JP2004161729A - Medicinal composition - Google Patents
Medicinal composition Download PDFInfo
- Publication number
- JP2004161729A JP2004161729A JP2003031592A JP2003031592A JP2004161729A JP 2004161729 A JP2004161729 A JP 2004161729A JP 2003031592 A JP2003031592 A JP 2003031592A JP 2003031592 A JP2003031592 A JP 2003031592A JP 2004161729 A JP2004161729 A JP 2004161729A
- Authority
- JP
- Japan
- Prior art keywords
- acidic
- basic
- injection according
- injection
- cephem antibiotic
- 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
- 239000000203 mixture Substances 0.000 title description 6
- 239000007924 injection Substances 0.000 claims abstract description 63
- 238000002347 injection Methods 0.000 claims abstract description 63
- 150000007514 bases Chemical class 0.000 claims abstract description 51
- 230000003115 biocidal effect Effects 0.000 claims abstract description 47
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 45
- 150000001782 cephems Chemical class 0.000 claims abstract description 41
- 230000002378 acidificating effect Effects 0.000 claims abstract description 39
- 239000000243 solution Substances 0.000 claims abstract description 27
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 239000001488 sodium phosphate Substances 0.000 claims abstract description 20
- 239000000126 substance Substances 0.000 claims abstract description 20
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims abstract description 19
- 235000019801 trisodium phosphate Nutrition 0.000 claims abstract description 19
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims abstract description 19
- 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 claims abstract description 18
- 235000001014 amino acid Nutrition 0.000 claims abstract description 18
- 150000001413 amino acids Chemical class 0.000 claims abstract description 18
- 229960003194 meglumine Drugs 0.000 claims abstract description 18
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims abstract description 14
- 235000019797 dipotassium phosphate Nutrition 0.000 claims abstract description 14
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims abstract description 14
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims abstract description 14
- 235000011121 sodium hydroxide Nutrition 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 53
- 239000002245 particle Substances 0.000 claims description 34
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 26
- 150000007524 organic acids Chemical class 0.000 claims description 26
- 239000000843 powder Substances 0.000 claims description 26
- 229960003791 cefmenoxime Drugs 0.000 claims description 24
- 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 24
- 229960002642 cefozopran Drugs 0.000 claims description 24
- 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 24
- 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 23
- 229960001242 cefotiam Drugs 0.000 claims description 23
- 150000007522 mineralic acids Chemical class 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 20
- 239000001569 carbon dioxide Substances 0.000 claims description 13
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 13
- 239000002504 physiological saline solution Substances 0.000 claims description 13
- 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 claims description 9
- 239000008103 glucose Substances 0.000 claims description 9
- -1 organic acid salt Chemical class 0.000 claims description 9
- 238000006386 neutralization reaction Methods 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000011812 mixed powder Substances 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 239000004475 Arginine Substances 0.000 claims description 5
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 5
