CA1068603A - Preparations comprising phosphonomycin and another antibiotic - Google Patents
Preparations comprising phosphonomycin and another antibioticInfo
- Publication number
- CA1068603A CA1068603A CA252,625A CA252625A CA1068603A CA 1068603 A CA1068603 A CA 1068603A CA 252625 A CA252625 A CA 252625A CA 1068603 A CA1068603 A CA 1068603A
- Authority
- CA
- Canada
- Prior art keywords
- composition according
- phosphonomycin
- cephalosporin
- penicillin
- constituent
- 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
Links
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 title claims abstract description 26
- 230000003115 biocidal effect Effects 0.000 title description 3
- 238000002360 preparation method Methods 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims abstract description 27
- 239000000470 constituent Substances 0.000 claims abstract description 22
- 229930186147 Cephalosporin Natural products 0.000 claims abstract description 14
- 229940124587 cephalosporin Drugs 0.000 claims abstract description 14
- 150000001780 cephalosporins Chemical class 0.000 claims abstract description 14
- 229930182555 Penicillin Natural products 0.000 claims abstract description 11
- DYDCUQKUCUHJBH-UHFFFAOYSA-N D-Cycloserine Natural products NC1CONC1=O DYDCUQKUCUHJBH-UHFFFAOYSA-N 0.000 claims abstract description 6
- DYDCUQKUCUHJBH-UWTATZPHSA-N D-Cycloserine Chemical compound N[C@@H]1CONC1=O DYDCUQKUCUHJBH-UWTATZPHSA-N 0.000 claims abstract description 6
- 229960003077 cycloserine Drugs 0.000 claims abstract description 6
- 150000002960 penicillins Chemical class 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 108010001478 Bacitracin Proteins 0.000 claims abstract description 4
- 229960003071 bacitracin Drugs 0.000 claims abstract description 4
- 229930184125 bacitracin Natural products 0.000 claims abstract description 4
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 claims abstract description 4
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 claims abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 14
- 229960001139 cefazolin Drugs 0.000 claims description 7
- 229940049954 penicillin Drugs 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 5
- 229930195708 Penicillin V Natural products 0.000 claims description 4
- 229940106164 cephalexin Drugs 0.000 claims description 4
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 229940056367 penicillin v Drugs 0.000 claims description 4
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 claims description 4
- WZOZEZRFJCJXNZ-ZBFHGGJFSA-N cefoxitin Chemical compound N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)CC1=CC=CS1 WZOZEZRFJCJXNZ-ZBFHGGJFSA-N 0.000 claims description 3
- 229960002682 cefoxitin Drugs 0.000 claims description 3
- -1 cephadrin Chemical compound 0.000 claims description 3
- 229940056360 penicillin g Drugs 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- UQLLWWBDSUHNEB-CZUORRHYSA-N Cefaprin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CSC1=CC=NC=C1 UQLLWWBDSUHNEB-CZUORRHYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 claims description 2
- 239000001828 Gelatine Substances 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims 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 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 229960003022 amoxicillin Drugs 0.000 claims description 2
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 claims description 2
- 229960000723 ampicillin Drugs 0.000 claims description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 2
- ODFHGIPNGIAMDK-NJBDSQKTSA-N azidocillin Chemical compound C1([C@@H](N=[N+]=[N-])C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 ODFHGIPNGIAMDK-NJBDSQKTSA-N 0.000 claims description 2
- 229960004328 azidocillin Drugs 0.000 claims description 2
- 239000008280 blood Substances 0.000 claims description 2
- 210000004369 blood Anatomy 0.000 claims description 2
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 claims description 2
- 229960003669 carbenicillin Drugs 0.000 claims description 2
- JIRBAUWICKGBFE-MNRDOXJOSA-N carindacillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(=O)OC=1C=C2CCCC2=CC=1)C1=CC=CC=C1 JIRBAUWICKGBFE-MNRDOXJOSA-N 0.000 claims description 2
