unfavorable use conditions (rapid temperature rise) that are not normally assumed. It is an object to provide a composition.
本発明者らは、上記の目的を達成すべく鋭意研究を重ねた結果、酸性医薬化合物と炭酸塩以外の塩基性化合物とを含有する注射用組成物に、特定の量比で炭酸塩を配合することにより、通常想定されないような好ましくない使用条件下(急激な温度上昇)で使用された場合でもバイアル内気圧の過度の上昇のない酸性医薬化合物含有注射用組成物が得られることを見出し、本発明を完成するに至った。 As a result of intensive studies to achieve the above-mentioned object, the present inventors formulated carbonates at a specific quantitative ratio into injectable compositions containing acidic pharmaceutical compounds and basic compounds other than carbonates. By doing so, it is found that an acidic pharmaceutical compound-containing injectable composition that does not excessively increase the pressure inside the vial even when used under an unfavorable use condition (rapid temperature rise) that is not normally assumed can be obtained, The present invention has been completed.
すなわち、本発明は、下記の通りである。
（１）酸性医薬化合物、炭酸塩および炭酸塩以外の塩基性化合物を含有し、少なくとも酸性医薬化合物が固体である注射用組成物。
（２）水性溶媒中において炭酸塩と酸性医薬化合物とを混合した時に少量の二酸化炭素が発生することを特徴とする上記（１）記載の注射用組成物。
（３）酸性医薬化合物が酸性セフェム系抗生物質である上記（１）記載の注射用組成物。
（４）酸性医薬化合物が、セフォチアム、セフメノキシム、セフォゾプランまたは式
That is, the present invention is as follows.
(1) An injectable composition containing an acidic pharmaceutical compound, a carbonate and a basic compound other than carbonate, wherein at least the acidic pharmaceutical compound is solid.
(2) The injectable composition as described in (1) above, wherein a small amount of carbon dioxide is generated when a carbonate and an acidic pharmaceutical compound are mixed in an aqueous solvent.
(3) The injectable composition according to the above (1), wherein the acidic pharmaceutical compound is an acidic cephem antibiotic.
(4) the acidic pharmaceutical compound is cefotiam, cefmenoxime, cefozopran or formula
で表される化合物の、有機酸塩、無機酸塩、有機酸付加物または無機酸付加物である上記（１）記載の注射用組成物。
（５）酸性医薬化合物が、セフォチアム、セフメノキシム、またはセフォゾプランの塩酸塩である上記（１）記載の注射用組成物。
（６）酸性医薬化合物が塩酸セフォチアムである上記（１）記載の注射用組成物。
（７）炭酸塩以外の塩基性化合物が、塩基性アミノ酸、リン酸三ナトリウム、リン酸二ナトリウム、水酸化ナトリウム、およびメグルミンからなる群より選ばれる１または２以上の塩基性化合物である上記（１）記載の注射用組成物。
（８）炭酸塩以外の塩基性化合物がアルギニンである上記（１）記載の注射用組成物。
（９）炭酸塩が炭酸ナトリウム、炭酸水素ナトリウムまたはその混合物である上記（１）記載の注射用組成物。
（１０）炭酸塩が炭酸ナトリウムである上記（１）記載の注射用組成物。
The injectable composition according to the above (1), which is an organic acid salt, inorganic acid salt, organic acid adduct or inorganic acid adduct of the compound represented by
(5) The injectable composition according to the above (1), wherein the acidic pharmaceutical compound is cefotiam, cefmenoxime, or cefozopran hydrochloride.
(6) The injectable composition according to the above (1), wherein the acidic pharmaceutical compound is cefotiam hydrochloride.
(7) The basic compound other than carbonate is one or more basic compounds selected from the group consisting of basic amino acids, trisodium phosphate, disodium phosphate, sodium hydroxide, and meglumine ( 1) The composition for injection as described.
(8) The injectable composition according to the above (1), wherein the basic compound other than carbonate is arginine.
(9) The injectable composition according to the above (1), wherein the carbonate is sodium carbonate, sodium bicarbonate or a mixture thereof.
(10) The composition for injection according to the above (1), wherein the carbonate is sodium carbonate.
（１１）溶解後のｐＨが約３．５〜約９．５である上記（１）記載の注射用組成物。
（１２）炭酸塩および炭酸塩以外の塩基性化合物の総量が、酸性医薬化合物１当量に対して約０．３〜約６．２当量である上記（１）記載の注射用組成物。
（１３）炭酸塩および炭酸塩以外の塩基性化合物の総量が、酸性医薬化合物１重量部に対して約０．０７〜約０．８２重量部である上記（１）記載の注射用組成物。
（１４）炭酸塩の量が、酸性医薬化合物１当量に対して約０．１〜約３．４当量である上記（１）記載の注射用組成物。
（１５）炭酸塩の量が、酸性医薬化合物１重量部に対して約０．０１〜約０．２２重量部である上記（１）記載の注射用組成物。
（１６）炭酸塩以外の塩基性化合物の量が、酸性医薬化合物１当量に対して約０．２〜約２．８当量である上記（１）記載の注射用組成物。
（１７）炭酸塩以外の塩基性化合物の量が、酸性医薬化合物１重量部に対して約０．０６〜約０．６０重量部である上記（１）記載の注射用組成物。
（１８）上記（１）記載の注射用組成物を含有するバイアル製剤。
（１９）２５℃における内気圧が約４０〜約１００ｋＰａである上記（１８）記載のバイアル製剤。
（２０）上記（１）記載の注射用組成物を含有するキット製剤。
(11) The composition for injection according to (1) above, wherein the pH after dissolution is about 3.5 to about 9.5.
(12) The injectable composition according to the above (1), wherein the total amount of carbonate and basic compounds other than carbonate is about 0.3 to about 6.2 equivalents per equivalent of acidic pharmaceutical compound.
(13) The injectable composition according to the above (1), wherein the total amount of carbonate and a basic compound other than carbonate is about 0.07 to about 0.82 parts by weight per 1 part by weight of the acidic pharmaceutical compound.
(14) The injectable composition according to (1), wherein the amount of carbonate is about 0.1 to about 3.4 equivalents relative to 1 equivalent of acidic pharmaceutical compound.
(15) The injectable composition according to the above (1), wherein the amount of carbonate is about 0.01 to about 0.22 parts by weight with respect to 1 part by weight of the acidic pharmaceutical compound.
(16) The injectable composition according to the above (1), wherein the amount of the basic compound other than the carbonate is about 0.2 to about 2.8 equivalents relative to 1 equivalent of the acidic pharmaceutical compound.
(17) The injectable composition according to the above (1), wherein the amount of the basic compound other than carbonate is about 0.06 to about 0.60 parts by weight with respect to 1 part by weight of the acidic pharmaceutical compound.
(18) A vial preparation containing the injectable composition according to (1) above.
(19) The vial preparation according to the above (18), wherein the internal pressure at 25 ° C. is about 40 to about 100 kPa.
(20) A kit preparation containing the composition for injection according to (1) above.
（２１）上記（１）記載の注射用組成物を含有する３〜５０ｍＬのバイアルを含有し、当該バイアルの２５℃における内気圧が約４０〜約１００ｋＰａである上記（２０）記載のキット製剤。
（２２）上記（１）記載の注射用組成物を含有する５１〜３００ｍＬのバイアルを含有し、当該バイアルの２５℃における内気圧が約０.５〜約３９ｋＰａである上記（２０）記載のキット製剤。
（２３）（ｉ）固体である上記（１）記載の注射用組成物が封入されている部屋と、（ｉｉ）注射用の生理食塩液またはブドウ糖液が封入されている部屋とを有し、当該２部屋が用時に開通されるように構成されている上記（１）記載の注射用組成物。
（２４）上記（１）記載の組成物の溶液を凍結乾燥してなる注射用組成物。
（２５）上記（１）記載の組成物の溶液を凍結してなる注射用組成物。
(21) The kit preparation according to the above (20), comprising a 3 to 50 mL vial containing the injectable composition according to the above (1), wherein the internal pressure of the vial at 25 ° C. is about 40 to about 100 kPa.
(22) The kit according to the above (20), comprising a 51 to 300 mL vial containing the injectable composition according to the above (1), wherein the internal pressure of the vial at 25 ° C. is about 0.5 to about 39 kPa. Formulation.
(23) (i) a room in which the injectable composition according to (1), which is a solid, is enclosed; and (ii) a room in which a physiological saline solution or glucose liquid for injection is enclosed, The injectable composition according to (1), wherein the two rooms are configured to be opened at the time of use.
(24) An injectable composition obtained by freeze-drying a solution of the composition described in (1) above.
(25) An injectable composition obtained by freezing a solution of the composition described in (1) above.