- 238000010298 pulverizing process Methods 0.000 claims 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 claims description 3
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims 1
- 229940102223 injectable solution Drugs 0.000 claims 1
- 150000003839 salts Chemical class 0.000 description 25
- 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 13
- 229960004700 cefotiam hydrochloride Drugs 0.000 description 13
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 11
- 229930064664 L-arginine Natural products 0.000 description 11
- 235000014852 L-arginine Nutrition 0.000 description 11
- 239000003242 anti bacterial agent Substances 0.000 description 10
- 239000002253 acid Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 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
- 238000004090 dissolution Methods 0.000 description 6
- 0 CCc1ccc(C2N=C(SC(CSC(C3C[*+](CC4OC)C4SC(*O)=N)C4C3=I=C)C4Cl)SC2)cc1 Chemical compound CCc1ccc(C2N=C(SC(CSC(C3C[*+](CC4OC)C4SC(*O)=N)C4C3=I=C)C4Cl)SC2)cc1 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 235000009697 arginine Nutrition 0.000 description 4
- 238000013329 compounding Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000005192 partition Methods 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 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
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 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
- 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 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-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
- 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 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
- 150000008043 acidic salts Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 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 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229960003085 meticillin Drugs 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
- 239000012453 solvate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000012360 testing method Methods 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-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
- 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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 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
- 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
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- 239000008186 active pharmaceutical agent Substances 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
- 239000006067 antibiotic powder Substances 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
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000010419 fine particle Substances 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
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid 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
- 238000001802 infusion Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007794 irritation Effects 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
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000002156 mixing Methods 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
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、抗生物質として有用な化合物の注射用組成物に関する。詳細には、１）抗生物質の有機酸または無機酸の塩または付加物と２）所定の塩基性化合物とからなる注射用組成物に関する。
【０００２】
【従来の技術】
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。たとえば臨床上有用に使用される下記式、
【化３】
下記式、
【化４】
下記式、
【化５】
【０００３】
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）に有効な下記式、
【化６】
【０００４】
これらの有機酸または無機酸の塩または付加物を形成している抗生物質は、投与時には刺激性等の問題で酸性の塩または付加物としては投与が困難であり、炭酸ナトリウム等で用時中和もしくはｐＨを調整して用いるよう製品化されている場合がある。例えば、特開昭５３−２９９３６号公報や特開平１−２５０３２２号公報には炭酸塩を含有する製剤が開示されている。それは、水に難溶性の抗生物質の場合溶解性を高めるため酸性の塩または付加物としていることもあり、前記のような中和等の工程に炭酸ナトリウム等を使用することで、発生する二酸化炭素の攪拌効果により主薬の溶解を促進させる狙いもある。
【０００５】
【特許文献１】
特開昭５３−２９９３６号公報
【特許文献２】