- 229960000717 carindacillin Drugs 0.000 claims description 2
- 229960003972 cefacetrile Drugs 0.000 claims description 2
- RRYMAQUWDLIUPV-BXKDBHETSA-N cefacetrile Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC#N)[C@@H]12 RRYMAQUWDLIUPV-BXKDBHETSA-N 0.000 claims description 2
- 229960000603 cefalotin Drugs 0.000 claims description 2
- XIURVHNZVLADCM-IUODEOHRSA-N cefalotin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CC1=CC=CS1 XIURVHNZVLADCM-IUODEOHRSA-N 0.000 claims description 2
- 229960004350 cefapirin Drugs 0.000 claims description 2
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 claims description 2
- 229960003326 cloxacillin Drugs 0.000 claims description 2
- HGBLNBBNRORJKI-WCABBAIRSA-N cyclacillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C1(N)CCCCC1 HGBLNBBNRORJKI-WCABBAIRSA-N 0.000 claims description 2
- 229960004244 cyclacillin Drugs 0.000 claims description 2
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 claims description 2
- 229960001585 dicloxacillin Drugs 0.000 claims description 2
- 229960004273 floxacillin Drugs 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 229960003884 hetacillin Drugs 0.000 claims description 2
- DXVUYOAEDJXBPY-NFFDBFGFSA-N hetacillin Chemical compound C1([C@@H]2C(=O)N(C(N2)(C)C)[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 DXVUYOAEDJXBPY-NFFDBFGFSA-N 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 229960003085 meticillin Drugs 0.000 claims description 2
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 claims description 2
- 229960001019 oxacillin Drugs 0.000 claims description 2
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 claims description 2
- NONJJLVGHLVQQM-JHXYUMNGSA-N phenethicillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(C)OC1=CC=CC=C1 NONJJLVGHLVQQM-JHXYUMNGSA-N 0.000 claims description 2
- 229960004894 pheneticillin Drugs 0.000 claims description 2
- ZEMIJUDPLILVNQ-ZXFNITATSA-N pivampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OCOC(=O)C(C)(C)C)=CC=CC=C1 ZEMIJUDPLILVNQ-ZXFNITATSA-N 0.000 claims description 2
- 229960003342 pivampicillin Drugs 0.000 claims description 2
- 229960003672 propicillin Drugs 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 235000012222 talc Nutrition 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 claims description 2
- 229960004659 ticarcillin Drugs 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims 2
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 claims 2
- 150000003863 ammonium salts Chemical class 0.000 claims 1
- CZTQZXZIADLWOZ-CRAIPNDOSA-N cefaloridine Chemical compound O=C([C@@H](NC(=O)CC=1SC=CC=1)[C@H]1SC2)N1C(C(=O)[O-])=C2C[N+]1=CC=CC=C1 CZTQZXZIADLWOZ-CRAIPNDOSA-N 0.000 claims 1
- 159000000011 group IA salts Chemical group 0.000 claims 1
- HOCWPKXKMNXINF-XQERAMJGSA-N propicillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(CC)OC1=CC=CC=C1 HOCWPKXKMNXINF-XQERAMJGSA-N 0.000 claims 1
- 239000011343 solid material Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 description 8
- 239000012895 dilution Substances 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 241000588769 Proteus <enterobacteria> Species 0.000 description 5
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 230000000973 chemotherapeutic effect Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 229960002588 cefradine Drugs 0.000 description 3
- RDLPVSKMFDYCOR-UEKVPHQBSA-N cephradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 241000219470 Mirabilis Species 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000305071 Enterobacterales Species 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
ABSTRACT
Disclosed is a pharmaceutical composition comprising phosphonomycin and at least one further constituent selected from penicillins, cephalosporins, cycloserine, bacitracin and vanomycin, wherein the ratio of the amount of phosphonomycin to the total amount of the at least one further constituent is in e range 1:1 to 10:1 by weight. Preferably the composition includes a pharmacologically compatible carrier and the constituent or constituents may be present in the form of physiologically miscible salts.