本発明によれば、通常想定されないような好ましくない使用条件下（急激な温度上昇）でもバイアル内気圧の過度の上昇や点滴筒内の液面低下を引き起こすことなく、かつ各成分が速やかに溶解し、さらに固体成分が溶解したことの目視による確認を速やかに行うことができる酸性セフェム系抗生物質含有注射用組成物を提供することができる。 According to the present invention, each component dissolves rapidly without causing excessive rise in the pressure inside the vial or lowering of the liquid level in the drip tube even under unfavorable use conditions (rapid temperature rise) that are not normally assumed. Furthermore, it is possible to provide an injectable composition containing an acidic cephem antibiotic that can quickly confirm that the solid component has been dissolved visually.
以下本発明の内容を詳細に説明する。
本発明の酸性医薬化合物としては、注射用精製水に溶解したときに酸性を示す医薬化合物が用いられる。かかる医薬化合物としては注射用精製水に溶解したときに酸性を示す酸性セフェム系抗生物質等が好ましい。当該酸性セフェム系抗生物質としては、例えば、セフォチアム、セフメノキシム、セフォゾプラン、セフピロム、セフェピム、および下記式
The contents of the present invention will be described in detail below.
As the acidic pharmaceutical compound of the present invention, a pharmaceutical compound that shows acidity when dissolved in purified water for injection is used. As such a pharmaceutical compound, an acidic cephem antibiotic which shows acidity when dissolved in purified water for injection is preferable. Examples of the acidic cephem antibiotics include cefotiam, cefmenoxime, cefozopran, cefpirom, cefepime, and the following formula:
で表される化合物の有機酸もしくは無機酸の塩または付加物あるいはそれ自体が酸性物質であるセフタジジムが挙げられる。 Or a salt or adduct of an organic acid or an inorganic acid of the compound represented by the formula, or ceftazidime, which itself is an acidic substance.
有機酸または無機酸としては、薬学上許容されるものであれば特に限定されないが、例えば有機酸としてはギ酸、酢酸、トリフルオロ酢酸、フマール酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、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、アスパラギン酸、グルタミン酸等；無機酸としては塩酸、臭化水素酸、硝酸、硫酸、リン酸等を用いることができる。好ましくは塩酸、酢酸、ｐ−トルエンスルホン酸等である。 The organic acid or inorganic acid is not particularly limited as long as it is pharmaceutically acceptable. For example, the organic acid is formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid. Acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid and the like; hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be used as the inorganic acid. Preferred are hydrochloric acid, acetic acid, p-toluenesulfonic acid and the like.
酸性セフェム系抗生物質の好ましい例として、具体的には、たとえば次式： As preferable examples of acidic cephem antibiotics, specifically, for example, the following formula:
で表される塩酸セフォチアム（ｃｅｆｏｔｉａｍ ｈｙｄｒｏｃｈｌｏｒｉｄｅ：ＣＴＭ）、次式： Cefotiam hydrochloride (CTM) represented by the following formula:
で表される塩酸セフメノキシム（ｃｅｆｍｅｎｏｘｉｍｅ ｈｅｍｉｈｙｄｒｏｃｈｌｏｒｉｄｅ：ＣＭＸ）および次式： Cefmenoxime hydrochloride (CMX) represented by the following formula:
で表される塩酸セフォゾプラン（ｃｅｆｏｚｏｐｒａｎ ｈｙｄｒｏｃｈｌｏｒｉｄｅ：ＣＺＯＰ）、硫酸セフピロム（Ｃｅｆｐｉｒｏｍｅ ｓｕｌｆａｔｅ：ＣＰＲ）、セフタジジム(Ｃｅｆｔａｚｉｄｉｍｅ：ＣＡＺ)、塩酸セフェピム(Ｃｅｆｅｐｉｍｅ Ｄｉｈｙｄｒｏｃｈｌｏｒｉｄｅ：ＣＦＰＭ)、硫酸セフピロム（Ｃｅｆｐｉｒｏｍｅ Ｓｕｌｆａｔｅ）ならびに、次式： Cefozopran hydrochloride (CZOP), cefpirom sulfate (CPR), ceftazidime (CAZ), cefepimediCF
で表される化合物の酢酸塩（以下、単に化合物（Ｉ）酢酸塩と称する場合がある）等が挙げられる。
これらの酸性セフェム系抗生物質は単独で用いてもよく、２以上の化合物を併用してもよい。
And the like (hereinafter sometimes referred to simply as compound (I) acetate).
These acidic cephem antibiotics may be used alone or in combination of two or more compounds.
本発明において用いられるセフォチアム、セフメノキシム、セフォゾプランおよび前記一般式（Ｉ）で表される化合物は、公知の方法または一般有機合成法を用いて製造することができるが、例えば以下の公報に開示の方法で製造することができる。
セフォチアムは、例えば特開昭５３−２９９１３号公報開示の方法および公知の一般有機合成法を用いて製造することができる。
セフメノキシムは、例えば特開昭５５−７９３９３号公報開示の方法および公知の一般有機合成法を用いて製造することができる。
セフォゾプランは、例えば特開平１−２５０３２２号公報開示の方法および公知の一般有機合成法を用いて製造することができる。
前記式（Ｉ）で表される化合物は、例えば特開平１１−２５５７７２号公報開示の方法および公知の一般有機合成法を用いて製造することができる。
これらの化合物は公知の方法または前記の公報記載の方法で有機酸または無機酸の塩または付加物とすることができる。
これらの抗生物質またはその有機酸または無機酸の塩または付加物は、さらに溶媒付加物（溶媒和物）または非溶媒付加物（非溶媒和物）、特に水和物または非水和物であってもよい。また、これらの化合物が、コンフィギュレーショナル アイソマー（配置異性体）、ジアステレオマー、コンフォーマー等として存在する場合には、所望により、公知の分離、精製手段によりそれぞれを単離することができ、また、これらの化合物がラセミ体である場合には、通常の光学分割手段によりＳ体及びＲ体に分離することができる。これらの化合物に立体異性体が存在する場合には、この異性体が単独の場合及びそれらの混合物の場合も本発明に含まれ、さらに、これらの化合物は同位元素（例、３Ｈ、１４Ｃ、３５Ｓ）等で標識されていてもよい。
The cefotiam, cefmenoxime, cefozopran and the compound represented by the general formula (I) used in the present invention can be produced using a known method or a general organic synthesis method. For example, the method disclosed in the following publications Can be manufactured.
Cefotiam can be produced using, for example, the method disclosed in JP-A-53-29913 and a known general organic synthesis method.
Cefmenoxime can be produced, for example, using the method disclosed in JP-A-55-79393 and a known general organic synthesis method.
Cefozopran can be produced, for example, using the method disclosed in JP-A-1-250322 and a known general organic synthesis method.
The compound represented by the formula (I) can be produced, for example, using the method disclosed in JP-A-11-255572 and a known general organic synthesis method.
These compounds can be converted into salts or adducts of organic acids or inorganic acids by a known method or the method described in the above publication.
These antibiotics or their organic or inorganic acid salts or adducts may further be solvent adducts (solvates) or non-solvent adducts (non-solvates), in particular hydrates or nonhydrates. May be. In addition, when these compounds exist as configurational isomers (configuration isomers), diastereomers, conformers, etc., they can be isolated by known separation and purification means, if desired. When these compounds are racemic, they can be separated into S-form and R-form by ordinary optical resolution means. When stereoisomers exist in these compounds, the case where these isomers are singly or in a mixture thereof is also included in the present invention. Further, these compounds are also isotopes (eg, 3 H, 14 C , 35 S) or the like.
本発明に用いられる炭酸塩は、特に限定されるものではないが、好ましくはアルカリ金属の炭酸塩（例、炭酸ナトリウム、炭酸カリウム等）もしくは重炭酸塩（例、炭酸水素ナトリウム、炭酸水素カリウム等）またはアルカリ土類金属の炭酸塩（例、炭酸マグネシウム、炭酸カルシウム等）、より好ましくはアルカリ金属の炭酸塩もしくは重炭酸塩、さらに好ましくは炭酸ナトリウムまたは炭酸水素ナトリウム、最も好ましくは炭酸ナトリウムである。これらの炭酸塩は、１つの化合物を単独で用いても、２以上の化合物を組み合わせて用いてもよい。 The carbonate used in the present invention is not particularly limited, but is preferably an alkali metal carbonate (eg, sodium carbonate, potassium carbonate, etc.) or bicarbonate (eg, sodium bicarbonate, potassium bicarbonate, etc.). ) Or an alkaline earth metal carbonate (eg, magnesium carbonate, calcium carbonate, etc.), more preferably an alkali metal carbonate or bicarbonate, more preferably sodium carbonate or sodium bicarbonate, most preferably sodium carbonate. . These carbonates may be used alone or in combination of two or more compounds.