特開平１−２５０３２２号公報
【０００６】
【発明が解決しようとする課題】
しかし、この場合一般には下記の問題がある。
１）使用時に中和等することにより二酸化炭素が発生する。注射剤のようにガラスバイアルを用いる場合、内圧が高くなることを防止するために、予め減圧にする等の措置が必要となる。
２）中和等時に発生した炭酸ガスが薬液に溶け込み、投与中に溶け込んだ二酸化炭素が徐々にガス化する可能性を払拭できない。
従って、二酸化炭素が発生しないか、またはほとんど発生しない医薬製剤の開発が待望されている。
【０００７】
本発明者らは、これらの問題点を解決すべく鋭意研究を重ねた結果、意外にも塩基性アミノ酸を使用するとガラスバイアルを直接容器として用いる場合でも、バイアル内部を予め減圧とする等の措置は不要であり前記の問題が解決できること、また主薬の溶解性の問題も各成分の粒子径バランスをとること及び混合度を高めることにより解決できること、たとえ炭酸塩を配合する場合でも塩基性アミノ酸を共存させることにより炭酸塩の配合量を減らすことでほぼ前記の問題を解決できること等を見出し、これらに基づいて本発明を完成した。
【０００８】
【課題を解決するための手段】
すなわち、本発明は、
（１） 酸性セフェム系抗生物質と塩基性化合物とを含有し、中和時に二酸化炭素を発生しない注射剤、
（２） 酸性セフェム系抗生物質が、セフォチアム、セフメノキシム、セフォゾプランまたは式
【化７】
（３） 酸性セフェム系抗生物質が、セフォチアム、セフメノキシム、セフォゾプランまたは式
【化８】
（４） 塩基性化合物が、塩基性アミノ酸、リン酸三ナトリウム、リン酸二カリウム、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）記載の注射剤、
（５） 塩基性化合物がアルギニンである上記（１）記載の注射剤、
（６） 酸性セフェム系抗生物質１重量部に対する塩基性物質の量が０．１重量部以上である上記（１）記載の注射剤、
（７） 酸性セフェム系抗生物質１重量部に対する塩基性物質の量が０．２重量部以上である上記（１）記載の注射剤、
（８） 酸性セフェム系抗生物質に対して０．５〜７当量の塩基性化合物を含有する上記（１）記載の注射剤、
（９） 中和後のｐＨが３．５〜９．５である上記（１）記載の注射剤、
（１０） 酸性セフェム系抗生物質が粉末である上記（１）記載の注射剤、
（１１） 酸性セフェム系抗生物質および塩基性物質がそれぞれ粉末であり、それらが混合されている上記（１）記載の注射剤、
（１２） 酸性セフェム系抗生物質の粉末の平均粒子径が約２００μｍ以下である上記（１０）または（１１）記載の注射剤、
（１３） 塩基性物質の粉末の平均粒子系が約２０μｍ〜約２００μｍである上記（１１）記載の注射剤、
（１４） 酸性セフェム系抗生物質の粉末の平均粒子径が約２００μｍ以下であり、塩基性物質の粉末の平均粒子系が約２０μｍ〜約２００μｍである上記（１１）記載の注射剤、
（１５） 塩基性化合物の粉末が、そのＥＲＨ以下の低湿環境下で粉砕されて得られた粉末である上記（１１）記載の注射剤、
（１６） バイアル製剤またはキット製剤である上記（１）記載の注射剤、
（１７） （ｉ）酸性セフェム系抗生物質および塩基性物質の混合粉末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キット製剤である上記（１２）記載の注射剤、
（１８） 酸性セフェム系抗生物質１重量部に対する塩基性物質の量が０．１重量部以上である上記（１６）記載の注射剤、
（１９） 酸性セフェム系抗生物質および塩基性物質が生理食塩液中またはブドウ糖液中に溶解している上記（１）記載の注射剤溶液、
（２０） 凍結して保管され、用時に解凍される上記（１９）記載の注射剤溶液、
（２１） 約−８０℃〜約０℃の温度で保管される上記（２０）記載の注射剤溶液、
（２２） （ｉ）酸性セフェム系抗生物質、（ｉｉ）塩基性アミノ酸、リン酸三ナトリウム、リン酸二カリウム、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、ならびに（ｉｉｉ）ＮａＨＣＯ３またはＮａ２ＣＯ３を含有し、中和時にほとんど二酸化炭素を発生しない注射剤、
（２３） 酸性セフェム系抗生物質を塩基性化合物で中和する方法であって、塩基性アミノ酸、リン酸三ナトリウム、リン酸二カリウム、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を用いることを特徴とする方法に関する。
【０００９】
さらに、本発明は、
（１’） 酸性セフェム系抗生物質と、塩基性アミノ酸、リン酸三ナトリウム、リン酸二カリウム、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とを含有してなる医薬製剤、
（２’） １）セフォチアム、セフメノキシム、セフォゾプランおよび式
【化９】
（３’） 前記１）で選ばれた１または２以上の化合物および前記塩基性化合物が粉末の状態でいっしょに包装された前記（２’）記載の注射剤、
（４’） 用時溶解時に二酸化炭素を発生しない前記（１’）または（２’）記載の剤、
（５’） 前記塩基性化合物の配合量が、セフォチアム、セフメノキシム、セフォゾプランおよび式
【化１０】
（６’） 前記塩基性化合物の配合量が、０．２重量部以上である前記（５’）記載の注射剤、
（７’） セフォチアム、セフメノキシム、セフォゾプランおよび式
【化１１】
（８’） 前記塩基性化合物の平均粒子径が約２０μｍ〜２００μｍである前記（３’）記載の注射剤、
（９’） セフォチアム、セフメノキシム、セフォゾプランおよび式
【化１２】
（１０’） 無機酸塩が塩酸塩である前記（２’）記載の注射剤、
（１１’） 前記塩基性化合物がアルギニンである前記（２’）記載の注射剤、
（１２’） 用時溶解したときの水溶液のｐＨが３．５〜９．５となるよう調製された１）セフォチアム、セフメノキシム、セフォゾプランおよび式
【化１３】
（１３’） バイアル製剤またはキット製剤である前記（２’）または（１２’）記載の剤、
（１４’） 注射剤を用時調製する場合において、セフォチアム、セフメノキシム、セフォゾプランおよび式
【化１４】
（１５’） １）セフォチアム、セフメノキシム、セフォゾプランおよび式
【化１５】
（１６’） セフォチアム、セフメノキシム、セフォゾプランおよび式
【化１６】
（１７’） 前記塩基性化合物の配合量が、セフォチアム、セフメノキシム、セフォゾプランおよび式
【化１７】
（１８’） １）セフォチアム、セフメノキシム、セフォゾプランおよび式
【化１８】
（１９’） １）セフォチアム、セフメノキシム、セフォゾプランおよび式
【化１９】
（２０’） 凍結して保管され、用時解凍して用いられる前記（１９’）記載の注射剤、
（２１’） 約−８０℃〜約０℃に保持された前記（１９’）記載の注射剤、
（２２’） 前記塩基性化合物がその化合物のＥＲＨ（Ｅｑｕｉｌｉｂｒｉｕｍ ｒｅｌａｔｉｖｅ ｈｕｍｉｄｉｔｙ（平衡相対湿度））以下の低湿環境下で粉砕され、配合される前記（３’）記載の注射剤、および
（２３’） 酸性セフェム系抗生物質と、塩基性化合物とを含有し、用時溶解時に二酸化炭素を発生しない医薬製剤等に関する。
【００１０】
【発明の実施の形態】
以下本発明の内容を詳細に説明する。
酸性セフェム系抗生物質とは、セフォチアム、セフメノキシム、セフォゾプランおよび下記式
【化２０】
有機酸または無機酸とは、好ましくは薬学上許容されるものであって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。
酸の塩または付加物であり、酸と塩を構成してもよいし、酸が単なる付加物となっていてもよい。
【００１１】
本発明に用いられる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、リシン、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。
粉末の状態とは砕けて細かくなったものをいい、結晶でも非晶質でもよい。
用時溶解型の注射剤とは、特に限定されないが好ましくはバイアル製剤または点滴用バッグ製剤等のキット製剤である。
【００１２】
本願発明において、主薬としての抗生物質と前記塩基性化合物は、それぞれを粉末として混合し、溶解液と別に包装しておいてもよく、また前記塩基性化合物を含む溶解液と主薬としての抗生物質とを別に包装しておいてもよく、さらに主薬としての抗生物質、前記塩基性化合物および溶解液をそれぞれ別に包装して提供し、用時三者を混合して用いてもよく、特に限定されない。少なくとも主薬としての抗生物質が粉末で提供されることが好ましい。