Disclosed is a pharmaceutical composition comprising phosphonomycin and at least one further constituent selected from penicillins, cephalosporins, cycloserine, bacitracin and vanomycin, wherein the ratio of the amount of phosphonomycin to the total amount of the at least one further constituent is in e range 1:1 to 10:1 by weight. Preferably the composition includes a pharmacologically compatible carrier and the constituent or constituents may be present in the form of physiologically miscible salts.
Description
~ o~
PREPARATIONS COMPRISING PHOSPHONOMYCIN AND ANOTHER ANTIBIOTIC
The present invention relates to a pharmaceutical preparation with antibiotic action.
Phosphonomycin alone shows only a moderate chemotherapeutic action. The present invention enables phosphonomycin to be made usable for fully effective chemotherapy.
It has now been surprisingly discovered that the dosage of phosphonomycin may be reduced and, either with a reduced dosage or with the full dosage, thé activity spectrum of phosphonomycin may be extended to gram negative problem germs such as proteus, enterobacterial and pseudomonas germs, if the phosphonomycin is combined with a penicillin and/or a cephalosporin and/or cycloserine and/or bacitracin and/or . . .. .
VanOmyCln, The invention provides a pharmaceutical composition comprising phosphonomycin and at least one further constituent . .
selected from penicillins, cephalosporins, cycloserine, bacitracin and vanomycin, wherein the ratio of the amount of phosphonomycin to the total amount of the at least one further constituent is in the range 1:1 to 10:1 by weight.
Preferably the composition includes a pharmacologlcally compatible carrier and any of the further constituents may be present in the form of physiologically miscible salts.
Preferably, when the composition contains penicillin, the ratio of the amount of phosphonomycin to the amount of penicillin is in the ratio 1:1 to 5:1 by weight.
,' ' ~ " , ' . ' .
. , , ~
06136~3 Preferably, when the composi-tlon contains cephalosporin, the ratio of the amount of phosphonomycin to the amount of the cephalosporin is in the range 1:1 to 8:1 by weight.
The fo:llowing penicillins may be used in the composltion o~ the invention: penicillin G, penicillin V, - propicillin, phenethicillin, azidocillin, dicloxacillin, flucloxacillin, oxacillin, cloxacillin, methicillin, carbenicillin, indanyl-carbenicillin, ticarcillin, ampicillin, amoxicillin, pivampicillin, hetacillin and ciclacillin.
; The following cephalosporins may be used in the composition of the invention: cephazolin, cephradin, ~ :
; cephoxitin, cephalorldin, cephalotin, cephacetril, cephalexin, ~ ~ -cephamandol and cephapirin. ; `
The discovery on which the invention is based is very surprising, in that a clear synergistic effect appears with all `~
combinations of phosphonomycin with the further constituents i.e. the activity of the compositlon is greater than the sum of the activities of the individual constituents. It is known that ;
in a great many cases antibiotics with known activity cannot be combined together without careful consideration and not always with advantage, as no prediction can be made beforehand -regarding the combined activity of two or more antibiotics. -There is often absolute `antagonism when a further chemotherapeutical substance supervenes, so that the combination may be absolutely less active than either of the ~ ~ -; individual components. The above specified constituents of the composition of the invention are antibiotics which inhibit cell wall synthesis. It is however not clear whether and to what ` 30 extent this action mechanism influences the properties of the composition of the invention. -~
The synergistic behaviour of the constituents of compositions according to the invention in relation to gram-.
: ~ - 2 -:,. ;;-i 106~36~3 positive and gram-negative microorganisms is clear from -the activity diagrams shown in Figs. 1 - 9 of the accompanying drawings (MIC = minlmum inhibitory concentration).
In order to prepare the diagrams of Figs. 1 - 9, combination tests were carried out with reference to S. Loewe, Arzneimittel-Forschung 3, 285 (1953) and H.F. ZipE, Arzneimittel-Forschung 3, 398 (1953). For this, dilution series were made up which contained the chemotherapeutic substance A or the chemotherapeutic substance B. These two dilution series were arranged in the form of a right angle and then made up to a complete square, so that each concentration of one substance was ~
present with each concentration of the other in a tube. The -; -minimum inhibitory concentrations should for both preparations lie in the region of the higher concentrations in the dilution series.