本発明に用いられる炭酸塩以外の塩基性化合物としては、（１）塩基性アミノ酸等の有機塩基類、ならびに（２）炭酸塩類以外の無機塩基類が挙げられる。塩基性アミノ酸としては、例えばアルギニン、リジン、ヒスチジン、オルニチン等を用いることができる。中でも、好ましくはアルギニンである。Ｄ−体、Ｌ−体どちらも用いることができるがＬ−体が好ましい。炭酸塩類以外の無機塩基類としては、リン酸三ナトリウム、リン酸二ナトリウム、水酸化ナトリウム、メグルミン等を用いることができる。中でも、好ましくはリン酸三ナトリウムである。これらの塩基性化合物は、１つの化合物を単独で用いても、２以上の化合物を組み合わせて用いてもよい。 Examples of basic compounds other than carbonates used in the present invention include (1) organic bases such as basic amino acids, and (2) inorganic bases other than carbonates. As the basic amino acid, for example, arginine, lysine, histidine, ornithine and the like can be used. Of these, arginine is preferable. Both D-form and L-form can be used, but L-form is preferred. As inorganic bases other than carbonates, trisodium phosphate, disodium phosphate, sodium hydroxide, meglumine, and the like can be used. Among them, trisodium phosphate is preferable. These basic compounds may be used alone or in combination of two or more compounds.
また、本発明の注射用組成物は、必要に応じ、緩衝液（例、リン酸二水素ナトリウム、リン酸水素二ナトリウム等）、等張化剤（例、グルコース、塩化ナトリウム等）、安定化剤（例、亜硫酸水素ナトリウム等）、無痛化剤（例、グルコース、ベンジルアルコール、塩酸メピバカイン、塩酸キシロカイン、塩酸プロカイン、塩酸カルボカイン等）、防腐剤（例、パラオキシ安息香酸メチル等のパラオキシ安息香酸エステル、チメロサール、クロロブタノール、ベンジルアルコール等）等を含有していてもよい。
また、本発明の注射用組成物はビタミン類などを含有していてもよい。
さらに、本発明の注射用組成物は、必要に応じ、水性溶媒を含有していてもよい。水性溶媒としては、例えば、注射用精製水、生理食塩水、およびブドウ糖液が挙げられる。
Moreover, the composition for injection of the present invention can be stabilized with a buffer solution (eg, sodium dihydrogen phosphate, disodium hydrogen phosphate, etc.), an isotonic agent (eg, glucose, sodium chloride, etc.), if necessary. Agents (eg, sodium bisulfite), soothing agents (eg, glucose, benzyl alcohol, mepivacaine hydrochloride, xylocaine hydrochloride, procaine hydrochloride, carbocaine hydrochloride, etc.), preservatives (eg, paraoxybenzoic acid esters such as methyl paraoxybenzoate) , Thimerosal, chlorobutanol, benzyl alcohol, etc.).
The injectable composition of the present invention may contain vitamins and the like.
Furthermore, the injectable composition of the present invention may contain an aqueous solvent, if necessary. Examples of the aqueous solvent include purified water for injection, physiological saline, and glucose solution.
本発明の注射用組成物においては、少なくとも酸性医薬化合物は固体である。炭酸塩、および炭酸塩以外の塩基性化合物は、それぞれ固体であってもよく、上記のような水性溶媒に溶解した溶液等の液体であってもよい。好ましくは、これら３成分が全て固体である。ここで「固体」とは、通常の意味に用いられ、結晶および非晶質を包含する。固体の成分の形態は特に限定されないが、溶解速度の観点から粉末が好ましい。 In the injectable composition of the present invention, at least the acidic pharmaceutical compound is a solid. Each of the carbonate and the basic compound other than the carbonate may be a solid or a liquid such as a solution dissolved in the above aqueous solvent. Preferably, all three components are solid. Here, the term “solid” is used in the ordinary sense and includes crystal and amorphous. The form of the solid component is not particularly limited, but powder is preferable from the viewpoint of dissolution rate.
本発明の注射用組成物は、水性溶媒中において炭酸塩と酸性医薬化合物とを混合した時に少量の二酸化炭素が発生するが、その気泡は速やかに消失することを特徴とする。このとき、驚くべきことに、気泡の発生は少量であるにも関わらず上記の固体成分は速やかに溶解する。また、生じた気泡が速やかに消失することにより、固体成分が溶解したことの目視による確認を速やかに行うことができる。
「水性溶媒中において炭酸塩と酸性医薬化合物とを混合する」とは、例えば（１）炭酸塩と酸性医薬化合物とを含有する固体と、水性溶媒とを混合すること、および（２）酸性医薬化合物の固体と炭酸塩含有水溶液とを混合すること等をいう。すなわち、この水性溶媒は別途用意したものである場合と、本発明の組成物に含まれるものである場合がある。
このとき炭酸塩以外の塩基性化合物は必ずしも同時に混合しなくてもよいが、同時に混合することが好ましい。
The injectable composition of the present invention is characterized in that a small amount of carbon dioxide is generated when carbonate and an acidic pharmaceutical compound are mixed in an aqueous solvent, but the bubbles disappear rapidly. At this time, surprisingly, the solid component dissolves rapidly in spite of a small amount of bubbles. Further, since the generated bubbles disappear quickly, it can be quickly confirmed visually that the solid component has dissolved.
“Mixing carbonate and acidic pharmaceutical compound in aqueous solvent” means, for example, (1) mixing solid containing carbonate and acidic pharmaceutical compound with aqueous solvent, and (2) acidic pharmaceutical. This refers to mixing a solid compound and a carbonate-containing aqueous solution. That is, this aqueous solvent may be prepared separately or may be included in the composition of the present invention.
At this time, basic compounds other than carbonates do not necessarily have to be mixed at the same time, but are preferably mixed at the same time.
「少量（の二酸化炭素が発生）」とは、例えば、（１）本発明の組成物をバイアル製剤とする場合において、予めバイアル内を真空に近いレベル（具体的には、内気圧１３．３ｋＰａ以下）に減圧しなくても、注射剤溶液を注射器内に吸入する時に液漏れを生じない程度に二酸化炭素の発生量が少ないこと、あるいは（２）本発明の注射用組成物をバイアル製剤またはバックを含むキット製剤として、一般的な輸液セット（例、テルフュージョン輸液セット（商品名）、テルモ株式会社）に接続して点滴操作を行う場合において、ブドウ糖液を比較対照とした点滴筒内の液面低下が１０ｍｍ以下（さらに好ましくは７ｍｍ以下、特に好ましくは５ｍｍ以下、最も好ましくは３ｍｍ以下）である程度に二酸化炭素の発生量が少ないことをいう。
本明細書中、「少量の二酸化炭素が発生する注射用組成物」とは、より具体的には、例えば、室温下で、容量３５ｍＬ、内気圧約７７ｋＰａのバイアル中で、１ｇ力価の本発明の注射用組成物の固形成分を溶解して５ｍＬの注射用溶液を調製した場合に、溶解後のバイアルの内気圧が約９０〜約１４０ｋＰａとなるような注射用組成物を意味する。
“Small amount of carbon dioxide is generated” means, for example, (1) when the composition of the present invention is used as a vial preparation, a level close to a vacuum in the vial in advance (specifically, an internal pressure of 13.3 kPa) (2) the amount of carbon dioxide generated is small enough not to cause liquid leakage when the injectable solution is inhaled into the syringe without reducing the pressure, or (2) the injectable composition of the present invention As a kit preparation containing a bag, when a drip operation is performed by connecting to a general infusion set (eg, Terffusion Infusion Set (trade name), Terumo Co., Ltd.) It means that the amount of carbon dioxide generated is small to some extent when the liquid level is 10 mm or less (more preferably 7 mm or less, particularly preferably 5 mm or less, most preferably 3 mm or less).
In the present specification, the “injectable composition in which a small amount of carbon dioxide is generated” more specifically means, for example, a 1 g titer book in a vial having a volume of 35 mL and an internal pressure of about 77 kPa at room temperature. When the solid component of the injectable composition of the invention is dissolved to prepare a 5 mL injectable solution, the injectable composition has an internal pressure of about 90 to about 140 kPa after dissolution.
上記した二酸化炭素の発生量は、炭酸塩の配合当量（または配合量）を調製することにより、調製することができる。
炭酸塩の配合当量（または配合量）は、酸性医薬化合物の種類などによっても異なるが、炭酸塩の配合当量については、通常、酸性医薬化合物１当量に対し、約０．１〜約３．４当量用いることができる。好ましくは約０．２〜約３．０当量、より好ましくは約０．３〜約２．０当量、さらに好ましくは約０．４〜約１．３当量である。より具体的には、例えば酸性医薬化合物が塩酸セフォチアムの場合、塩酸セフォチアム１当量に対し、通常は約０．１〜約１．０当量、好ましくは約０．２〜約０．７当量、さらに好ましくは約０．３〜約０．６当量であり、化合物（Ｉ）酢酸塩の場合、当該塩の１当量に対し、通常は約０．３〜約３．４当量、好ましくは約０．６〜約２．３当量、さらに好ましくは約１．０〜約２．０当量である。一方、炭酸塩の配合量については、酸性医薬化合物１重量部に対し、通常は約０．０１〜約０．２２重量部、好ましくは約０．０３〜約０．２０重量部、より好ましくは約０．０５〜約０．１３重量部、さらに好ましくは約０．０６〜約０．０９重量部である。より具体的には、例えば酸性医薬化合物が塩酸セフォチアムの場合、塩酸セフォチアム１重量部に対し、通常は約０．０１〜約０．１７重量部、好ましくは約０．０３〜約０．１２重量部、さらに好ましくは約０．０５〜約０．１０重量部であり、化合物（Ｉ）酢酸塩の場合、当該塩１重量部に対し、通常は約０．０２〜約０．２２重量部、好ましくは約０．０３〜約０．１５重量部、さらに好ましくは約０．０６〜約０．１３重量部である。
The amount of carbon dioxide generated as described above can be prepared by adjusting the blending equivalent (or blending amount) of carbonate.