用時溶解用製剤として提供される場合、一体成型された二つの部屋からなるバッグの１室に抗生物質と前記塩基性化合物を封入し、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、用時両者を混合し溶解して用いることのできる製剤とすることが好ましい。また、前記塩基性化合物を予め生理食塩液またはブドウ糖液に溶解した形態とすることもできる。更に、当該バッグに３室を構成し、それぞれに抗生物質、前記塩基性化合物または溶解液を充填し、用時各部屋の隔壁を容易に開通させることができるような形態で製剤化することもできる。
さらには抗生物質と前記塩基性化合物が溶解された注射液を、冷凍または凍結保存し、用時解凍等して用いる製剤とすることもできる。この場合の保存温度は約−８０℃〜約０℃が好ましく、凍結していることが好ましい。
【００１３】
溶解液としては、生理食塩液やブドウ糖液が好ましい。
主薬に対する溶解液の使用量は特に限定されないが、例えば点滴静注製剤の場合主薬１ｇ（力価）に対して例えば１００ｍLを用いることができる。
【００１４】
前記塩基性化合物の配合量は、塩を形成もしくは付加した酸の種類や、酸の当量によっても異なるが、通常１）酸性セフェム系抗生物質または２）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を形成したものまたは付加したもの１重量部に対し、０．１重量部以上が用いられる。好ましくは０．１〜１．５重量部である。さらに好ましくは０．２重量部〜１重量部である。
【００１５】
前記塩基性化合物の配合当量は、塩を形成もしくは付加した酸の種類や、酸の当量によっても異なるが、通常１）酸性セフェム系抗生物質または２）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を形成したものまたは付加したもの１当量に対し、０．５〜７当量用いることができる。好ましくは０．８〜６当量、より好ましくは１〜５当量、さらに好ましくは１．３〜４当量であり、さらにより好ましくは１．５〜３当量である。
【００１６】
本願発明製剤には、１）酸性セフェム系抗生物質または２）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を形成したものまたは付加したものと前記塩基性化合物に加えてＮａＨＣＯ３またはＮａ２ＣＯ３を配合することもできる。この場合、ＮａＨＣＯ３またはＮａ２ＣＯ３の配合量は抗生物質１当量に対し、０．１〜２当量使用することが好ましく、より好ましくは０．３〜１．７当量であり、さらに好ましくは０．５〜１．０当量である。前記塩基性化合物との共存下において二酸化炭素が発生しないかほとんど発生しない量が好ましい。
【００１７】
１）酸性セフェム系抗生物質または２）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平均粒子径（体積基準粒度分布）は約２００μｍ以下が好ましい。より好ましくは１３０μｍ以下である。
前記塩基性化合物の平均粒子径（体積基準粒度分布）は通常約２０μｍ〜２００μｍであり、約２０μｍ〜１００μｍが好ましい。より好ましくは約３０μｍ〜８０μｍであり、さらに好ましくは約３０μｍ〜６０μｍである。
前記塩基性化合物はその化合物のＥＲＨ（Ｅｑｕｉｌｉｂｒｉｕｍ ｒｅｌａｔｉｖｅ ｈｕｍｉｄｉｔｙ（平衡相対湿度））以下の低湿環境下で粉砕されることが好ましい。より好ましくは３０％ＲＨ以下の環境が好ましい。
これらの化合物の粉砕には一般に用いられている粉砕機を使用することができ、特に限定されないが、パワーミルやジェットミルを使用することができる。
【００１８】
１）酸性セフェム系抗生物質または２）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と前記塩基性化合物を用時溶解したときの水溶液のｐＨは好ましくは３．５〜９．５であり、より好ましくは４．５〜９であり、さらに好ましくは５．５〜８．５であり、さらにより好ましくは６〜８である。
【００１９】
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。
【００２０】
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。
【００２１】
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、投与ルート、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。
【００２２】
【実施例】
以下に実施例および試験例を用いて、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平均粒子径の測定は、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、平均粒子径とは、この方法で測定した数値を意味する。
・平均粒子径の測定方法
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平均粒子径（ＶＭＤ）を読み取った。
【００２３】
実施例１
平均粒子径が約１２０μｍの塩酸セフォチアム１０ｋｇ力価に対して平均粒子径が約６０μｍのＬ−アルギニン７，１２７ｇを添加し、クロスミキサーにて４０分間よく混合した。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の一室に生理食塩液１００ｍLを充填し、他の一室に前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。
【００２４】
実施例２
平均粒子径が約１２０μｍの塩酸セフォチアム１０ｋｇ力価に対して平均粒子径が約６０μｍのＬ−アルギニン７，１２７ｇを添加し、クロスミキサーにて４０分間よく混合した。内容積３５ｍＬのガラスバイアルに前記混合末の塩酸セフォチアム１ｇ力価相当分を充填しバイアル製品とした。
【００２５】
実施例３
Ｌ−アルギニン７１２．７ｍｇを１００ｍＬの生理食塩液で溶解し、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の一室に充填し、一方、平均粒子径が約１２０μｍの塩酸セフォチアム１ｇ力価相当分をもう一室に充填しバッグ製品とした。
【００２６】
実施例４
Ｌ−アルギニン７１２．７ｍｇおよび平均粒子径が約１２０μｍの塩酸セフォチアム１ｇ力価相当分を１００ｍＬの生理食塩液で溶解し、ソフトバッグに充填した後−２０℃で凍結し、バッグ製品とした。
【００２７】
実施例５
平均粒子径が約１２０μｍの塩酸セフォチアム１ｋｇ力価に対して、平均粒子径が６０μｍのリン酸３ナトリウム１．４４７ｋｇを配合し、ロッキングミキサーにて４０分間混合した。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の一室に生理食塩液１００ｍＬを充填し、他の一室に前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。
【００２８】
実施例６
平均粒子径が約１２０μｍの塩酸セフォチアム１ｋｇ力価に対して、平均粒子径が６０μｍのリン酸３ナトリウム７２３ｇを配合し、ロッキングミキサーにて４０分間混合した。内容量３５ｍＬのガラスバイアルに前記混合末の塩酸セフォチアム１ｇ力価相当分を充填し製品とした。
【００２９】
試験例１
実施例３のバッグ製剤においてＬ−アルギニンを含む溶解液が充填された部屋と塩酸セフォチアムが充填された部屋の間の隔壁を開通し、塩酸セフォチアムを溶液が均一になるように溶解したところ、問題となる二酸化炭素等のガスの発生はまったくなかった。また、実施例６のバッグ製剤でも、同様の結果が得られた。
【００３０】
【発明の効果】
以前記載したごとく、本発明によれば、安全性、安定性、溶解性すべてを満足した二酸化炭素を発生しないかほとんど発生しない注射用抗生物質製剤を得ることができ臨床上非常に有用である。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to injectable compositions of compounds useful as antibiotics. Specifically, the present invention relates to an injectable composition comprising 1) a salt or an adduct of an organic or inorganic acid of an antibiotic and 2) a predetermined basic compound.