They are both put at 100%, and the remaining dilution stages are expressed as % of the active concentration. The medium used for the series dilution procedure was Standard-I- ;
Bouillon nutrient (Merck) pH 6.5. It was inoculated dropwise -with the corresponding dilu-tion of a 20 hour Bouillon culture.
After 18 hours of incubation, the degree of turbidity was read off with the naked eye. The table shows the minimum inhibitory -concentrations of the individual substances in the combination in comparison with those of the individual components. The values given in the table as "minimum inhibitory concentration in combination" are each marked in the corresponding graph with a circle around the measuring point. The respective minimum ~
inhibitory concentration was read off from each graph at the -point closest to the origin on the line joining the plotted points.
`': , - 3 -~
:;
.. ... : .
. ~
8~;03 T A B L E 1 ~
--:
Germ Type Minimum inhibitory concentration in llg/ml .
Strain No. ( ) of the in of the in individual combination individual combination . .
constituent constituent Phosphonomycin Pencillin G .:
Staphylococcus : :
aureus (12) 7.8 2.6 0.0072 0.0016 :
Proteus mirabilis (279) 3.2. 0.8 2.4 0.4 :
.
Pencillin V
Staphylococcus -aureus (12) 8.0 . 2.0 0.016 0.004 ~ .
Proteus .: -mirabilis (279) 4.0 0.5 16 2.0 Cefazolin Escherichia :
coli (108) 1.0 0.25 1.0 0,5 Proteus .:~::
mirabilis (279): 2.0 0.125 8.0 1.0 `:- :
Cefradin .: : --~
Staphylococcus aureus (12) 16 2.0 . 2.0 0.5 : Proteus ;,mirabilis (279) 2.0 0.5 64 16 Cycloserine Proteus ; mirabl1is (279) 4.0 1.0128 16 ;
`' :
:, ::.-~, .
. .
.. :. , ~ ~68603 The combined action of the antibiotics used according to the invention makes it possible basically to reduce the dosage of the indivldual components relative to the single use of either of the two components. Fundamentally, by using full doses the activity spectrum can be widened, but it is also possible to obtain widening of the activity spectrum using slightly smaller doses. By this means pathogenic agen-ts are therapeutically covered which are not covered by either indivi.dual. component.
Any of the constituents (i.e. phosphonomycin, penicillins, cephalosporins, cycloserine, bactracin and vanomycin) of compositions according to the invention may be used in the form of salts, for example alkaline or ammonium ~; -salts. Compositions according to the invention include all the : : ' usual forms for oral, parenteral and rectal application, for example tablets, capsules, sugar coated pills, syrup solutions, suspensions, drops, suppositories and injection solutions. For this purpose the substance is mixed with solid or liquid carriers and then made up into the required form. Examples of solid carriers are lactose, mannite starch, talcum, methylcellulose, magnesium stearate and gelatine, to which ; colouring and f;lavouring substances may be added as required.
Liquid carriers for injection solutions, preferably aqueous or aqueous/alcoholic solutions isotonic with human blood, must be sterile and pyrogen-free. They are advantageously placed in ampoules.
Compositions according to the invention may for example be used in infections of the respiratory organs, of the gall ducts and of the urinary tracts.
One or other form of application is preferred according to the combination used, e.g. the oral form of ~- application for a combination of penicillin V and cephalexin, and the parenteral form for penicillin G and cephazolin. Both .~_~ _ 5 .. ~ .
. : :
- ~L06~6~3 forms of applicatlon may however be used, such as in the combination with cephradin.
The mixing ratio between phosphonomycin and any of the further constituents may range from 1 : 1 to 10 : 1 by ;
weight.
The daily dose consists of about three individual doses, each of 1 or 2 Galenic units (e.g. capsules or ampoules).