The blending equivalent (or blending amount) of the carbonate varies depending on the kind of the acidic pharmaceutical compound, but the blending equivalent of the carbonate is usually about 0.1 to about 3.4 with respect to 1 equivalent of the acidic pharmaceutical compound. An equivalent amount can be used. The amount is preferably about 0.2 to about 3.0 equivalents, more preferably about 0.3 to about 2.0 equivalents, and still more preferably about 0.4 to about 1.3 equivalents. More specifically, for example, when the acidic pharmaceutical compound is cefotiam hydrochloride, it is usually about 0.1 to about 1.0 equivalent, preferably about 0.2 to about 0.7 equivalent, and more preferably about 0.1 to about 0.7 equivalent to 1 equivalent of cefotiam hydrochloride. The amount is preferably about 0.3 to about 0.6 equivalents, and in the case of Compound (I) acetate, it is usually about 0.3 to about 3.4 equivalents, preferably about 0.0. 6 to about 2.3 equivalents, more preferably about 1.0 to about 2.0 equivalents. On the other hand, the amount of carbonate is usually about 0.01 to about 0.22 parts by weight, preferably about 0.03 to about 0.20 parts by weight, more preferably 1 part by weight of the acidic pharmaceutical compound. About 0.05 to about 0.13 parts by weight, more preferably about 0.06 to about 0.09 parts by weight. More specifically, for example, when the acidic pharmaceutical compound is cefotiam hydrochloride, it is usually about 0.01 to about 0.17 parts by weight, preferably about 0.03 to about 0.12 parts by weight with respect to 1 part by weight of cefotiam hydrochloride. Parts, more preferably about 0.05 to about 0.10 parts by weight. In the case of Compound (I) acetate, usually about 0.02 to about 0.22 parts by weight per 1 part by weight of the salt, The amount is preferably about 0.03 to about 0.15 parts by weight, more preferably about 0.06 to about 0.13 parts by weight.
本発明の組成物を溶解した注射剤のｐＨは、注射時の疼痛を抑制する観点からは、約３．５〜約９．５が好ましく、約４．５〜約９がさらに好ましく、約５．５〜約８．５が特に好ましく、約６〜約８が最も好ましい。
当該ｐＨは、炭酸塩および炭酸塩以外の塩基性化合物の配合当量（または配合量）を調整することによって、容易に調整することができる。
The pH of the injection in which the composition of the present invention is dissolved is preferably about 3.5 to about 9.5, more preferably about 4.5 to about 9, more preferably about 5 from the viewpoint of suppressing pain during injection. .5 to about 8.5 is particularly preferred, and about 6 to about 8 is most preferred.
The said pH can be easily adjusted by adjusting the compounding equivalent (or compounding quantity) of basic compounds other than carbonate and carbonate.
すなわちｐＨ調整の観点から、本発明の注射用組成物における炭酸塩および炭酸塩以外の塩基性化合物の配合当量（または配合量）の合計（以下、単に「塩基性化合物の総量」と称する場合がある）は、酸性医薬化合物の種類などによっても異なるが、塩基性化合物の総量（配合当量）については、通常、酸性医薬化合物１当量に対し、約０．３〜約６．２当量を用いることができる。好ましくは約０．６〜約５．７当量、より好ましくは約０．９〜約４．６当量、さらに好ましくは約１．５〜約３．８当量である。より具体的には、例えば酸性医薬化合物が塩酸セフォチアムの場合、塩酸セフォチアム１当量に対し、通常は約０．３〜約３．０当量、好ましくは約０．６〜約２．６当量、さらに好ましくは約１．４〜約２．４当量であり、化合物（Ｉ）酢酸塩の場合、当該塩の１当量に対して通常は約０．６〜約６．２当量、好ましくは約１．１〜約５．０当量、さらに好ましくは約２．６〜約４．６当量である。一方、塩基性化合物の総量（配合量）については、酸性医薬化合物１重量部に対し、通常は約０．０７〜約０．８２重量部、好ましくは約０．１４〜約０．７７重量部、より好ましくは約０．２５〜約０．６９重量部、さらに好ましくは約０．３６〜約０．６４重量部である。より具体的には、例えば酸性医薬化合物が塩酸セフォチアムの場合、塩酸セフォチアム１重量部に対し、通常は約０．０７〜約０．７２重量部、好ましくは約０．１４〜約０．６４重量部、さらに好ましくは約０．３５〜約０．５６重量部であり、化合物（Ｉ）酢酸塩の場合、当該塩１重量部に対し、通常は約０．０８〜約０．８２重量部、好ましくは約０．１４〜約０．７１重量部、さらに好ましくは約０．３９〜約０．６８重量部である。 That is, from the viewpoint of pH adjustment, the total of the blending equivalents (or blending amounts) of the carbonate and the basic compound other than the carbonate in the injectable composition of the present invention (hereinafter sometimes simply referred to as “total amount of the basic compound”). Is) depending on the type of acidic pharmaceutical compound, etc., but the total amount of the basic compound (formulation equivalent) is usually about 0.3 to about 6.2 equivalents per equivalent of acidic pharmaceutical compound. Can do. The amount is preferably about 0.6 to about 5.7 equivalents, more preferably about 0.9 to about 4.6 equivalents, and even more preferably about 1.5 to about 3.8 equivalents. More specifically, for example, when the acidic pharmaceutical compound is cefotiam hydrochloride, it is usually about 0.3 to about 3.0 equivalents, preferably about 0.6 to about 2.6 equivalents, and more preferably about 0.6 to about 2.6 equivalents per 1 equivalent of cefotiam hydrochloride. The amount is preferably about 1.4 to about 2.4 equivalents, and in the case of Compound (I) acetate, usually about 0.6 to about 6.2 equivalents, preferably about 1. 1 to about 5.0 equivalents, more preferably about 2.6 to about 4.6 equivalents. On the other hand, the total amount (blending amount) of the basic compound is usually about 0.07 to about 0.82 parts by weight, preferably about 0.14 to about 0.77 parts by weight per 1 part by weight of the acidic pharmaceutical compound. More preferably from about 0.25 to about 0.69 parts by weight, still more preferably from about 0.36 to about 0.64 parts by weight. More specifically, for example, when the acidic pharmaceutical compound is cefotiam hydrochloride, it is usually about 0.07 to about 0.72 parts by weight, preferably about 0.14 to about 0.64 parts by weight per 1 part by weight of cefotiam hydrochloride. Parts, more preferably about 0.35 to about 0.56 parts by weight. In the case of Compound (I) acetate, usually about 0.08 to about 0.82 parts by weight per 1 part by weight of the salt, The amount is preferably about 0.14 to about 0.71 part by weight, more preferably about 0.39 to about 0.68 part by weight.