[0002]
[Prior art]
Cephem antibiotics sometimes use salts or adducts of acidic substances, which have advantages in stability and production, as the drug substance. For example, the following formula used clinically usefully,
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The following formula,
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The following formula,
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[0003]
The following formula effective for MRSA (methicillin resistant S. aureus: methicillin-resistant Staphylococcus aureus), which has recently become a clinical problem:
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[0004]
Antibiotics that form salts or adducts of these organic or inorganic acids are difficult to administer as acidic salts or adducts due to problems such as irritation during administration. In some cases, the product has been commercialized so as to adjust the sum or pH. For example, JP-A-53-29936 and JP-A-1-250322 disclose formulations containing carbonate. In the case of antibiotics that are hardly soluble in water, an acidic salt or an adduct may be used in order to enhance the solubility. The aim is to promote the dissolution of the main drug by the stirring effect of carbon.
[0005]
[Patent Document 1]
JP-A-53-29936
[Patent Document 2]
JP-A-1-250322
[0006]
[Problems to be solved by the invention]
However, in this case, there are generally the following problems.
1) Carbon dioxide is generated by neutralization during use. When a glass vial is used like an injection, measures such as reducing the pressure in advance are required to prevent the internal pressure from increasing.
2) It is not possible to dispel the possibility that the carbon dioxide gas generated during neutralization or the like dissolves in the chemical solution and the carbon dioxide dissolved during administration gradually gasifies.
Therefore, development of pharmaceutical preparations that generate little or no carbon dioxide has been desired.
[0007]
The present inventors have conducted intensive studies to solve these problems, and surprisingly, when a basic amino acid is used, even when a glass vial is directly used as a container, measures such as reducing the pressure inside the vial in advance are used. Is unnecessary and the above problem can be solved.The solubility problem of the main drug can also be solved by balancing the particle size of each component and increasing the degree of mixing. The inventors have found that the above-mentioned problems can be almost solved by reducing the amount of the carbonate incorporated by coexistence, and the like, and completed the present invention based on these.
[0008]
[Means for Solving the Problems]
That is, the present invention
(1) an injection which contains an acidic cephem antibiotic and a basic compound and does not generate carbon dioxide during neutralization;
(2) The acidic cephem antibiotic is cefotiam, cefmenoxime, cefozopran or the formula
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(3) The acidic cephem antibiotic is cefotiam, cefmenoxime, cefozopran or the formula
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(4) The above (1), wherein the basic compound is one or more basic compounds selected from the group consisting of basic amino acids, trisodium phosphate, dipotassium phosphate, sodium hydroxide, and meglumine. Injections,
(5) The injection according to the above (1), wherein the basic compound is arginine;
(6) The injection according to the above (1), wherein the amount of the basic substance is 0.1 parts by weight or more based on 1 part by weight of the acidic cephem antibiotic;
(7) The injection according to the above (1), wherein the amount of the basic substance is 0.2 parts by weight or more based on 1 part by weight of the acidic cephem antibiotic.
(8) The injection according to the above (1), which contains 0.5 to 7 equivalents of a basic compound with respect to the acidic cephem antibiotic.
(9) The injection according to the above (1), wherein the pH after neutralization is 3.5 to 9.5.
(10) The injection according to the above (1), wherein the acidic cephem antibiotic is powder.
(11) The injection according to the above (1), wherein the acidic cephem antibiotic and the basic substance are each a powder, and they are mixed.
(12) The injection according to the above (10) or (11), wherein the acidic cephem antibiotic powder has an average particle size of about 200 μm or less,
(13) The injection according to the above (11), wherein the basic substance powder has an average particle system of about 20 μm to about 200 μm.
(14) The injection according to the above (11), wherein the average particle diameter of the powder of the acidic cephem antibiotic is about 200 μm or less, and the average particle diameter of the powder of the basic substance is about 20 μm to about 200 μm.
(15) The injection according to the above (11), wherein the powder of the basic compound is a powder obtained by pulverizing the powder in a low-humidity environment of its ERH or lower.
(16) The injection according to the above (1), which is a vial preparation or a kit preparation,
(17) (i) a room in which a mixed powder of an acidic cephem antibiotic and a basic substance is enclosed, and (ii) a room in which a physiological saline or glucose solution for injection is enclosed. The injection according to the above (12), wherein the two rooms are kit preparations opened at the time of use,
(18) The injection according to the above (16), wherein the amount of the basic substance is at least 0.1 part by weight relative to 1 part by weight of the acidic cephem antibiotic,
(19) The injection solution according to the above (1), wherein the acidic cephem antibiotic and the basic substance are dissolved in a physiological saline solution or a glucose solution.
(20) The injection solution according to (19), which is stored frozen and thawed at the time of use,
(21) The injection solution according to the above (20), which is stored at a temperature of about -80 ° C to about 0 ° C,
(22) (i) an acidic cephem antibiotic, (ii) one or more basic compounds selected from the group consisting of basic amino acids, trisodium phosphate, dipotassium phosphate, sodium hydroxide, and meglumine; And (iii) NaHCO 3 Or Na 2 CO 3 Which contains almost no carbon dioxide during neutralization,
(23) A method for neutralizing an acidic cephem antibiotic with a basic compound, comprising one or two selected from the group consisting of a basic amino acid, trisodium phosphate, dipotassium phosphate, sodium hydroxide, and meglumine. The present invention relates to a method characterized by using the above basic compound.