The dosages of the combinations may be deduced from the normal daily doses of the individual components and the mix ratios. The reduced dose is the daily dose reduced to about 25%. This may be inferred for example from the following examples fox oral and parenteral forms of application.
Example 1 Combination of phosphonomycin + penicillin V (oral):
Ratio of phosphonomycin to pencillin V approximately 1:1 to 5 by weight (average ratio approximately 2.5:1 by weight).
Proposed dosage per Galenic unit (e.g. capsule): 325 ~ 130 mg (normal dose) to 160 + 65 mg (reduced dose).
- Daily dose: 3 lndividual doses each of 2 Galenic unlts for -~
normal dosage, 3 lndividual doses each of 1 Galenic unlt for reduced dosage.
Example 2 - -- :
Combination of phosphonomycin + cephazolin (intravenous - I.V.):
Ratio of phosphonomycin to cephazolin 1:1 to 8:1 by weight (average ratio approximately 4:1 by weight).
Proposed dosage per Galenic unit (e.g. ampoule): 2600 + 650 mg (normal dose) to 650 + 160 mg (reduced dose)~
Daily dose: 3 individual doses each of 1 Galenic unit, both for : . : . ~, normal dosage and for reduced dosage.
` 30 ~
.'.: -. .:
' 30 . .
,~
. :. ' . ' ', : ' , ., .', .. ', ' .: : .,: :: .: , .'' ~ .. . . ' :
. : : . . . . . . . . .... .
PREPARATIONS COMPRISING PHOSPHONOMYCIN AND ANOTHER ANTIBIOTIC
The present invention relates to a pharmaceutical preparation with antibiotic action.
Phosphonomycin alone shows only a moderate chemotherapeutic action. The present invention enables phosphonomycin to be made usable for fully effective chemotherapy.
It has now been surprisingly discovered that the dosage of phosphonomycin may be reduced and, either with a reduced dosage or with the full dosage, thé activity spectrum of phosphonomycin may be extended to gram negative problem germs such as proteus, enterobacterial and pseudomonas germs, if the phosphonomycin is combined with a penicillin and/or a cephalosporin and/or cycloserine and/or bacitracin and/or . . .. .
VanOmyCln, The invention provides a pharmaceutical composition comprising phosphonomycin and at least one further constituent . .
selected from penicillins, cephalosporins, cycloserine, bacitracin and vanomycin, wherein the ratio of the amount of phosphonomycin to the total amount of the at least one further constituent is in the range 1:1 to 10:1 by weight.
Preferably the composition includes a pharmacologlcally compatible carrier and any of the further constituents may be present in the form of physiologically miscible salts.
Preferably, when the composition contains penicillin, the ratio of the amount of phosphonomycin to the amount of penicillin is in the ratio 1:1 to 5:1 by weight.
,' ' ~ " , ' . ' .
. , , ~
06136~3 Preferably, when the composi-tlon contains cephalosporin, the ratio of the amount of phosphonomycin to the amount of the cephalosporin is in the range 1:1 to 8:1 by weight.
The fo:llowing penicillins may be used in the composltion o~ the invention: penicillin G, penicillin V, - propicillin, phenethicillin, azidocillin, dicloxacillin, flucloxacillin, oxacillin, cloxacillin, methicillin, carbenicillin, indanyl-carbenicillin, ticarcillin, ampicillin, amoxicillin, pivampicillin, hetacillin and ciclacillin.
; The following cephalosporins may be used in the composition of the invention: cephazolin, cephradin, ~ :
; cephoxitin, cephalorldin, cephalotin, cephacetril, cephalexin, ~ ~ -cephamandol and cephapirin. ; `
The discovery on which the invention is based is very surprising, in that a clear synergistic effect appears with all `~
combinations of phosphonomycin with the further constituents i.e. the activity of the compositlon is greater than the sum of the activities of the individual constituents. It is known that ;
in a great many cases antibiotics with known activity cannot be combined together without careful consideration and not always with advantage, as no prediction can be made beforehand -regarding the combined activity of two or more antibiotics. -There is often absolute `antagonism when a further chemotherapeutical substance supervenes, so that the combination may be absolutely less active than either of the ~ ~ -; individual components. The above specified constituents of the composition of the invention are antibiotics which inhibit cell wall synthesis. It is however not clear whether and to what ` 30 extent this action mechanism influences the properties of the composition of the invention. -~
The synergistic behaviour of the constituents of compositions according to the invention in relation to gram-.