本発明の注射用組成物における炭酸塩以外の塩基性化合物の配合当量（または配合量）は、上記の量で配合される炭酸塩および、所望するｐＨならびに塩基性化合物の総量から決定される。具体的には、炭酸塩以外の塩基性化合物の配合当量（または配合量）は、酸性医薬化合物の種類などによっても異なるが、炭酸塩以外の塩基性化合物の配合当量については、通常、酸性医薬化合物１当量に対し、約０．２〜約２．８当量用いることができ、好ましくは約０．４〜約２．７当量、より好ましくは約０．６〜約２．６当量、さらに好ましくは約１．１〜約２．５当量である。より具体的には、例えば塩酸セフォチアムの場合、塩酸セフォチアム１当量に対し、通常は約０．２〜約２．０当量、好ましくは約０．４〜約１．９当量、さらに好ましくは約１．１〜約１．８当量であり、化合物（Ｉ）酢酸塩の場合、当該塩の１当量に対し、通常は約０．３〜約２．８当量、好ましくは約０．５〜約２．７当量、さらに好ましくは約１．６〜約２．６当量である。一方、炭酸塩以外の塩基性化合物の配合量については、酸性医薬化合物１重量部に対して通常は約０．０６〜約０．６０重量部、好ましくは約０．１１〜約０．５７重量部、より好ましくは約０.２０〜約０.５６重量部、さらに好ましくは約０．３０〜約０．５５重量部である。より具体的には、例えば酸性医薬化合物が塩酸セフォチアムの場合、塩酸セフォチアム１重量部に対し、通常は約０．０６〜約０．５５重量部、好ましくは約０．１１〜約０．５２重量部、さらに好ましくは約０．３０〜約０．４６重量部であり、化合物（Ｉ）酢酸塩の場合、当該塩１重量部に対し、通常は約０．０６〜約０．６０重量部、好ましくは約０．１１〜約０．５６重量部、さらに好ましくは約０．３３〜約０．５５重量部である。 The blending equivalent (or blending amount) of the basic compound other than the carbonate in the injectable composition of the present invention is determined from the carbonate blended in the above amount, the desired pH, and the total amount of the basic compound. Specifically, the compounding equivalent (or compounding amount) of the basic compound other than the carbonate varies depending on the type of the acidic pharmaceutical compound, but the compounding equivalent of the basic compound other than the carbonate is usually an acidic pharmaceutical. About 0.2 to about 2.8 equivalents can be used per 1 equivalent of the compound, preferably about 0.4 to about 2.7 equivalents, more preferably about 0.6 to about 2.6 equivalents, still more preferably Is about 1.1 to about 2.5 equivalents. More specifically, for example, in the case of cefotiam hydrochloride, it is usually about 0.2 to about 2.0 equivalents, preferably about 0.4 to about 1.9 equivalents, more preferably about 1 to 1 equivalent of cefotiam hydrochloride. 0.1 to about 1.8 equivalents, and in the case of Compound (I) acetate, it is usually about 0.3 to about 2.8 equivalents, preferably about 0.5 to about 2 to 1 equivalent of the salt. 0.7 equivalents, more preferably about 1.6 to about 2.6 equivalents. On the other hand, the compounding amount of the basic compound other than the carbonate is usually about 0.06 to about 0.60 parts by weight, preferably about 0.11 to about 0.57 parts by weight per 1 part by weight of the acidic pharmaceutical compound. Parts, more preferably about 0.20 to about 0.56 parts by weight, still more preferably about 0.30 to about 0.55 parts by weight. More specifically, for example, when the acidic pharmaceutical compound is cefotiam hydrochloride, it is usually about 0.06 to about 0.55 parts by weight, preferably about 0.11 to about 0.52 parts by weight with respect to 1 part by weight of cefotiam hydrochloride. Parts, more preferably about 0.30 to about 0.46 parts by weight. In the case of Compound (I) acetate, usually about 0.06 to about 0.60 parts by weight per 1 part by weight of the salt, The amount is preferably about 0.11 to about 0.56 parts by weight, more preferably about 0.33 to about 0.55 parts by weight.
本発明の組成物の形態としては、バイアル製剤およびキット製剤等の種々の形態を採用する事ができる。
その形態の例としては、
形態１：酸性医薬化合物、炭酸塩および炭酸塩以外の塩基性化合物を含有する固体（例、粉末、顆粒など）；
形態２：形態１の固体を封入したバイアル製剤；
形態３：形態１の固体と水性溶媒とからなるキット製剤；および
形態４：酸性医薬化合物および炭酸塩以外の塩基性化合物を含有する固体と炭酸塩溶液からなるキット製剤；等が挙げられる。
本発明の組成物がバイアル製剤（好ましくは、形態２のバイアル製剤）である場合、そのバイアルの大きさは、その使用目的に応じて適宜選択される。例えば、当該バイアルに水性溶媒を注入し、注射用組成物の固形成分を溶解させて調製された注射溶液を注射器に吸入して使用する場合には、バイアルの大きさは約３〜約５０ｍＬ、好ましくは約５〜約４５ｍＬ、より好ましくは約５〜約４０ｍＬである。注射器内への吸入時の液漏れを防止する観点および注射器内への吸入し易さの観点から、当該バイアルに水性溶媒を注入して注射用組成物の固形成分を溶解させ注射用溶液を調製した際の当該バイアルの内気圧は、約９０〜約１４０ｋＰａであることが好ましい。
このため、使用前のバイアルの常温（２５℃）での内気圧は、好ましくは約４０〜約１００ｋＰａ、更に好ましくは約５０〜約９０ｋＰａ、特に好ましくは約７５〜約８５ｋＰａであることが好ましい。また、この場合の酸性医薬化合物の量は、例えば３５ｍＬバイアルの場合、０．２〜５ｇが好ましく、０．５〜２ｇが更に好ましい。１７ｍＬのバイアルの場合、０．２〜４ｇが好ましく、０．２５〜１ｇが更に好ましい。９ｍＬのバイアルの場合、０．２〜４ｇが好ましく、０．３〜０．５ｇが更に好ましい。
As the form of the composition of the present invention, various forms such as a vial preparation and a kit preparation can be adopted.
As an example of its form,
Form 1: solid (eg, powder, granule, etc.) containing acidic pharmaceutical compound, carbonate and basic compound other than carbonate;
Form 2: A vial formulation enclosing the solid of Form 1;
Form 3: a kit preparation comprising a solid of form 1 and an aqueous solvent; and form 4: a kit preparation comprising a solid containing a basic compound other than an acidic pharmaceutical compound and carbonate; and a carbonate solution; and the like.
When the composition of the present invention is a vial preparation (preferably a vial preparation of Form 2), the size of the vial is appropriately selected according to the purpose of use. For example, when an injection solution prepared by injecting an aqueous solvent into the vial and dissolving a solid component of the injectable composition is inhaled into a syringe, the size of the vial is about 3 to about 50 mL, Preferably about 5 to about 45 mL, more preferably about 5 to about 40 mL. From the viewpoint of preventing liquid leakage during inhalation into the syringe and ease of inhalation into the syringe, an aqueous solvent is injected into the vial to dissolve the solid components of the injectable composition to prepare an injection solution The internal pressure of the vial is preferably about 90 to about 140 kPa.
Therefore, the internal pressure of the vial before use at room temperature (25 ° C.) is preferably about 40 to about 100 kPa, more preferably about 50 to about 90 kPa, and particularly preferably about 75 to about 85 kPa. In addition, the amount of the acidic pharmaceutical compound in this case is preferably 0.2 to 5 g, and more preferably 0.5 to 2 g in the case of a 35 mL vial, for example. In the case of a 17 mL vial, 0.2 to 4 g is preferable, and 0.25 to 1 g is more preferable. In the case of a 9 mL vial, 0.2 to 4 g is preferable, and 0.3 to 0.5 g is more preferable.
例えば、より多量の注射用溶液を一度に調製する必要のある点滴用として用いる場合には、バイアルの大きさは約５１〜約３００ｍＬ、好ましくは約７０〜約２００ｍＬ、より好ましくは約９０〜約１５０ｍＬである。注射器内への吸入時の液漏れの防止という観点から、また、点滴用容器（例えば１３０ｍＬバイアル等）への吸入のし易さという観点から、当該バイアルに水性溶媒を注入して注射用組成物の固形成分を溶解させ点滴用溶液を調製した際の当該バイアルの内気圧は、約９０〜約１１０ｋＰａであることが好ましい。
このため、使用前のバイアルの常温（２５℃）での内気圧は、好ましくは約０.５〜約３９ｋＰａ、更に好ましくは約０.７〜約２０ｋＰａ、特に好ましくは約１〜約１０ｋＰａである。また、この場合の酸性医薬化合物の量は、例えば３００ｍＬバイアルの場合、２〜８ｇが好ましく、３〜６ｇが更に好ましい。２００ｍＬのバイアルの場合、１〜６ｇが好ましく、２〜４ｇが更に好ましい。１００ｍＬのバイアルの場合、０.２〜５ｇが好ましく、１〜３ｇが更に好ましい。
For example, when used for infusions where a larger volume of injectable solution needs to be prepared at once, the vial size is about 51 to about 300 mL, preferably about 70 to about 200 mL, more preferably about 90 to about 150 mL. From the viewpoint of preventing liquid leakage during inhalation into a syringe, and from the viewpoint of ease of inhalation into an infusion container (for example, a 130 mL vial), an injection composition is prepared by injecting an aqueous solvent into the vial. It is preferable that the internal pressure of the vial when the solid component is dissolved to prepare an infusion solution is about 90 to about 110 kPa.
For this reason, the internal pressure at normal temperature (25 ° C.) of the vial before use is preferably about 0.5 to about 39 kPa, more preferably about 0.7 to about 20 kPa, and particularly preferably about 1 to about 10 kPa. . In addition, the amount of the acidic pharmaceutical compound in this case is preferably 2 to 8 g, and more preferably 3 to 6 g in the case of a 300 mL vial, for example. In the case of a 200 mL vial, 1 to 6 g is preferable, and 2 to 4 g is more preferable. In the case of a 100 mL vial, 0.2 to 5 g is preferable, and 1 to 3 g is more preferable.