[0009]
Further, the present invention provides
(1 ′) containing an acidic cephem antibiotic and one or more basic compounds selected from the group consisting of basic amino acids, trisodium phosphate, dipotassium phosphate, sodium hydroxide, and meglumine Pharmaceutical preparations,
(2 ') 1) Cefotiam, cefmenoxime, cefozopran and formula
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(3 ′) The injection according to (2 ′), wherein the one or more compounds selected in 1) and the basic compound are packaged together in a powder state.
(4 ′) the agent according to (1 ′) or (2 ′), which does not generate carbon dioxide upon dissolution at the time of use;
(5 ′) When the compounding amount of the basic compound is cefotiam, cefmenoxime, cefozopran and the formula
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(6 ′) The injection according to (5 ′), wherein the compounding amount of the basic compound is 0.2 parts by weight or more,
(7 ') Cefotiam, cefmenoxime, cefozopran and formula
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(8 ′) The injection according to (3 ′), wherein the basic compound has an average particle size of about 20 μm to 200 μm.
(9 ') Cefotiam, cefmenoxime, cefozopran and formula
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(10 ′) The injection according to the above (2 ′), wherein the inorganic acid salt is a hydrochloride,
(11 ′) The injection according to the above (2 ′), wherein the basic compound is arginine,
(12 ′) 1) Cefotium, cefmenoxime, cefozopran and formula prepared so that the pH of the aqueous solution when dissolved before use is 3.5 to 9.5.
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(13 ′) the agent according to the above (2 ′) or (12 ′), which is a vial preparation or a kit preparation;
(14 ′) When preparing an injection at the time of use, cefotiam, cefmenoxime, cefozopran and formula
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(15 ') 1) Cefotiam, cefmenoxime, cefozopran and formula
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(16 ') Cefotiam, cefmenoxime, cefozopran and formula
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(17 ′) When the compounding amount of the basic compound is cefotiam, cefmenoxime, cefozopran and the formula
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(18 ') 1) Cefotiam, cefmenoxime, cefozopran and formula
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(19 ') 1) Cefotiam, cefmenoxime, cefozopran and formula
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(20 ′) The injection according to (19 ′), which is stored frozen and thawed before use,
(21 ′) The injection according to the above (19 ′), which is maintained at about −80 ° C. to about 0 ° C.
(22 ′) The injection according to (3 ′), wherein the basic compound is pulverized and compounded in a low humidity environment of ERH (Equilibrium relative humidity) or less of the compound, and
(23 ') A pharmaceutical preparation containing an acidic cephem antibiotic and a basic compound, which does not generate carbon dioxide when dissolved at the time of use.
[0010]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the contents of the present invention will be described in detail.
Acid cephem antibiotics include cefotiam, cefmenoxime, cefozopran and
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The organic acid or inorganic acid is preferably pharmaceutically acceptable and not particularly limited. Examples of the organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, and citric acid. Succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid and the like; as inorganic acids, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be used . Preferred are hydrochloric acid, acetic acid, p-toluenesulfonic acid and the like.
It is a salt or an adduct of an acid, and may form a salt with an acid, or the acid may be a simple adduct.
[0011]
Examples of the basic compound 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. Among them, arginine is preferred. Both the D-form and the L-form can be used, but the 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 preferred.
The powder state refers to a state that has been broken into fine particles, and may be crystalline or amorphous.
The injectable preparation for use at the time of use is not particularly limited, but is preferably a kit preparation such as a vial preparation or an infusion bag preparation.
[0012]
In the present invention, the antibiotic as the main drug and the basic compound may be mixed as powders and packaged separately from the dissolution solution, or the solution containing the basic compound and the antibiotic as the main drug may be mixed. May be separately packaged, and furthermore, the antibiotic as the main drug, the basic compound and the solution may be separately packaged and provided, and the three may be mixed and used at the time of use, and are not particularly limited. . It is preferred that at least the antibiotic as the principal drug be provided in powder form.
When provided as a preparation for dissolution at the time of use, an antibiotic and the basic compound are sealed in one chamber of a two-piece molded bag, and a physiological saline solution or a glucose solution is used as a dissolution solution in the other chamber. It is preferable to form a preparation which can be easily opened at the time of use, and which can be mixed and dissolved at the time of use. Alternatively, the basic compound may be dissolved in a physiological saline solution or a glucose solution in advance. Further, the bag may be composed of three chambers, each of which is filled with an antibiotic, the basic compound, or a solution, and may be formulated in such a form that the partition of each room can be easily opened at the time of use. it can.
Further, the injection solution in which the antibiotic and the basic compound are dissolved may be frozen or frozen and stored, and then thawed at the time of use to prepare a preparation for use. The storage temperature in this case is preferably about -80 ° C to about 0 ° C, and is preferably frozen.
[0013]
As the dissolution solution, a physiological saline solution or a glucose solution is preferable.
The amount of the dissolving solution used for the main drug is not particularly limited. For example, in the case of an intravenous drip formulation, 100 mL can be used for 1 g (titer) of the main drug.