: ~ - 2 -:,. ;;-i 106~36~3 positive and gram-negative microorganisms is clear from -the activity diagrams shown in Figs. 1 - 9 of the accompanying drawings (MIC = minlmum inhibitory concentration).
In order to prepare the diagrams of Figs. 1 - 9, combination tests were carried out with reference to S. Loewe, Arzneimittel-Forschung 3, 285 (1953) and H.F. ZipE, Arzneimittel-Forschung 3, 398 (1953). For this, dilution series were made up which contained the chemotherapeutic substance A or the chemotherapeutic substance B. These two dilution series were arranged in the form of a right angle and then made up to a complete square, so that each concentration of one substance was ~
present with each concentration of the other in a tube. The -; -minimum inhibitory concentrations should for both preparations lie in the region of the higher concentrations in the dilution series.
They are both put at 100%, and the remaining dilution stages are expressed as % of the active concentration. The medium used for the series dilution procedure was Standard-I- ;
Bouillon nutrient (Merck) pH 6.5. It was inoculated dropwise -with the corresponding dilu-tion of a 20 hour Bouillon culture.
After 18 hours of incubation, the degree of turbidity was read off with the naked eye. The table shows the minimum inhibitory -concentrations of the individual substances in the combination in comparison with those of the individual components. The values given in the table as "minimum inhibitory concentration in combination" are each marked in the corresponding graph with a circle around the measuring point. The respective minimum ~
inhibitory concentration was read off from each graph at the -point closest to the origin on the line joining the plotted points.
`': , - 3 -~
:;
.. ... : .
. ~
8~;03 T A B L E 1 ~
--:
Germ Type Minimum inhibitory concentration in llg/ml .
Strain No. ( ) of the in of the in individual combination individual combination . .
constituent constituent Phosphonomycin Pencillin G .:
Staphylococcus : :
aureus (12) 7.8 2.6 0.0072 0.0016 :
Proteus mirabilis (279) 3.2. 0.8 2.4 0.4 :
.
Pencillin V
Staphylococcus -aureus (12) 8.0 . 2.0 0.016 0.004 ~ .
Proteus .: -mirabilis (279) 4.0 0.5 16 2.0 Cefazolin Escherichia :
coli (108) 1.0 0.25 1.0 0,5 Proteus .:~::
mirabilis (279): 2.0 0.125 8.0 1.0 `:- :
Cefradin .: : --~
Staphylococcus aureus (12) 16 2.0 . 2.0 0.5 : Proteus ;,mirabilis (279) 2.0 0.5 64 16 Cycloserine Proteus ; mirabl1is (279) 4.0 1.0128 16 ;
`' :
:, ::.-~, .
. .
.. :. , ~ ~68603 The combined action of the antibiotics used according to the invention makes it possible basically to reduce the dosage of the indivldual components relative to the single use of either of the two components. Fundamentally, by using full doses the activity spectrum can be widened, but it is also possible to obtain widening of the activity spectrum using slightly smaller doses. By this means pathogenic agen-ts are therapeutically covered which are not covered by either indivi.dual. component.
Any of the constituents (i.e. phosphonomycin, penicillins, cephalosporins, cycloserine, bactracin and vanomycin) of compositions according to the invention may be used in the form of salts, for example alkaline or ammonium ~; -salts. Compositions according to the invention include all the : : ' usual forms for oral, parenteral and rectal application, for example tablets, capsules, sugar coated pills, syrup solutions, suspensions, drops, suppositories and injection solutions. For this purpose the substance is mixed with solid or liquid carriers and then made up into the required form. Examples of solid carriers are lactose, mannite starch, talcum, methylcellulose, magnesium stearate and gelatine, to which ; colouring and f;lavouring substances may be added as required.