形態３のキット製剤として、好適な具体例としては、一体成型され、隔壁により仕切られた二つの部屋からなるバッグの１室に酸性医薬化合物、炭酸塩および炭酸塩以外の塩基性化合物を含有する固体を封入し、他方の部屋に溶解液としての生理食塩液またはブドウ糖液を封入し、両部屋の隔壁を用時容易に開通できるよう構成し、用時両者を混合・溶解して用いることのできるキット製剤；ならびに、形態２のバイアル製剤と、水性溶媒のハーフキットとの組み合わせであるキット製剤等が挙げられる。
形態３における水性溶媒および形態４における溶液の量は、特に限定されるものではないが、酸性医薬化合物１ｇに対して、通常約５０ｍＬ〜約２００ｍＬ、好ましくは約８０ｍＬ〜約１２０ｍＬである。
As a preferred specific example of the kit preparation of Form 3, an acidic pharmaceutical compound, carbonate and a basic compound other than carbonate are contained in one chamber of a bag formed of two chambers that are integrally molded and partitioned by a partition wall. A solid solution is enclosed, and a saline solution or glucose solution as a solution is enclosed in the other chamber so that the partition walls in both chambers can be easily opened at the time of use. Kit preparations that can be used; and kit preparations that are a combination of a vial preparation of Form 2 and a half kit of an aqueous solvent.
The amount of the aqueous solvent in Form 3 and the amount of the solution in Form 4 is not particularly limited, but is usually about 50 mL to about 200 mL, preferably about 80 mL to about 120 mL, with respect to 1 g of acidic pharmaceutical compound.
本発明の組成物は、その形態に応じた慣用の方法を採用して製造することができる。
例えば、形態１の固体の場合、周知慣用の粉砕機（例、パワーミル、ジェットミルなど）を用いて各化合物を粉砕して得られた粉末を、周知慣用の混合機（例、クロスミキサー、ロッキングミキサーなど）を用いて酸性医薬品化合物と混合することにより調製することができる。特に、炭酸塩以外の塩基性化合物は、吸湿性が高く、吸湿して高水分を含有した場合においては、製品の安定性を損なうため、その平衡相対湿度以下の低湿環境下で粉砕されて得られた粉末であることが好ましい。
溶解速度および取り扱い易さの観点などから、本発明の注射用組成物における酸性医薬化合物の粒度としては、例えば酸性セフェム系抗生物質の粒度(メジアン径、体積基準粒度分布)では、約２００μｍ以下が好ましい。より好ましくは約１５０μｍ以下である。また、炭酸塩以外の塩基性化合物の粒度(メジアン径、体積基準粒度分布)は約２５０μｍ以下であることが好ましく、約２００μｍ以下がより好ましい。さらに、炭酸塩の粒度(メジアン径、体積基準粒度分布）としては約２５０μｍ以下が好ましく、約２００μｍ以下がより好ましい。
The composition of this invention can be manufactured by employ | adopting the usual method according to the form.
For example, in the case of Form 1 solid, a powder obtained by pulverizing each compound using a well-known and conventional pulverizer (eg, power mill, jet mill, etc.) is mixed with a well-known and conventional mixer (eg, cross mixer, rocking). It can be prepared by mixing with an acidic pharmaceutical compound using a mixer or the like. In particular, basic compounds other than carbonates are highly hygroscopic and can be obtained by being pulverized in a low-humidity environment below their equilibrium relative humidity in order to impair product stability when they absorb moisture and contain high moisture. It is preferable that it is the obtained powder.
From the viewpoint of dissolution rate and ease of handling, the particle size of the acidic pharmaceutical compound in the injectable composition of the present invention is, for example, about 200 μm or less for the particle size (median diameter, volume-based particle size distribution) of acidic cephem antibiotics. preferable. More preferably, it is about 150 μm or less. The particle size (median diameter, volume-based particle size distribution) of basic compounds other than carbonate is preferably about 250 μm or less, and more preferably about 200 μm or less. Further, the particle size (median diameter, volume-based particle size distribution) of the carbonate is preferably about 250 μm or less, and more preferably about 200 μm or less.
上記で説明した本発明の注射用組成物の溶液、当該溶液を凍結乾燥させて得られる注射用組成物、当該溶液を凍結してなる注射用組成物もまた本発明の注射用組成物の一形態であり、本発明の範囲内である。 The above-described solution of the injectable composition of the present invention, the injectable composition obtained by freeze-drying the solution, and the injectable composition obtained by freezing the solution are also one of the injectable compositions of the present invention. Is within the scope of the present invention.
本発明の注射用組成物は、その形態に応じた通常の方法で、注射液とし、患者に投与することができる。 The injectable composition of the present invention can be administered to a patient as an injection solution by a usual method according to the form.
本発明においてセフォチアム、セフメノキシム、セフォゾプランおよび前記一般式（Ｉ）で表される化合物からなる群より選ばれる１または２以上の化合物の有機酸または無機酸の塩または付加物の投与量は、化合物の種類、症状等によって異なるが、例えば１日０．１〜４ｇ力価を１回または２〜４回に分けて投与することができる。 In the present invention, the dosage of the organic acid or inorganic acid salt or adduct of one or more compounds selected from the group consisting of cefotiam, cefmenoxime, cefozopran and the compound represented by the general formula (I) is: For example, a daily 0.1 to 4 g titer can be administered once or divided into 2 to 4 times, depending on the type and symptoms.
以下に実施例および実験例を用いて、本発明をさらに詳細に説明するが、本発明はこれらに限定されるものではない。
実施例１、２、３、４で使用したＬ−アルギニンの粉砕は、Ｌ−アルギニンのＥＲＨ（Ｅｑｕｉｌｉｂｒｉｕｍ ｒｅｌａｔｉｖｅ ｈｕｍｉｄｉｔｙ（平衡相対湿度））以下の湿度環境下（３０％ＲＨ以下）で行った。粗粉砕機にはパワーミル（昭和化学工作所製）、微粉砕はジェットミル（日本ニューマチック工業製）を使用した。
粉砕したＬ−アルギニン等の粉末の粒度(メジアン径)の測定は、レーザー回折式粒度分布測定機（ＨＥＲＯＳ ＆ ＲＯＤＯＳ ＳＹＭＰＡＴＥＣ社製）を用いて、以下の方法で行った。本明細書中、粒度(メジアン径)とは、この方法で測定した数値を意味する。
・粒度(メジアン径)の測定方法
粉砕したＬ−アルギニン等をそれぞれ適当な分散媒（例、Ｌ−アルギニンの場合、Ｌ−アルギニンの飽和エタノール溶液）に分散させ、湿式測定法（ＣＵＶＥＴＴＥ分散）により粒度分布を測定した。得られた体積基準粒度分布から粒度(メジアン径)を読み取った。
Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples, but the present invention is not limited thereto.
The pulverization of L-arginine used in Examples 1, 2, 3, and 4 was performed in a humidity environment (30% RH or less) below L-arginine ERH (Equilibrium relative humidity). A power mill (manufactured by Showa Kagaku Kogyo) was used for the coarse pulverizer, and a jet mill (manufactured by Nippon Pneumatic Industry) was used for fine pulverization.
The particle size (median diameter) of the pulverized powder such as L-arginine was measured using a laser diffraction particle size distribution analyzer (manufactured by HEROS & RODOS SYMPATEC) by the following method. In the present specification, the particle size (median diameter) means a numerical value measured by this method.
・ Measuring method of particle size (median diameter) Each of pulverized L-arginine and the like is dispersed in an appropriate dispersion medium (for example, in the case of L-arginine, a saturated ethanol solution of L-arginine), and wet measuring method (CUVETTE dispersion). The particle size distribution was measured. The particle size (median diameter) was read from the obtained volume-based particle size distribution.
実施例１
内容量３５ｍＬのガラスバイアルにメジアン径約１２０μｍの塩酸セフォチアム１ｇ（力価）、メジアン径約１００μｍの炭酸ナトリウム８１ｍｇ及びメジアン径約１７０μｍのＬ−アルギニン５０８ｍｇを充填し、約７７ｋＰａの減圧下でゴム栓を打栓したバイアル製品とした。このバイアルに注射用精製水約５ｍＬを加え、軽く振とうすると、内容物は速やかに溶解した。
Example 1
A glass vial with an internal volume of 35 mL is filled with 1 g of cefotiam hydrochloride (titer) having a median diameter of about 120 μm, 81 mg of sodium carbonate having a median diameter of about 100 μm, and 508 mg of L-arginine having a median diameter of about 170 μm, and a rubber stopper under a reduced pressure of about 77 kPa Was made into a vial product. When about 5 mL of purified water for injection was added to this vial and shaken gently, the contents quickly dissolved.