[0014]
The amount of the basic compound varies depending on the type of acid forming or adding a salt and the equivalent of the acid, but is usually 1) an acidic cephem antibiotic or 2) cefotiam, cefmenoxime, cefozopran and the formula (I). 0.1 part by weight or more is used per 1 part by weight of a compound formed or added with a salt of an organic acid or an inorganic acid of one or more compounds selected from the group consisting of the compounds represented by Preferably it is 0.1 to 1.5 parts by weight. More preferably, the amount is 0.2 parts by weight to 1 part by weight.
[0015]
The compounding equivalent of the basic compound varies depending on the kind of the acid forming or adding the salt and the equivalent of the acid, but is usually 1) an acidic cephem antibiotic or 2) cefotiam, cefmenoxime, cefozopran and the formula (I). Can be used in an amount of 0.5 to 7 equivalents to 1 equivalent of an organic acid or an inorganic acid salt formed or added of one or more compounds selected from the group consisting of the compounds represented by It is preferably 0.8 to 6 equivalents, more preferably 1 to 5 equivalents, still more preferably 1.3 to 4 equivalents, and still more preferably 1.5 to 3 equivalents.
[0016]
The preparation of the present invention includes 1) an acidic cephem antibiotic or 2) an organic acid or an inorganic acid of one or more compounds selected from the group consisting of cefotiam, cefmenoxime, cefozopran and the compound represented by the formula (I). NaHCO in addition to the salt formed or added and the basic compound 3 Or Na 2 CO 3 Can also be blended. In this case, NaHCO 3 Or Na 2 CO 3 Is preferably used in an amount of 0.1 to 2 equivalents, more preferably 0.3 to 1.7 equivalents, and still more preferably 0.5 to 1.0 equivalents to 1 equivalent of the antibiotic. . An amount in which carbon dioxide is not generated or hardly generated in the presence of the basic compound is preferable.
[0017]
1) an acidic cephem antibiotic or 2) a salt or adduct of an organic or inorganic acid of one or more compounds selected from the group consisting of cefotiam, cefmenoxime, cefozopran and the compound represented by the formula (I). The average particle size (volume-based particle size distribution) is preferably about 200 μm or less. It is more preferably 130 μm or less.
The average particle size (volume-based particle size distribution) of the basic compound is usually about 20 μm to 200 μm, preferably about 20 μm to 100 μm. It is more preferably about 30 μm to 80 μm, and still more preferably about 30 μm to 60 μm.
The basic compound is preferably pulverized in a low humidity environment of ERH (Equilibrium relative humidity) or less of the compound. More preferably, an environment of 30% RH or less is preferable.
A commonly used pulverizer can be used for pulverizing these compounds, and is not particularly limited, but a power mill or a jet mill can be used.
[0018]
1) an acidic cephem antibiotic or 2) a salt or adduct of an organic acid or an inorganic acid of one or more compounds selected from the group consisting of cefotiam, cefmenoxime, cefozopran and the compound represented by the formula (I). The pH of the aqueous solution when the basic compound is dissolved at the time of use is preferably 3.5 to 9.5, more preferably 4.5 to 9, and still more preferably 5.5 to 8.5. And still more preferably 6 to 8.
[0019]
Cefotiam, cefmenoxime, cefozopran and the compound represented by the general formula (I) used in the present invention can be produced by a known method or a general organic synthesis method, and for example, the methods disclosed in the following publications Can be manufactured.
Cefotiam can be produced, for example, by the method disclosed in JP-A-53-29913 and a known general organic synthesis method.
Cefmenoxime can be produced, for example, by 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, by the method disclosed in JP-A-11-255772 and a known general organic synthesis method.
These compounds can be converted into salts or adducts of organic acids or inorganic acids by known methods or methods described in the above-mentioned publications.
[0020]
These antibiotics or their salts or adducts of organic or inorganic acids may further be solvent adducts (solvates) or non-solvent adducts (non-solvates), especially hydrates or non-hydrates. You may. When these compounds exist as configurational isomers (configuration isomers), diastereomers, conformers, and the like, they can be isolated by known separation and purification means, if desired. When these compounds are in a racemic form, they can be separated into S-form and R-form by ordinary optical resolution means. When stereoisomers exist in these compounds, the isomers alone and in the case of a mixture thereof are also included in the present invention. 3 H, 14 C, 35 S) or the like.
[0021]
In the present invention, the dose of the salt or adduct of an organic acid or inorganic acid of one or more compounds selected from the group consisting of cefotiam, cefmenoxime, cefozopran and the compound represented by the general formula (I) is determined by the administration route. Depending on the condition and the like, for example, a titer of 0.1 to 4 g per day can be administered once or in 2 to 4 divided doses.
[0022]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Examples and Test 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 (equal to or less than 30% RH) of ERH (equilibrium relative humidity) of L-arginine. A power mill (manufactured by Showa Chemical Industry Co., Ltd.) was used as the coarse crusher, and a jet mill (manufactured by Nippon Pneumatic) was used for fine crushing.
The average particle size of the pulverized powder such as L-arginine was measured using a laser diffraction particle size distribution analyzer (manufactured by HEROS & RODOS SYMATETEC) by the following method. In the present specification, the average particle diameter means a numerical value measured by this method.