Liquid carriers for injection solutions, preferably aqueous or aqueous/alcoholic solutions isotonic with human blood, must be sterile and pyrogen-free. They are advantageously placed in ampoules.
Compositions according to the invention may for example be used in infections of the respiratory organs, of the gall ducts and of the urinary tracts.
One or other form of application is preferred according to the combination used, e.g. the oral form of ~- application for a combination of penicillin V and cephalexin, and the parenteral form for penicillin G and cephazolin. Both .~_~ _ 5 .. ~ .
. : :
- ~L06~6~3 forms of applicatlon may however be used, such as in the combination with cephradin.
The mixing ratio between phosphonomycin and any of the further constituents may range from 1 : 1 to 10 : 1 by ;
weight.
The daily dose consists of about three individual doses, each of 1 or 2 Galenic units (e.g. capsules or ampoules).
The dosages of the combinations may be deduced from the normal daily doses of the individual components and the mix ratios. The reduced dose is the daily dose reduced to about 25%. This may be inferred for example from the following examples fox oral and parenteral forms of application.
Example 1 Combination of phosphonomycin + penicillin V (oral):
Ratio of phosphonomycin to pencillin V approximately 1:1 to 5 by weight (average ratio approximately 2.5:1 by weight).
Proposed dosage per Galenic unit (e.g. capsule): 325 ~ 130 mg (normal dose) to 160 + 65 mg (reduced dose).
- Daily dose: 3 lndividual doses each of 2 Galenic unlts for -~
normal dosage, 3 lndividual doses each of 1 Galenic unlt for reduced dosage.
Example 2 - -- :
Combination of phosphonomycin + cephazolin (intravenous - I.V.):
Ratio of phosphonomycin to cephazolin 1:1 to 8:1 by weight (average ratio approximately 4:1 by weight).
Proposed dosage per Galenic unit (e.g. ampoule): 2600 + 650 mg (normal dose) to 650 + 160 mg (reduced dose)~
Daily dose: 3 individual doses each of 1 Galenic unit, both for : . : . ~, normal dosage and for reduced dosage.
` 30 ~
.'.: -. .:
' 30 . .
,~
. :. ' . ' ', : ' , ., .', .. ', ' .: : .,: :: .: , .'' ~ .. . . ' :
. : : . . . . . . . . .... .
Claims (19)
1. A pharmaceutical composition comprising phosphonomycin and at least one further constituent selected from penicillins, cephalosporins, cycloserine, bacitracin and vanomycin, wherein the ratio of the amount of phosphonomycin to the total amount of said at least one further constituent is in the range 1:1 to 10:1 by weight.
2. The composition according to claim 1 wherein said at least one further constituent is present in the form of a physiologically miscible salt.
3. The composition according to claim 2 wherein the salt is an alkaline or ammonium salt.
4. The composition according to claim 1 including a pharmacologically compatible carrier.
5. The composition according to claim 4, wherein the carrier is a solid material selected from lactose, mannite, starch, talcum, methylcellulose, magnesium stearate and gelatine.
6. The composition according to claim 4, wherein the carrier is a liquid.
7. The composition according to claim 6, wherein the liquid is an aqueous solution isotonic with human blood.
8. The pharmaceutical preparation, according to claim 6, wherein the aqueous solution is an aqueous alcoholic solution.
9. The composition according to claim 1 wherein said at least one further constituent is a penicillin selected from the group consisting of penicillin G, penicillin V, propicillin, phenethicillin, azidocillin, dicloxacillin, flucloxacillin, oxacillin, cloxacillin, methicillin, carbenicillin, indanyl-carbenicillin, ticarcillin, ampicillin, amoxicillin, pivampicillin, hetacillin or ciclacillin.
10. The composition according to claim 9 wherein the penicillin constituent is pencillin V.
11. The composition according to claim 9 wherein the penicillin constituent is pencillin G.
12. A pharmaceutical preparation according to claim 9, 10 or 11, in which the ratio of phosphonomycin to pencillin is from 1:1 to 5:1 by weight.