実施例２
メジアン径約１２０μｍの塩酸セフォチアム１００ｇ（力価）に対して、メジアン径約２０μｍの炭酸ナトリウム８．１ｇを添加し、混合機でよく混合する。内容量３５ｍＬのガラスバイアルに上記混合末の塩酸セフォチアム１ｇ（力価）相当分とメジアン径約１７０μｍのＬ−アルギニン５０８ｍｇを充填し、約７７ｋＰａの減圧下でゴム栓を打栓したバイアル製品とした。このバイアルに注射用精製水約５ｍＬを加え、軽く振とうすると、内容物は速やかに溶解した。
Example 2
To 100 g (potency) of cefotiam hydrochloride having a median diameter of about 120 μm, 8.1 g of sodium carbonate having a median diameter of about 20 μm is added and mixed well with a mixer. A glass vial with an internal volume of 35 mL was filled with 1 g (titer) equivalent of cefotiam hydrochloride in the mixed powder and 508 mg of L-arginine with a median diameter of about 170 μm, and a vial product was made by plugging a rubber stopper under a reduced pressure of about 77 kPa. . When about 5 mL of purified water for injection was added to this vial and shaken gently, the contents quickly dissolved.
実施例３
メジアン径約１２０μｍの塩酸セフォチアム１ｋｇ（力価）に対して、メジアン径約２０μｍの炭酸ナトリウム８１ｇを添加し、混合機でよく混合する。内容量３５ｍＬのガラスバイアルに上記混合末の塩酸セフォチアム１ｇ（力価）相当分とメジアン径約１７０μｍのＬ−アルギニン５０８ｍｇを充填し、約７７ｋＰａの減圧下でゴム栓を打栓したバイアル製品とした。このバイアルを生理食塩液ハーフキット（１００ｍＬ）と連通後、生理食塩液約１０ｍＬをバイアル内に移し、軽く振とうすると、内容物は速やかに溶解した。内容液全量をハーフキットのプラボトル内に移した後、バイアルと両頭針を取り外した。プラボトルに輸液セットをセットし、点滴高さ約１ｍ、点滴時間２時間の条件で、点滴操作を行ったところ、点滴筒内の液面低下はほとんどなかった。
Example 3
To 1 kg (potency) of cefotiam hydrochloride having a median diameter of about 120 μm, 81 g of sodium carbonate having a median diameter of about 20 μm is added and mixed well with a mixer. A glass vial with an internal volume of 35 mL was filled with 1 g (titer) of cefotiam hydrochloride in the above mixed powder and 508 mg of L-arginine with a median diameter of about 170 μm, and a vial was plugged with a rubber stopper under a reduced pressure of about 77 kPa. . After this vial was communicated with a physiological saline half kit (100 mL), about 10 mL of physiological saline was transferred into the vial and shaken gently to dissolve the contents quickly. After transferring the entire content of the solution into the plastic bottle of the half kit, the vial and the double-ended needle were removed. When an infusion set was set in a plastic bottle and the infusion operation was performed under the conditions of an infusion height of about 1 m and an infusion time of 2 hours, there was almost no drop in the liquid level in the infusion tube.
実施例４
メジアン径約１２０μｍの塩酸セフォチアム１ｋｇ（力価）に対して、メジアン径約２０μｍの炭酸ナトリウム８１ｇを添加し、混合機でよく混合する。この混合末にメジアン径約１７０μｍのＬ−アルギニン５０８ｇを添加し、混合機でよく混合する。内容量３５ｍＬのガラスバイアルに上記混合末の塩酸セフォチアム１ｇ（力価）相当分を充填し、約７７ｋＰａの減圧下でゴム栓を打栓したバイアル製品とした。このバイアルを５℃で保管した生理食塩液ハーフキット（１００ｍＬ）と連通後、生理食塩液約１０ｍＬをバイアル内に移し、軽く振とうすると、内容物は速やかに溶解した。内容液全量をハーフキットのプラボトル内に移した後、バイアルと両頭針を取り外した。プラボトルに輸液セットをセットし、４０℃の温度環境下、点滴高さ約１ｍ、点滴時間２時間の条件で、点滴操作を行ったところ、点滴筒内の液面は約３ｍｍで、生理食塩液単独で点滴操作を行ったときとほとんど差はなかった。
Example 4
To 1 kg (potency) of cefotiam hydrochloride having a median diameter of about 120 μm, 81 g of sodium carbonate having a median diameter of about 20 μm is added and mixed well with a mixer. To this mixed powder, 508 g of L-arginine having a median diameter of about 170 μm is added and mixed well with a mixer. A glass vial having an internal volume of 35 mL was filled with 1 g (titer) equivalent of cefotiam hydrochloride in the above mixed powder, and a vial product was made by plugging a rubber stopper under a reduced pressure of about 77 kPa. After the vial was communicated with a physiological saline half kit (100 mL) stored at 5 ° C., about 10 mL of physiological saline was transferred into the vial and shaken gently to dissolve the contents quickly. After transferring the entire content of the solution into the plastic bottle of the half kit, the vial and the double-ended needle were removed. An infusion set was set in a plastic bottle, and the drip operation was performed under the conditions of a drip height of about 1 m and a drip time of 2 hours under a temperature environment of 40 ° C. The liquid level in the drip tube was about 3 mm, and the physiological saline solution There was almost no difference from the drip operation performed alone.
実施例５
メジアン径約１２０μｍの塩酸セフォチアム５００ｇ（力価）に対して、メジアン径約２０μｍの炭酸ナトリウム３００ｇを添加し、混合機でよく混合する。内容量３５ｍＬのガラスバイアルに上記混合末の塩酸セフォチアム１ｇ（力価）相当分とメジアン径約１７０μｍのＬ−アルギニン５８０ｍｇを充填し、約７７ｋＰａの減圧下でゴム栓を打栓したバイアル製品とした。このバイアルに注射用精製水約５ｍＬを加え、軽く振とうすると、内容物は速やかに溶解した。
Example 5
To 500 g (potency) of cefotiam hydrochloride having a median diameter of about 120 μm, 300 g of sodium carbonate having a median diameter of about 20 μm is added and mixed well with a mixer. A glass vial with an internal volume of 35 mL was filled with 1 g (titer) equivalent of cefotiam hydrochloride and 580 mg of median diameter of about 170 μm in the above-mentioned mixed powder, and a vial product was made by plugging a rubber stopper under a reduced pressure of about 77 kPa. . When about 5 mL of purified water for injection was added to this vial and shaken gently, the contents quickly dissolved.
実施例６
メジアン径約１２０μｍの塩酸セフォチアム１ｋｇ（力価）に対して、メジアン径約２０μｍの炭酸ナトリウム１１３．９ｇを添加し、混合機でよく混合する。この混合末にメジアン径約３５μｍのＬ−アルギニン４５７．５ｇを加え、混合機でよく混合する。簡単な操作にて開通可能な隔壁で隔てられた２室を有するソフトバッグでその一室に予め生理食塩液が充填されたバッグのもう一室に上記混合末の塩酸セフォチアム１ｇ（力価）相当分を充填し、バッグ製品とした。このバッグの溶解液側を押さえ、隔壁部を開通させ、ポンピング操作を２〜３回行うと、内容物は速やかに溶解した。バッグに輸液セットをセットし、点滴高さ約１ｍ、点滴時間１時間の条件で、点滴操作を行ったところ、点滴筒内の液面低下はほとんどなかった。
Example 6
To 1 kg (potency) of cefotiam hydrochloride having a median diameter of about 120 μm, 113.9 g of sodium carbonate having a median diameter of about 20 μm is added and mixed well with a mixer. To this mixed powder, 457.5 g of L-arginine having a median diameter of about 35 μm is added and mixed well with a mixer. A soft bag with two chambers separated by a septum that can be opened by a simple operation. One of the bags is prefilled with physiological saline, and the other is equivalent to 1 g (titer) of cefotiam hydrochloride in the mixed powder. The portion was filled into a bag product. When the solution side of the bag was pressed to open the partition wall and the pumping operation was performed 2 to 3 times, the contents were quickly dissolved. When an infusion set was set in the bag and an infusion operation was performed under the conditions of an infusion height of about 1 m and an infusion time of 1 hour, there was almost no drop in the liquid level in the infusion tube.
実施例７
メジアン径約１２０μｍの塩酸セフォチアム１ｋｇ（力価）に対して、メジアン径約２０μｍの炭酸ナトリウム１１３．９ｇを添加し、混合機でよく混合する。この混合末にメジアン径約３５μｍのＬ−アルギニン４５７．５ｇを添加し、混合機でよく混合する。内容量３５ｍＬのガラスバイアルに上記混合末の塩酸セフォチアム１ｇ（力価）相当分を充填し、約８５ｋＰａの減圧下でゴム栓を打栓したバイアル製品とした。このバイアルに注射用精製水約２０ｍＬを加え、軽く振とうすると、内容物は速やかに溶解した。
Example 7
To 1 kg (potency) of cefotiam hydrochloride having a median diameter of about 120 μm, 113.9 g of sodium carbonate having a median diameter of about 20 μm is added and mixed well with a mixer. To this mixed powder, 457.5 g of L-arginine having a median diameter of about 35 μm is added and mixed well with a mixer. A glass vial with an internal volume of 35 mL was filled with 1 g (titer) equivalent of cefotiam hydrochloride in the above-mentioned mixed powder, and a vial product was made by plugging a rubber stopper under a reduced pressure of about 85 kPa. When about 20 mL of purified water for injection was added to this vial and shaken lightly, the contents quickly dissolved.