・ Measurement method of average particle size
Each of the pulverized L-arginine and the like was dispersed in an appropriate dispersion medium (eg, in the case of L-arginine, a saturated ethanol solution of L-arginine), and the particle size distribution was measured by a wet measurement method (CUVETTE dispersion). The average particle size (VMD) was read from the obtained volume-based particle size distribution.
[0023]
Example 1
To 127 kg of cefotiam hydrochloride having an average particle diameter of about 120 μm, 7,127 g of L-arginine having an average particle diameter of about 60 μm was added and mixed well with a cross mixer for 40 minutes. One chamber of a soft bag having two chambers separated by a partition which can be opened by a simple operation is filled with 100 mL of physiological saline, and the other chamber is filled with the equivalent of 1 g of cefotiam hydrochloride of the mixed powder. It was a bag product.
[0024]
Example 2
To 127 kg of cefotiam hydrochloride having an average particle diameter of about 120 μm, 7,127 g of L-arginine having an average particle diameter of about 60 μm was added and mixed well with a cross mixer for 40 minutes. A glass vial having an inner volume of 35 mL was filled with the equivalent of 1 g of cefotiam hydrochloride of the mixed powder to obtain a vial product.
[0025]
Example 3
712.7 mg of L-arginine is dissolved in 100 mL of physiological saline, and filled in a soft bag having two chambers separated by a septum that can be opened by a simple operation, while the average particle diameter is about 120 μm. Was filled into another chamber to obtain a bag product.
[0026]
Example 4
712.7 mg of L-arginine and 1 g of cefotiam hydrochloride having an average particle size of about 120 μm were dissolved in 100 mL of physiological saline, filled in a soft bag, and frozen at −20 ° C. to obtain a bag product.
[0027]
Example 5
1.447 kg of trisodium phosphate having an average particle diameter of 60 μm was mixed with 1 kg of cefotiam hydrochloride having an average particle diameter of about 120 μm, and mixed with a rocking mixer for 40 minutes. One chamber of a soft bag having two chambers separated by a partition which can be opened by a simple operation is filled with 100 mL of physiological saline, and the other chamber is charged with a titer equivalent to 1 g of cefotiam hydrochloride of the mixed powder. Bag products.
[0028]
Example 6
To 1 kg titer of cefotiam hydrochloride having an average particle diameter of about 120 μm, 723 g of trisodium phosphate having an average particle diameter of 60 μm was mixed and mixed with a rocking mixer for 40 minutes. A glass vial having an inner volume of 35 mL was filled with the equivalent of 1 g of cefotiam hydrochloride in the mixed powder to obtain a product.
[0029]
Test example 1
In the bag preparation of Example 3, the partition wall between the room filled with the dissolving solution containing L-arginine and the room filled with cefotiam hydrochloride was opened to dissolve cefotiam hydrochloride so that the solution became uniform. No gas such as carbon dioxide was generated. Similar results were obtained with the bag preparation of Example 6.
[0030]
【The invention's effect】
As described above, according to the present invention, it is possible to obtain an injectable antibiotic preparation which does not generate or rarely generates carbon dioxide, which satisfies all of safety, stability and solubility, and is very useful clinically.
Claims (23)
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| JP2003031592A Expired - Lifetime JP3865698B2 (en) | 2002-02-08 | 2003-02-07 | Pharmaceutical composition |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004096279A1 (en) * | 2003-04-28 | 2004-11-11 | Takeda Pharmaceutical Company Limited | Composition for injection |
| JP2007238491A (en) * | 2006-03-08 | 2007-09-20 | Nipro Corp | Pharmaceutical formulation |
| JP2009062382A (en) * | 2001-10-03 | 2009-03-26 | Nipro Corp | Multi-chamber formulation |
| WO2009138847A3 (en) * | 2008-05-14 | 2010-04-22 | Orchid Chemicals And Pharmaceuticals Ltd. | An improved process for the preparation of cefozopran |
| CN105769770A (en) * | 2016-05-12 | 2016-07-20 | 浙江永宁药业股份有限公司 | Cefotiam hydrochloride powder injection preparation for injection |
| CN107519172A (en) * | 2017-09-11 | 2017-12-29 | 浙江永宁药业股份有限公司 | A kind of cefotiam chloride organic base combination thing and preparation method thereof |
-
2003
- 2003-02-07 JP JP2003031592A patent/JP3865698B2/en not_active Expired - Lifetime
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009062382A (en) * | 2001-10-03 | 2009-03-26 | Nipro Corp | Multi-chamber formulation |
| WO2004096279A1 (en) * | 2003-04-28 | 2004-11-11 | Takeda Pharmaceutical Company Limited | Composition for injection |
| JP2007238491A (en) * | 2006-03-08 | 2007-09-20 | Nipro Corp | Pharmaceutical formulation |
| WO2009138847A3 (en) * | 2008-05-14 | 2010-04-22 | Orchid Chemicals And Pharmaceuticals Ltd. | An improved process for the preparation of cefozopran |
| CN105769770A (en) * | 2016-05-12 | 2016-07-20 | 浙江永宁药业股份有限公司 | Cefotiam hydrochloride powder injection preparation for injection |
| CN107519172A (en) * | 2017-09-11 | 2017-12-29 | 浙江永宁药业股份有限公司 | A kind of cefotiam chloride organic base combination thing and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3865698B2 (en) | 2007-01-10 |
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