13. The composition according to claim 1 wherein said at least one further constituent is a cephalosporin selected from the group consisting of cephazolin, cephadrin, cephoxitin, cephaloridin, cephalotin, cephacetril, cephalexin, cephamandol, and cephapirin.
14. The composition according to claim 13 wherein said cephalosporin is cephazolin.
15. The composition according to claim 1, 2 or 4 wherein the cephalosporin is cephadrin.
16. The composition according to claim 1, 2 or 4 wherein the cepholosporin is cephalexin.
17. The composition according to claim 1, 2 or 4 wherein the cephalosporin is cephoxitin.
18. The composition according to claim 13, 14 or 15 in which the ratio of phosphonomycin to cephalosporin is from 1:1 to 8:1 by weight.
19. The composition according to claim 16 or 17 in which the ratio of phosphonomycin to cephalosporin is from 1:1 to 8:1 by weight.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19752522081 DE2522081A1 (en) | 1975-05-17 | 1975-05-17 | ANTIBIOTICALLY EFFECTIVE PREPARATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1068603A true CA1068603A (en) | 1979-12-25 |
Family
ID=5946844
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA252,625A Expired CA1068603A (en) | 1975-05-17 | 1976-05-14 | Preparations comprising phosphonomycin and another antibiotic |
Country Status (7)
| Country | Link |
|---|---|
| BE (1) | BE841775A (en) |
| CA (1) | CA1068603A (en) |
| DE (1) | DE2522081A1 (en) |
| FR (1) | FR2311551A1 (en) |
| GB (1) | GB1530017A (en) |
| IE (1) | IE43373B1 (en) |
| SE (1) | SE7605551L (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2018864A1 (en) | 2007-07-23 | 2009-01-28 | Biomet Deutschland GmbH | Pharmaceutical composition, substrate comprising a pharmaceutical composition, and use of a pharmaceutical composition |
| DE102008046610A1 (en) * | 2008-09-09 | 2010-03-11 | Biomet Deutschland Gmbh | Use of a pharmaceutical composition for local infection therapy and medical device |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL6814976A (en) * | 1968-05-15 | 1969-11-18 | ||
| DE1924205B2 (en) * | 1969-05-12 | 1973-01-04 | Rilco Maschinenfabrik Gmbh & Co Kg, 7407 Dusslingen | Pressure medium-operated device for generating a reciprocating movement |
| US3678163A (en) * | 1969-06-02 | 1972-07-18 | Merck & Co Inc | Stabilized aqueous suspension of calcium (-) (cis-1,2-epoxypropyl)-phosphonate |
| FR2100969A2 (en) * | 1970-07-30 | 1972-03-24 | Merck & Co Inc | Antibiotic compns - contng (-) (cis-1,2-epoxypropyl) phosphonic acid |
-
1975
- 1975-05-17 DE DE19752522081 patent/DE2522081A1/en active Granted
-
1976
- 1976-05-13 GB GB19800/76A patent/GB1530017A/en not_active Expired
- 1976-05-13 BE BE166980A patent/BE841775A/en not_active IP Right Cessation
- 1976-05-13 FR FR7614462A patent/FR2311551A1/en active Granted
- 1976-05-14 SE SE7605551A patent/SE7605551L/en unknown
- 1976-05-14 IE IE1031/76A patent/IE43373B1/en unknown
- 1976-05-14 CA CA252,625A patent/CA1068603A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2311551B1 (en) | 1978-11-17 |
| SE7605551L (en) | 1976-11-18 |
| BE841775A (en) | 1976-09-01 |
| DE2522081A1 (en) | 1976-11-25 |
| DE2522081C2 (en) | 1987-07-30 |
| IE43373B1 (en) | 1981-02-11 |
| GB1530017A (en) | 1978-10-25 |
| IE43373L (en) | 1976-11-17 |
| FR2311551A1 (en) | 1976-12-17 |
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