実施例８
内容量３５ｍＬのガラスバイアルに化合物（Ｉ）酢酸塩１ｇ（力価）、炭酸ナトリウム１２３．８ｍｇ、Ｌ−アルギニン４５８ｍｇおよび亜硫酸ナトリウム１８．４ｍｇを充填し、約７７ｋＰａの減圧下でゴム栓を打栓したバイアル製品とした。このバイアルに注射用精製水約１０ｍＬを加え、軽く振とうすると、内容物は速やかに溶解した。
Example 8
A glass vial with an internal volume of 35 mL is filled with 1 g (titer) of Compound (I) acetate, 123.8 mg of sodium carbonate, 458 mg of L-arginine and 18.4 mg of sodium sulfite, and a rubber stopper is plugged under a reduced pressure of about 77 kPa. Vial product. When about 10 mL of purified water for injection was added to this vial and shaken lightly, the contents quickly dissolved.
実施例９
化合物（Ｉ）酢酸塩１００ｇ（力価）に対して、炭酸ナトリウム１２．３８ｇを添加し、混合機でよく混合する。内容量３５ｍＬのガラスバイアルに上記混合末の化合物（Ｉ）酢酸塩１ｇ（力価）相当分とＬ−アルギニン４５８ｍｇおよび亜硫酸ナトリウム１８．４ｍｇを充填し、約７７ｋＰａの減圧下でゴム栓を打栓したバイアル製品とした。このバイアルに注射用精製水約１０ｍＬを加え、軽く振とうすると、内容物は速やかに溶解した。
Example 9
Add 12.38 g of sodium carbonate to 100 g of compound (I) acetate (titer) and mix well with a mixer. Fill a glass vial with an internal volume of 35 mL with 1 g (titer) equivalent of compound (I) acetate of the above mixed powder, 458 mg of L-arginine and 18.4 mg of sodium sulfite, and plug the rubber stopper under a reduced pressure of about 77 kPa. Vial product. When about 10 mL of purified water for injection was added to this vial and shaken lightly, the contents quickly dissolved.
実施例１０
内容量３５ｍＬのガラスバイアルに化合物（Ｉ）酢酸塩１ｇ（力価）を充填し、約７７ｋＰａの減圧下でゴム栓を打栓したバイアル製品とした。
専用溶解液として、炭酸ナトリウム１２３．８ｍｇ、Ｌ−アルギニン４５８ｍｇおよび亜硫酸ナトリウム１８．４ｍｇを１０ｍＬの蒸留水に溶解し、アンプルに充填し、空間部を窒素置換し熔閉した。
バイアル製品に専用溶解液を加え、軽く振とうすると、内容物は速やかに溶解した。
Example 10
A glass vial with an internal volume of 35 mL was filled with 1 g (titer) of Compound (I) acetate, and a vial product was obtained by plugging a rubber stopper under a reduced pressure of about 77 kPa.
As an exclusive solution, 123.8 mg of sodium carbonate, 458 mg of L-arginine and 18.4 mg of sodium sulfite were dissolved in 10 mL of distilled water, filled into an ampoule, and the space portion was purged with nitrogen and sealed.
When the exclusive solution was added to the vial product and shaken lightly, the contents quickly dissolved.
実施例１１
化合物（Ｉ）酢酸塩１００ｇ（力価）に対して、炭酸ナトリウム１２．３８ｇを添加し、混合機でよく混合する。内容量３５ｍＬのガラスバイアルに上記混合末の化合物（Ｉ）酢酸塩１ｇ（力価）相当分を充填し、約７７ｋＰａの減圧下でゴム栓を打栓したバイアル製品とした。
専用溶解液として、Ｌ−アルギニン４５８ｍｇおよび亜硫酸ナトリウム１８．４ｍｇを１０ｍＬの蒸留水に溶解し、アンプルに充填し、空間部を窒素置換し熔閉した。
バイアル製品に専用溶解液を加え、軽く振とうすると、内容物は速やかに溶解した。
Example 11
Add 12.38 g of sodium carbonate to 100 g of compound (I) acetate (titer) and mix well with a mixer. A glass vial with an internal volume of 35 mL was filled with 1 g (titer) equivalent of Compound (I) acetate in the above mixed powder, and a vial product was obtained by plugging a rubber stopper under a reduced pressure of about 77 kPa.
As an exclusive solution, 458 mg of L-arginine and 18.4 mg of sodium sulfite were dissolved in 10 mL of distilled water, filled into an ampoule, and the space was purged with nitrogen and sealed.
When the exclusive solution was added to the vial product and shaken lightly, the contents quickly dissolved.
実験例１
内気圧を７７ｋＰａに調整したことを除き、実施例１と同様に製造したバイアル製品を２５℃の製品温度に調整し、注射器で同温度の注射用精製水約５ｍＬを加え、軽く振とうし、内容物を完全に溶解させた後の内気圧を測定した結果、１０９ｋＰａであり、溶液を注射器で抜き出したところ、溶液の漏れなく、容易に抜き出すことができた。
Experimental example 1
Except that the internal pressure was adjusted to 77 kPa, the vial product produced in the same manner as in Example 1 was adjusted to a product temperature of 25 ° C., about 5 mL of purified water for injection at the same temperature was added with a syringe, and shaken lightly. As a result of measuring the internal pressure after completely dissolving the contents, it was 109 kPa, and when the solution was extracted with a syringe, it could be easily extracted without leakage of the solution.
本発明によれば、通常想定されないような好ましくない使用条件下（急激な温度上昇）でもバイアル内気圧の過度の上昇や点滴筒内の液面低下を引き起こすことなく、かつ各成分が速やかに溶解し、さらに固体成分が溶解したことの目視による確認を速やかに行うことができる酸性医薬化合物含有注射用組成物を提供することができる。 According to the present invention, each component dissolves rapidly without causing excessive rise in the pressure inside the vial or lowering of the liquid level in the drip tube even under unfavorable use conditions (rapid temperature rise) that are not normally assumed. Furthermore, it is possible to provide an injectable composition containing an acidic pharmaceutical compound that can quickly confirm visually that the solid component has been dissolved.
Claims (17)
該酸性医薬化合物が、セフォチアム、セフメノキシム、セフォゾプランまたは式
炭酸ナトリウムおよびアルギニンの総量が、酸性医薬化合物１当量に対して０．３〜６．２当量であり、
炭酸ナトリウムの量が、酸性医薬化合物１当量に対して０．１〜３．４当量である、注射用組成物。 An injectable composition comprising an acidic pharmaceutical compound, sodium carbonate and arginine , wherein at least the acidic pharmaceutical compound is a solid ,
The acidic pharmaceutical compound is cefotiam, cefmenoxime, cefozopran or formula
The total amount of sodium carbonate and arginine is 0.3 to 6.2 equivalents per equivalent of acidic pharmaceutical compound;
An injectable composition, wherein the amount of sodium carbonate is 0.1 to 3.4 equivalents per equivalent of acidic pharmaceutical compound .
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| JPS5973518A (en) * | 1982-09-10 | 1984-04-25 | グラクソ・グル−プ・リミテツド | Pharmacological composition |
| JPH01250322A (en) * | 1987-12-04 | 1989-10-05 | Takeda Chem Ind Ltd | Antibiotic composition |
| JPH0390019A (en) * | 1989-08-18 | 1991-04-16 | F Hoffmann La Roche Ag | Method for preparing pharmaceutically active substance capable of dozed non-orally |
| JPH03264531A (en) * | 1990-03-13 | 1991-11-25 | Mochida Pharmaceut Co Ltd | Freeze-dried cephalosporin preparation |
| JPH04338332A (en) * | 1991-05-13 | 1992-11-25 | Takeda Chem Ind Ltd | Cephalosporin injection and its preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5973518A (en) * | 1982-09-10 | 1984-04-25 | グラクソ・グル−プ・リミテツド | Pharmacological composition |
| JPH01250322A (en) * | 1987-12-04 | 1989-10-05 | Takeda Chem Ind Ltd | Antibiotic composition |
| JPH0390019A (en) * | 1989-08-18 | 1991-04-16 | F Hoffmann La Roche Ag | Method for preparing pharmaceutically active substance capable of dozed non-orally |
| JPH03264531A (en) * | 1990-03-13 | 1991-11-25 | Mochida Pharmaceut Co Ltd | Freeze-dried cephalosporin preparation |
| JPH04338332A (en) * | 1991-05-13 | 1992-11-25 | Takeda Chem Ind Ltd | Cephalosporin injection and its preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2007238491A (en) * | 2006-03-08 | 2007-09-20 | Nipro Corp | Medical preparation |
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